Immunological Mechanisms in the Pathophysiology of Non-Alcoholic Steatohepatitis

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Sven Francque

2013-10-01

Full Text Available Non-alcoholic steatohepatitis (NASH is characterized by the presence of steatosis, inflammation and hepatocyte injury and constitutes hepatic manifestation of the metabolic syndrome. The pathogenesis of NASH is complex and implicates cross-talk between different metabolically active sites, such as liver and adipose tissue. Obesity is considered a chronic low-grade inflammatory state and the liver has been recognized as being an “immunological organ”. The complex role of the immune system in the pathogenesis of NASH is currently raising great interest, also in view of the possible therapeutic potential of immunotherapy in NASH. This review focuses on the disturbances of the cells constituting the innate and adaptive immune system in the liver and in adipose tissue.

Early diet-induced non-alcoholic steatohepatitis in APOE2 knock-in mice and its prevention by fibrates

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Shiri-Sverdlov, Ronit; Wouters, Kristiaan; van Gorp, Patrick J.; Gijbels, Marion J.; Noel, Benoit; Buffat, Laurent; Staels, Bart; Maeda, Nobuyo; van Bilsen, Marc; Hofker, Marten H.

2006-01-01

The molecular mechanisms leading to Non-Alcoholic Steatohepatitis (NASH) are not fully understood. In mice, NASH can be inhibited by fenofibrate, a synthetic agonist for the nuclear receptor peroxisome proliferator activated receptor alpha, which regulates hepatic triglyceride metabolism. This study

Gasdermin D plays a key role as a pyroptosis executor of non-alcoholic steatohepatitis in humans and mice.

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Xu, Bing; Jiang, Mingzuo; Chu, Yi; Wang, Weijie; Chen, Di; Li, Xiaowei; Zhang, Zhao; Zhang, Di; Fan, Daiming; Nie, Yongzhan; Shao, Feng; Wu, Kaichun; Liang, Jie

2017-12-20

Gasdermin D (GSDMD)-executed programmed necrosis is involved in inflammation and controls interleukin (IL)-1β release. However, the role of GSDMD in non-alcoholic steatohepatitis (NASH) remains unclear. We investigated the role of GSDMD in the pathogenesis of steatohepatitis. Human liver tissues from patients with non-alcoholic fatty liver disease (NAFLD) and control individuals were obtained to evaluate GSDMD expression. Gsdmd knockout (Gsdmd -/- ) mice, obese db/db mice and their wild-type (WT) littermates were fed with methionine-choline deficient (MCD) or control diet to induce steatohepatitis. The Gsdmd -/- and WT mice were also used in a high-fat diet (HFD)-induced NAFLD model. In addition, Alb-Cre mice were administered an adeno-associated virus (AAV) vector that expressed the gasdermin-N domain (AAV9-FLEX-GSDMD-N) and were fed with either MCD or control diet for 10 days. GSDMD and its pyroptosis-inducing fragment GSDMD-N were upregulated in liver tissues of human NAFLD/NASH. Importantly, hepatic GSDMD-N protein levels were significantly higher in human NASH and correlated with the NAFLD activity score and fibrosis. GSDMD-N remained a potential biomarker for the diagnosis of NASH. MCD-fed Gsdmd -/- mice exhibit decreased severity of steatosis and inflammation compared with WT littermates. GSDMD was associated with the secretion of pro-inflammatory cytokines (IL-1β, TNF-α, and MCP-1 [CCL2]) and persistent activation of the NF-ĸB signaling pathway. Gsdmd -/- mice showed lower steatosis, mainly because of reduced expression of the lipogenic gene Srebp1c (Srebf1) and upregulated expression of lipolytic genes, including Pparα, Aco [Klk15], Lcad [Acadl], Cyp4a10 and Cyp4a14. Alb-Cre mice administered with AAV9-FLEX-GSDMD-N showed significantly aggravated steatohepatitis when fed with MCD diet. As an executor of pyroptosis, GSDMD plays a key role in the pathogenesis of steatohepatitis, by controlling cytokine secretion, NF-ĸB activation, and lipogenesis

Celecoxib Ameliorates Non-Alcoholic Steatohepatitis in Type 2 Diabetic Rats via Suppression of the Non-Canonical Wnt Signaling Pathway Expression

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Tian, Feng; Zhang, Ya Jie; Li, Yu; Xie, Ying

2014-01-01

Our aim was to test whether pharmacological inhibition of cycloxygenase-2 (COX-2) reverses non-alcoholic steatohepatitis (NASH) in type 2 diabetes mellitus (T2DM) rats via suppression of the non-canonical Wnt signaling pathway expression. Twenty-four male Sprague-Dawley rats were randomly distributed to two groups and were fed with a high fat and sucrose (HF-HS) diet or a normal chow diet, respectively. After four weeks, rats fed with a HF-HS diet were made diabetic with low-dose streptozotocin. At the 9th week the diabetic rats fed with a HF-HS diet or the non-diabetic rats fed with a normal chow diet were further divided into two subgroups treated with vehicle or celecoxib (a selective COX-2 inhibitor, 10 mg/Kg/day, gavage) for the last 4 weeks, respectively. At the end of the 12th week, rats were anesthetized. NASH was assessed by histology. Related cytokine expression was measured at both the protein and gene levels through immunohistochemistry (IHC), Western blot and real-time PCR. T2DM rats fed with a HF-HS diet developed steatohepatitis and insulin resistance associated with elevated serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), insulin levels and the non-alcoholic fatty liver disease (NAFLD) activity score (NAS). The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 were all significantly increased in the T2DM-NASH group compared with the control and control-cele group. Hepatic injury was improved by celecoxib in T2DM-NASH-Cele group indicated by reduced serum ALT and AST levels and hepatic inflammation was reduced by celecoxib showed by histology and the NAFLD activity score (NAS). Serum related metabolic parameters, HOMA-IR and insulin sensitivity index were all improved by celecoxib. The expression of Wnt5a, JNK1, NF-κB p65, and COX-2 expression were all suppressed by celecoxib in T2DM-NASH-Cele group. The results of the present study indicated that celecoxib ameliorated NASH in T2DM rats via suppression of the non-canonical Wnt

Nitrosamine exposure exacerbates high fat diet-mediated type 2 diabetes mellitus, non-alcoholic steatohepatitis, and neurodegeneration with cognitive impairment

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de la Monte Suzanne M

2009-12-01

Full Text Available Abstract Background The current epidemics of type 2 diabetes mellitus (T2DM, non-alcoholic steatohepatitis (NASH, and Alzheimer's disease (AD all represent insulin-resistance diseases. Previous studies linked insulin resistance diseases to high fat diets or exposure to streptozotocin, a nitrosamine-related compound that causes T2DM, NASH, and AD-type neurodegeneration. We hypothesize that low-level exposure to nitrosamines that are widely present in processed foods, amplifies the deleterious effects of high fat intake in promoting T2DM, NASH, and neurodegeneration. Methods Long Evans rat pups were treated with N-nitrosodiethylamine (NDEA by i.p. Injection, and upon weaning, they were fed with high fat (60%; HFD or low fat (5%; LFD chow for 6 weeks. Rats were evaluated for cognitive impairment, insulin resistance, and neurodegeneration using behavioral, biochemical, molecular, and histological methods. Results NDEA and HFD ± NDEA caused T2DM, NASH, deficits in spatial learning, and neurodegeneration with hepatic and brain insulin and/or IGF resistance, and reductions in tau and choline acetyltransferase levels in the temporal lobe. In addition, pro-ceramide genes, which promote insulin resistance, were increased in livers and brains of rats exposed to NDEA, HFD, or both. In nearly all assays, the adverse effects of HFD+NDEA were worse than either treatment alone. Conclusions Environmental and food contaminant exposures to low, sub-mutagenic levels of nitrosamines, together with chronic HFD feeding, function synergistically to promote major insulin resistance diseases including T2DM, NASH, and AD-type neurodegeneration. Steps to minimize human exposure to nitrosamines and consumption of high-fat content foods are needed to quell these costly and devastating epidemics.

Myeloid DLL4 Does Not Contribute to the Pathogenesis of Non-Alcoholic Steatohepatitis in Ldlr-/- Mice.

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Mike L J Jeurissen

Full Text Available Non-alcoholic steatohepatitis (NASH is characterized by liver steatosis and inflammation. Currently, the underlying mechanisms leading to hepatic inflammation are not fully understood and consequently, therapeutic options are poor. Non-alcoholic steatohepatitis (NASH and atherosclerosis share the same etiology whereby macrophages play a key role in disease progression. Macrophage function can be modulated via activation of receptor-ligand binding of Notch signaling. Relevantly, global inhibition of Notch ligand Delta-Like Ligand-4 (DLL4 attenuates atherosclerosis by altering the macrophage-mediated inflammatory response. However, the specific contribution of macrophage DLL4 to hepatic inflammation is currently unknown. We hypothesized that myeloid DLL4 deficiency in low-density lipoprotein receptor knock-out (Ldlr-/- mice reduces hepatic inflammation. Irradiated Ldlr-/- mice were transplanted (tp with bone marrow from wild type (Wt or DLL4f/fLysMCre+/0 (DLL4del mice and fed either chow or high fat, high cholesterol (HFC diet for 11 weeks. Additionally, gene expression was assessed in bone marrow-derived macrophages (BMDM of DLL4f/fLysMCreWT and DLL4f/fLysMCre+/0 mice. In contrast to our hypothesis, inflammation was not decreased in HFC-fed DLL4del-transplanted mice. In line, in vitro, there was no difference in the expression of inflammatory genes between DLL4-deficient and wildtype bone marrow-derived macrophages. These results suggest that myeloid DLL4 deficiency does not contribute to hepatic inflammation in vivo. Since, macrophage-DLL4 expression in our model was not completely suppressed, it can't be totally excluded that complete DLL4 deletion in macrophages might lead to different results. Nevertheless, the contribution of non-myeloid Kupffer cells to notch signaling with regard to the pathogenesis of steatohepatitis is unknown and as such it is possible that, DLL4 on Kupffer cells promote the pathogenesis of steatohepatitis.

Manifestation of Non-Alcoholic Fatty Liver Disease/Non-Alcoholic Steatohepatitis in Different Dietary Mouse Models

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Vera HI Fengler

2016-05-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD and non-alcoholic steatohepatitis (NASH, which are usually associated with obesity and metabolic syndrome, are considerable health and economic issues due to the rapid increase of their prevalence in Western society. Histologically, the diseases are characterised by steatosis, hepatic inflammation, and if further progressed, fibrosis. Dietary-induced mouse models are widely used in investigations of the development and progression of NAFLD and NASH; these models attempt to mimic the histological and metabolic features of the human diseases. However, the majority of dietary mouse models fail to reflect the whole pathophysiological spectrum of NAFLD and NASH. Some models exhibit histological features similar to those seen in humans while lacking the metabolic context, while others resemble the metabolic conditions leading to NAFLD in humans but fail to mimic the whole histological spectrum, including progression from steatosis to liver fibrosis, and thus fail to mimic NASH. This review summarises the advantages and disadvantages of the different dietary-induced mouse models of NAFLD and NASH, with a focus on the genetic background of several commonly used wild-type mouse strains as well as gender and age, which influence the development and progression of these liver diseases.

A Young Man with Non-alcoholic Steatohepatitis and Serum Anti-mitochondrial Antibody Positivity: A Case Report.

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Seike, Takuya; Komura, Takuya; Shimizu, Yoshiaki; Omura, Hitoshi; Kumai, Tatsuo; Kagaya, Takashi; Ohta, Hajime; Kawashima, Atsuhiro; Harada, Kenichi; Kaneko, Shuichi; Unoura, Masashi

2018-06-06

A 37-year-old obese man who was a social drinker was admitted to our hospital to undergo a detailed examination for liver injury with anti-mitochondrial antibody positivity. Abdominal ultrasonography revealed moderate fatty liver. A histological analysis showed steatosis of approximately 30% of the hepatocytes, focal necrosis, a few ballooning hepatocytes and lobular inflammation suggestive of steatohepatitis, epithelioid granuloma and irregularity of the sequence of the bile duct epithelium accompanied by lymphocyte infiltration suggestive of chronic cholangitis. He was diagnosed with non-alcoholic steatohepatitis complicated with primary biliary cholangitis. His liver injury was improved by weight loss and high-dose ursodeoxycholic acid treatment.

Novel Molecular Mechanisms in the Development of Non-Alcoholic Steatohepatitis

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Davide Povero

2016-02-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is one of the most common causes of chronic liver disease in adults and children worldwide. NAFLD has become a severe health issue and it can progress towards a more severe form of the disease, the non-alcoholic steatohepatitis (NASH. A combination of environmental factors, host genetics, and gut microbiota leads to excessive accumulation of lipids in the liver (steatosis, which may result in lipotoxicity and trigger hepatocyte cell death, liver inflammation, fibrosis, and pathological angiogenesis. NASH can further progress towards liver cirrhosis and cancer. Over the last few years, cell-derived extracellular vesicles (EVs have been identified as effective cell-to-cell messengers that transfer several bioactive molecules in target cells, modulating the pathogenesis and progression of NASH. In this review, we focused on recently highlighted aspects of molecular pathogenesis of NASH, mediated by EVs via their bioactive components. The studies included in this review summarize the state of art regarding the role of EVs during the progression of NASH and bring novel insight about the potential use of EVs for diagnosis and therapeutic strategies for patients with this disease.

Mirtoselect, an anthocyanin-rich bilberry extract, attenuates non-alcoholic steatohepatitis and associated fibrosis in ApoE*3Leiden mice

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Morrison, Martine C.; Liang, Wen; Mulder, Petra; Verschuren, Lars; Pieterman, Elsbet; Toet, Karin; Heeringa, Peter; Wielinga, Peter Y.; Kooistra, Teake; Kleemann, Robert

Background & Aims: Anthocyanins may have beneficial effects on lipid metabolism and inflammation and are demonstrated to have hepatoprotective properties in models of restraint-stressand chemically-induced liver damage. However, their potential to protect against non-alcoholic steatohepatitis (NASH)

Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?

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A.L. Chagas

2009-10-01

Full Text Available Non-alcoholic steatohepatitis (NASH has been associated with hepatocellular carcinoma (HCC often arising in histologically advanced disease when steatohepatitis is not active (cryptogenic cirrhosis. Our objective was to characterize patients with HCC and active, histologically defined steatohepatitis. Among 394 patients with HCC detected by ultrasound imaging over 8 years and staged by the Barcelona Clinic Liver Cancer (BCLC criteria, we identified 7 cases (1.7% with HCC occurring in the setting of active biopsy-proven NASH. All were negative for other liver diseases such as hepatitis C, hepatitis B, autoimmune hepatitis, Wilson disease, and hemochromatosis. The patients (4 males and 3 females, age 63 ± 13 years were either overweight (4 or obese (3; 57% were diabetic and 28.5% had dyslipidemia. Cirrhosis was present in 6 of 7 patients, but 1 patient had well-differentiated HCC in the setting of NASH without cirrhosis (fibrosis stage 1 based on repeated liver biopsies, the absence of portal hypertension by clinical and radiographic evaluations and by direct surgical inspection. Among the cirrhotic patients, 71.4% were clinically staged as Child A and 14.2% as Child B. Tumor size ranged from 1.0 to 5.2 cm and 5 of 7 patients were classified as early stage; 46% of all nodules were hyper-echoic and 57% were <3 cm. HCC was well differentiated in 1/6 and moderately differentiated in 5/6. Alpha-fetoprotein was <100 ng/mL in all patients. HCC in patients with active steatohepatitis is often multifocal, may precede clinically advanced disease and occurs without diagnostic levels of alpha-fetoprotein. Importantly, HCC may occur in NASH in the absence of cirrhosis. More aggressive screening of NASH patients may be warranted.

Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients?

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A.L. Chagas

Full Text Available Non-alcoholic steatohepatitis (NASH has been associated with hepatocellular carcinoma (HCC often arising in histologically advanced disease when steatohepatitis is not active (cryptogenic cirrhosis. Our objective was to characterize patients with HCC and active, histologically defined steatohepatitis. Among 394 patients with HCC detected by ultrasound imaging over 8 years and staged by the Barcelona Clinic Liver Cancer (BCLC criteria, we identified 7 cases (1.7% with HCC occurring in the setting of active biopsy-proven NASH. All were negative for other liver diseases such as hepatitis C, hepatitis B, autoimmune hepatitis, Wilson disease, and hemochromatosis. The patients (4 males and 3 females, age 63 ± 13 years were either overweight (4 or obese (3; 57% were diabetic and 28.5% had dyslipidemia. Cirrhosis was present in 6 of 7 patients, but 1 patient had well-differentiated HCC in the setting of NASH without cirrhosis (fibrosis stage 1 based on repeated liver biopsies, the absence of portal hypertension by clinical and radiographic evaluations and by direct surgical inspection. Among the cirrhotic patients, 71.4% were clinically staged as Child A and 14.2% as Child B. Tumor size ranged from 1.0 to 5.2 cm and 5 of 7 patients were classified as early stage; 46% of all nodules were hyper-echoic and 57% were <3 cm. HCC was well differentiated in 1/6 and moderately differentiated in 5/6. Alpha-fetoprotein was <100 ng/mL in all patients. HCC in patients with active steatohepatitis is often multifocal, may precede clinically advanced disease and occurs without diagnostic levels of alpha-fetoprotein. Importantly, HCC may occur in NASH in the absence of cirrhosis. More aggressive screening of NASH patients may be warranted.

Intervention with a caspase-1 inhibitor reduces obesity-associated hyperinsulinemia, non-alcoholic steatohepatitis and hepatic fibrosis in LDLR-/-.Leiden mice

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Morrison, M. C.; Mulder, P.; Salic, K.; Verheij, J.; Liang, W.; van Duyvenvoorde, W.; Menke, A.; Kooistra, T.; Kleemann, R.; Wielinga, P. Y.

BACKGROUND/OBJECTIVES: Non-alcoholic steatohepatitis (NASH) is a serious liver condition, closely associated with obesity and insulin resistance. Recent studies have suggested an important role for inflammasome/caspase-1 in the development of NASH, but the potential therapeutic value of caspase-1

Toll-like receptor-2 deficiency enhances non-alcoholic steatohepatitis

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Brady Kristen

2010-05-01

Full Text Available Abstract Background Previously we reported that mice deficient in toll-like receptor 4 (TLR-4 signalling were protected from diet-induced non-alcoholic steatohepatitis (NASH. Another member of the toll-like receptor family, TLR-2, has been shown to play a role in lipid trafficking via uptake of diacylated lipoproteins. However, a role for TLR-2 in NASH has not been elucidated. The objectives of the current study were to examine the influence of dietary fat quality and TLR-2 on NASH pathogenesis. Methods Steatohepatitis was induced in male Db, C57BL/6 and TLR-2-/- mice by feeding an L-amino acid-defined diet that was deficient in methionine and choline (MCDD. Mice fed the base diet supplemented with methionine and choline (control diet; CD were used as controls. To determine the role of fat quality, MCDD was enriched with polyunsaturated corn oil (PUFA or coconut oil that is comprised mostly of saturated fat (SAFA; the total amount of each fat was 112.9 g/kg of diet. After 8 weeks of feeding CD or MCDD, hepatic steatosis, inflammation and necrosis were evaluated in histological sections. Total RNA was extracted from frozen liver samples and mRNA expression of TNFα, collagen α1, IL-10, peroxisome proliferator-activated receptor-γ (PPAR-γ, TLR-4, and CD14, was analyzed via real-time PCR. Protein levels of TLR-2 were analyzed by western blot. Results Panlobular macrovessicular steatosis and diffuse leukocyte infiltration were noted in PUFA-fed Db mice. Histological scores demonstrated significantly less steatosis, inflammation and necrosis in SAFA-fed mice of all mouse strains. However, compared to wild type mice, hepatocellular damage was notably more severe in TLR-2-/- mice. Consistent with histological findings, mRNA expression of TNFα was elevated by approximately 3-fold in TLR-2-/- mice; PPAR-γ expression was blunted in this strain compared to wild type. Expression of the matrix protein collagen αI was also significantly higher in TLR-2

Mitochondrial gene polymorphisms alter hepatic cellular energy metabolism and aggravate diet-induced non-alcoholic steatohepatitis

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Torsten Schröder

2016-04-01

Full Text Available Objective: Non-alcoholic fatty liver disease (NAFLD is the most common chronic liver disease and is associated with an enhanced risk for liver and cardiovascular diseases and mortality. NAFLD can progress from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH. However, the mechanisms predisposing to this progression remain undefined. Notably, hepatic mitochondrial dysfunction is a common finding in patients with NASH. Due to a lack of appropriate experimental animal models, it has not been evaluated whether this mitochondrial dysfunction plays a causative role for the development of NASH. Methods: To determine the effect of a well-defined mitochondrial dysfunction on liver physiology at baseline and during dietary challenge, C57BL/6J-mtFVB/N mice were employed. This conplastic inbred strain has been previously reported to exhibit decreased mitochondrial respiration likely linked to a non-synonymous gene variation (nt7778 G/T of the mitochondrial ATP synthase protein 8 (mt-ATP8. Results: At baseline conditions, C57BL/6J-mtFVB/N mice displayed hepatic mitochondrial dysfunction characterized by decreased ATP production and increased formation of reactive oxygen species (ROS. Moreover, genes affecting lipid metabolism were differentially expressed, hepatic triglyceride and cholesterol levels were changed in these animals, and various acyl-carnitines were altered, pointing towards an impaired mitochondrial carnitine shuttle. However, over a period of twelve months, no spontaneous hepatic steatosis or inflammation was observed. On the other hand, upon dietary challenge with either a methionine and choline deficient diet or a western-style diet, C57BL/6J-mtFVB/N mice developed aggravated steatohepatitis as characterized by lipid accumulation, ballooning of hepatocytes and infiltration of immune cells. Conclusions: We observed distinct metabolic alterations in mice with a mitochondrial polymorphism associated hepatic mitochondrial

Non-alcoholic steatohepatitis: review of a growing medical problem.

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Te Sligte, K.; Bourass, I.; Sels, J.P.; Driessen, A.; Stockbrugger, R.W.; Koek, G.H.

2004-02-01

Non-alcoholic steatohepatitis (NASH) is a metabolic liver disorder that is seen in 2-6% of the general population. It manifests itself by elevated liver enzymes, frequently without symptoms. The histological findings include steatosis, inflammation, fibrosis, and cirrhosis. Three case reports are presented to illustrate features of NASH. A two-hit model has been proposed in the pathogenesis of NASH. The first hit is hepatic steatosis. A hypercaloric diet with high levels of carbohydrates and saturated fatty acids results in elevated plasma free fatty acids (FFA) and expands the adipose tissue. Insulin resistance develops and augments steatosis. Oxidation of FFA yields toxic free radicals, resulting in lipid peroxidation. They cause the second hits: increased oxidative stress on hepatocytes and induction of pro-inflammatory cytokines. When the antioxidant capacities of the liver are insufficient, mitochondrial dysfunction and tumor necrosis factor alpha (TNF-alpha) cause inflammation and fibrosis. Treatment consists of life style modifications, particularly weight loss and exercise. Many drugs have been tried in the treatment of NASH. The insulin-sensitizing drugs metformin, rosiglitazone, and pioglitazone, and the antioxidant vitamin E show promising results. Further investigation of therapeutic options is needed to direct the choice of therapy in the future.

Recurrent and de novo non-alcoholic steatohepatitis following orthotopic liver transplantation Recurrência e "de novo" esteatohepatite não-alcoólica após transplante ortotópico de fígado

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Raquel F. Liermann GARCIA

2001-10-01

Full Text Available Background — Non-alcoholic steatohepatitis was coined in 1980 to describe pathological and clinical features of non-alcoholic disease associated with pathological features, commonly seen in alcoholic-liver disease itself. It is now a well-recognised cause of end-stage liver disease and a rare cause of orthotopic liver transplantation. A small number of cases with recurrent non-alcoholic steatohepatitis following liver transplantation have been reported, however de novo non-alcoholic steatohepatitis in the liver allograft is not well recognised. Aims/Results - We report four cases of non-alcoholic steatohepatitis following orthotopic liver transplantation describing the factors related with the pathology. The recurrence of fatty infiltration occurred within 21 months and transition from mild steatosis to non-alcoholic steatohepatitis and early fibrosis was observed within 60 months post transplant in all four patients. All four cases had association with one or multiples risk factors (obesity, type 2 diabetes and/or hyperlipidemia. Conclusions - Management of this risk factors may play a therapeutic role in the prevention of recurrent and de novo non-alcoholic steatohepatitis following orthotopic liver transplantation.Racional — O termo NASH (esteatohepatite não-alcoólica foi introduzida em 1980 para descrever "características patológicas e clínicas de doença não-alcoólica observadas comumente na própria doença alcoólica". Atualmente é causa reconhecida de doença hepática crônica e rara indicação de transplante hepático. Pequeno número de casos de recurrência de NASH pós-transplante foram descritos na literatura; entretanto, de novo NASH no enxerto jamais foi relatado. Objetivos/Resultados - Reportam-se quatro casos de NASH pós-transplante, descrevendo fatores associados a esta patologia. A média de recurrência da infiltração gordurosa foi de 21 meses com transição para esteatohepatite/fibrose aos 60 meses p

L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model with upregulation of mitochondrial pathway.

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Hisashi Ishikawa

Full Text Available Non-alcoholic steatohepatitis (NASH is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC. Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid, an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1 high-fat diet (HFD (control group; 2 HFD mixed with 0.28% L-carnitine (L-carnitine group; and 3 HFD mixed with 0.01% α-tocopherol (α-tocopherol group. After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial β-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although α-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis. Conclusion: L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by

Multiparametric magnetic resonance imaging for the assessment of non-alcoholic fatty liver disease severity.

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Pavlides, Michael; Banerjee, Rajarshi; Tunnicliffe, Elizabeth M; Kelly, Catherine; Collier, Jane; Wang, Lai Mun; Fleming, Kenneth A; Cobbold, Jeremy F; Robson, Matthew D; Neubauer, Stefan; Barnes, Eleanor

2017-07-01

The diagnosis of non-alcoholic steatohepatitis and fibrosis staging are central to non-alcoholic fatty liver disease assessment. We evaluated multiparametric magnetic resonance in the assessment of non-alcoholic steatohepatitis and fibrosis using histology as standard in non-alcoholic fatty liver disease. Seventy-one patients with suspected non-alcoholic fatty liver disease were recruited within 1 month of liver biopsy. Magnetic resonance data were used to define the liver inflammation and fibrosis score (LIF 0-4). Biopsies were assessed for steatosis, lobular inflammation, ballooning and fibrosis and classified as non-alcoholic steatohepatitis or simple steatosis, and mild or significant (Activity ≥2 and/or Fibrosis ≥2 as defined by the Fatty Liver Inhibition of Progression consortium) non-alcoholic fatty liver disease. Transient elastography was also performed. Magnetic resonance success rate was 95% vs 59% for transient elastography (Pliver inflammation and fibrosis (r s =.51, Pliver inflammation and fibrosis for the diagnosis of cirrhosis was 0.85. Liver inflammation and fibrosis score for ballooning grades 0, 1 and 2 was 1.2, 2.7 and 3.5 respectively (Pliver inflammation and fibrosis (1.3) compared to patients with non-alcoholic steatohepatitis (3.0) (PLiver inflammation and fibrosis scores for patients with mild and significant non-alcoholic fatty liver disease were 1.2 and 2.9 respectively (Pliver inflammation and fibrosis for the diagnosis of significant non-alcoholic fatty liver disease was 0.89. Multiparametric magnetic resonance is a promising technique with good diagnostic accuracy for non-alcoholic fatty liver disease histological parameters, and can potentially identify patients with non-alcoholic steatohepatitis and cirrhosis. © 2017 The Authors Liver International Published by John Wiley & Sons Ltd.

Rapid Recovery from Acute Liver Failure Secondary to Pancreatoduodenectomy-Related Non-Alcoholic Steatohepatitis

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Kazushige Nirei

2013-01-01

Full Text Available This report describes a case of liver failure secondary to pancreatoduodenectomy and rapid recovery following treatment. A 68-year-old woman with cancer on the ampulla of Vater underwent surgery for pancreatoduodenectomy. The patient developed liver failure 3 months postsurgically. She was hospitalized after presenting with jaundice, hypoalbuminemia and decreased serum zinc. Computed tomography (CT of the abdomen showed a reduction in CT attenuation values postoperatively. We suspected fatty liver due to impaired absorption caused by pancreatoduodenectomy. We initiated treatment with branched-chain amino acids and a zinc formulation orally. Trace elements were administered intravenously. Two months after treatment, there was a noticeable improvement in CT findings. The patient’s jaundice and hypoalbuminemia prompted a liver biopsy, which led to a diagnosis of non-alcoholic steatohepatitis.

Non-alcoholic steatohepatitis (NASH) in patients with polycystic ovarian syndrome (PCOS).

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Hossain, Noreen; Stepanova, Maria; Afendy, Arian; Nader, Fatema; Younossi, Youssef; Rafiq, Nila; Goodman, Zachary; Younossi, Zobair M

2011-04-01

Both non-alcoholic steatohepatitis (NASH) and polycystic ovary syndrome (PCOS) are associated with metabolic syndrome (MS) and insulin resistance (IR). Except for a few case reports, there are no systematic assessments of NASH in PCOS patients. To determine the prevalence of NASH and independent factors associated with NASH in a cohort of patients with documented PCOS. Patients with established diagnosis of PCOS and matched controls (matched for gender, age, and body mass index (BMI)) were included in the study. Causes of other liver diseases were systematically excluded by clinical and laboratory tests. Excessive alcohol use was defined as alcohol consumption of greater than 10 g/day. All liver biopsies were read by a single pathologist blinded to the clinical data. Histologic NASH was defined as steatosis with lobular inflammation and ballooning degeneration of hepatocytes with or without Mallory-Denk bodies or pericellular fibrosis. Univariate and multivariate analyses with logistic regression were performed to compare PCOS to matched controls. Sixty-six patients were included in the study (34 PCOS and 32 matched controls). Of PCOS patients, 73% had a liver biopsy while 78% of the matched controls had a liver biopsy. In comparing PCOS patients to the matched controls, clinical (BMI, waist circumference, type 2 diabetes, MS, or its components, any alcohol consumption in the prior year, ethnic background, age, gender, etc.) and laboratory data (aminotransferases, ferritin, glucose, etc.) were not significantly different (p > 0.05). However, PCOS patients tended to have more histologic NASH on their liver biopsies (44.0% vs. 20.8%, p = 0.08). Independent predictors of histologic NASH in PCOS patients were elevated aspartate aminotransferase (AST), high triglycerides and small amounts of alcohol consumption (p = 0.019, 10-fold cross-validated AUC = 0.80, 95% CI = 0.56-0.94). Although about half of PCOS patients did not report any alcohol consumption, 50% did report

Polychlorinated Biphenyl-Xenobiotic Nuclear Receptor Interactions Regulate Energy Metabolism, Behavior, and Inflammation in Non-alcoholic-Steatohepatitis.

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Wahlang, Banrida; Prough, Russell A; Falkner, K Cameron; Hardesty, Josiah E; Song, Ming; Clair, Heather B; Clark, Barbara J; States, J Christopher; Arteel, Gavin E; Cave, Matthew C

2016-02-01

Polychlorinated biphenyls (PCBs) are environmental pollutants associated with non-alcoholic-steatohepatitis (NASH), diabetes, and obesity. We previously demonstrated that the PCB mixture, Aroclor 1260, induced steatohepatitis and activated nuclear receptors in a diet-induced obesity mouse model. This study aims to evaluate PCB interactions with the pregnane-xenobiotic receptor (Pxr: Nr1i2) and constitutive androstane receptor (Car: Nr1i3) in NASH. Wild type C57Bl/6 (WT), Pxr(-/-) and Car(-/-) mice were fed the high fat diet (42% milk fat) and exposed to a single dose of Aroclor 1260 (20 mg/kg) in this 12-week study. Metabolic phenotyping and analysis of serum, liver, and adipose was performed. Steatohepatitis was pathologically similar in all Aroclor-exposed groups, while Pxr(-/-) mice displayed higher basal pro-inflammatory cytokine levels. Pxr repressed Car expression as evident by increased basal Car/Cyp2b10 expression in Pxr(-/-) mice. Both Pxr(-/-) and Car(-/-) mice showed decreased basal respiratory exchange rate (RER) consistent with preferential lipid metabolism. Aroclor increased RER and carbohydrate metabolism, associated with increased light cycle activity in both knockouts, and decreased food consumption in the Car(-/-) mice. Aroclor exposure improved insulin sensitivity in WT mice but not glucose tolerance. The Aroclor-exposed, Pxr(-/-) mice displayed increased gluconeogenic gene expression. Lipid-oxidative gene expression was higher in WT and Pxr(-/-) mice although RER was not changed, suggesting PCB-mediated mitochondrial dysfunction. Therefore, Pxr and Car regulated inflammation, behavior, and energy metabolism in PCB-mediated NASH. Future studies should address the 'off-target' effects of PCBs in steatohepatitis. Published by Oxford University Press on behalf of the Society of Toxicology 2015. This work is written by US Government employees and is in the public domain in the US.

Liver biopsy in type 2 diabetes mellitus: Steatohepatitis represents the sole feature of liver damage.

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Masarone, Mario; Rosato, Valerio; Aglitti, Andrea; Bucci, Tommaso; Caruso, Rosa; Salvatore, Teresa; Sasso, Ferdinando Carlo; Tripodi, Marie Francoise; Persico, Marcello

2017-01-01

Recent studies report a prevalence of non-alcoholic fatty liver disease (NAFLD) of between 70% and 80% in patients with metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Nevertheless, it is not possible to differentiate between simple steatosis and non-alcoholic steatohepatitis (NASH) with non-invasive tests. The aim of this study was to differentiate between simple steatosis and NASH by liver biopsy in patients with hypertransaminasemia and MS or T2DM. Two hundred and fifteen patients with increased ALT levels and MS, and 136 patients at their first diagnosis of T2DM regardless of ALT values were consecutively admitted to a tertiary hepatology center between January 2004 and November 2014. Exclusion criteria were other causes of liver disease/ALT increase. Each patient underwent a clinical, laboratory and ultrasound evaluation, and a liver biopsy. Gender distribution, age, and body mass index were similar in the two groups of patients, whereas cholesterol levels, glycemia and blood pressure were significantly different between the two groups. The prevalence of NAFLD was 94.82% in MS patients and 100% in T2DM patients. NASH was present in 58.52% of MS patients and 96.82% of T2DM. Consequently, this study reveals that, by using liver biopsy, almost all patients with T2DM or MS have NAFLD, which in patients with T2DM means NASH. Importantly, it suggests that NASH may be one of the early complications of T2DM due to its pathophysiological correlation with insulin resistance.

Liver biopsy in type 2 diabetes mellitus: Steatohepatitis represents the sole feature of liver damage.

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Mario Masarone

Full Text Available Recent studies report a prevalence of non-alcoholic fatty liver disease (NAFLD of between 70% and 80% in patients with metabolic syndrome (MS and type 2 diabetes mellitus (T2DM. Nevertheless, it is not possible to differentiate between simple steatosis and non-alcoholic steatohepatitis (NASH with non-invasive tests. The aim of this study was to differentiate between simple steatosis and NASH by liver biopsy in patients with hypertransaminasemia and MS or T2DM. Two hundred and fifteen patients with increased ALT levels and MS, and 136 patients at their first diagnosis of T2DM regardless of ALT values were consecutively admitted to a tertiary hepatology center between January 2004 and November 2014. Exclusion criteria were other causes of liver disease/ALT increase. Each patient underwent a clinical, laboratory and ultrasound evaluation, and a liver biopsy. Gender distribution, age, and body mass index were similar in the two groups of patients, whereas cholesterol levels, glycemia and blood pressure were significantly different between the two groups. The prevalence of NAFLD was 94.82% in MS patients and 100% in T2DM patients. NASH was present in 58.52% of MS patients and 96.82% of T2DM. Consequently, this study reveals that, by using liver biopsy, almost all patients with T2DM or MS have NAFLD, which in patients with T2DM means NASH. Importantly, it suggests that NASH may be one of the early complications of T2DM due to its pathophysiological correlation with insulin resistance.

Clinical and histological features of non-Alcoholic steatohepatitis in Iranian patients

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"Ebrahimi Daryani N

2003-05-01

Full Text Available Non-alcoholic steatohepatitis (NASH is a disease of unknown origin characterized histologically by alcoholic-like liver injury in the absence in the absence of significant alcohol intake. This study was conducted to assess the clinical and pathological features of NASH patients in Iran. Patients with elevated liver transaminases, negative serologic markers of viral or autoimmune hepatitis and no findings in favor of metabolic liver disease were enrolled. A careful history was taken with special attention to alcohol intake and ultrasonography and liver biopsy were performed in those with no evidence of significant alcohol intake. A histology showing moderate to gross macrovesicular fatty change with inflammation (lobular or portal, with or without Mallory bodies, fibrosis, or cirrhosis, was considered diagnostic for NASH. Patients with mild steatosis were rechecked for the presence of hepatitis C virus (HCV infection. Fifty-three patients who met the above criteria entered the study. Thirty-two patients (60.4% were male and 21 (39.6% were female with the mean age of 37.8±11.3 years. Twenty-six patients (55.3% were diabetic. Mean AST to ALT ratio was 0.95±0.52; 65.3%of patients had a ratio below than 1, and 95.9% were below of 2. Ultrasonography was abnormal in 32 (76.2% patients. Liver biopsy showed mild steatosis in 35.7% moderate steatosis in 53.6% and severe forms in 10.7%. In 80.2% of patients, portal inflammation was present, and 15.1% had some degrees of fibrosis. The amount of increase in liver enzymes bore no relationship with the presence of fibrosis, portal inflammation, and degree of steatosis (P>0.05. The patients wee somewhat younger than other studies, and most of them were male which might be due to the low rate of alcohol consumption in our country. Most of the patients had body mass index (BMI higher than normal. Our findings show that NASH must not be considered a disease confined to high-risk groups only, and its impact be

Moderate alcohol consumption aggravates high fat-diet induced steatohepatitis in rats

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Background: Nonalcoholic steatohepatitis (NASH) develops in the absence of chronic and excessive alcohol consumption. However, it remains unknown whether moderate alcohol consumption aggravates liver inflammation in pre-existing NASH condition. Methods: Sprague-Dawley rats were first fed ad libitum...

Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma: Implications for Lycopene Intervention

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Ip, Blanche C.; Wang, Xiang-Dong

2013-01-01

Increased prevalence of non-alcoholic fatty liver disease (NAFLD) is one of the consequences of the current obesity epidemic. NAFLD is a major form of chronic liver disease that is highly prevalent in obese and overweight adults and children. Nonalcoholic steatohepatitis (NASH) is the severe form of NAFLD, and uncontrolled inflammation as displayed in NASH has been identified as one of the key events in enhancing hepatic carcinogenesis. Lycopene is a non-provitamin A carotenoid and the pigment principally responsible for the characteristic deep-red color of ripe tomato and tomato products, as well as some fruits and vegetables. Lycopene’s innate antioxidant and anti-inflammatory properties have generated research interests on its capacity to protect against human diseases that are associated with oxidative stress and inflammation. In addition, differential mechanisms of lycopene metabolism including endogenous cleavage by carotenoid cleavage oxygenases (BCOs), generate lycopene metabolites that may also have significant impact on human disease development. However, it remains to be elucidated as to whether lycopene or its metabolites apolycopenoids have protective effects against obesity-related complications including inflammation and tumorigenesis. This article summarizes the in vivo experiments that elucidated molecular mechanisms associated with obesity-related hepatic inflammation and carcinogenesis. This review also provides an overview of lycopene metabolism, and the molecular pathways involved in the potential beneficial properties of lycopene and apolycopenoids. More research is clearly needed to fully unravel the importance of BCOs in tomato carotenoid metabolism and the consequence on human health and diseases. PMID:24379011

Strategies, models and biomarkers in experimental non-alcoholic fatty liver disease research

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Willebrords, Joost; Pereira, Isabel Veloso Alves; Maes, Michaël; Yanguas, Sara Crespo; Colle, Isabelle; Van Den Bossche, Bert; Da silva, Tereza Cristina; Oliveira, Cláudia P; Andraus, Wellington; Alves, Venâncio Avancini Ferreira; Cogliati, Bruno; Vinken, Mathieu

2015-01-01

Non-alcoholic fatty liver disease encompasses a spectrum of liver diseases, including simple steatosis, steatohepatitis, liver fibrosis and cirrhosis and hepatocellular carcinoma. Non-alcoholic fatty liver disease is currently the most dominant chronic liver disease in Western countries due to the fact that hepatic steatosis is associated with insulin resistance, type 2 diabetes mellitus, obesity, metabolic syndrome and drug-induced injury. A variety of chemicals, mainly drugs, and diets is known to cause hepatic steatosis in humans and rodents. Experimental non-alcoholic fatty liver disease models rely on the application of a diet or the administration of drugs to laboratory animals or the exposure of hepatic cell lines to these drugs. More recently, genetically modified rodents or zebrafish have been introduced as non-alcoholic fatty liver disease models. Considerable interest now lies in the discovery and development of novel non-invasive biomarkers of non-alcoholic fatty liver disease, with specific focus on hepatic steatosis. Experimental diagnostic biomarkers of non-alcoholic fatty liver disease, such as (epi)genetic parameters and ‘-omics’-based read-outs are still in their infancy, but show great promise. . In this paper, the array of tools and models for the study of liver steatosis is discussed. Furthermore, the current state-of-art regarding experimental biomarkers such as epigenetic, genetic, transcriptomic, proteomic and metabonomic biomarkers will be reviewed. PMID:26073454

Fatty Acid Elongation in Non-Alcoholic Steatohepatitis and Hepatocellular Carcinoma

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Sonja M. Kessler

2014-04-01

Full Text Available Non-alcoholic steatohepatitis (NASH represents a risk factor for the development of hepatocellular carcinoma (HCC and is characterized by quantitative and qualitative changes in hepatic lipids. Since elongation of fatty acids from C16 to C18 has recently been reported to promote both hepatic lipid accumulation and inflammation we aimed to investigate whether a frequently used mouse NASH model reflects this clinically relevant feature and whether C16 to C18 elongation can be observed in HCC development. Feeding mice a methionine and choline deficient diet to model NASH not only increased total hepatic fatty acids and cholesterol, but also distinctly elevated the C18/C16 ratio, which was not changed in a model of simple steatosis (ob/ob mice. Depletion of Kupffer cells abrogated both quantitative and qualitative methionine-and-choline deficient (MCD-induced alterations in hepatic lipids. Interestingly, mimicking inflammatory events in early hepatocarcinogenesis by diethylnitrosamine-induced carcinogenesis (48 h increased hepatic lipids and the C18/C16 ratio. Analyses of human liver samples from patients with NASH or NASH-related HCC showed an elevated expression of the elongase ELOVL6, which is responsible for the elongation of C16 fatty acids. Taken together, our findings suggest a detrimental role of an altered fatty acid pattern in the progression of NASH-related liver disease.

Dual role of protein tyrosine phosphatase 1B in the progression and reversion of non-alcoholic steatohepatitis

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Águeda González-Rodríguez

2018-01-01

Full Text Available Objectives: Non-alcoholic fatty liver disease (NAFLD is the most common chronic liver disease in Western countries. Protein tyrosine phosphatase 1B (PTP1B, a negative modulator of insulin and cytokine signaling, is a therapeutic target for type 2 diabetes and obesity. We investigated the impact of PTP1B deficiency during NAFLD, particularly in non-alcoholic steatohepatitis (NASH. Methods: NASH features were evaluated in livers from wild-type (PTP1BWT and PTP1B-deficient (PTP1BKO mice fed methionine/choline-deficient diet (MCD for 8 weeks. A recovery model was established by replacing MCD to chow diet (CHD for 2–7 days. Non-parenchymal liver cells (NPCs were analyzed by flow cytometry. Oval cells markers were measured in human and mouse livers with NASH, and in oval cells from PTP1BWT and PTP1BKO mice. Results: PTP1BWT mice fed MCD for 8 weeks exhibited NASH, NPCs infiltration, and elevated Fgf21, Il6 and Il1b mRNAs. These parameters decreased after switching to CHD. PTP1B deficiency accelerated MCD-induced NASH. Conversely, after switching to CHD, PTP1BKO mice rapidly reverted NASH compared to PTP1BWT mice in parallel to the normalization of serum triglycerides (TG levels. Among NPCs, a drop in cytotoxic natural killer T (NKT subpopulation was detected in PTP1BKO livers during recovery, and in these conditions M2 macrophage markers were up-regulated. Oval cells markers (EpCAM and cytokeratin 19 significantly increased during NASH only in PTP1B-deficient livers. HGF-mediated signaling and proliferative capacity were enhanced in PTP1BKO oval cells. In NASH patients, oval cells markers were also elevated. Conclusions: PTP1B elicits a dual role in NASH progression and reversion. Additionally, our results support a new role for PTP1B in oval cell proliferation during NAFLD. Keywords: PTP1B, Steatosis, Steatohepatitis, Inflammation, Oval cells

Imaging of non alcoholic fatty liver disease: A road less travelled

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Divya Singh

2013-01-01

Full Text Available Non alcoholic fatty liver disease (NAFLD is a spectrum that includes simple steatosis, nonalcoholic steatohepatitis and cirrhosis. It is increasingly emerging as a cause of elevated liver enzymes, cryptogenic cirrhosis and hepatocellular carcinoma. The morbidity and mortality related to NAFLD is expected to rise with the upsurge of obesity and type 2 diabetes mellitus. The need of the hour is to devise techniques to estimate and then accurately follow-up hepatic fat content in patients with NAFLD. There are lots of imaging modalities in the radiological armamentarium, namely, ultrasonography with the extra edge of elastography, computed tomography, and magnetic resonance imaging with chemical shift imaging and spectroscopy to provide an estimation of hepatic fat content.

Hepatic crown-like structure: a unique histological feature in non-alcoholic steatohepatitis in mice and humans.

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Michiko Itoh

Full Text Available Although macrophages are thought to be crucial for the pathogenesis of chronic inflammatory diseases, how they are involved in disease progression from simple steatosis to non-alcoholic steatohepatitis (NASH is poorly understood. Here we report the unique histological structure termed "hepatic crown-like structures (hCLS" in the mouse model of human NASH; melanocortin-4 receptor deficient mice fed a Western diet. In hCLS, CD11c-positive macrophages aggregate to surround hepatocytes with large lipid droplets, which is similar to those described in obese adipose tissue. Histological analysis revealed that hCLS is closely associated with activated fibroblasts and collagen deposition. When treatment with clodronate liposomes effectively depletes macrophages scattered in the liver, with those in hCLS intact, hepatic expression of inflammatory and fibrogenic genes is unaffected, suggesting that hCLS is an important source of inflammation and fibrosis during the progression of NASH. Notably, the number of hCLS is positively correlated with the extent of liver fibrosis. We also observed increased number of hCLS in the liver of non-alcoholic fatty liver disease/NASH patients. Collectively, our data provide evidence that hCLS is involved in the development of hepatic inflammation and fibrosis, thereby suggesting its pathophysiologic role in disease progression from simple steatosis to NASH.

A preliminary study of inflammatory markers in non-alcoholic steatohepatitis patients

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Manopriya T. Priya

2010-03-01

Full Text Available It was reported that C-reactive protein (CRP levels increase in parallel with the progression of chronic liver diseases, such as chronic hepatitis and liver cirrhosis. Inflammatory markers, such as high sensitive C-reactive protein (hsCRP, ferritin, transferrin, albumin, alpha-1 acid glycoprotein (AAG, alpha-2 macroglobulin (AMG, alpha-1 anti-trypsin (AAT and lipoprotein a [Lp(a] were measured in coronary artery disease patients (CAD and CAD patients with non-alcoholic steatohepatitis (NASH. In the present preliminary study an attempt was made to study whether there is an increase in the levels of CRP in CAD patients associated with NASH. CAD patients showed an increase in CRP and serum ferritin levels. In CAD patients with NASH along with an increase in the levels of serum ferittin (p<0.001, the levels of serum AMG and ceruloplasmin (CP were also increased (p<0.01. The CAD patients with NASH had a higher proportion of diabetes, hypertension and dyslipidaemia compared to CAD patients. But how this difference contributes to the elevation in acute inflammatory markers particularly AMG and CP levels in CAD patients with NASH cannot be explained. This study shows that a substantial number of CAD patients may be associated with NASH. Non-invasive simple parameters that reflect the degree of inflammation and fibrosis of the liver in patients with NASH would facilitate improved understanding and treatment of the disease. Further studies may be necessary to evaluate the percentage of NASH patients progressing to CAD.

C-reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patients

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Zimmermann, Esther; Anty, Rodolphe; Tordjman, Joan

2011-01-01

Non-alcoholic fatty liver disease (NAFLD) is a major hepatic consequence of obesity. It has been suggested that the high sensitivity C-reactive protein (hs-CRP) is an obesity-independent surrogate marker of severity of NAFLD, especially development of non-alcoholic steato-hepatitis (NASH), but th......Non-alcoholic fatty liver disease (NAFLD) is a major hepatic consequence of obesity. It has been suggested that the high sensitivity C-reactive protein (hs-CRP) is an obesity-independent surrogate marker of severity of NAFLD, especially development of non-alcoholic steato-hepatitis (NASH...

Non-Alcoholic Fatty Liver Disease: The Emerging Burden in Cardiometabolic and Renal Diseases.

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Han, Eugene; Lee, Yong Ho

2017-12-01

As the number of individuals with non-alcoholic fatty liver disease (NAFLD) has increased, the influence of NAFLD on other metabolic diseases has been highlighted. Accumulating epidemiologic evidence indicates that NAFLD not only affects the liver but also increases the risk of extra-hepatic diseases such as type 2 diabetes mellitus, metabolic syndrome, dyslipidemia, hypertension, cardiovascular or cerebrovascular diseases, and chronic kidney disease. Non-alcoholic steatohepatitis, an advanced type of NAFLD, can aggravate these inter-organ relationships and lead to poorer outcomes. NAFLD induces insulin resistance and exacerbates systemic chronic inflammation and oxidative stress, which leads to organ dysfunction in extra-hepatic tissues. Although more research is needed to identify the pathophysiological mechanisms and causal relationship between NAFLD and cardiometabolic and renal diseases, screening for heart, brain, and kidney diseases, risk assessment for diabetes, and a multidisciplinary approach for managing these patients should be highly encouraged. Copyright © 2017 Korean Diabetes Association.

Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH): cascade of events, clinical aspects, and pharmacotherapy options.

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Teschke, Rolf

2018-06-01

Clinicians caring for patients with alcoholic hepatitis (AH) are often confronted with the question of the best pharmacotherapy to be used. Areas covered: This article covers metabolic aspects of alcohol as the basis of understanding pharmacotherapy and to facilitate choosing the drug therapeutic options for patients with severe AH. Expert opinion: Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH) as terms are often used interchangeably in scientific literature but a stringent differentiation is recommended for proper clarity. As opposed to ASH, the clinical course of AH is often severe and requires an effective drug treatment strategy, in addition to absolute alcohol abstinence and nutritional support. Drug options include corticosteroids as a first choice and pentoxifylline, an inhibitor of phosphodiesterase, as a second line therapy, especially in patients with contraindications for a corticosteroid therapy such as infections or sepsis. At seven days under corticosteroids, treatment should be terminated in non-responders, and patients must then be evaluated for liver transplantation. Pentoxifylline is not effective as a rescue therapy for these patients. Other treatments such as infliximab, propylthiouracil, N-acetylcysteine, silymarin, colchicine, insulin and glucagon, oxandrolone, testosterone, and polyunsaturated lecithin are not effective in severe AH. For liver transplantation, few patients will be eligible.

EXPERIENCE OF ORNITHINE ASPARTATE (HEPA-MERZ AND PROBIOTICS BIOFLORUM FORTE IN THE TREATMENT OF NON-SEVERE FORMS OF ALCOHOLIC AND NON-ALCOHOLIC FATTY LIVER DISEASE

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L. Yu. Ilchenko

2016-01-01

Full Text Available Aim: to evaluate the efficacy and tolerability of ornithine aspartate, probiotic Bioflorum Forte and their combination with steatosis and steatohepatitis in patients  with alcohol and non-alcoholic  fatty  liver disease. Materials and methods.  An open, randomized,  comparative  clinical study, which included 30 outpatients and inpatients with a diagnosis of steatosis, steatohepatitis. We analyzed the clinical symptoms, functional state of the liver. With the help of questionnaires  (Grids LeGo and post intoxication alcohol syndrome have established the presence of chronic alcohol intoxication. Test transmissions of numbers used to characterize the cognitive function, as well as detection  of minimal hepatic encephalopathy. Quality of life was assessed by questionnaire for patients with chronic liver disease — CLDQ (The chronic liver disease questionnaire. The duration of treatment was4 weeks. Results: all three treatment regimens have demonstrated therapeutic  efficacy: clinical improvement, recovery of liver function and results in cognitive function. When combined therapy also produced a significant improvement  in patients’ quality of life. It is shown that  the safety and tolerability of the means employed, adverse events were not reported. Conclusion: the results obtained allow us to recommend the use of ornithine aspartate (Hepa-Merz, both as monotherapy and as part of complex therapy of steatosis,  steatohepatitis with probiotic Bioflorum Forte in patients with alcoholic and non-alcoholic fatty liver disease.

Chemokine-Like Receptor 1 mRNA Weakly Correlates with Non-Alcoholic Steatohepatitis Score in Male but Not Female Individuals

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Maximilian Neumann

2016-08-01

Full Text Available The chemokine-like receptor 1 (CMKLR1 ligands resolvin E1 and chemerin are known to modulate inflammatory response. The progression of non-alcoholic fatty liver disease (NAFLD to non-alcoholic steatohepatitis (NASH is associated with inflammation. Here it was analyzed whether hepatic CMKLR1 expression is related to histological features of NASH. Therefore, CMKLR1 mRNA was quantified in liver tissue of 33 patients without NAFLD, 47 patients with borderline NASH and 38 patients with NASH. Hepatic CMKLR1 mRNA was not associated with gender and body mass index (BMI in the controls and the whole study group. CMKLR1 expression was similar in controls and in patients with borderline NASH and NASH. In male patients weak positive correlations with inflammation, fibrosis and NASH score were identified. In females CMKLR1 was not associated with features of NAFLD. Liver CMKLR1 mRNA tended to be higher in type 2 diabetes patients of both genders and in hypercholesterolemic women. In summary, this study shows that hepatic CMKLR1 mRNA is weakly associated with features of NASH in male patients only.

Modulatory role of Co-enzyme Q10 on methionine and choline deficient diet-induced non-alcoholic steatohepatitis (NASH) in albino rats.

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Saleh, Dalia O; Ahmed, Rania F; Amin, Mohamed M

2017-03-01

The present study aimed to evaluate the hepato-protective and neuro-protective activity of Co-enzyme Q10 (CoQ10) on non-alcoholic steatohepatitis (NASH) in albino rats induced by methionine and choline-deficient (MCD) diet. Rats were fed an MCD diet for 8 weeks to induce non-alcoholic steatohepatitis. CoQ10 (10 mg/(kg·day) -1 ) was orally administered for 2 consecutive weeks. Twenty-four hours after the last dose of the drug, the behavioral test, namely the activity cage test, was performed and the activity counts were recorded. Serum alanine transaminase, aspartate aminotransferase, alkaline phosphatase, gamma-glutamyl transferase, total/direct bilirubin, and albumin were valued to assess liver function. Moreover, hepatic cytokines interleukin-6 as well as its modulator nuclear factor kappa-light-chain-enhancer of activated B cells were determined. In addition, brain biomarkers, viz ammonia, nitric oxide, and brain-derived neurotrophic factor (BDNF), were measured as they are reliable indices to assess brain damage. Histopathological and immunohistochemical examination of brain proliferating cell nuclear antigen in brain and liver tissues were also evaluated. Results revealed that MCD-induced NASH showed impairment in the liver functions with an increase in the liver inflammatory markers. Moreover, NASH resulted in pronounced brain dysfunction as evidenced by hyper-locomotor activity, a decrease in the BDNF level, as well as an increase in the brain nitric oxide and ammonia contents. Oral treatment of MCD-diet-fed rats with CoQ10 for 14 days showed a marked improvement in all the assigned parameters. Finally, it can be concluded that CoQ10 has a hepatoprotective and neuroprotective role in MCD-diet-induced NASH in rats.

Associations of Fatty Liver Disease with Hypertension, Diabetes, and Dyslipidemia: Comparison between Alcoholic and Nonalcoholic Steatohepatitis

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Nobuyuki Toshikuni

2017-01-01

Full Text Available Alcoholic steatohepatitis (ASH and nonalcoholic steatohepatitis (NASH are representative types of fatty liver disease (FLD and have similar histologic features. In this study, we aimed to compare the associations of the two FLD types with hypertension (HT, diabetes mellitus (DM, and dyslipidemia (DL. A nationwide survey investigating FLD status included 753 Japanese subjects (median age 55 years; male 440, female 313 with biopsy-proven ASH (n=172 or NASH (n=581. We performed a multiple logistic regression analysis to identify the factors associated with HT, DM, or DL. Older age and a higher body mass index were significant factors associated with HT. Older age, female sex, a higher body mass index, advanced liver fibrosis, and the NASH type of FLD (odds ratio 2.77; 95% confidence interval 1.78–4.31; P<0.0001 were significant factors associated with DM. Finally, the NASH type of FLD (odds ratio 4.05; 95% confidence interval 2.63–6.24; P<0.0001 was the only significant factor associated with DL. Thus, the associations of NASH with DM and DL were stronger than those of ASH with DM and DL. In the management of FLD subjects, controlling DM and DL is particularly important for NASH subjects.

Usefulness of Cytokeratin-18M65 in Diagnosing Non-Alcoholic Steatohepatitis in Japanese Population.

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Hasegawa, Yutaka; Kim, Soo Ryang; Hatae, Takashi; Ohta, Mitsuhiro; Fujinami, Aya; Sugimoto, Kayo; Kim, Ke Ih; Imoto, Susumu; Tohyama, Madoka; Kim, Soo Ki; Ikura, Yoshihiro; Kudo, Masatoshi

2015-10-01

The aim of this study was to evaluate cytokeratin-18M65 (CK-18M65) for distinguishing between simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) against healthy individuals (HIs) in Japanese population. The serum from 24 HIs, 21 patients with SS and 20 patients with NASH were examined. Serum CK-18M65 was measured by enzyme-linked immunosorbent assay. Aspartate aminotransferase was significantly different between NASH patients and HIs with p fashion in HIs and also in SS and NASH patients. Multivariate logistic regression analysis revealed that NASH could be diagnosed with the use of CK-18M65 alone (p = 0.0285, OR 1.0038, 95% CI 1.0004-1.0073). At the optimal cut-off level of 548 U/l, CK-18M65 had an AUC value of 0.7369, 60.00% sensitivity and 85.70% specificity. In patients with NASH, no significant difference was observed between low fibrosis (Stage 0-1, 794.30 ± 454.41, n = 10) and high fibrosis (Stage 2-3, 809.70 ± 641.43, n = 10; p = 0.5967) and between slight steatosis (Japanese population. © 2015 S. Karger AG, Basel.

Non-alcoholic fatty liver disease in obese persons with diabetes

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Tomašević Ratko

2007-01-01

Full Text Available Background. Obesity, diabetes and different lipid metabolic disorders are the most frequent risk factors for nonalcoholic fatty liver disease, presented with a high variability in clinical and histological findings. Case report. We presented a case of 37-year-old male, suffering from type 2 diabetes mellitus, grade III obesity (BMI 45 kg/m2 and multiple metabolic disorders. Abdominal ultrasound revealed hepatomegaly during the last six months. Laboratory diagnostics showed increased serum transaminase levels. Serologic markers for viral hepatitis B and C were negative. The patient denied significant alcohol consumption. Liver biopsy and pathohistologic finding revealed macro- (III grade and microvesicular (I grade fatty degeneration, as well as mixed-cell portal infiltration with moderate liver fibrosis, corresponding to the typical presentation of NASH (Non Alcoholic Steatohepatitis. Conclusion. NASH treatment options include the reduction of body mass and an adequate antidiabetic and dislipidemia treatment. The aim of all therapeutic measures was to stop the progression of the disease, to prevent the progression of fibrosis and the development of of cirrhosis. .

Roux-en Y gastric bypass results in long-term remission of hepatocyte apoptosis and hepatic histological features of non-alcoholic steatohepatitis

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Anne-Sophie Schneck

2016-08-01

Full Text Available The long-term effects of bariatric surgery on non alcoholic steatohepatitis (NASH, focusing on liver injury and hepatocyte apoptosis,are not well established. We here performed a longitudinal study with paired liver biopsies of 9 morbidly obese women (median BMI: 42 [38.7; 45.1] kg/m2 with NASH with a median follow-up of 55 [44; 75] months after laparoscopic Roux-en-Y gastric bypass (LRYGB surgery. LRYGB surgery was associated with significant weight loss (median BMI loss –13.7 [–16.4; –9.5] kg/m2, improved hepatic steatosis in all patients (55.5% with total resolution, and resolution of hepatic inflammation and hepatocyte ballooning in 100% and 88.8% of cases, respectively. Alanine aminotransferase levels dropped to normal values while hepatic activated cleaved caspase 3levels strongly decreased after a median follow-up of 55 months. Hepatocyte apoptosis, as evaluated by serum caspase-generated keratin-18 fragment, improved within the first year following LRYGB and these improvements persisted for at least 55 months. LRYGB in morbidly obese patients with NASH is thus associated with a long-lasting beneficial impact on hepatic steatohepatitis and hepatocyte death.

Roux-En Y Gastric Bypass Results in Long-Term Remission of Hepatocyte Apoptosis and Hepatic Histological Features of Non-alcoholic Steatohepatitis.

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Schneck, Anne-Sophie; Anty, Rodolphe; Patouraux, Stéphanie; Bonnafous, Stéphanie; Rousseau, Déborah; Lebeaupin, Cynthia; Bailly-Maitre, Beatrice; Sans, Arnaud; Tran, Albert; Gugenheim, Jean; Iannelli, Antonio; Gual, Philippe

2016-01-01

The long-term effects of bariatric surgery on non-alcoholic steatohepatitis (NASH), focusing on liver injury and hepatocyte apoptosis, are not well-established. We here performed a longitudinal study with paired liver biopsies of nine morbidly obese women (median BMI: 42 [38.7; 45.1] kg/m(2)) with NASH with a median follow-up of 55 [44; 75] months after laparoscopic Roux-en-Y gastric bypass (LRYGB) surgery. LRYGB surgery was associated with significant weight loss (median BMI loss -13.7 [-16.4; -9.5] kg/m(2)), improved hepatic steatosis in all patients (55.5% with total resolution), and resolution of hepatic inflammation and hepatocyte ballooning in 100 and 88.8% of cases, respectively. Alanine aminotransferase levels dropped to normal values while hepatic activated cleaved caspase-3 levels strongly decreased after a median follow-up of 55 months. Hepatocyte apoptosis, as evaluated by serum caspase-generated keratin-18 fragment, improved within the first year following LRYGB and these improvements persisted for at least 55 months. LRYGB in morbidly obese patients with NASH is thus associated with a long-lasting beneficial impact on hepatic steatohepatitis and hepatocyte death.

Simultaneous MR quantification of hepatic fat content, fatty acid composition, transverse relaxation time and magnetic susceptibility for the diagnosis of non-alcoholic steatohepatitis.

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Leporq, B; Lambert, S A; Ronot, M; Vilgrain, V; Van Beers, B E

2017-10-01

Non-alcoholic steatohepatitis (NASH) is characterized at histology by steatosis, hepatocyte ballooning and inflammatory infiltrates, with or without fibrosis. Although diamagnetic material in fibrosis and inflammation can be detected with quantitative susceptibility imaging, fatty acid composition changes in NASH relative to simple steatosis have also been reported. Therefore, our aim was to develop a single magnetic resonance (MR) acquisition and post-processing scheme for the diagnosis of steatohepatitis by the simultaneous quantification of hepatic fat content, fatty acid composition, T 2 * transverse relaxation time and magnetic susceptibility in patients with non-alcoholic fatty liver disease. MR acquisition was performed at 3.0 T using a three-dimensional, multi-echo, spoiled gradient echo sequence. Phase images were unwrapped to compute the B 0 field inhomogeneity (ΔB 0 ) map. The ΔB 0 -demodulated real part images were used for fat-water separation, T 2 * and fatty acid composition quantification. The external and internal fields were separated with the projection onto dipole field method. Susceptibility maps were obtained after dipole inversion from the internal field map with single-orientation Bayesian regularization including spatial priors. Method validation was performed in 32 patients with biopsy-proven, non-alcoholic fatty liver disease from which 12 had simple steatosis and 20 NASH. Liver fat fraction and T 2 * did not change significantly between patients with simple steatosis and NASH. In contrast, the saturated fatty acid fraction increased in patients with NASH relative to patients with simple steatosis (48 ± 2% versus 44 ± 4%; p magnetic susceptibility decreased (-0.30 ± 0.27 ppm versus 0.10 ± 0.14 ppm; p magnetic susceptibility as NASH marker was 0.91 (95% CI: 0.79-1.0). Simultaneous MR quantification of fat content, fatty acid composition, T 2 * and magnetic susceptibility is feasible in the liver. Our preliminary results

Sorafenib prevents liver fibrosis in a non-alcoholic steatohepatitis (NASH) rodent model

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Stefano, J.T.; Pereira, I.V.A.; Torres, M.M.; Bida, P.M. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Coelho, A.M.M. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Xerfan, M.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Cogliati, B. [Departamento de Patologia, Faculdade de Medicina Veterinária e Zootecnia, Universidade de São Paulo, São Paulo, SP (Brazil); Barbeiro, D.F. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Mazo, D.F.C. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Kubrusly, M.S.; D' Albuquerque, L.A.C. [Disciplina de Transplante de Órgãos do Aparelho Digestivo (LIM-37), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Souza, H.P. [Disciplina de Emergências Clínicas (LIM-51), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil); Carrilho, F.J.; Oliveira, C.P. [Disciplina de Gastroenterologia Clínica (LIM-07), Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP (Brazil)

2015-02-24

Liver fibrosis occurring as an outcome of non-alcoholic steatohepatitis (NASH) can precede the development of cirrhosis. We investigated the effects of sorafenib in preventing liver fibrosis in a rodent model of NASH. Adult Sprague-Dawley rats were fed a choline-deficient high-fat diet and exposed to diethylnitrosamine for 6 weeks. The NASH group (n=10) received vehicle and the sorafenib group (n=10) received 2.5 mg·kg{sup -1}·day{sup -1} by gavage. A control group (n=4) received only standard diet and vehicle. Following treatment, animals were sacrificed and liver tissue was collected for histologic examination, mRNA isolation, and analysis of mitochondrial function. Genes related to fibrosis (MMP9, TIMP1, TIMP2), oxidative stress (HSP60, HSP90, GST), and mitochondrial biogenesis (PGC1α) were evaluated by real-time quantitative polymerase chain reaction (RT-qPCR). Liver mitochondrial oxidation activity was measured by a polarographic method, and cytokines by enzyme-linked immunosorbent assay (ELISA). Sorafenib treatment restored mitochondrial function and reduced collagen deposition by nearly 63% compared to the NASH group. Sorafenib upregulated PGC1α and MMP9 and reduced TIMP1 and TIMP2 mRNA and IL-6 and IL-10 protein expression. There were no differences in HSP60, HSP90 and GST expression. Sorafenib modulated PGC1α expression, improved mitochondrial respiration and prevented collagen deposition. It may, therefore, be useful in the treatment of liver fibrosis in NASH.

Non-Alcoholic Fatty Liver Disease in HIV Infection.

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Macías, Juan; Pineda, Juan A; Real, Luis M

2017-01-01

Non-alcoholic fatty liver disease is one of the most frequent chronic hepatic conditions worldwide. The spectrum of non-alcoholic fatty liver disease goes from hepatic steatosis to steatohepatitis, cirrhosis, and hepatocellular carcinoma. Risk factors for non-alcoholic fatty liver disease are metabolic, mainly obesity and the accompanying consequences. Treatment and prevention of non-alcoholic fatty liver disease should target those metabolic abnormalities. The frequency of and the factors associated with hepatic steatosis in HIV infection seem to be similar to those reported in the general population, though direct comparisons are lacking. Hepatic steatosis in HIV infection may also be secondary to antiretroviral drugs or HCV-related factors in HCV-coinfected subjects. However, more recent data suggest that hepatic steatosis in HIV infection represents true non-alcoholic fatty liver disease. As such, management of non-alcoholic fatty liver disease in HIV infection should follow the same principles as in the general population.

Resolution of non-alcoholic steatohepatitis by rosuvastatin monotherapy in patients with metabolic syndrome.

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Kargiotis, Konstantinos; Athyros, Vasilios G; Giouleme, Olga; Katsiki, Niki; Katsiki, Evangelia; Anagnostis, Panagiotis; Boutari, Chrysoula; Doumas, Michael; Karagiannis, Asterios; Mikhailidis, Dimitri P

2015-07-07

To investigate the effect of rosuvastatin monotherapy on non-alcoholic steatohepatitis (NASH). At present there is no effective treatment for non-alcoholic fatty liver disease or its advanced form NASH. This prospective study included 20 biopsy proven patients with NASH, metabolic syndrome (MetS) and dyslipidaemia. Biochemical parameters of the blood of the patients and an ultrasonography of the liver were performed at baseline. Then patients received lifestyle advice and were treated for a 12 mo period with rosuvastatin (10 mg/d) monotherapy. Patients were re-evaluated during the study at 3 mo intervals, during which biochemical parameters of the blood were measured including liver enzymes. A repeat biopsy and ultrasonography of the liver were performed at the end of the study in all 20 patients. Changes in liver enzymes, fasting plasma glucose, serum creatinine, serum uric acid (SUA), high sensitivity C reactive protein (hsCRP) and lipid profile were assessed every 3 mo. The primary endpoint was the resolution of NASH and the secondary endpoints were the changes in liver enzyme and lipid values. The repeat liver biopsy and ultrasonography showed complete resolution of NASH in 19 patients, while the 20(th), which had no improvement but no deterioration either, developed arterial hypertension and substantial rise in triglyceride levels during the study, probably due to changes in lifestyle including alcohol abuse. Serum alanine transaminase, aspartate transaminase, and γ-glutamyl transpeptidase were normalised by the 3(rd) treatment month (ANOVA P < 0.001), while alkaline phosphatase activities by the 6(th) treatment month (ANOVA, P = 0.01). Fasting plasma glucose and glycated haemoglobin were significantly reduced (P < 0.001). Lipid values were normalised by the 3(rd) treatment month. No patient had MetS by the 9(th) treatment month. Body mass index and waist circumference remained unchanged during the study. Thus, changes in liver pathology and function should

Detection of non-alcoholic steatohepatitis in patients with morbid obesity before bariatric surgery: preliminary evaluation with acoustic radiation force impulse imaging

International Nuclear Information System (INIS)

Guzman-Aroca, F.; Reus, M.; Dios Berna-Serna, Juan de; Frutos-Bernal, M.D.; Lujan-Mompean, J.A.; Parrilla, P.; Bas, A.

2012-01-01

To investigate the utility of acoustic radiation force impulse (ARFI) imaging, with the determination of shear wave velocity (SWV), to differentiate non-alcoholic fatty liver disease (NAFLD) from non-alcoholic steatohepatitis (NASH) in patients with morbid obesity before bariatric surgery. Thirty-two patients with morbid obesity were evaluated with ARFI and conventional ultrasound before bariatric surgery. The ARFI and ultrasound results were compared with liver biopsy findings, which is the reference standard. The patients were classed according to their histological findings into three groups: group A, simple steatosis; group B, inflammation; and group C, fibrosis. The median SWV was 1.57 ± 0.79 m/s. Hepatic alterations were observed in the histopathological findings for all the patients in the study (100 %), with the results of the laboratory tests proving normal. Differences in SWV were also observed between groups A, B and C: 1.34 ± 0.90 m/s, 1.55 ± 0.79 m/s and 1.86 ± 0.75 m/s (P < 0.001), respectively. The Az for differentiating NAFLD from NASH or fibrosis was 0.899 (optimal cut-off value 1.3 m/s; sensitivity 85 %; specificity 83.3 %). The ARFI technique is a useful diagnostic tool for differentiating NAFLD from NASH in asymptomatic patients with morbid obesity. (orig.)

Detection of non-alcoholic steatohepatitis in patients with morbid obesity before bariatric surgery: preliminary evaluation with acoustic radiation force impulse imaging

Energy Technology Data Exchange (ETDEWEB)

Guzman-Aroca, F.; Reus, M.; Dios Berna-Serna, Juan de [Virgen de la Arrixaca University Hospital, Department of of Radiology, El Palmar, Murcia (Spain); Frutos-Bernal, M.D.; Lujan-Mompean, J.A.; Parrilla, P. [Virgen de la Arrixaca University Hospital, Department of Surgery, El Palmar, Murcia (Spain); Bas, A. [Virgen de la Arrixaca University Hospital, Department of Pathology, El Palmar, Murcia (Spain)

2012-11-15

To investigate the utility of acoustic radiation force impulse (ARFI) imaging, with the determination of shear wave velocity (SWV), to differentiate non-alcoholic fatty liver disease (NAFLD) from non-alcoholic steatohepatitis (NASH) in patients with morbid obesity before bariatric surgery. Thirty-two patients with morbid obesity were evaluated with ARFI and conventional ultrasound before bariatric surgery. The ARFI and ultrasound results were compared with liver biopsy findings, which is the reference standard. The patients were classed according to their histological findings into three groups: group A, simple steatosis; group B, inflammation; and group C, fibrosis. The median SWV was 1.57 {+-} 0.79 m/s. Hepatic alterations were observed in the histopathological findings for all the patients in the study (100 %), with the results of the laboratory tests proving normal. Differences in SWV were also observed between groups A, B and C: 1.34 {+-} 0.90 m/s, 1.55 {+-} 0.79 m/s and 1.86 {+-} 0.75 m/s (P < 0.001), respectively. The Az for differentiating NAFLD from NASH or fibrosis was 0.899 (optimal cut-off value 1.3 m/s; sensitivity 85 %; specificity 83.3 %). The ARFI technique is a useful diagnostic tool for differentiating NAFLD from NASH in asymptomatic patients with morbid obesity. (orig.)

Experimental non-alcoholic fatty liver disease results in decreased hepatic uptake transporter expression and function in rats

NARCIS (Netherlands)

Fisher, Craig D.; Lickteig, Andrew J.; Augustine, Lisa M.; Oude Elferink, Ronald P. J.; Besselsen, David G.; Erickson, Robert P.; Cherrington, Nathan J.

2009-01-01

Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of diagnoses ranging from simple fatty liver (SFL), to non-alcoholic steatohepatitis (NASH). This study aimed to determine the effect of moderate and severe NAFLD on hepatic transporter expression and function in vivo. Rats were fed a

Connection Between Non-Alcoholic Fatty Liver Disease and Diabetes Mellitus

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Oprea-Călin Gabriela

2014-06-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD is the commonest liver condition in the world, accounting for 20-30% of the adult population, and encompasses a spectrum of liver disorders characterized by fat accumulation within the liver, associated or not with varying degrees of hepatic inflammation and liver fibrosis through to cirrhosis. The prevalence of NAFLD increases significantly in the presence of obesity (60-80% and type 2 diabetes (60%. NAFLD is associated with metabolic disorders (type 2 diabetes, obesity and hyperlipidemia grouped together as the metabolic syndrome (MetS. It is now regarded as the hepatic manifestation of this syndrome and is closely linked to insulin resistance (IR.The presence of NAFLD predicts the development of type 2 diabetes independent of established risk factors. NAFLD patients should therefore be screened for diabetes, including by the Oral Glucose Tolerance Test (OGTT if there any abnormalities of fasting blood glucose (FBG and given appropriate lifestyle advice. Early diagnosis with the institution of lifestyle measures could help prevent or retard the onset of these metabolic disorders. Type 2 diabetes causes more severe non-alcoholic steatohepatitis (NASH, and patients with diabetes have an increased risk for cirrhosis and the development of hepatocellular carcinoma (HCC

Presence of alcoholic steatohepatitis, but no selective histological feature, indicates an increased risk of cirrhosis and premature death

DEFF Research Database (Denmark)

Semb, Synne; Neermark, Søren; Dam-Larsen, Sanne

2016-01-01

OBJECTIVE: The prognostic impact of early stages of histologically confirmed alcoholic liver disease is uncertain. Our aim was to determine the risk of cirrhosis and premature death, and identify prognostic markers, in patients with biopsy-proven alcoholic steatohepatitis - and to compare prognos...

Deleterious effect of n-3 polyunsaturated fatty acids in non-alcoholic steatohepatitis in the fat-1 mouse model

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Diana Shefer-Weinberg

2017-04-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD represents a spectrum of pathologies, ranging from hepatocellular steatosis to non-alcoholic steatohepatitis (NASH, fibrosis and cirrhosis. It has been suggested that fish oil containing n-3 polyunsaturated fatty acids (n-3 PUFA induce beneficial effects in NAFLD. However, n-3 PUFA are sensitive to peroxidation that generate free radicals and reactive aldehydes. We aimed at determining whether changing the tissue ratio of n-3 to n-6 PUFA may be beneficial or alternatively harmful to the etiology of NAFLD. The transgenic Fat-1 mouse model was used to determine whether n-3 PUFA positively or negatively affect the development of NAFLD. fat-1mice express the fat-1 gene of Caenorhabditis elegans, which encodes an n-3 fatty-acid desaturase that converts n-6 to n-3 fatty acids. Wild-type C57BL/6 mice served as the control group. Both groups of mice were fed methionine and choline deficient (MCD diet, which induces NASH within 4 weeks. The study shows that NASH developed faster and was more severe in mice from the fat-1 group when compared to control C57BL/6 mice. This was due to enhanced lipid peroxidation of PUFA in the liver of the fat-1 mice as compared to the control group. Results of our mice study suggest that supplementing the diet of individuals who develop or have fatty livers with n-3 PUFA should be carefully considered and if recommended adequate antioxidants should be added to the diet in order to reduce such risk.

STUDY ON NONALCOHOLIC STEATOHEPATITIS (NASH IN PATIENTS OF OBESE, TYPE 2 DIABETES MELLITUS

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Uma Shankar Mishra

2018-02-01

Full Text Available BACKGROUND Nonalcoholic steatohepatitis (NASH represents only a part of a wide spectrum of non-alcoholic fatty liver disease (NAFLD and its prevalence is only 2-3% in the general population. Diabetes mellitus increases the risk for severe necroinflammation. The diagnosis rests on the hallmark histological features. Liver biopsy is essential for positive diagnosis and prognostication of NASH. The aim of this study was to evaluate the correlation between NASH and risk factor like diabetes, BMI and other risk factors. MATERIALS AND METHODS 36 patients with histologically confirmed NASH with elevated liver aminotransferase and negative markers for other diseases admitted to our institution from Sept-2012 to August-2014, were included in the study, meeting our inclusion & exclusion criteria. Investigations were done & data was collected. Data were pooled & interpreted using standard statistical methods. RESULTS Twenty out of thirty-six patients had diabetes in our study i.e. 55.6% were diabetes. 22 out of 36 patients i.e. 61.1% had BMI >28 kg/m2 . the mean waist circumference in our study was 93.13 Cm. 15 out of 24 female patients i.e. 62.5% females had WC>88 cm and 8 out of 12 male patients i.e. 66.7% males had WC >102 cm., 20 out of 36 patients i.e. 55.6% patients fulfilled at least 3 out of 5 criteria and therefore had insulin resistance syndrome or metabolic syndrome. CONCLUSION Patients with NASH are typically asymptomatic unless cirrhosis develops. 97.22% patients were dyslipidaemics. NASH may be considered an additional features of insulin resistance & metabolic syndrome. Age, gender, waist circumference, BMI, ALT, AST: ALT ratio, serum triglyceride levels, HTN & BAAT score are independent predictors of NASH.

Influence of non-alcoholic fatty liver disease on the development of diabetes mellitus.

Science.gov (United States)

Kasturiratne, Anuradhani; Weerasinghe, Sanjaya; Dassanayake, Anuradha S; Rajindrajith, Shaman; de Silva, Arjuna P; Kato, Norihiro; Wickremasinghe, A Rajitha; de Silva, H Janaka

2013-01-01

Non-alcoholic fatty liver disease (NAFLD) is linked to metabolic syndrome, and is known to be associated with impaired fasting glycemia and diabetes mellitus. This prospective community-based study was conducted to determine the association between NAFLD and incidence of diabetes mellitus in an urban adult population in Sri Lanka. Participants of the Ragama Health Study cohort were assessed for NAFLD using established ultrasound criteria in 2007. Those who were free of diabetes at baseline were followed up for 3 years. Incidence rates of diabetes mellitus were compared between subjects with and without NAFLD at baseline. Out of 2984 subjects, 926 had NAFLD and 676 had diabetes in 2007. Of the 2276 subjects who were free of diabetes in 2007, 1914 were re-assessed in 2010. After 3 years, 104 out of 528 subjects with NAFLD and 138 out of 1314 subjects without NAFLD had developed diabetes mellitus de novo. Incidence rates of diabetes were respectively 64.2 and 34 per 1000 person-years of follow up for those with and without NAFLD. NAFLD was an independent predictor of developing diabetes mellitus. Other independent predictors were impaired fasting glycemia and dyslipidemia. Subjects with ultrasonically diagnosed NAFLD have an increased risk of developing diabetes mellitus. Intervention for NAFLD through lifestyle modification may prevent progression of the current diabetes epidemic. © 2012 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Histological scoring and associated risk factors of non-alcoholic fatty liver disease.

Science.gov (United States)

Majid, N; Ali, Z; Rahman, M R; Akhter, A; Rajib, R C; Ahmad, F; Sharmin, S; Akond, A K; Huq, N

2013-10-01

Non alcoholic steatohepatitis is a hepatic disorder with histological features of alcohol induced liver disease that occurs in individual who do not consume significant alcohol. Liver biopsy is an important part of the evaluation in term of both grade & stage. A cross sectional study was carried out in the department of Pathology, Dhaka Medical College, Dhaka & department of Hepatology, Bangabandhu Sheikh Mujib Medical University (BSMMU) from July 2007 to June 2009. Total 55 adult subjects of both sex were included on the basis of predefined inclusion & exclusion criteria in this study to evaluate the histological pattern of non alcoholic fatty liver disease (NAFLD) and its correlation with risk factors. Liver biopsy was done and H & E and Masson's Trichrome stain slides were examined to evaluate the grade and stage of NAFLD. Scoring and semiquantitative assessment of steatosis and NAFLD severity was done according to Kleiner scale known as NAFLD activity score (NAS). The results of Pearson correlation showed only BMI and triglyceride level significantly correlated with NAS score. The results of Spearman's rank correlation showed that BMI, central obesity, triglyceridaemia and age significantly correlated with staging of fibrosis. The results of multiple regression analysis showed that variation of NAS depend on BMI and triglyceride level. The study also revealed that risk factors contributed about 29% risk for the occurrence of non alcoholic steatohepatitis.

'Non-alcoholic fatty liver disease' bij kinderen : een nieuwe complicatie van obesitas

NARCIS (Netherlands)

Bocca, Gianni; Stolk, R.P.; Scheenstra, R.; Sauer, P.J.

2008-01-01

Non-alcoholic fatty liver disease (NAFLD) comprises a range of chronic liver diseases from simple steatosis to steatohepatitis and cirrhosis with liver failure. In children, NAFLD is mainly associated with obesity and metabolic syndrome, the results of an unhealthy lifestyle. Insulin resistance and

Statins Increase Mitochondrial and Peroxisomal Fatty Acid Oxidation in the Liver and Prevent Non-Alcoholic Steatohepatitis in Mice

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Han-Sol Park

2016-04-01

Full Text Available BackgroundNon-alcoholic fatty liver disease is the most common form of chronic liver disease in industrialized countries. Recent studies have highlighted the association between peroxisomal dysfunction and hepatic steatosis. Peroxisomes are intracellular organelles that contribute to several crucial metabolic processes, such as facilitation of mitochondrial fatty acid oxidation (FAO and removal of reactive oxygen species through catalase or plasmalogen synthesis. Statins are known to prevent hepatic steatosis and non-alcoholic steatohepatitis (NASH, but underlying mechanisms of this prevention are largely unknown.MethodsSeven-week-old C57BL/6J mice were given normal chow or a methionine- and choline-deficient diet (MCDD with or without various statins, fluvastatin, pravastatin, simvastatin, atorvastatin, and rosuvastatin (15 mg/kg/day, for 6 weeks. Histological lesions were analyzed by grading and staging systems of NASH. We also measured mitochondrial and peroxisomal FAO in the liver.ResultsStatin treatment prevented the development of MCDD-induced NASH. Both steatosis and inflammation or fibrosis grades were significantly improved by statins compared with MCDD-fed mice. Gene expression levels of peroxisomal proliferator-activated receptor α (PPARα were decreased by MCDD and recovered by statin treatment. MCDD-induced suppression of mitochondrial and peroxisomal FAO was restored by statins. Each statin's effect on increasing FAO and improving NASH was independent on its effect of decreasing cholesterol levels.ConclusionStatins prevented NASH and increased mitochondrial and peroxisomal FAO via induction of PPARα. The ability to increase hepatic FAO is likely the major determinant of NASH prevention by statins. Improvement of peroxisomal function by statins may contribute to the prevention of NASH.

COMPARISON OF CLINICAL PROFILE OF DIABETES MELLITUS PATIENTS WITH OR WITHOUT NON-ALCOHOLIC FATTY LIVER DISEASES

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Satish Kumar

2017-11-01

Full Text Available BACKGROUND Non-alcoholic fatty liver disease represents a spectrum of conditions, which is characterised histologically by significant macrovesicular hepatic steatosis that occurs in those who do not consume alcohol in amounts considered to be harmful to liver and in the absence of known toxins, drugs, viral disease, etc. This disease is quite frequently seen in diabetes especially type 2 diabetes mellitus, which is probably related to altered glucose metabolism. The spectrum of non-alcoholic fatty liver disease is quite variable from mild alteration of transaminases, which is a benign disease to one with high morbidity and mortality. Type 2 diabetes mellitus is a risk factor for NAFLD and the prevalence of NAFLD in diabetic patients have been shown to be between 30-80%. MATERIALS AND METHODS In this study, normative survey technique was selected. Duration of the study was one year. The sample comprised of 100 diabetic patients age ranged 31-70 years. The sample was selected on the basis of inclusion and exclusion criteria. The tools such as clinical profile and checklist were administered. RESULTS The study found out that NAFLD is very common in diabetes mellitus. Diabetic patients with NAFLD has a longer duration of diabetes compared to that of diabetic patients without NAFLD diabetic patients with NAFLD had higher BMI, waist circumference and systolic blood pressure than that of patients without NAFLD. CONCLUSION All the patients within the spectrum of NAFLD should be considered potentially affected not only by a liver disease, but by a multisystem disease. Clinicians should be aware of the importance of a complete clinical evaluation for early diagnosis and treatment of liver disease as well as the different manifestations. All type 2 diabetic patients should be monitored for the development of NAFLD. Early diagnosis of NAFLD can prevent the progression to NASH and its complications.

Placental extract ameliorates non-alcoholic steatohepatitis (NASH by exerting protective effects on endothelial cells

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Akihiro Yamauchi

2017-09-01

Full Text Available Non-alcoholic steatohepatitis (NASH is a severe form of fatty liver disease that is defined by the presence of inflammation and fibrosis, ultimately leading to cirrhosis and hepatocellular carcinoma. Treatment with human placental extract (HPE reportedly ameliorates the hepatic injury. We evaluated the effect of HPE treatment in a mouse model of NASH. In the methione- and choline-deficient (MCD diet-induced liver injury model, fibrosis started from regions adjacent to the sinusoids. We administered the MCD diet with high-salt loading (8% NaCl in the drinking water to mice deficient in the vasoprotective molecule RAMP2 for 5 weeks, with or without HPE. In both the HPE and control groups, fibrosis was seen in regions adjacent to the sinusoids, but the fibrosis was less pronounced in the HPE-treated mice. Levels of TNF-α and MMP9 expression were also significantly reduced in HPE-treated mice, and oxidative stress was suppressed in the perivascular region. In addition, HPE dose-dependently increased survival of cultured endothelial cells exposed to 100 μM H2O2, and it upregulated expression of eNOS and the anti-apoptotic factors bcl-2 and bcl-xL. From these observations, we conclude that HPE ameliorates NASH-associated pathologies by suppressing inflammation, oxidative stress and fibrosis. These beneficially effects of HPE are in part attributable to its protective effects on liver sinusoidal endothelial cells. HPE could thus be an attractive therapeutic candidate with which to suppress progression from simple fatty liver to NASH.

[Role of the endocrine system in the pathogenesis of non-alcoholic fatty liver disease].

Science.gov (United States)

Hagymási, Krisztina; Reismann, Péter; Rácz, Károly; Tulassay, Zsolt

2009-11-29

The most frequent liver disorder in metabolic syndrome is the nonalcoholic fatty liver disease. Its pathogenesis is a complex, multifactorial process, characterized by insulin resistance and involvement of the endocrine system. Hypothyroidism may lead to nonalcoholic steatohepatitis via hyperlipidemia and obesity. Adult patients with growth hormone deficiency have a metabolic syndrome-like phenotype with obesity and many characteristic metabolic alterations. The chronic activation of the hypothalamic-pituitary-adrenal axis results in metabolic syndrome as well. Cushing's syndrome has also features of metabolic syndrome. Mild elevation of transaminase activities is commonly seen in patients with adrenal failure. Non-alcoholic steatosis is twice as common in postmenopusal as in premenopausal women and hormonal replacement therapy decreases the risk of steatosis. Insulin resistance, diabetes mellitus type 2, sleeping apnoe syndrome, cardiovascular disorders and non-alcoholic fatty liver disease are more frequent in polycystic ovary syndrome. Hypoandrogenism in males and hyperandrogenism in females may lead to fatty liver via obesity and insulin resistance. Adipokines (leptin, acylation stimulating protein, adiponectin) have a potential role in the pathogenesis of nonalcoholic fatty liver. The alterations of endocrine system must be considered in the background of cryptogenic liver diseases. The endocrine perspective may help the therapeutic approaches in the future.

Relationship between liver tissue stiffness and histopathological findings analyzed by shear wave elastography and compression testing in rats with non-alcoholic steatohepatitis.

Science.gov (United States)

Ogawa, Saori; Moriyasu, Fuminori; Yoshida, Keiko; Oshiro, Hisashi; Kojima, Mayumi; Sano, Takatomo; Furuichi, Yoshihiro; Kobayashi, Yoshiyuki; Nakamura, Ikuo; Sugimoto, Katsutoshi

2016-07-01

The aim of the present study was to investigate two methods of determining liver stiffness in rats with various degrees of non-alcoholic steatohepatitis induced by a methionine- and choline-deficient (MCD) diet by comparing each finding with reference to histopathological liver findings. Twenty male Wister rats were fed an MCD diet for up to 32 weeks, and four were fed a normal diet. Ultrasound-based shear wave elastography (SWE) and mechanical compression testing using an Instron Universal Testing machine were performed on each rat at designated time points. After each examination, liver histopathology was analyzed to evaluate the degrees of steatosis, inflammation, and fibrosis based on non-alcoholic fatty liver disease (NAFLD) activity score, and each finding was compared with reference to liver histopathologic findings. Median liver stiffness values measured using SWE showed a stepwise increase with increasing histological inflammation score (P = 0.002), hepatic fibrosis stage (P = 0.029), ballooning score (P = 0.012), and steatosis grade (P = 0.030). Median liver stiffness measured using an Instron machine showed a stepwise increase only with increasing histological fibrosis stage (P = 0.033). Degree of liver stiffness measured by SWE and the Instron machine differed. SWE reflected mainly inflammation, whereas Instron machine-derived values primarily reflected fibrosis. This is the main source of discrepancies between measurements made with these two modalities.

Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

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Winkler, Sandra; Borkham-Kamphorst, Erawan; Stock, Peggy; Brückner, Sandra; Dollinger, Matthias; Weiskirchen, Ralf; Christ, Bruno

2014-01-01

Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH

Human mesenchymal stem cells towards non-alcoholic steatohepatitis in an immunodeficient mouse model

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Winkler, Sandra, E-mail: sandra.pelz@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Borkham-Kamphorst, Erawan, E-mail: ekamphorst@ukaachen.de [Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen (Germany); Stock, Peggy, E-mail: peggy.stock@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Brückner, Sandra, E-mail: sandra.brueckner@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Dollinger, Matthias, E-mail: matthias.dollinger@uniklinik-ulm.de [Department for Internal Medicine I, University Hospital Ulm, Albert-Einstein-Allee 23, D-89081 Ulm (Germany); Weiskirchen, Ralf, E-mail: rweiskirchen@ukaachen.de [Institute of Clinical Chemistry and Pathobiochemistry, RWTH University Hospital Aachen, Pauwelsstraße 30, D-52074 Aachen (Germany); Christ, Bruno, E-mail: bruno.christ@medizin.uni-leipzig.de [Applied Molecular Hepatology Laboratory, Department of Visceral, Transplantation, Thoracic and Vascular Surgery, University Hospital Leipzig, Liebigstraße 21, D-04103 Leipzig (Germany); Translational Centre for Regenerative Medicine (TRM), University of Leipzig, Leipzig (Germany)

2014-08-15

Non-alcoholic steatohepatitis (NASH) is a frequent clinical picture characterised by hepatic inflammation, lipid accumulation and fibrosis. When untreated, NASH bears a high risk of developing liver cirrhosis and consecutive hepatocellular carcinoma requiring liver transplantation in its end-stage. However, donor organ scarcity has prompted the search for alternatives, of which hepatocyte or stem cell-derived hepatocyte transplantation are regarded auspicious options of treatment. Mesenchymal stem cells (MSC) are able to differentiate into hepatocyte-like cells and thus may represent an alternative cell source to primary hepatocytes. In addition these cells feature anti-inflammatory and pro-regenerative characteristics, which might favour liver recovery from NASH. The aim of this study was to investigate the potential benefit of hepatocyte-like cells derived from human bone marrow MSC in a mouse model of diet-induced NASH. Seven days post-transplant, human hepatocyte-like cells were found in the mouse liver parenchyma. Triglyceride depositions were lowered in the liver but restored to normal in the blood. Hepatic inflammation was attenuated as verified by decreased expression of the acute phase protein serum amyloid A, inflammation-associated markers (e.g. lipocalin 2), as well as the pro-inflammatory cytokine TNFα. Moreover, the proliferation of host hepatocytes that indicate the regenerative capacity in livers receiving cell transplants was enhanced. Transplantation of MSC-derived human hepatocyte-like cells corrects NASH in mice by restoring triglyceride depositions, reducing inflammation and augmenting the regenerative capacity of the liver. - Highlights: • First time to show NASH in an immune-deficient mouse model. • Human MSC attenuate NASH and improve lipid homeostasis. • MSC act anti-fibrotic and augment liver regeneration by stimulation of proliferation. • Pre-clinical assessment of human MSC for stem cell-based therapy of NASH.

Effects of dark chocolate on endothelial function in patients with non-alcoholic steatohepatitis.

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Loffredo, L; Baratta, F; Ludovica, P; Battaglia, S; Carnevale, R; Nocella, C; Novo, M; Pannitteri, G; Ceci, F; Angelico, F; Violi, F; Del Ben, M

2018-02-01

Oxidative stress plays a pivotal role in inducing endothelial dysfunction and progression from simple fatty liver steatosis (FLD) to non-alcoholic steatohepatitis (NASH). Polyphenols could reduce oxidative stress and restore endothelial function by inhibiting the nicotinamide-adenine-dinucleotide-phosphate (NADPH) oxidase isoform Nox2. The aim of this study was to assess endothelial function and oxidative stress in a population affected by simple FLD and NASH. Furthermore, we analysed the effect of high vs low content of cocoa polyphenols on endothelial function and oxidative stress in patients with NASH. In a cross-sectional study we analysed endothelial function, as assessed by flow-mediated dilation (FMD), and oxidative stress, as assessed by Nox2 activation, serum isoprostanes and nitric oxide bioavailability (NOx), in patients with NASH (n = 19), FLD (n = 19) and controls (n = 19). Then, we performed a randomized, cross-over study in 19 subjects with NASH comparing the effect of 14-days administration of 40 g of chocolate at high (dark chocolate, cocoa >85%) versus low content (milk chocolate, cocoa chocolate. A simple linear regression analysis showed that Δ (expressed by difference of values between before and after 14 days of chocolate assumption) of FMD was associated with Δ of Nox2 activity (Rs = -0.323; p = 0.04), serum isoprostanes (Rs: -0.553; p < 0.001) and NOx (Rs: 0.557; p < 0.001). Cocoa polyphenols improve endothelial function via Nox2 down-regulation in NASH patients. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Proteome Characteristics of Non-Alcoholic Steatohepatitis Liver Tissue and Associated Hepatocellular Carcinomas

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Anna Kakehashi

2017-02-01

Full Text Available To uncover mechanisms of nonalcoholic steatohepatitis (NASH associated hepatocarcinogenesis, we compared the proteomes of human NASH-associated liver biopsies, resected hepatocellular carcinomas (HCCs and HCCs of HCV+ patients with normal liver tissue of patients with gastrointestinal tumor metastasis, in formalin-fixed paraffin-embedded samples obtained after surgery in our hospital during the period from 2006 to 2011. In addition, proteome analysis of liver tumors in male STAM NASH-model mice was performed. Similar changes in the proteome spectrum such as overexpression of enzymes involved in lipid, cholesterol and bile acid biosynthesis and examples associated with suppression of fatty acid oxidation and catabolism, alcohol metabolism, mitochondrial function as well as low expression levels of cytokeratins 8 and 18 were observed in both human NASH biopsies and NASH HCCs, but not HCV+ HCCs. Alterations in downstream protein expression pointed to significant activation of transforming growth factor β, SMAD family member 3, β-catenin, Nrf2, SREBP-LXRα and nuclear receptor-interacting protein 1 (NRIP1, and inhibition of PPARs and p53 in human NASH biopsies and/or HCCs, suggesting their involvement in accumulation of lipids, development of fibrosis, oxidative stress, cell proliferation and suppression of apoptosis in NASH hepatocarcinogenesis. In STAM mice, PPARs inhibition was not obvious, while expression of cytokeratins 8 and 18 was elevated, indicative of essential differences between human and mouse NASH pathogenesis.

Pathogenesis, diagnosis and treatment of non-alcoholic fatty liver disease

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Verónica Martín-Domínguez

2013-08-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD includes a broad spectrum of alterations that go from simple steatosis to steatohepatitis and cirrhosis. Type 2 diabetes mellitus (DM-2 and obesity are the principle factors associated to NAFLD. A 20-30 % prevalence in general population has been described. The survival of this type of patient is lower than the general population's, showing a higher incidence of hepatic and cardiovascular complications. The aetiopathogenesis is still unclear, but we know the intervention of different factors that produce fatty-acid accumulation in hepatic parenchyma, causing oxidative stress, oxygen-free radicals and the synthesis of an inflammatory cascade, that determine the progression of this disease from steatosis up to advanced fibrosis. The diagnostic gold-standard is still the liver biopsy, even though the development of newer non-invasive techniques, like serological and imaging (radiology, have opened a new field for research that allows bloodless testing of these patients and better study of the natural history of this disease. Nowadays, there is still no specific treatment for NAFLD. The development of healthy life habits and moderate exercise continue to be the pillars of treatment. Different pharmacological approaches have been studied and applied, such as the control of insulin resistance, lowering cholesterol levels, antioxidants, and other alternatives in experimental trials.

Epigenetic Mechanisms Underlying the Link between Non-Alcoholic Fatty Liver Diseases and Nutrition

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Joo Ho Lee

2014-08-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is defined as a pathologic accumulation of fat in the form of triglycerides (TG in the liver (steatosis that is not caused by alcohol. A subgroup of NAFLD patients shows liver cell injury and inflammation coupled with the excessive fat accumulation (steatohepatitis, which is referred to as non-alcoholic steatohepatitis (NASH. Patients with NASH may develop cirrhosis and hepatocellular carcinoma (HCC. NAFLD shares the key features of metabolic syndrome including obesity, hyperlipidemia, hypertension, and insulin resistance. The pathogenesis of NAFLD is multi-factorial, however the oxidative stress seems to plays a major role in the development and progression of the disease. The emerging field of epigenetics provides a new perspective on the pathogenesis of NAFLD. Epigenetics is an inheritable but reversible phenomenon that affects gene expression without altering the DNA sequence and refers to DNA methylation, histone modifications and microRNAs. Epigenetic manipulation through metabolic pathways such as one-carbon metabolism has been proposed as a promising approach to retard the progression of NAFLD. Investigating the epigenetic modifiers in NAFLD may also lead to the development of preventive or therapeutic strategies for NASH-associated complications.

A Public Health Issue that Increased Prevelance: Non-Acholic Fatty Liver Disease

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Muammer Kara

2014-02-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD, is a liver disease, that occur in non alcohol users, with same histological features of alcoholic liver disease. The increased importance of NAFLD is depends on its close relation of current problems such as Type 2 Diabetes Mellitus and hyperlipidemia, and its high prevalence as %20-30, in Europe and Middle East. NAFLD has a wide spectrum from simple steatozis (SS, liver cell damage, non alcoholic steatohepatitis (NASH with inflammation to high stage fibrosis, and cirrhosis. Hepathocellular cancer and liver failure might develop in cirrhosis patients. Biopsy is gold standard for NAFLD diagnosis; differentiate from SS and NASH and defining NASH stages. Nutrition regulations and slow and continuous weight loss with regular exercises is still best treatment method [TAF Prev Med Bull 2014; 13(1.000: 65-76

[Metabolic parameters in patients with steatosis non alcoholic liver and controlled diabetes type 2 versus uncontrolled diabetes type 2].

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Miranda Manrique, Gonzalo

2016-01-01

Non-alcoholic fatty liver (NASH) is widely distributed around the world and is more common in subjects with dyslipidemia, metabolic syndrome obese and DM2 (34-74%). However, the prevalence of cirrhosis by NASH in general population is unknown which is still subject of research. To determine if there are significant differences between metabolic parameters of non-alcoholic fatty liver in controlled versus uncontrolled diabetes type 2 of recent diagnosis. retrospective case-control study, performed in the Hospital Guillermo Almenara Irigoyen, Lima, Peru from November 2014 to February 2015.This study included 231 patients: 147 patients (NASH with DM2 of recent diagnosis and poor control) and 84 patients (NASH with DM2 ofrecent diagnosis and adequate control). Levene test for evaluating homogeneity of variances intra groups and parametric test for independent samples. After applying Levene test of homogeneity and student test, significant metabolic parameters were the triglycerides, HbA1C level, metformin dose and gender. It is important in diabetic patients to diagnose NASH early for a tighter control, not only of glucose but other metabolic parameters mainly triglycerides which strongly supports existing concept of "multiple hits" which considers NASH affects glucose homeostasis, and it could be the starting point of new research to improve interventions for decreasing progression from to cirrhosis in diabetic patients and also to delay progression of diabetes mellitus in patients with non alcoholic steatohepatitis.

Pediatric Non-Alcoholic Fatty Liver Disease

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Haley Bush

2017-06-01

Full Text Available Abstract: With the increase in the prevalence of obesity, non-alcoholic fatty liver disease (NAFLD has become among the leading causes of chronic liver disease in the pediatric age group. Once believed to be a “two-hit process”, it is now clear that the actual pathophysiology of NAFLD is complex and involves multiple pathways. Moreover, NAFLD is not always benign, and patients with non-alcoholic steatohepatitis (NASH are at increased risk of developing advanced stages of liver disease. It has also been shown that NAFLD is not only a liver disease, but is also associated with multiple extrahepatic manifestations, including cardiovascular diseases, type 2 diabetes, and low bone mineral density. Although the data is scarce in the pediatric population, some studies have suggested that long-term mortality and the requirement of liver transplantation will continue to increase in patients with NAFLD. More studies are needed to better understand the natural history of NAFLD, especially in the pediatric age group.

Expression of cytokine signaling genes in morbidly obese patients with non-alcoholic steatohepatitis and hepatic fibrosis.

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Estep, J Michael; Baranova, Ancha; Hossain, Noreen; Elariny, Hazem; Ankrah, Kathy; Afendy, Arian; Chandhoke, Vikas; Younossi, Zobair M

2009-05-01

White adipose tissue (WAT) from visceral adiposity plays an important role in the pathogenesis of non-alcoholic steatohepatitis (NASH). Development of NASH and its progression to fibrosis is partially due to cytokines and adipokines produced by WAT. The aim of this study was to assess the association of hepatic fibrosis and NASH by evaluating the intrinsic differences in the inflammatory cytokine signaling in the visceral adipose tissue obtained from morbidly obese patients. We used targeted microarrays representing human genes involved in the inflammatory and fibrogenic reactions to profile visceral adipose samples of 15 well-matched NASH patients with and without fibrosis. Additionally, visceral adipose samples were subjected to real-time polymerase chain reaction profiling of 84 inflammations related genes. Eight genes (CCL2, CCL4, CCL18, CCR1, IL10RB, IL15RA, and LTB) were differentially expressed in NASH with fibrosis. Additionally, an overlapping but distinct list of the differentially expressed genes were found in NASH with type II diabetes (DM; IL8, BLR1, IL2RA, CD40LG, IL1RN, IL15RA, and CCL4) as compared to NASH without DM. Inflammatory cytokines are differentially expressed in the adipose tissue of NASH with fibrosis, as well in NASH with DM. These findings point at the interaction of adipose inflammatory cytokines, DM, hepatic fibrosis in NASH, and its progression to cirrhosis and end-stage liver disease.

Effects of dark chocolate on NOX-2-generated oxidative stress in patients with non-alcoholic steatohepatitis.

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Loffredo, L; Del Ben, M; Perri, L; Carnevale, R; Nocella, C; Catasca, E; Baratta, F; Ceci, F; Polimeni, L; Gozzo, P; Violi, F; Angelico, F

2016-08-01

Activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase is considered a pathogenetic mechanism determining fibrosis and disease progression in non-alcoholic steatohepatitis (NASH). Polyphenols exert antioxidant action and inhibit NADPH oxidase in humans. To analyse the effect of cocoa polyphenols on NADPH oxidase isoform 2 (NOX2) activation, oxidative stress and hepatocyte apoptosis in a population affected by NASH. In a cross-sectional study comparing 19 NASH and 19 controls, oxidative stress, as assessed by serum NOX2 activity and F2-isoprostanes, and hepatocyte apoptosis, as assessed by serum cytokeratin-18 (CK-18) levels, were measured. Furthermore, the 19 NASH patients were randomly allocated in a crossover design to 40 g/day of dark chocolate (>85% cocoa) or 40 g/day of milk chocolate (chocolate intake. Compared to controls, NASH patients had higher sNOX2-dp, serum isoprostanes and CK-18 levels. A significant difference for treatments was found in subjects with respect to sNOX2-dp, serum isoprostanes and serum CK-18. The pairwise comparisons showed that, compared to baseline, after 14 days of dark chocolate intake, a significant reduction in sNOX2-dp serum isoprostanes and CK-18 M30 was found. No change was observed after milk chocolate ingestion. A simple linear regression analysis showed that ∆ of sNOX2-dp was associated with ∆ of serum isoprostanes. Cocoa polyphenols exert an antioxidant activity via NOX2 down-regulation in NASH patients. © 2016 John Wiley & Sons Ltd.

Nonalcoholic steatohepatitis and obesity as one of the main predictors of metabolic syndrome development in children and adolescents

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O.Yu. Belousova

2017-03-01

Full Text Available This article deals with the importance of isolating the metabolic syndrome in pediatric gastroenterological practice, since almost all the major components of the metabolic syndrome are already found in childhood. In addition, this condition diagnosed at early stages of the disease development is theoretically reversible, that is with the prescription of an adequate treatment, it is possible to reduce the severity of its main manifestations and to prevent diabetes mellitus type 2, dyslipidemia and cardiovascular diseases. The main predictors of the development of this pathology are obesity, whose growth tends to increase constantly, and non-alcoholic steatohepatitis, often manifested in adolescence. The advisability of using drugs that affect hepatic metabolism and are able to exert a lipid-regulating effects, in particular, essential phospholipids, is discussed.

Diabetes Mellitus Type 2 and Non-alcoholic Fatty Liver Disease. The Effects of Metformin

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V.I. Pankiv

2013-08-01

Full Text Available Diabetes mellitus (DM type 2 in clinical practice is often associated with non-alcoholic fatty liver disease (NAFLD, which has a number of clinical and morphological forms and develops in patients who do not abuse alcohol. The combination of DM type 2 and NAFLD is associated not only with a high risk of developing liver cirrhosis and hepatocellular carcinoma in these patients. Although all aspects of the etiology of NAFLD is not fully known, it is points to the role of insulin resistance in its development. This concept has facilitated a number of clinical studies using metformin as the insulin sensitizer in insulin-resistant patients with NAFLD. The findings emphasize the importance of metformin in the treatment of NAFLD in combination with a hypocaloric diet and the control of body weight. It is also reported about other tissue effects of metformin in NAFLD.

Clinical and metabolic effects associated with weight changes and obeticholic acid in non-alcoholic steatohepatitis.

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Hameed, B; Terrault, N A; Gill, R M; Loomba, R; Chalasani, N; Hoofnagle, J H; Van Natta, M L

2018-03-01

In a 72-week, randomised controlled trial of obeticholic acid (OCA) in non-alcoholic steatohepatitis (NASH), OCA was superior to placebo in improving serum ALT levels and liver histology. OCA therapy also reduced weight. Because weight loss by itself can improve histology, to perform a post hoc analysis of the effects of weight loss and OCA treatment in improving clinical and metabolic features of NASH. The analysis was limited to the 200 patients with baseline and end-of-treatment liver biopsies. Weight loss was defined as a relative decline from baseline of 2% or more at treatment end. Weight loss occurred in 44% (45/102) of OCA and 32% (31/98) of placebo-treated patients (P = 0.08). The NAFLD Activity score (NAS) improved more in those with than without weight loss in both the OCA- (-2.4 vs -1.2, POCA- (-43 vs -34 U/L, P = 0.12) and placebo-treated patients (-29 vs -10 U/L, P = 0.02). However, among those who lost weight, OCA was associated with opposite effects from placebo on changes in alkaline phosphatase (+21 vs -12 U/L, POCA leads to weight loss in up to 44% of patients with NASH, and OCA therapy and weight loss have additive benefits on serum aminotransferases and histology. However, favourable effects of weight loss on alkaline phosphatase, lipids and blood glucose seen in placebo-treated patients were absent or reversed on OCA treatment. These findings stress the importance of assessing concomitant metabolic effects of new therapies of NASH. Clinical trial number: NCT01265498. © 2018 John Wiley & Sons Ltd.

Heme oxygenase-1 prevents non-alcoholic steatohepatitis through suppressing hepatocyte apoptosis in mice

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Fu Na

2010-10-01

Full Text Available Abstract Objective Heme oxygenase-1 (HO-1, the rate-limiting enzyme in heme catabolism, has been reported to have potential antioxidant properties. However, the role of HO-1 on hepatocyte apoptosis remains unclear. We aim to elucidate the effects of HO-1 on oxidative stress related hepatocellular apoptosis in nutritional steatohepatitis in mice. Methods C57BL/6J mice were fed with methionine-choline deficient (MCD diet for four weeks to induce hepatic steatohepatitis. HO-1 chemical inducer (hemin, HO-1 chemical inhibitor zinc protoporphyrin IX (ZnPP-IX and/or adenovirus carrying HO-1 gene (Ad-HO-1 were administered to mice, respectively. Hepatocyte apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL assay, the mRNA and protein expression of apoptosis related genes were assayed by quantitative real-time PCR and Western blot. Results Hepatocyte signs of oxidative related apoptotic injury were presented in mice fed with MCD diet for 4 weeks. Induction of HO-1 by hemin or Ad-HO-1 significantly attenuated the severity of liver histology, which was associated with decreased hepatic lipid peroxidation content, reduced number of apoptotic cells by TUNEL staining, down-regulated expression of pro-apoptosis related genes including Fas/FasL, Bax, caspase-3 and caspase-9, reduced expression of cytochrome p4502E1 (CYP2E1, inhibited cytochrome c (Cyt-c release, and up-regulated expression of anti-apoptosis gene Bcl-2. Whereas, inhibition of HO-1 by ZnPP-IX caused oxidative stress related hepatic injury, which concomitant with increased number of TUNEL positive cells and up-regulated expression of pro-apoptosis related genes. Conclusions The present study provided evidences for the protective role of HO-1 in preventing nutritional steatohepatitis through suppressing hepatocyte apoptosis in mice.

The benefits of exercise for patients with non-alcoholic fatty liver disease.

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Keating, Shelley E; George, Jacob; Johnson, Nathan A

2015-01-01

As exercise is now an established therapy for the management of non-alcoholic fatty liver disease (NAFLD), recent investigations have sought to identify the optimal dose (type, intensity and amount) of exercise for hepatic benefit. Here, the authors discuss the following: the role of aerobic exercise for the modulation of hepatic steatosis; the limited evidence for the role of resistance training in reducing liver fat; the lack of evidence from clinical trials on the role of exercise in non-alcoholic steatohepatitis; and the benefits of exercise for patients with NAFLD, beyond steatosis. Based on current evidence, the authors provide recommendations for exercise prescription for patients with NAFLD.

Type 2 diabetes mellitus and non-alcoholic fatty liver disease: a systematic review and meta-analysis.

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Amiri Dash Atan, Nasrin; Koushki, Mehdi; Motedayen, Morteza; Dousti, Majid; Sayehmiri, Fatemeh; Vafaee, Reza; Norouzinia, Mohsen; Gholami, Reza

2017-01-01

The aim of this study was the evaluation of the prevalence of NAFLD in patients with type 2 diabetes mellitus. Non-alcoholic fatty liver disease (NAFLD) is an emerging disease with high prevalence in patients with type 2 diabetes mellitus (T2DM). Many studies have reported the prevalence of NAFLD in type 2 diabetes mellitus patients. However, these results are inconsistent. A Literature search was conducted in PubMed, Scopus, web of science and Science Direct from 2005 to August 2017. The necessary information was extracted. Heterogeneity was evaluated using I 2 statistic. Meta-regression analyses were performed to the estimation of the relationship between the year of study and sample size with the prevalence of NAFLD. Publication bias was assessed by both Begg rank correlation and Egger tests. Subgroup analysis was performed for identification of sources heterogeneity. Seventeen studies involving 10897 type 2 diabetes mellitus patients with NAFLD were included in this meta-analysis. The overall prevalence of NAFLD in type 2 diabetes mellitus patients by random effects models was 54% (95% CI, 45%- 64%). There is a significant heterogeneity across studies with (I 2 = 99%, p> 0.01). The funnel plot as graphically and Begg and Egger as statistically showed no publication bias among studies. Subgroup analysis indicated that the prevalence of NAFLD in type 2 diabetes mellitus patients differed in predictive factors such as lipid profile, BMI, HbA1c, AST, and ALT. This finding in spite of heterogeneity of documents is corresponding to the positive correlation between NAFLD and type 2 diabetes mellitus. The findings indicated that the overall prevalence of NAFLD among type 2 diabetes mellitus patients is significantly higher. It can be concluded that type 2 diabetes mellitus patients should be managed to prevent NAFLD.

Impact of smoking habit on surgical outcomes in non-B non-C patients with curative resection for hepatocellular carcinoma.

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Kai, Keita; Koga, Hiroki; Aishima, Shinichi; Kawaguchi, Atsushi; Yamaji, Koutaro; Ide, Takao; Ueda, Junji; Noshiro, Hirokazu

2017-02-28

To analyzed the correlation between smoking status and surgical outcomes in patients with non-B non-C hepatocellular carcinoma (NBNC-HCC), and we investigated the patients' clinicopathological characteristics according to smoking status. We retrospectively analyzed the consecutive cases of 83 NBNC-HCC patients who underwent curative surgical treatment for the primary lesion at Saga University Hospital between 1984 and December 2012. We collected information about possibly carcinogenic factors such as alcohol abuse, diabetes mellitus, obesity and smoking habit from medical records. Smoking habits were subcategorized as never, ex- and current smoker at the time of surgery. The diagnosis of non-alcoholic steatohepatitis (NASH) was based on both clinical information and pathological confirmation. Alcohol abuse, diabetes mellitus, obesity and NASH had no significant effect on the surgical outcomes. Current smoking status was strongly correlated with both overall survival ( P = 0.0058) and disease-specific survival ( P = 0.0105) by multivariate analyses. Subset analyses revealed that the current smokers were significantly younger at the time of surgery ( P = 0.0002) and more likely to abuse alcohol ( P = 0.0188) and to have multiple tumors ( P = 0.023). Current smoking habit at the time of surgical treatment is a risk factor for poor long-term survival in NBNC-HCC patients. Current smokers tend to have multiple HCCs at a younger age than other patients.

Comparison between the efficacies of curcumin and puerarin in C57BL/6 mice with steatohepatitis induced by a methionine- and choline-deficient diet

OpenAIRE

WANG, YUNLIANG; LI, JIAN; ZHUGE, LI; SU, DONGMEI; YANG, MEIJUAN; TAO, SHIYING; LI, JUNXIANG

2013-01-01

Non-alcoholic fatty liver disease (NAFLD) is a prevalent disease, which features an abnormal accumulation of lipids inside hepatocytes. Steatohepatitis plays a critical role in the process resulting in liver fibrosis and cirrhosis. Curcumin and puerarin are herbal products widely used in Asia, which are believed to have therapeutic benefits for alleviating the symptoms of steatohepatitis. In this study, mice models of steatohepatitis induced by a methionine- and choline-deficient diet (MCD) w...

Biochemical parameters response to weight loss in patients with non ...

African Journals Online (AJOL)

Background: Non-alcoholic steatohepatitis (NASH) is a chronic liver disease that is capable of progressing to end-stage liver disease, but generally has a benign course. Non-alcoholic steatohepatitis (NASH) is a growing public health problem with no approved therapy. NASH projected to be the leading cause of liver ...

Molecular pathways in non-alcoholic fatty liver disease

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Berlanga A

2014-07-01

Full Text Available Alba Berlanga,1,* Esther Guiu-Jurado,1,* José Antonio Porras,1,2 Teresa Auguet1,21Group GEMMAIR (AGAUR and Applied Medicine Research Group, Department of Medicine and Surgery, Universitat Rovira i Virgili (URV, IISPV, Hospital Universitari Joan XXIII, Tarragona, Spain; 2Department of Internal Medicine, Hospital Universitari Joan XXIII Tarragona, Tarragona, Spain *These authors contributed equally to this workAbstract: Non-alcoholic fatty liver disease (NAFLD is a clinicopathological change characterized by the accumulation of triglycerides in hepatocytes and has frequently been associated with obesity, type 2 diabetes mellitus, hyperlipidemia, and insulin resistance. It is an increasingly recognized condition that has become the most common liver disorder in developed countries, affecting over one-third of the population and is associated with increased cardiovascular- and liver-related mortality. NAFLD is a spectrum of disorders, beginning as simple steatosis. In about 15% of all NAFLD cases, simple steatosis can evolve into non-alcoholic steatohepatitis, a medley of inflammation, hepatocellular injury, and fibrosis, often resulting in cirrhosis and even hepatocellular cancer. However, the molecular mechanism underlying NAFLD progression is not completely understood. Its pathogenesis has often been interpreted by the "double-hit" hypothesis. The primary insult or the "first hit" includes lipid accumulation in the liver, followed by a "second hit" in which proinflammatory mediators induce inflammation, hepatocellular injury, and fibrosis. Nowadays, a more complex model suggests that fatty acids (FAs and their metabolites may be the true lipotoxic agents that contribute to NAFLD progression; a multiple parallel hits hypothesis has also been suggested. In NAFLD patients, insulin resistance leads to hepatic steatosis via multiple mechanisms. Despite the excess hepatic accumulation of FAs in NAFLD, it has been described that not only de novo FA

Lispro insulin in people with non-alcoholic liver cirrhosis and type 2 diabetes mellitus.

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Gentile, S; Guarino, G; Strollo, F; Romano, M; Genovese, S; Masarone, M; Ceriello, A

2016-03-01

To compare metabolic control under lispro and recombinant regular human insulin (RHI) in people with diet-unresponsive type 2 diabetes mellitus (T2DM) and compensated non-alcoholic liver disease (CLD). 108 people with T2DM and CLD were randomly allocated to RHI or lispro according to a 12+12 week cross-over protocol. A 1-week continuous glucose monitoring (CGM) session was performed at the end of each treatment period followed by a standard meal test with a 12IU lispro or RHI shot ahead. CGM showed higher glycemic excursions under RHI than under lispro (pliver glucose output expected from its earlier hepatic distribution. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Increased parenchymal damage and steatohepatitis in Caucasian non-alcoholic fatty liver disease patients with common IL1B and IL6 polymorphisms.

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Nelson, J E; Handa, P; Aouizerat, B; Wilson, L; Vemulakonda, L A; Yeh, M M; Kowdley, K V

2016-12-01

Non-alcoholic fatty liver disease (NAFLD) is a complex, multifactorial disease affected by diet, lifestyle and genetics. Proinflammatory cytokines like IL-1β and IL-6 have been shown to be elevated in non-alcoholic steatohepatitis (NASH). To investigate the relationship between IL1B and IL6 gene polymorphisms and histological features of NAFLD in the NASH CRN cohort. A total of 604 adult (≥18 years) non-Hispanic Caucasians with biopsy-proven NAFLD were genotyped for the following SNPs: IL1B, rs16944, rs1143634; IL6, rs1800795, rs10499563. Logistic regression was used to examine the relationship between genotype and a definitive diagnosis and advanced histological features of NASH after controlling for the following variables selected a priori: age, sex, diabetes, obesity and HOMA-IR level. The IL6 rs10499563 C allele was independently associated with the presence of definitive NASH, and increased ballooning and Mallory bodies. The IL1B rs1143634 TT genotype was associated with advanced fibrosis and increased Mallory bodies. The IL6 rs1800795 C allele was associated with not only increased risk for severe steatosis, >66% but also decreased risk for advanced fibrosis and lobular inflammation and Mallory body formation. These results suggest that common variants in the IL6 and IL1B genes may increase susceptibility for NASH and confer a higher risk of hepatic parenchymal damage including increased ballooning, increased Mallory bodies, and bridging fibrosis or cirrhosis. In contrast, the IL6 rs1800795 C allele may confer a higher risk for steatosis, but less parenchymal damage. Our findings support the development of therapeutics aimed at IL-1β and IL-6 suppression. © 2016 John Wiley & Sons Ltd.

A clinical and biochemical profile of biopsy-proven non-alcoholic fatty liver disease subjects

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Khurram, M.; Mushraf, M.

2007-01-01

To describe clinical and biochemical features of patients with biopsy-proven non-alcoholic fatty liver disease (NAFLD). Fifty patients of either and of all ages were included, who had ultrasound evidence of fatty liver, deranged liver enzymes, and negative history of alcohol uptake. Serological/biochemical tests/markers of other liver diseases were negative. Each subject underwent liver biopsy reported by a single histopathologist. Clinical (symptoms, hypertension, hepatomegaly, and obesity) and biochemical evaluation (for diabetes, lipid abnormalities, and aspartate to alanine aminotransferase ratio (AST/ALT)) of each subject was done. Chi-square and t-tests were used for p-value calculation for finding significant difference between fatty liver and non-alcoholic steato-hepatitis groups. Thirty three (66%) patients were female and 34% were male. Mean age was 45.50+-11.50 years. Histopathologically, 62% subjects had fatty liver alone, while 38% had nonalcoholic steatohepatitis (NASH). Fatigue (100%), hypertriglyceridemia (80%), hepatomegaly (72%), AST/ALT ratio <1 (72%), and obesity/overweight (54%) were common NAFLD-related features. Except for hypertriglycedemia (p-value 0.008), no statistically significant association was noted between these features and histopathological subtypes of NAFLD. NAFLD-related clinical and biochemical features included fatigue, obesity, hepatomegaly, AST/ALT ratio <1, and hypertriglycedemia. Significant relationship existed between hypertriglyceridemia and NASH. (author)

Andrographolide Ameliorates Inflammation and Fibrogenesis and Attenuates Inflammasome Activation in Experimental Non-Alcoholic Steatohepatitis

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Cabrera, Daniel; Wree, Alexander; Povero, Davide; Solís, Nancy; Hernandez, Alejandra; Pizarro, Margarita; Moshage, Han; Torres, Javiera; Feldstein, Ariel E; Cabello-Verrugio, Claudio; Brandan, Enrique; Barrera, Francisco; Arab, Juan Pablo; Arrese, Marco

2017-01-01

Therapy for nonalcoholic steatohepatitis (NASH) is limited. Andrographolide (ANDRO), a botanical compound, has a potent anti-inflammatory activity due to its ability to inhibit NF-kB. ANDRO has been also shown to inhibit the NLRP3 inflammasome, a relevant pathway in NASH. Our aim was to evaluate the

Deregulation of fatty acid metabolism and cannabinoid receptors in liver of morbidly obese women with non-alcoholic fatty liver disease

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Berlanga Bustos, Alba

2015-01-01

Non-alcoholic fatty liver disease (NAFLD) encompasses a histological spectrum from simple steatosis (SS) to non-alcoholic steatohepatitis (NASH), with the latter being more frequently progressive. Due to lipid accumulation in the human liver seems to be a crucial mechanism in the NAFLD pathogenesis, an improved understanding of the underlying mechanisms leading to the initial hepatic lipid accumulation could be of great interest for controlling the progression of NAFLD. It has also been repor...

Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.

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Konuma, Kuniha; Itoh, Michiko; Suganami, Takayoshi; Kanai, Sayaka; Nakagawa, Nobutaka; Sakai, Takeru; Kawano, Hiroyuki; Hara, Mitsuko; Kojima, Soichi; Izumi, Yuichi; Ogawa, Yoshihiro

2015-01-01

Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH), while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO) mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS), where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA), a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.

Eicosapentaenoic acid ameliorates non-alcoholic steatohepatitis in a novel mouse model using melanocortin 4 receptor-deficient mice.

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Kuniha Konuma

Full Text Available Many attempts have been made to find novel therapeutic strategies for non-alcoholic steatohepatitis (NASH, while their clinical efficacy is unclear. We have recently reported a novel rodent model of NASH using melanocortin 4 receptor-deficient (MC4R-KO mice, which exhibit the sequence of events that comprise hepatic steatosis, liver fibrosis, and hepatocellular carcinoma with obesity-related phenotypes. In the liver of MC4R-KO mice, there is a unique histological feature termed hepatic crown-like structures (hCLS, where macrophages interact with dead hepatocytes and fibrogenic cells, thereby accelerating inflammation and fibrosis. In this study, we employed MC4R-KO mice to examine the effect of highly purified eicosapentaenoic acid (EPA, a clinically available n-3 polyunsaturated fatty acid, on the development of NASH. EPA treatment markedly prevented the development of hepatocyte injury, hCLS formation and liver fibrosis along with lipid accumulation. EPA treatment was also effective even after MC4R-KO mice developed NASH. Intriguingly, improvement of liver fibrosis was accompanied by the reduction of hCLS formation and plasma kallikrein-mediated transforming growth factor-β activation. Moreover, EPA treatment increased the otherwise reduced serum concentrations of adiponectin, an adipocytokine with anti-inflammatory and anti-fibrotic properties. Collectively, EPA treatment effectively prevents the development and progression of NASH in MC4R-KO mice along with amelioration of hepatic steatosis. This study unravels a novel anti-fibrotic mechanism of EPA, thereby suggesting a clinical implication for the treatment of NASH.

Metabolic syndrome and risk factors for non-alcoholic fatty liver disease

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Mônica Rodrigues de Araújo Souza

2012-03-01

Full Text Available CONTEXT: Non-alcoholic fatty liver disease (NAFLD, hepatic manifestation of metabolic syndrome, has been considered the most common liver disease nowadays, which is also the most frequent cause of elevated transaminases and cryptogenic cirrhosis. The greatest input of fatty acids into the liver and consequent increased beta-oxidation contribute to the formation of free radicals, release of inflammatory cytokines and varying degrees of hepatocytic aggression, whose histological expression may vary from steatosis (HS to non-alcoholic steatohepatitis (NASH. The differentiation of these forms is required by the potential risk of progression to cirrhosis and development of hepatocellular carcinoma. OBJECTIVE: To review the literature about the major risk factors for NAFLD in the context of metabolic syndrome, focusing on underlying mechanisms and prevention. METHOD: PubMed, MEDLINE and SciELO data basis analysis was performed to identify studies describing the link between risk factors for metabolic syndrome and NAFLD. A combination of descriptors was used, non-alcoholic fatty liver disease, non-alcoholic steatohepatitis, metabolic syndrome and risk factors. At the end, 96 clinical and experimental studies, cohorts, meta-analysis and systematic reviews of great impact and scientific relevance to the topic, were selected. RESULTS: The final analysis of all these data, pointed out the central obesity, type 2 diabetes, dyslipidemia and hypertension as the best risk factors related to NAFLD. However, other factors were highlighted, such as gender differences, ethnicity, genetic factors and the role of innate immunity system. How these additional factors may be involved in the installation, progression and disease prognosis is discussed. CONCLUSION: Risk factors for NAFLD in the context of metabolic syndrome expands the prospects to 1 recognize patients with metabolic syndrome at high risk for NAFLD, 2 elucidate pathways common to other co-morbidities, 3

Prevalence of nonalcoholic steatohepatitis among patients with resectable intrahepatic cholangiocarcinoma.

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Reddy, Srinevas K; Hyder, Omar; Marsh, J Wallis; Sotiropoulos, Georgios C; Paul, Andreas; Alexandrescu, Sorin; Marques, Hugo; Pulitano, Carlo; Barroso, Eduardo; Aldrighetti, Luca; Geller, David A; Sempoux, Christine; Herlea, Vlad; Popescu, Irinel; Anders, Robert; Rubbia-Brandt, Laura; Gigot, Jean-Francois; Mentha, Giles; Pawlik, Timothy M

2013-04-01

The objective of this report was to determine the prevalence of underlying nonalcoholic steatohepatitis in resectable intrahepatic cholangiocarcinoma. Demographics, comorbidities, clinicopathologic characteristics, surgical treatments, and outcomes from patients who underwent resection of intrahepatic cholangiocarcinoma at one of eight hepatobiliary centers between 1991 and 2011 were reviewed. Of 181 patients who underwent resection for intrahepatic cholangiocarcinoma, 31 (17.1 %) had underlying nonalcoholic steatohepatitis. Patients with nonalcoholic steatohepatitis were more likely obese (median body mass index, 30.0 vs. 26.0 kg/m(2), p < 0.001) and had higher rates of diabetes mellitus (38.7 vs. 22.0 %, p = 0.05) and the metabolic syndrome (22.6 vs. 10.0 %, p = 0.05) compared with those without nonalcoholic steatohepatitis. Presence and severity of hepatic steatosis, lobular inflammation, and hepatocyte ballooning were more common among nonalcoholic steatohepatitis patients (all p < 0.001). Macrovascular (35.5 vs. 11.3 %, p = 0.01) and any vascular (48.4 vs. 26.7 %, p = 0.02) tumor invasion were more common among patients with nonalcoholic steatohepatitis. There were no differences in recurrence-free (median, 17.0 versus 19.4 months, p = 0.42) or overall (median, 31.5 versus 36.3 months, p = 0.97) survival after surgical resection between patients with and without nonalcoholic steatohepatitis. Nonalcoholic steatohepatitis affects up to 20 % of patients with resectable intrahepatic cholangiocarcinoma.

Enhanced offspring predisposition to steatohepatitis with maternal high-fat diet is associated with epigenetic and microbiome alterations

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Non-alcoholic fatty liver disease (NAFLD) is an important co-morbidity associated with obesity and a precursor to steatohepatitis. However, the contributions of gestational and early life influences on development of NAFLD and NASH remain poorly appreciated. Two independent studies were performed to...

Probiotics as a novel treatment for non-alcoholic Fatty liver disease; a systematic review on the current evidences.

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Kelishadi, Roya; Farajian, Sanam; Mirlohi, Maryam

2013-04-01

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease, with 5-10% of liver having extra fat. Increase in its prevalence in all age groups is linked with obesity and Type II diabetes. The treatment of NAFLD remains controversial. A growing body of evidence suggests a relation between overgrowth of gut microbiota with NAFLD and non-alcoholic steatohepatitis (NASH). The objective of this review is to provide an overview on experimental and clinical studies assessing all positive and negative effects of probiotics. We made a critical appraisal on various types of documents published from 1999 to March 2012 in journals, electronic books, seminars, and symposium contexts including Medline, PubMed, and Cochrane Central Register of Controlled Trials databases. We used the key words: "non-alcoholic fatty liver disease, probiotics, non-alcoholic steatohepatitis, liver disease, and fatty liver". Probiotics, as biological factors, control the gut microbiota and result in its progression. It is in this sense that they are suggestive of a new and a natural way of promoting liver function. Correspondingly, limited evidence suggests that probiotics could be considered as a new way of treatment for NAFLD. Various experimental studies and clinical trials revealed promising effects of probiotics in improving NAFLD; however given the limited experience in this field, generalization of probiotics as treatment of NAFLD needs substantiation through more trials with a larger sample sizes and with longer-term follow up.

[Balneotherapeutics of non-alcoholic fatty liver disease with the use of the Essentuki-type drinking mineral waters].

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Fedorova, T E; Efimenko, N V; Kaĭsinova, A S

2012-01-01

The objective of the present work was to estimate the effectiveness of combined spa-and-resort treatment with the use of the Essentuki-type drinking mineral waters for the patients presenting with non-alcoholic fatty liver disease. A total of 40 patients presening with non-alcoholic fatty liver disease (NOFLD) were available for the examination. The study has demonstrated positive dynamics of clinical symptoms and results of liver functional tests, characteristics of intrahepatic dynamics, lipid metabolism, antioxidant hemostais, and the hormonal status of the patients with non-alcoholic fatty liver disease. The intake of the Essentuki-type drinking mineral waters promoted normalization of adiponectin and leptin levels in conjunction with the reduction in the degree of insulin resistance, i.e., the key pathogenetic factors responsible for hepatic steatosis and non-alcoholic steatohepatitis. It is concluded that the Essentuki-type drinking mineral waters may be recommended for the inclusion in the combined treatment and prevention of the progression of non-alcoholic fatty liver disease.

Alcoholism and Diabetes Mellitus

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Soo-Jeong Kim

2012-04-01

Full Text Available Chronic use of alcohol is considered to be a potential risk factor for the incidence of type 2 diabetes mellitus (T2DM, which causes insulin resistance and pancreatic β-cell dysfunction that is a prerequisite for the development of diabetes. However, alcohol consumption in diabetes has been controversial and more detailed information on the diabetogenic impact of alcohol seems warranted. Diabetes, especially T2DM, causes dysregulation of various metabolic processes, which includes a defect in the insulin-mediated glucose function of adipocytes, and an impaired insulin action in the liver. In addition, neurobiological profiles of alcoholism are linked to the effects of a disruption of glucose homeostasis and of insulin resistance, which are affected by altered appetite that regulates the peptides and neurotrophic factors. Since conditions, which precede the onset of diabetes that are associated with alcoholism is one of the crucial public problems, researches in efforts to prevent and treat diabetes with alcohol dependence, receives special clinical interest. Therefore, the purpose of this mini-review is to provide the recent progress and current theories in the interplay between alcoholism and diabetes. Further, the purpose of this study also includes summarizing the pathophysiological mechanisms in the neurobiology of alcoholism.

Sida rhomboidea.Roxb extract alleviates pathophysiological changes in experimental in vivo and in vitro models of high fat diet/fatty acid induced non-alcoholic steatohepatitis.

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Thounaojam, Menaka C; Jadeja, Ravirajsinh N; Dandekar, Deven S; Devkar, Ranjitsinh V; Ramachandran, A V

2012-03-01

The present study was aim to evaluate protective role of Sida rhomboidea.Roxb (SR) extract against high fat diet/fatty acid induced pathophysiological alterations in experimental model of non-alcoholic steatohepatitis (NASH). Effect of SR extract on plasma levels of markers of hepatic damage, plasma and hepatic lipids, mitochondrial oxidative stress, status of enzymatic and non-enzymatic antioxidants and histopathological changes in liver tissue were evaluated in high fat diet fed C57BL/6J mice. Also, the effect of SR supplementation on lipid accumulation, lipid peroxidation, cytotoxicity and cell viability were evaluated in oleic acid treated HepG2 cells. Supplementation of NASH mice with SR extract prevented high fat diet induced elevation in plasma marker enzymes of liver damage, plasma and hepatic lipids, mitochondrial oxidative stress and compromised enzymatic and non-enzymatic antioxidant status. Further, addition of SR extract to in vitro HepG2 cells minimized oleic acid induced lipid accumulation, higher lipid peroxidation, cytotoxicity and reduced cell viability. These in vivo and in vitro studies suggest that SR extract has the potential of preventing high fat/fatty acid induced NASH mainly due to its hypolipidemic and antioxidant activities. Copyright © 2010 Elsevier GmbH. All rights reserved.

Involvement of a periodontal pathogen, Porphyromonas gingivalis on the pathogenesis of non-alcoholic fatty liver disease

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Yoneda Masato

2012-02-01

Full Text Available Abstract Background Non-alcoholic fatty liver disease (NAFLD is a hepatic manifestation of metabolic syndrome that is closely associated with multiple factors such as obesity, hyperlipidemia and type 2 diabetes mellitus. However, other risk factors for the development of NAFLD are unclear. With the association between periodontal disease and the development of systemic diseases receiving increasing attention recently, we conducted this study to investigate the relationship between NAFLD and infection with Porphyromonas gingivalis (P. gingivalis, a major causative agent of periodontitis. Methods The detection frequencies of periodontal bacteria in oral samples collected from 150 biopsy-proven NAFLD patients (102 with non-alcoholic steatohepatitis (NASH and 48 with non-alcoholic fatty liver (NAFL patients and 60 non-NAFLD control subjects were determined. Detection of P. gingivalis and other periodontopathic bacteria were detected by PCR assay. In addition, effect of P. gingivalis-infection on mouse NAFLD model was investigated. To clarify the exact contribution of P. gingivalis-induced periodontitis, non-surgical periodontal treatments were also undertaken for 3 months in 10 NAFLD patients with periodontitis. Results The detection frequency of P. gingivalis in NAFLD patients was significantly higher than that in the non-NAFLD control subjects (46.7% vs. 21.7%, odds ratio: 3.16. In addition, the detection frequency of P. gingivalis in NASH patients was markedly higher than that in the non-NAFLD subjects (52.0%, odds ratio: 3.91. Most of the P. gingivalis fimbria detected in the NAFLD patients was of invasive genotypes, especially type II (50.0%. Infection of type II P. gingivalis on NAFLD model of mice accelerated the NAFLD progression. The non-surgical periodontal treatments on NAFLD patients carried out for 3 months ameliorated the liver function parameters, such as the serum levels of AST and ALT. Conclusions Infection with high-virulence P

Bee's honey attenuates non-alcoholic steatohepatitis-induced hepatic injury through the regulation of thioredoxin-interacting protein-NLRP3 inflammasome pathway.

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Xiao, Jia; Liu, Yingxia; Xing, Feiyue; Leung, Tung Ming; Liong, Emily C; Tipoe, George L

2016-06-01

We aim to examine whether honey ameliorates hepatic injury in non-alcoholic steatohepatitis (NASH) animal and cell line steatosis models. NASH was induced in female Sprague-Dawley rat by 8-week feeding with a high-fat diet. During the experiment, 5 g/kg honey was intragastrically fed daily. Rat normal hepatocyte BRL-3A cell was treated with sodium palmitate (SP) to induce steatosis in the absence or presence of honey pre-treatment or specific siRNA/overexpress plasmid of thioredoxin-interacting protein (TXNIP) or antagonist/agonist of Nod-like receptor protein 3 (NLRP3). Honey significantly improved the high-fat-diet-induced hepatic injury, steatosis, fibrosis, oxidative stress, and inflammation in rats. Honey also inhibited the overexpression of TXNIP and the activation of NLRP3 inflammasome. These effects were replicated in BRL-3A cell line which showed that the down-regulation of TXNIP or inhibition of NLRP3 contributed to the suppression of NLRP3 inflammasome activation, inflammation, and re-balanced lipid metabolism. In contrast, overexpression of TXNIP or agonism of NLRP3 exacerbated the cellular damage induced by SP. Suppression of the TXNIP-NLRP3 inflammasome pathway may partly contribute to the amelioration of hepatic injury during the progression of NASH by honey. Targeting hepatic TXNIP-NLRP3 inflammasome pathway is a potential therapeutic way for the prevention and treatment of NASH.

[Advances in the pathogenesis of non alcoholic fatty liver disease].

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Pár, Alajos; Pár, Gabriella

2017-06-01

Non alcoholic fatty liver disease is the hepatic manifestation of metabolic syndrome, and the most common liver disease. Its more aggressive form is the non alcoholic steatohepatitis. Multiple genetic and environmental factors lead to the accumulation of triglicerides and the inflammatory cascade. High fat diet, obesity, adipocyte dysfunction with cytokine production, insulin resistance and increased lipolysis with free fatty acid flux into the liver - all are the drivers of liver cell injury. Activation of inflammasome by damage- or pathogen-associated molecular patterns results in "steril inflammation" and immune response, while the hepatic stellate cells and progenitor cells lead to fibrogenesis. Small intestinal bacterial overgrowth and gut dysbiosis are also of pivotal importance in the inflammation. Among the susceptible genetic factors, mutations of patatin-like phospholipase domain containing 3 and the transmembrane 6 superfamily 2 genes play a role in the development and progression of the disease, similarly as do epigenetic regulators such as microRNAs and extracellular vesicles. Better understanding of the pathogenesis of non alcoholic fatty liver disease may identify novel therapeutic agents that improve the outcome of the disease. Orv Hetil. 2017; 158(23): 882-894.

Microvesicles released from fat-laden cells promote activation of hepatocellular NLRP3 inflammasome: A pro-inflammatory link between lipotoxicity and non-alcoholic steatohepatitis.

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Stefania Cannito

Full Text Available Non-Alcoholic Fatty Liver Disease (NAFLD is a major form of chronic liver disease in the general population in relation to its high prevalence among overweight/obese individuals and patients with diabetes type II or metabolic syndrome. NAFLD can progress to steatohepatitis (NASH, fibrosis and cirrhosis and end-stage of liver disease but mechanisms involved are still incompletely characterized. Within the mechanisms proposed to mediate the progression of NAFLD, lipotoxicity is believed to play a major role. In the present study we provide data suggesting that microvesicles (MVs released by fat-laden cells undergoing lipotoxicity can activate NLRP3 inflammasome following internalization by either cells of hepatocellular origin or macrophages. Inflammasome activation involves NF-kB-mediated up-regulation of NLRP3, pro-caspase-1 and pro-Interleukin-1, then inflammasome complex formation and Caspase-1 activation leading finally to an increased release of IL-1β. Since the release of MVs from lipotoxic cells and the activation of NLRP3 inflammasome have been reported to occur in vivo in either clinical or experimental NASH, these data suggest a novel rational link between lipotoxicity and increased inflammatory response.

Current management of non-alcoholic fatty liver disease

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LISBOA, QUELSON COELHO; COSTA, SILVIA MARINHO FEROLLA; COUTO, CLÁUDIA ALVES

2016-01-01

SUMMARY Non-alcoholic fatty liver disease (NAFLD) is characterized by hepatic accumulation of lipid in patients who do not consume alcohol in amounts generally considered harmful to the liver. NAFLD is becoming a major liver disease in Eastern countries and it is related to insulin resistance and metabolic syndrome. Treatment has focused on improving insulin sensitivity, protecting the liver from oxidative stress, decreasing obesity and improving diabetes mellitus, dyslipidemia, hepatic infla...

Nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus and its association with cardiovascular disease.

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Vanjiappan, Sivabal; Hamide, Abdoul; Ananthakrishnan, Ramesh; Periyasamy, Senthilkumar Gandhipuram; Mehalingam, Vadivelan

2018-01-31

Non-alcoholic fatty liver disease (NAFLD) encompasses a wide spectrum of liver disease that ranges from hepatic steatosis to non-alcoholic steatohepatitis. Obesity and diabetes mellitus are the prime risk factors for NAFLD. The aim of this study was to find out the prevalence of NAFLD among patients with type 2 diabetes mellitus and to detect the association of NAFLD with cardiovascular disease in them. Prospective observational study. The study was conducted on 300 patients with type 2 diabetes mellitus attending the outpatient department of a tertiary care teaching hospital. All patients underwent hepatic ultrasonography to look for hepatic steatosis. Among the 300 patients, 124 were divided into NAFLD and non-NAFLD groups based on the ultrasound findings. These patients were subjected to electrocardiogram, 2D echocardiogram, carotid intima media thickness (CIMT) measurement and ankle brachial pressure index measurement along with measurement of markers of oxidative stress. Hepatic steatosis was present in 61% of diabetic patients in this study. Cardiovascular disease was not found to be significantly associated in diabetic patients with NAFLD. However, cardiovascular risk factors like CIMT, high sensitivity c-reactive protein (hs-CRP) and malondialdehyde (MDA) were elevated in these patients. hs-CRP and MDA levels were found to be significantly associated with the severity of NAFLD. There is a high prevalence of NAFLD in type 2 diabetic patients. No correlation was detected between the presence of NAFLD and cardiovascular disease in them; although there was an association between cardiovascular risk factors and NAFLD. Copyright © 2018. Published by Elsevier Ltd.

Sodium 4-phenylbutyrate prevents murine dietary steatohepatitis caused by trans-fatty acid plus fructose.

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Morinaga, Maki; Kon, Kazuyoshi; Saito, Hiroaki; Arai, Kumiko; Kusama, Hiromi; Uchiyama, Akira; Yamashina, Shunhei; Ikejima, Kenichi; Watanabe, Sumio

2015-11-01

Excess consumption of trans-fatty acid could increase the risk of non-alcoholic steatohepatitis (NASH); however, treatment targeting trans-fatty acid-induced NASH has not been examined. Here we focused on the influence of trans-fatty acid intake on endoplasmic reticulum (ER) stress in hepatocytes, so we investigated the effect of the chemical chaperone 4-phenylbutyric acid (PBA), on trans-fatty acid-caused steatohepatitis using diabetic KK-A(y) mice. Elaidic acid (EA, trans-fatty acid) alone did not cause definitive liver injury. In contrast, EA plus low-dose fructose induced extensive apoptosis in hepatocytes with severe fat accumulation. EA plus fructose significantly increased ER stress markers such as glucose-regulated protein 78 (GRP78), eukaryotic initiation factor 2α (eIF2α) and phosphorylated c-jun N-terminal kinase (JNK), while PBA significantly reduced this response. In vitro, EA promoted expression of GRP78 and phosphorylation of eIF2α in primary-cultured hepatocytes. EA also increased hepatocellular susceptibility to low-dose tert-butyl hydroperoxide. Treatment with PBA significantly reduced these responses. In conclusion, EA potentiates susceptibly to non-hazardous dose of fructose, and increases ER and oxidative stress. PBA improved steatohepatitis induced by EA plus fructose through amelioration of ER stress. Therefore, ER stress-targeted therapy using a chemical chaperone is a promising novel strategy for trans-fatty acid-induced steatohepatitis.

Over-expressing the soluble gp130-Fc does not ameliorate methionine and choline deficient diet-induced non alcoholic steatohepatitis in mice.

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Helene L Kammoun

Full Text Available Non-alcoholic steatohepatitis (NASH is a liver disease with the potential to lead to cirrhosis and hepatocellular carcinoma. Interleukin-6 (IL-6 has been implicated in the pathogenesis of NASH, with the so-called IL-6 'trans-signaling' cascade being responsible for the pro-inflammatory actions of this cytokine. We aimed to block IL-6 'trans-signaling', using a transgenic mouse that overexpresses human soluble glycoprotein130 (sgp130Fc Tg mice fed a commonly used dietary model of inducing NASH (methionine and choline deficient-diet; MCD diet and hypothesized that markers of NASH would be ameliorated in such mice. Sgp130Fc Tg and littermate control mice were fed a MCD or control diet for 4 weeks. The MCD diet induced many hallmarks of NASH including hepatomegaly, steatosis, and liver inflammation. However, in contrast with other mouse models and, indeed, human NASH, the MCD diet model did not increase the mRNA or protein expression of IL-6. Not surprisingly, therefore, markers of MCD diet-induced NASH were unaffected by sgp130Fc transgenic expression. While the MCD diet model induces many pathophysiological markers of NASH, it does not induce increased IL-6 expression in the liver, a key hallmark of human NASH. We, therefore, caution the use of the MCD diet as a viable mouse model of NASH.

An update on non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in Asia.

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Hsu, Ching-Sheng; Kao, Jia-Horng

2017-08-01

Non-alcoholic fatty liver disease (NAFLD) has become the most overwhelming liver disease in Asia. In consideration of its increasing medical and economic impact on Asian people, it is time for us to review the update data in Asian countries and formulate strategies to cope with this emerging health problem in Asia. Moreover, growing data indicates that NAFLD may be a systemic disease, not just confined to liver-specific morbidity and mortality, but also associated with several extra-hepatic manifestations, such as cardiovascular diseases, chronic renal diseases, and malignancy. As the co-occurrence of NAFLD and viral hepatitis is common in Asia, issues related to the impact of NAFLD on the clinical outcomes and management of viral hepatitis remain to be elucidated. Areas covered: In this article, a narrative review was conducted, searching for literature from PubMed, Ovid MEDLINE, and the Cochrane Library database till August 2016. Studies relevant to the emerging data of NAFLD in Asia, including the diagnosis, risk factors, the assessment and management of Asian NAFLD patients were examined and discussed. Expert commentary: Collaboration in Asian countries to develop an effective and practical measurement to assess the severity of NAFLD is urgently required.

Pathogenesis of hepatic steatosis: the link between hypercortisolism and non-alcoholic fatty liver disease.

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Tarantino, Giovanni; Finelli, Carmine

2013-10-28

Based on the available literature, non alcoholic fatty liver disease or generally speaking, hepatic steatosis, is more frequent among people with diabetes and obesity, and is almost universally present amongst morbidly obese diabetic patients. Non alcoholic fatty liver disease is being increasingly recognized as a common liver condition in the developed world, with non alcoholic steatohepatitis projected to be the leading cause of liver transplantation. Previous data report that only 20% of patients with Cushing's syndrome have hepatic steatosis. Aiming at clarifying the reasons whereby patients suffering from Cushing's syndrome - a condition characterized by profound metabolic changes - present low prevalence of hepatic steatosis, the Authors reviewed the current concepts on the link between hypercortisolism and obesity/metabolic syndrome. They hypothesize that this low prevalence of fat accumulation in the liver of patients with Cushing's syndrome could result from the inhibition of the so-called low-grade chronic-inflammation, mainly mediated by Interleukin 6, due to an excess of cortisol, a hormone characterized by an anti-inflammatory effect. The Cushing's syndrome, speculatively considered as an in vivo model of the hepatic steatosis, could also help clarify the mechanisms of non alcoholic fatty liver disease.

Non-Alcoholic Fatty Liver Disease: From patient to population

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E.M. Koehler (Edith)

2013-01-01

textabstractNon-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease in Western countries, in parallel with epidemics in obesity and type 2 diabetes mellitus. NAFLD comprises a wide range of histological findings, extending from simple steatosis to

Non-alcoholic fatty liver disease: What the clinician needs to know

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Machado, Mariana Verdelho; Cortez-Pinto, Helena

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) is the most frequent cause of liver disease in the Western world. Furthermore, it is increasing worldwide, paralleling the obesity pandemic. Though highly frequent, only about one fifth of affected subjects are at risk of developing the progressive form of the disease, non-alcoholic steatohepatitis with fibrosis. Even in the latter, liver disease is slowly progressive, though, since it is so prevalent, it is already the third cause of liver transplantation in the United States, and it is predicted to get to the top of the ranking in few years. Of relevance, fatty liver is also associated with increased overall mortality and particularly increased cardiovascular mortality. The literature and amount of published papers on NAFLD is increasing as fast as its prevalence, which makes it difficult to keep updated in this topic. This review aims to summarize the latest knowledge on NAFLD, in order to help clinicians understanding its pathogenesis and advances on diagnosis and treatment. PMID:25278691

Deoxyribonucleic acid telomere length shortening can predict the incidence of non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus.

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Ping, Fan; Li, Zeng-Yi; Lv, Ke; Zhou, Mei-Cen; Dong, Ya-Xiu; Sun, Qi; Li, Yu-Xiu

2017-03-01

To investigate the effect of telomere shortening and other predictive factors of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus patients in a 6-year prospective cohort study. A total of 70 type 2 diabetes mellitus (mean age 57.8 ± 6.7 years) patients without NAFLD were included in the study, and 64 of them were successfully followed up 6 years later, excluding four cases with significant alcohol consumption. NAFLD was diagnosed by the hepatorenal ratio obtained by a quantitative ultrasound method using NIH image analysis software. The 39 individuals that developed NAFLD were allocated to group A, and the 21 individuals that did not develop NAFLD were allocated to group B. Fluorescent real-time quantitative polymerase chain reaction was used to measure telomere length. There was no significant difference between the two groups in baseline telomere length; however, at the end of the 6th year, telomere length had become shorter in group A compared with group B. There were significant differences between these two groups in baseline body mass index, waistline, systolic blood pressure, glycated hemoglobin and fasting C-peptide level. In addition, the estimated indices of baseline insulin resistance increased in group A. Fasting insulin level, body mass index, systolic blood pressure at baseline and the shortening of telomere length were independent risk factors of NAFLD in type 2 diabetes mellitus patients. Telomere length became shorter in type 2 diabetes mellitus patients who developed NAFLD over the course of 6 years. Type 2 diabetes mellitus patients who developed NAFLD had more serious insulin resistance compared with those who did not develop NAFLD a long time ago. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Insulinorresistencia e hígado graso no alcohólico, ¿existe relación causa-efecto entre ambas condiciones? Insulin-resistance and non-alcoholic fatty liver, is there a cause-effect relationship between both conditions?

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Raúl Orlando Calderín Bouza

2009-04-01

prevalence between 21 % and 63 %, and prevalence of steatohepatitis fluctuates between 2 % and 3 % of population. We must to mark that this prevalence is increasing together with the prevalence increase of insulin resistance syndrome, obesity, and type 2 diabetes mellitus. The non-alcohol fatty liver is the more frequent cause of a persistent high level of transaminase, of chronic liver disease, and of idiopathic liver cirrhosis. An age similar or higher than 40 years, presence of insulin resistance, insulin resistance syndrome, obesity, and type 2 diabetes mellitus darken the prognosis of patients presenting with non-alcoholic fatty liver, so the presence of above mentioned factors is considered as a poor prognosis factors in patient presenting non-alcoholic fatty liver.

Staging of fibrosis in experimental non-alcoholic steatohepatitis by quantitative molecular imaging in rat models

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Schnabl, Bernd; Farshchi-Heydari, Salman; Loomba, Rohit; Mattrey, Robert F.; Hoh, Carl K.; Sirlin, Claude B.; Brenner, David A.; Behling, Cynthia A.; Vera, David R.

2016-01-01

Objectives: The aim of this study was to test the ability of hepatocyte-specific functional imaging to stage fibrosis in experimental rat models of liver fibrosis and progressive NASH. Using ROC analysis we tested the ability of a functional imaging metric to discriminate early (F1) from moderate (F2) fibrosis in the absence and presence of non-alcoholic steatohepatitis, which has not been achieved by any modality other than biopsy. Methods: Galactosyl Human Serum Albumin (GSA) was radiolabeled with the positron-emitter, 68 Ga, and injected (i.v., 45–95 μCi, 1.5 pmol/g TBW) into 44 healthy, 19 DEN-, and 22 CDAA-treated male rats. Quantification of liver function was achieved by calculating T90, defined as the time for the liver to accumulate 90 percent of the [ 68 Ga]GSA plateau value. All livers were excised immediately after imaging and prepared for a “blinded” histologic examination, which included fibrosis and fat content scores. Two sets of fibrosis scores were recorded for all of animals. The dominant fibrosis stage was recorded as the “Dominant Pattern” score and the “Maximum Pattern” score was assigned if a smaller distinct region with a higher fibrosis score was observed. Results: Animals with Dominant Pattern F0–F1 liver fibrosis (D − = 39) demonstrated significantly (P < 0.0001) faster accumulation of [ 68 Ga]GSA (2.40 ± 0.52 min) than those with moderate to advanced Dominant Pattern fibrosis F2 and F4 (D + = 26) (3.48 ± 1.01 min). ROC analysis (F0–F1 vs F2–F4) produced an area under the binormal curve (AUC) of 0.867 ± 0.045. Twenty-seven of the 65 rats had small regions with higher fibrosis scores. Six of these Maximum Pattern scores reclassified the animals from D − to D + . ROC analysis of F0–F1 versus F2–F4 rats without liver fat produced AUCs of 0.881 ± 0.053 for the Dominant Pattern Score and 0.944 ± 0.035 for the Maximum Pattern Score. Conclusions: PET Functional Imaging of [ 68 Ga]GSA accurately discriminates

Coffee and non-alcoholic fatty liver disease: brewing evidence for hepatoprotection?

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Chen, Shaohua; Teoh, Narci C; Chitturi, Shiv; Farrell, Geoffrey C

2014-03-01

Coffee is one of the most popular beverages in the world. Several studies consistently show that coffee drinkers with chronic liver disease have a reduced risk of cirrhosis and a lower incidence of hepatocellular carcinoma regardless of primary etiology. With the increasing prevalence of non-alcoholic fatty liver disease (NAFLD) worldwide, there is renewed interest in the effect of coffee intake on NAFLD severity and positive clinical outcomes. This review gives an overview of growing epidemiological and clinical evidence which indicate that coffee consumption reduces severity of NAFLD. These studies vary in methodology, and potential confounding factors have not always been completely excluded. However, it does appear that coffee, and particular components other than caffeine, reduce NAFLD prevalence and inflammation of non-alcoholic steatohepatitis. Several possible mechanisms underlying coffee's hepatoprotective effects in NAFLD include antioxidative, anti-inflammatory, and antifibrotic effects, while a chemopreventive effect against hepatocarcinogenesis seems likely. The so-far limited data supporting such effects will be discussed, and the need for further study is highlighted. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Low physical activity and energy dense Malaysian foods are associated with non-alcoholic fatty liver disease in centrally obese but not in non-centrally obese patients with diabetes mellitus.

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Chan, Wah-Kheong; Tan, Alexander Tong-Boon; Vethakkan, Shireene Ratna; Tah, Pei-Chien; Vijayananthan, Anushya; Goh, Khean-Lee

2015-01-01

To study the dietary intake and level of physical activity (PA) of patients with diabetes mellitus and the association with non-alcoholic fatty liver disease (NAFLD). Consecutive adult patients with type 2 diabetes mellitus seen in our hospital diabetes clinic were enrolled. The Global Physical Activity Questionnaire and a semi-quantitative food-frequency questionnaire were used to assess PA and dietary intake, respectively. Diagnosis of NAFLD was ultrasound-based and following exclusion of significant alcohol intake and other causes of chronic liver disease. Data for 299 patients were analyzed (mean age 63.3±10.5 years old, 41.1% male). Prevalence of NAFLD was 49.2%. Patients with low PA were more likely to have NAFLD (OR=1.75, 95% CI=1.03-2.99, p=0.029). There was no significant difference in energy intake, intake of macronutrients and percentage energy intake from each macronutrient, high sugar food, high cholesterol food and high SFA food between patients with and without NAFLD. Among centrally obese patients, patients with low PA and in the highest quartile of percentage energy intake from fat (OR=4.03, 95% CI=1.12-15.0, p=0.015), high cholesterol food (OR=3.61, 95% CI=1.37-9.72, p=0.004) and high SFA food (OR=2.67, 95% CI=1.08-6.67, p=0.019) were most likely to have NAFLD. Among those who were not centrally obese, PA and percentage energy intake from fat, high cholesterol food and high SFA food was not associated with NAFLD. Low PA and high percentage energy intake from fat, high cholesterol food and high SFA food is associated with NAFLD in centrally obese but not in non-centrally obese patients with diabetes mellitus.

Nutritional Modulation of Non-Alcoholic Fatty Liver Disease and Insulin Resistance

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Hannele Yki-Järvinen

2015-11-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD covers a spectrum of disorders ranging from simple steatosis (non-alcoholic fatty liver, NAFL to non-alcoholic steatohepatitis (NASH and cirrhosis. NAFL increases the risk of liver fibrosis. If the liver is fatty due to causes of insulin resistance such as obesity and physical inactivity, it overproduces glucose and triglycerides leading to hyperinsulinemia and a low high-density lipoprotein (HDL cholesterol concentration. The latter features predispose to type 2 diabetes and cardiovascular disease (CVD. Understanding the impact of nutritional modulation of liver fat content and insulin resistance is therefore of interest for prevention and treatment of NAFLD. Hypocaloric, especially low carbohydrate ketogenic diets rapidly decrease liver fat content and associated metabolic abnormalities. However, any type of caloric restriction seems effective long-term. Isocaloric diets containing 16%–23% fat and 57%–65% carbohydrate lower liver fat compared to diets with 43%–55% fat and 27%–38% carbohydrate. Diets rich in saturated (SFA as compared to monounsaturated (MUFA or polyunsaturated (PUFA fatty acids appear particularly harmful as they increase both liver fat and insulin resistance. Overfeeding either saturated fat or carbohydrate increases liver fat content. Vitamin E supplementation decreases liver fat content as well as fibrosis but has no effect on features of insulin resistance.

Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage.

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Neuman, Manuela G; French, Samuel W; Zakhari, Samir; Malnick, Stephen; Seitz, Helmut K; Cohen, Lawrence B; Salaspuro, Mikko; Voinea-Griffin, Andreea; Barasch, Andrei; Kirpich, Irina A; Thomes, Paul G; Schrum, Laura W; Donohue, Terrence M; Kharbanda, Kusum K; Cruz, Marcus; Opris, Mihai

2017-02-01

This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed

[Clinical and biochemical characteristics in patients with histology compatible with steatothepatitis in National Hospital Arzobispo Loayza, Lima, Peru, from 2010 to 2012].

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Alegría Matos, Paola Hilda; Tafur Cabello, Kelly Stephanie; Lozano Miranda, Adelina; Loza Munarriz, Cesar; Lozano Miranda, Zenaida

2015-01-01

Describe the clinical and biochemical characteristics of patients with histopathological findings compatible with steatohepatitis of HNAL patients between 2010-2012. Determine the frequency of alcoholic and non-alcoholic steatohepatitis, presence of metabolic syndrome and other factors associated to non-alcoholic steatohepatitis, its main indications for liver biopsy and biochemical characteristics according to the severity of the histological findings. We evaluated all histological slides of liver biopsies of the period between 2010-2012, of which, those with the diagnosis of steatohepatitis were selected. Their medical records were then reviewed. 32 patients met inclusion criteria. 28 were female and 4 male, the average age was 49±12 years. Two patients had a history of chronic alcohol consumption, representing the group of alcoholic steatohepatitis. The more frequent clinical finding in patients with NASH (non-alcoholic steatohepatitis), was obesity (37%). 50% of patients had AST/ALT ratio <1. Among population studied, non-alcoholic steatohepatitis was more common than alcoholic steatohepatitis, being obesity the most associated factor.

Development of a Representative Mouse Model with Nonalcoholic Steatohepatitis.

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Verbeek, Jef; Jacobs, Ans; Spincemaille, Pieter; Cassiman, David

2016-06-01

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disease in the Western world. It represents a disease spectrum ranging from isolated steatosis to non-alcoholic steatohepatitis (NASH). In particular, NASH can evolve to fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. The development of novel treatment strategies is hampered by the lack of representative NASH mouse models. Here, we describe a NASH mouse model, which is based on feeding non-genetically manipulated C57BL6/J mice a 'Western style' high-fat/high-sucrose diet (HF-HSD). HF-HSD leads to early obesity, insulin resistance, and hypercholesterolemia. After 12 weeks of HF-HSD, all mice exhibit the complete spectrum of features of NASH, including steatosis, hepatocyte ballooning, and lobular inflammation, together with fibrosis in the majority of mice. Hence, this model closely mimics the human disease. Implementation of this mouse model will lead to a standardized setup for the evaluation of (i) underlying mechanisms that contribute to the progression of NAFLD to NASH, and (ii) therapeutic interventions for NASH. © 2016 by John Wiley & Sons, Inc. Copyright © 2016 John Wiley & Sons, Inc.

Effects of dietary supplementation with betaine on a nonalcoholic steatohepatitis (NASH) mouse model.

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Kawakami, Sakura; Han, Kyu-Ho; Nakamura, Yumi; Shimada, Ken-ichiro; Kitano, Tomoko; Aritsuka, Tsutomu; Nagura, Taizo; Ohba, Kiyoshi; Nakamura, Kimihide; Fukushima, Michihiro

2012-01-01

The effects of betaine supplementation on non-alcoholic steatohepatitis (NASH) model mice were examined by measuring the accumulation of fat in the livers of NASH model mice compared to a control. Betaine from sugar beets was provided to the model mice as a dietary supplement. After 3 wk of dietary supplementation, there were no significant differences in body weight or liver weight between the groups. However, the liver to body weight ratio in the high-fat diet with betaine (HFB) group was significantly (pNASH model mice.

Prevalence and determinants of non-alcoholic fatty liver disease in lifelines: A large Dutch population cohort.

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Eline H van den Berg

Full Text Available Non-alcoholic fatty liver disease is an increasing health issue that develops rather unnoticed with obesity, type 2 diabetes mellitus and metabolic syndrome. We investigated prevalence, determinants and associated metabolic abnormalities of non-alcoholic fatty liver disease in the largest population-based cohort to date.Biochemical characteristics, type 2 diabetes mellitus and metabolic syndrome were determined in the Lifelines Cohort Study (N = 167,729, a population-based cohort in the North of the Netherlands. Non-alcoholic fatty liver disease was defined as Fatty Liver Index (FLI≥60. Exclusion criteria were age <18 years, immigrants, missing data to assess FLI and metabolic syndrome, excessive alcohol use, previous-diagnosed hepatitis or cirrhosis and non-fasting blood sampling.Out of 37,496 included participants (median age 44 years, 62.1% female, 8,259 (22.0% had a FLI≥60. Individuals with a FLI≥60 were more often male, older, obese, had higher levels of hemoglobinA1c, fasting glucose, liver enzymes, total cholesterol, low-density lipoprotein cholesterol, triglycerides, c-reactive protein and leucocytes and lower high-density lipoprotein cholesterol (all P<0.0001. Participants with a FLI≥60 showed higher prevalence of type 2 diabetes mellitus (9.3% vs. 1.4%, metabolic syndrome (54.2% vs. 6.2%, impaired renal function (20.1% vs. 8.7% and cardiovascular disease (4.6% vs. 1.6% (all P<0.0001. Multivariable logistic analysis showed that smoking, hemoglobin, leucocytes, c-reactive protein, platelets, alanine aminotransferase, alkaline phosphatase, albumin, impaired renal function (OR 1.27, 95%CI 1.15-1.41, metabolic syndrome (OR 11.89, 95%CI 11.03-12.82 and its individual components hyperglycemia (OR 2.53, 95%CI 2.34-2.72, hypertension (OR 1.89, 95%CI 1.77-2.01 and reduced high-density lipoprotein cholesterol (OR 3.44, 95%CI 3.22-3.68 were independently associated with suspected non-alcoholic fatty liver disease (all P<0.0001.Twenty

The effects of diet-induced obesity on hepatocyte insulin signaling pathways and induction of non-alcoholic liver damage

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Sameer Fatani

2011-03-01

Full Text Available Sameer Fatani1, Imose Itua2, Paul Clark3, Christopher Wong3, Ebrahim K Naderali21Obesity Biology Unit, School of Clinical Sciences, University of Liverpool, Liverpool, UK; 2Department of Health and Applied Social Sciences, Liverpool Hope University, Hope Park, Liverpool UK; 3Aintree University Hospital NHS Foundation Trust, Longmoor Lane, Liverpool, UKAbstract: The prevalence of diet-induced obesity is increasing amongst adults and children worldwide, predisposing millions of people to an array of health problems that include metabolic syndrome, non-alcoholic fatty liver disease and non-alcoholic steatohepatitis. In this study we used experimental animals to investigate the effects of dietary obesity on markers of hepatic insulin signaling as well as structural changes in hepatocytes. Adult male Wistar rats were randomized and assigned to either a control group or a test group. Controls were fed standard laboratory pelleted diet (chow-fed, while the test group had free access to a highly-palatable diet (HPD. After eight weeks, the HPD-fed animals were subdivided into three subgroups and their diets altered as follows: HPD-to-chow, HPD with the addition of fenofibrate given by oral gavage for a further seven weeks, or HPD with vehicle (1% carboxymethylcellulose at 1 mL/kg body weight given by oral gavage for a further seven weeks, respectively. Untreated diet-fed animals had significantly higher body weight, liver weight, and all measured metabolic profiles compared with chow-fed and treated diet-fed groups. Expression of kinases IRβ, IRS-1, AKt, eNOS, Shc and ERK1/2 were unaffected by obesity, while IRS-2 and P I3 kinase levels were significantly reduced in untreated HPD animals. Compared with chow-fed animals, steatosis and steatohepatitis were almost doubled in animals from untreated HPD, while removal of HPD and fenofibrate-treatment reduced steatosis by 40% and 80% respectively. These data suggest that diet-induced obesity affects

The impact of non-alcoholic fatty liver disease on incident type 2 diabetes mellitus in non-overweight individuals.

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Fukuda, Takuya; Hamaguchi, Masahide; Kojima, Takao; Hashimoto, Yoshitaka; Ohbora, Akihiro; Kato, Takahiro; Nakamura, Naoto; Fukui, Michiaki

2016-02-01

The aim of this study was to evaluate the impact of non-alcoholic fatty liver disease (NAFLD) on incident type 2 diabetes mellitus (T2DM) in non-overweight individuals with NAFLD. A population-based retrospective cohort study of 4629 participants who were enrolled in a health check-up programme for more than 10 years. A standardized questionnaire and abdominal ultrasonography were used to diagnose NAFLD. A cut-off point of BMI 23 kg/m(2) was used to define overweight (≥23.0 kg/m(2)) or non-overweight (<23.0 kg/m(2)). The primary outcome was incident T2DM. Over a mean follow-up of 12.8 years, 351 participants (7.6%) developed T2DM. The incidence rate of T2DM was 3.2% in the non-overweight without NAFLD group, 14.4% in the non-overweight with NAFLD group, 8.0% in the overweight without NAFLD group and 26.4% in the overweight with NAFLD group. The adjusted hazard ratios for incident T2DM compared with the non-overweight without NAFLD group were as follows: 3.59 (95% CI: 2.14-5.76) in the non-overweight with NAFLD group, 1.99 (95% CI: 1.47-2.69) in the overweight without NAFLD group and 6.77 (95% CI: 5.17-8.91) in the overweight with NAFLD group. The adjusted hazard ratio in the non-overweight with NAFLD group was significantly higher than that in the overweight without NAFLD group or that in the non-overweight without NAFLD group. Non-overweight individuals with NAFLD had a high risk of incident T2DM. Diagnosis of NAFLD is important in non-overweight individuals, and therefore it might be necessary to follow their health conditions on a long-term basis after detection of NAFLD. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

β-glycosphingolipids ameliorated non-alcoholic steatohepatitis in the Psammomys obesus model

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Zigmond E

2014-10-01

Full Text Available Ehud Zigmond,1,* Oshrat Tayer-Shifman,1,* Gadi Lalazar,1 Ami Ben Ya'acov,1 Sarah Weksler-Zangen,2 David Shasha,1 Miriam Sklair-Levy,3 Lidya Zolotarov,1 Zvi Shalev,1 Rony Kalman,2 Ehud Ziv,2 Itamar Raz,2 Yaron Ilan1 1Liver Unit, 2Diabetes Unit, 3Department of Radiology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel *These authors contributed equally to this workAbstract: Liver steatosis is a common characteristic of obesity and type 2 diabetes, and fatty liver disease is increasingly recognized as a major health burden. Accumulating evidence suggests that β-glycosphingolipids play an important role in insulin sensitivity and thus could affect hepatic steatosis. To determine the effect associated with β-glycosphingolipid-mediated amelioration of liver injury, seven groups of Psammomys obesus on a high-energy diet were studied. Animals were treated with daily injections of β-glucosylceramide, β-lactosylceramide, or a combination of both. β-glycosphingolipids ameliorated the hepatic injury manifested by decreased liver enzymes, liver weight, and hepatic fat, and improved liver histology. Administration of both β-glucosylceramide and β-lactosylceramide also decreased interferon (IFN-γ serum levels. These effects were associated with improved serum cholesterol and triglyceride levels. These data suggest that β-glycosphingolipids ameliorate liver injury in an animal model of nonalcoholic steatohepatitis.Keywords: NAFLD, glycolipids, STAT, NASH, insulin resistance, diabetes

Trypanosoma cruzi infection is a potent risk factor for non-alcoholic steatohepatitis enhancing local and systemic inflammation associated with strong oxidative stress and metabolic disorders.

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Luisina I Onofrio

2015-02-01

Full Text Available The immune mechanisms underlying experimental non-alcoholic steatohepatitis (NASH, and more interestingly, the effect of T. cruzi chronic infection on the pathogenesis of this metabolic disorder are not completely understood.We evaluated immunological parameters in male C57BL/6 wild type and TLR4 deficient mice fed with a standard, low fat diet, LFD (3% fat as control group, or a medium fat diet, MFD (14% fat in order to induce NASH, or mice infected intraperitoneally with 100 blood-derived trypomastigotes of Tulahuen strain and also fed with LFD (I+LFD or MFD (I+MFD for 24 weeks. We demonstrated that MFD by itself was able to induce NASH in WT mice and that parasitic infection induced marked metabolic changes with reduction of body weight and steatosis revealed by histological studies. The I+MFD group also improved insulin resistance, demonstrated by homeostasis model assessment of insulin resistance (HOMA-IR analysis; although parasitic infection increased the triglycerides and cholesterol plasma levels. In addition, hepatic M1 inflammatory macrophages and cytotoxic T cells showed intracellular inflammatory cytokines which were associated with high levels of IL6, IFNγ and IL17 plasmatic cytokines and CCL2 chemokine. These findings correlated with an increase in hepatic parasite load in I+MFD group demonstrated by qPCR assays. The recruitment of hepatic B lymphocytes, NK and dendritic cells was enhanced by MFD, and it was intensified by parasitic infection. These results were TLR4 signaling dependent. Flow cytometry and confocal microscopy analysis demonstrated that the reactive oxygen species and peroxinitrites produced by liver inflammatory leukocytes of MFD group were also exacerbated by parasitic infection in our NASH model.We highlight that a medium fat diet by itself is able to induce steatohepatitis. Our results also suggest a synergic effect between damage associated with molecular patterns generated during NASH and parasitic infection

Isocaloric Dietary Changes and Non-Alcoholic Fatty Liver Disease in High Cardiometabolic Risk Individuals

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Giuseppe Della Pepa

2017-09-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD incorporates an extensive spectrum of histologic liver abnormalities, varying from simple triglyceride accumulation in hepatocytes non-alcoholic fatty liver (NAFL to non-alcoholic steatohepatitis (NASH, and it is the most frequent chronic liver disease in the industrialized world. Beyond liver related complications such as cirrhosis and hepatocellular carcinoma, NAFLD is also an emerging risk factor for type 2 diabetes and cardiovascular disease. Currently, lifestyle intervention including strategies to reduce body weight and to increase regular physical activity represents the mainstay of NAFLD management. Total caloric intake plays a very important role in both the development and the treatment of NAFLD; however, apart from the caloric restriction alone, modifying the quality of the diet and modulating either the macro- or micronutrient composition can also markedly affect the clinical evolution of NAFLD, offering a more realistic and feasible treatment alternative. The aim of the present review is to summarize currently available evidence from randomized controlled trials on the effects of different nutrients including carbohydrates, lipids, protein and other dietary components, in isocaloric conditions, on NAFLD in people at high cardiometabolic risk. We also describe the plausible mechanisms by which different dietary components could modulate liver fat content.

[Non alcoholic fatty liver. A frequent entity with an unknown outcome].

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Barisio D'Angelo, María Gabriela; Mariel Actis, Andrea; Outomuro, Delia

2009-01-01

Non-alcoholic fatty liver disease (NAFLD), defined as excessive fat accumulation into the hepatocytes, has a prevalence of approximately 15 to 25%. Frequently associated risk factors for NAFLD are obesity, type 2 diabetes and dyslipidemia. It has been proponed that a mitochondrial dysfunction would play a crucial role in the disease development.On the other hand, focus is on insulin resistance syndrome, the only metabolic alteration strongly associated with this malady. The disease is suspected in individuals with insulina resistance characteristics such as metabolic syndrome and also in those with augmented serum aminotransferases levels. Different tests with biochemical markers have been proposed to predict the development of fibrosis or steatohepatitis. Therapeutic options in NAFLD patients are limited and weight lost remains as the most recommended one.

Fatty acids in non-alcoholic steatohepatitis: Focus on pentadecanoic acid.

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Wonbeak Yoo

Full Text Available Non-alcoholic fatty liver disease (NAFLD is the most common form of liver disease and ranges from isolated steatosis to NASH. To determine whether circulating fatty acids could serve as diagnostic markers of NAFLD severity and whether specific fatty acids could contribute to the pathogenesis of NASH, we analyzed two independent NAFLD patient cohorts and used the methionine- and choline-deficient diet (MCD NASH mouse model. We identified six fatty acids that could serve as non-invasive markers of NASH in patients with NAFLD. Serum levels of 15:0, 17:0 and 16:1n7t negatively correlated with NAFLD activity scores and hepatocyte ballooning scores, while 18:1n7c serum levels strongly correlated with fibrosis stage and liver inflammation. Serum levels of 15:0 and 17:0 also negatively correlated with fasting glucose and AST, while 16:1n7c and 18:1n7c levels positively correlated with AST and ferritin, respectively. Inclusion of demographic and clinical parameters improved the performance of the fatty acid panels in detecting NASH in NAFLD patients. The panel [15:0, 16:1n7t, 18:1n7c, 22:5n3, age, ferritin and APRI] predicted intermediate or advanced fibrosis in NAFLD patients, with 82% sensitivity at 90% specificity [AUROC = 0.92]. 15:0 and 18:1n7c were further selected for functional studies in vivo. Mice treated with 15:0-supplemented MCD diet showed reduced AST levels and hepatic infiltration of ceroid-laden macrophages compared to MCD-treated mice, suggesting that 15:0 deficiency contributes to liver injury in NASH. In contrast, 18:1n7c-supplemented MCD diet didn't affect liver pathology. In conclusion, 15:0 may serve as a promising biomarker or therapeutic target in NASH, opening avenues for the integration of diagnosis and treatment.

Non-alcoholic fatty liver disease (NAFLD) models in drug discovery.

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Cole, Banumathi K; Feaver, Ryan E; Wamhoff, Brian R; Dash, Ajit

2018-02-01

The progressive disease spectrum of non-alcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is a rapidly emerging public health crisis with no approved therapy. The diversity of various therapies under development highlights the lack of consensus around the most effective target, underscoring the need for better translatable preclinical models to study the complex progressive disease and effective therapies. Areas covered: This article reviews published literature of various mouse models of NASH used in preclinical studies, as well as complex organotypic in vitro and ex vivo liver models being developed. It discusses translational challenges associated with both kinds of models, and describes some of the studies that validate their application in NAFLD. Expert opinion: Animal models offer advantages of understanding drug distribution and effects in a whole body context, but are limited by important species differences. Human organotypic in vitro and ex vivo models with physiological relevance and translatability need to be used in a tiered manner with simpler screens. Leveraging newer technologies, like metabolomics, proteomics, and transcriptomics, and the future development of validated disease biomarkers will allow us to fully utilize the value of these models to understand disease and evaluate novel drugs in isolation or combination.

Epigenetic mechanisms in non-alcoholic fatty liver disease: An emerging field.

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Gallego-Durán, Rocío; Romero-Gómez, Manuel

2015-10-28

Non-alcoholic fatty liver disease (NAFLD) is an emerging health concern in both developed and non-developed world, encompassing from simple steatosis to non-alcoholic steatohepatitis (NASH), cirrhosis and liver cancer. Incidence and prevalence of this disease are increasing due to the socioeconomic transition and change to harmful diet. Currently, gold standard method in NAFLD diagnosis is liver biopsy, despite complications and lack of accuracy due to sampling error. Further, pathogenesis of NAFLD is not fully understood, but is well-known that obesity, diabetes and metabolic derangements played a major role in disease development and progression. Besides, gut microbioma and host genetic and epigenetic background could explain considerable interindividual variability. Knowledge that epigenetics, heritable events not caused by changes in DNA sequence, contribute to development of diseases has been a revolution in the last few years. Recently, evidences are accumulating revealing the important role of epigenetics in NAFLD pathogenesis and in NASH genesis. Histone modifications, changes in DNA methylation and aberrant profiles or microRNAs could boost development of NAFLD and transition into clinical relevant status. PNPLA3 genotype GG has been associated with a more progressive disease and epigenetics could modulate this effect. The impact of epigenetic on NAFLD progression could deserve further applications on therapeutic targets together with future non-invasive methods useful for the diagnosis and staging of NAFLD.

Elevation of liver endoplasmic reticulum stress in a modified choline-deficient l-amino acid-defined diet-fed non-alcoholic steatohepatitis mouse model.

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Muraki, Yo; Makita, Yukimasa; Yamasaki, Midori; Amano, Yuichiro; Matsuo, Takanori

2017-05-06

Endoplasmic reticulum (ER) stress caused by accumulation of misfolded proteins is observed in several kinds of diseases. Since ER stress is reported to be involved in the progression of non-alcoholic steatohepatitis (NASH), highly sensitive and simple measurement methods are required for research into developing novel therapy for NASH. To investigate the involvement of ER stress in NASH pathogenesis in a mouse model, an assay for liver ER stress was developed using ER stress activated indicator-luciferase (ERAI-Luc) mice. To establish the assay method for detection of ER stress in the liver, tunicamycin (TM) (0.3 mg/kg i. p.) was administered to ERAI-Luc mice, and the luciferase activity was measured in ex vivo and in vivo. To evaluate ER stress in the NASH model, ERAI-Luc mice were fed a modified choline-deficient l-amino acid-defined (mCDAA) diet for 14 weeks. After measurement of ER stress by luminescence imaging, levels of liver lipids and pro-fibrotic and pro-inflammatory gene expression were measured as NASH-related indexes. In non-invasive whole-body imaging, TM elevated luciferase activity in the liver, induced by activation of ER stress. The highest luminescence in the liver was confirmed by ex vivo imaging of isolated tissues. In parallel with progression of NASH, elevated luminescence induced by ER stress in liver was observed in mCDAA diet-fed ERAI-Luc mice. Luciferase activity was significantly and positively correlated to levels of triglyceride and free cholesterol in the liver, as well as to the mRNA expression of type 1 collagen α1 chain and tumor necrosis factor α. These data indicated that the use of ERAI-Luc mice was effective in the detection of ER stress in the liver. Moreover, the NASH model using ERAI-Luc mice can be a useful tool to clarify the role of ER stress in pathogenesis of NASH and to evaluate effects of drugs targeted against ER stress. Copyright © 2017 Elsevier Inc. All rights reserved.

Non alcoholic fatty liver disease in a Nigerian population with type II ...

African Journals Online (AJOL)

Introduction: Worldwide, Non-alcoholic fatty liver disease (NAFLD) has become an important cause of chronic liver disease and cardiovascular morbidity, even more so in subjects with Type II Diabetes Mellitus (T2DM). The aim of this study was to determine the prevalence and risk factors of NAFLD in an African population ...

Mechanistic review of drug-induced steatohepatitis

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Schumacher, Justin D.; Guo, Grace L.

2015-01-01

Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. - Highlights: • Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds • Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis. • Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs. • Chemotherapeutics that induce CASH are cationic amphiphilic drugs. • Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.

Mechanistic review of drug-induced steatohepatitis

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Schumacher, Justin D., E-mail: Justin.d.schumacher@rutgers.edu; Guo, Grace L.

2015-11-15

Drug-induced steatohepatitis is a rare form of liver injury known to be caused by only a handful of compounds. These compounds stimulate the development of steatohepatitis through their toxicity to hepatocyte mitochondria; inhibition of beta-oxidation, mitochondrial respiration, and/or oxidative phosphorylation. Other mechanisms discussed include the disruption of phospholipid metabolism in lysosomes, prevention of lipid egress from hepatocytes, targeting mitochondrial DNA and topoisomerase, decreasing intestinal barrier function, activation of the adenosine pathway, increasing fatty acid synthesis, and sequestration of coenzyme A. It has been found that the majority of compounds that induce steatohepatitis have cationic amphiphilic structures; a lipophilic ring structure with a side chain containing a cationic secondary or tertiary amine. Within the last decade, the ability of many chemotherapeutics to cause steatohepatitis has become more evident coining the term chemotherapy-associated steatohepatitis (CASH). The mechanisms behind drug-induced steatohepatitis are discussed with a focus on cationic amphiphilic drugs and chemotherapeutic agents. - Highlights: • Reviewed the mechanisms underlying drug-induced steatohepatitis for many compounds • Mitochondrial dysfunction is critical in the development of drug-induced steatohepatitis. • Majority of drugs that induce steatohepatitis are cationic amphiphilic drugs. • Chemotherapeutics that induce CASH are cationic amphiphilic drugs. • Majority of drugs that induce steatohepatitis are carnitine palmitoyltransferase-I inhibitors.

A randomised, double-blind, placebo-controlled phase 1 study of the safety, tolerability and pharmacodynamics of volixibat in overweight and obese but otherwise healthy adults: implications for treatment of non-alcoholic steatohepatitis.

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Palmer, Melissa; Jennings, Lee; Silberg, Debra G; Bliss, Caleb; Martin, Patrick

2018-03-16

Accumulation of toxic free cholesterol in hepatocytes may cause hepatic inflammation and fibrosis. Volixibat inhibits bile acid reuptake via the apical sodium bile acid transporter located on the luminal surface of the ileum. The resulting increase in bile acid synthesis from cholesterol could be beneficial in patients with non-alcoholic steatohepatitis. This adaptive dose-finding study investigated the safety, tolerability, pharmacodynamics, and pharmacokinetics of volixibat. Overweight and obese adults were randomised 3:1 to double-blind volixibat or placebo, respectively, for 12 days. Volixibat was initiated at a once-daily dose of 20 mg, 40 mg or 80 mg. Based on the assessment of predefined safety events, volixibat dosing was either escalated or reduced. Other dose regimens (titrations and twice-daily dosing) were also evaluated. Assessments included safety, tolerability, stool hardness, faecal bile acid (FBA) excretion, and serum levels of 7α-hydroxy-4-cholesten-3-one (C4) and lipids. All 84 randomised participants (volixibat, 63; placebo, 21) completed the study, with no serious adverse events at doses of up to 80 mg per day (maximum assessed dose). The median number of daily bowel evacuations increased from 1 (range 0-4) to 2 (0-8) during volixibat treatment, and stool was looser with volixibat than placebo. Volixibat was minimally absorbed; serum levels were rarely quantifiable at any dose or sampling time point, thereby precluding pharmacokinetic analyses. Mean daily FBA excretion was 930.61 μmol (standard deviation [SD] 468.965) with volixibat and 224.75 μmol (195.403) with placebo; effects were maximal at volixibat doses ≥20 mg/day. Mean serum C4 concentrations at day 12 were 98.767 ng/mL (standard deviation, 61.5841) with volixibat and 16.497 ng/mL (12.9150) with placebo. Total and low-density lipoprotein cholesterol levels decreased in the volixibat group, with median changes of - 0.70 mmol/L (range - 2.8 to 0.4) and - 0.6990�

Liver microRNA-21 is overexpressed in non-alcoholic steatohepatitis and contributes to the disease in experimental models by inhibiting PPARα expression

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Loyer, Xavier; Paradis, Valérie; Hénique, Carole; Vion, Anne-Clémence; Colnot, Nathalie; Guerin, Coralie L; Devue, Cécile; On, Sissi; Scetbun, Jérémy; Romain, Mélissa; Paul, Jean-Louis; Rothenberg, Marc E; Marcellin, Patrick; Durand, François; Bedossa, Pierre; Prip-Buus, Carina; Baugé, Eric; Staels, Bart; Boulanger, Chantal M; Tedgui, Alain; Rautou, Pierre-Emmanuel

2016-01-01

Objective Previous studies suggested that microRNA-21 may be upregulated in the liver in non-alcoholic steatohepatitis (NASH), but its role in the development of this disease remains unknown. This study aimed to determine the role of microRNA-21 in NASH. Design We inhibited or suppressed microRNA-21 in different mouse models of NASH: (a) low-density lipoprotein receptor-deficient (Ldlr−/−) mice fed a high-fat diet and treated with antagomir-21 or antagomir control; (b) microRNA-21-deficient and wild-type mice fed a methionine-choline-deficient (MCD) diet; (c) peroxisome proliferation-activator receptor α (PPARα)-deficient mice fed an MCD diet and treated with antagomir-21 or antagomir control. We assessed features of NASH and determined liver microRNA-21 levels and cell localisation. MicroRNA-21 levels were also quantified in the liver of patients with NASH, bland steatosis or normal liver and localisation was determined. Results Inhibiting or suppressing liver microRNA-21 expression reduced liver cell injury, inflammation and fibrogenesis without affecting liver lipid accumulation in Ldlr−/− fed a high-fat diet and in wild-type mice fed an MCD diet. Liver microRNA-21 was overexpressed, primarily in biliary and inflammatory cells, in mouse models as well as in patients with NASH, but not in patients with bland steatosis. PPARα, a known microRNA-21 target, implicated in NASH, was decreased in the liver of mice with NASH and restored following microRNA-21 inhibition or suppression. The effect of antagomir-21 was lost in PPARα-deficient mice. Conclusions MicroRNA-21 inhibition or suppression decreases liver injury, inflammation and fibrosis, by restoring PPARα expression. Antagomir-21 might be a future therapeutic strategy for NASH. PMID:26338827

Translational Aspects of Diet and Non-Alcoholic Fatty Liver Disease

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Nicolas Goossens

2017-09-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is a spectrum of diseases ranging from simple steatosis without inflammation or fibrosis to nonalcoholic steatohepatitis (NASH. Despite the strong association between dietary factors and NAFLD, no dietary animal model of NAFLD fully recapitulates the complex metabolic and histological phenotype of the disease, although recent models show promise. Although animal models have significantly contributed to our understanding of human diseases, they have been less successful in accurate translation to predict effective treatment strategies. We discuss strategies to overcome this challenge, in particular the adoption of big data approaches combining clinical phenotype, genomic heterogeneity, transcriptomics, and metabolomics changes to identify the ideal NAFLD animal model for a given scientific question or to test a given drug. We conclude by noting that novel big data approaches may help to bridge the translational gap for selecting dietary models of NAFLD.

The non-invasive 13C-methionine breath test detects hepatic mitochondrial dysfunction as a marker of disease activity in non-alcoholic steatohepatitis

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Banasch M

2012-06-01

Full Text Available Abstract Introduction Mitochondrial dysfunction plays a central role in the general pathogenesis of non-alcoholic fatty liver disease (NAFLD, increasing the risk of developing steatosis and subsequent hepatocellular inflammation. We aimed to assess hepatic mitochondrial function by a non-invasive 13C-methionine breath test (MeBT in patients with histologically proven NAFLD. Methods 118 NAFLD-patients and 18 healthy controls were examined by MeBT. Liver biopsy specimens were evaluated according to the NASH scoring system. Results Higher grades of NASH activity and fibrosis were independently associated with a significant decrease in cumulative 13C-exhalation (expressed as cPDR(%. cPDR1.5h was markedly declined in patients with NASH and NASH cirrhosis compared to patients with simple steatosis or borderline diagnosis (cPDR1.5h: 3.24 ± 1.12% and 1.32 ± 0.94% vs. 6.36 ± 0.56% and 4.80 ± 0.88% respectively; p 13C-exhalation further declined in the presence of advanced fibrosis which was correlated with NASH activity (r = 0.36. The area under the ROC curve (AUROC for NASH diagnosis was estimated to be 0.87 in the total cohort and 0.83 in patients with no or mild fibrosis (F0-1. Conclusion The 13C-methionine breath test indicates mitochondrial dysfunction in non-alcoholic fatty liver disease and predicts higher stages of disease activity. It may, therefore, be a valuable diagnostic addition for longitudinal monitoring of hepatic (mitochondrial function in non-alcoholic fatty liver disease.

[The effectiveness of the spa and health resort-based treatment with the application of Essentuki-type drinking mineral waters for the management of non-alcoholic fatty liver disease in the patients presenting with type 2 diabetes mellitus].

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Efimenko, N V; Kaĭsinova, A S; Fedorova, T E; Botvineva, L A

2015-01-01

The objective of the present study was to estimate the effectiveness of the spa and health resort-based treatment of non-alcoholic fatty liver disease in 40 patients at the mean age of 48,8 ± 5.7 years suffering from type 2 diabetes mellitus. All of them received combined therapy including the application of potable Essentuki-Novaya mineral water (20 patients) or Essentuki No 4 water (20 patients). This therapeutic modality resulted in positive dynamics of clinical symptoms of the disease, the functional liver tests, and parameters of intra-hepatic hemodynamics, lipid peroxidation homeostasis, and the hormonal status. It is concluded that the spa and health resort-based treatment with the application of local drinking Essentuki-type mineral waters for the management of non-alcoholic fatty liver disease in the patients presenting with type 2 diabetes mellitus leads to the improvement of the main functions of the liver, stabilizes carbohydrate and lipid metabolism, and prevents progression of the pathological process.

Endoplasmic reticulum stress does not contribute to steatohepatitis in obese and insulin-resistant high-fat-diet-fed foz/foz mice.

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Legry, Vanessa; Van Rooyen, Derrick M; Lambert, Barbara; Sempoux, Christine; Poekes, Laurence; Español-Suñer, Regina; Molendi-Coste, Olivier; Horsmans, Yves; Farrell, Geoffrey C; Leclercq, Isabelle A

2014-10-01

Non-alcoholic fatty liver (steatosis) and steatohepatitis [non-alcoholic steatohepatitis (NASH)] are hepatic complications of the metabolic syndrome. Endoplasmic reticulum (ER) stress is proposed as a crucial disease mechanism in obese and insulin-resistant animals (such as ob/ob mice) with simple steatosis, but its role in NASH remains controversial. We therefore evaluated the role of ER stress as a disease mechanism in foz/foz mice, which develop both the metabolic and histological features that mimic human NASH. We explored ER stress markers in the liver of foz/foz mice in response to a high-fat diet (HFD) at several time points. We then evaluated the effect of treatment with an ER stress inducer tunicamycin, or conversely with the ER protectant tauroursodeoxycholic acid (TUDCA), on the metabolic and hepatic features. foz/foz mice are obese, glucose intolerant and develop NASH characterized by steatosis, inflammation, ballooned hepatocytes and apoptosis from 6 weeks of HFD feeding. This was not associated with activation of the upstream unfolded protein response [phospho-eukaryotic initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α) activity and spliced X-box-binding protein 1 (Xbp1)]. Activation of c-Jun N-terminal kinase (JNK) and up-regulation of activating transcription factor-4 (Atf4) and CCAAT/enhancer-binding protein-homologous protein (Chop) transcripts were however compatible with a 'pathological' response to ER stress. We tested this by using intervention experiments. Induction of chronic ER stress failed to worsen obesity, glucose intolerance and NASH pathology in HFD-fed foz/foz mice. In addition, the ER protectant TUDCA, although reducing steatosis, failed to improve glucose intolerance, hepatic inflammation and apoptosis in HFD-fed foz/foz mice. These results show that signals driving hepatic inflammation, apoptosis and insulin resistance are independent of ER stress in obese diabetic mice with steatohepatitis.

Mediterranean Diet and Multi-Ingredient-Based Interventions for the Management of Non-Alcoholic Fatty Liver Disease

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Manuel Suárez

2017-09-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD comprises a wide spectrum of hepatic disorders, from simple steatosis to hepatic necro-inflammation leading to non-alcoholic steatohepatitis (NASH. Although the prevalence of these multifactorial pathologies is continuously increasing in the population, there is still not an established methodology for their treatment other than weight loss and a change in lifestyle habits, such as a hypocaloric diet and physical exercise. In this framework, there is increasing evidence that several food bioactives and dietary patterns are effective for reversing and preventing the onset of these pathologies. Some studies have claimed that better responses are obtained when treatments are performed under a multifaceted approach, using different bioactive compounds that act against complementary targets. Thus, in this work, current strategies for treating NAFLD and NASH based on multi-ingredient-based supplements or the Mediterranean diet, a dietary pattern rich in bioactive compounds, are reviewed. Furthermore, the usefulness of omics techniques to design effective multi-ingredient nutritional interventions and to predict and monitor their response against these disorders is also discussed.

Mediterranean Diet and Multi-Ingredient-Based Interventions for the Management of Non-Alcoholic Fatty Liver Disease

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Suárez, Manuel; Boqué, Noemí; del Bas, Josep M.; Arola, Lluís; Caimari, Antoni

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) comprises a wide spectrum of hepatic disorders, from simple steatosis to hepatic necro-inflammation leading to non-alcoholic steatohepatitis (NASH). Although the prevalence of these multifactorial pathologies is continuously increasing in the population, there is still not an established methodology for their treatment other than weight loss and a change in lifestyle habits, such as a hypocaloric diet and physical exercise. In this framework, there is increasing evidence that several food bioactives and dietary patterns are effective for reversing and preventing the onset of these pathologies. Some studies have claimed that better responses are obtained when treatments are performed under a multifaceted approach, using different bioactive compounds that act against complementary targets. Thus, in this work, current strategies for treating NAFLD and NASH based on multi-ingredient-based supplements or the Mediterranean diet, a dietary pattern rich in bioactive compounds, are reviewed. Furthermore, the usefulness of omics techniques to design effective multi-ingredient nutritional interventions and to predict and monitor their response against these disorders is also discussed. PMID:28937599

Comparative Analysis and Modeling of the Severity of Steatohepatitis in DDC-Treated Mouse Strains

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Pandey, Vikash; Sultan, Marc; Kashofer, Karl; Ralser, Meryem; Amstislavskiy, Vyacheslav; Starmann, Julia; Osprian, Ingrid; Grimm, Christina; Hache, Hendrik; Yaspo, Marie-Laure; Sültmann, Holger; Trauner, Michael; Denk, Helmut; Zatloukal, Kurt; Lehrach, Hans; Wierling, Christoph

2014-01-01

Background Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH) showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, and fibrosis. Ultimately, steatohepatitis can result in liver cirrhosis and hepatocellular carcinoma. Methodology and Results In this study we have analyzed three different mouse strains, A/J, C57BL/6J, and PWD/PhJ, that show different degrees of steatohepatitis when administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet. RNA-Seq gene expression analysis, protein analysis and metabolic profiling were applied to identify differentially expressed genes/proteins and perturbed metabolite levels of mouse liver samples upon DDC-treatment. Pathway analysis revealed alteration of arachidonic acid (AA) and S-adenosylmethionine (SAMe) metabolism upon other pathways. To understand metabolic changes of arachidonic acid metabolism in the light of disease expression profiles a kinetic model of this pathway was developed and optimized according to metabolite levels. Subsequently, the model was used to study in silico effects of potential drug targets for steatohepatitis. Conclusions We identified AA/eicosanoid metabolism as highly perturbed in DDC-induced mice using a combination of an experimental and in silico approach. Our analysis of the AA/eicosanoid metabolic pathway suggests that 5-hydroxyeicosatetraenoic acid (5-HETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin D2 (PGD2) are perturbed in DDC mice. We further demonstrate that a dynamic model can be used for qualitative prediction of metabolic changes based on transcriptomics data in a disease-related context. Furthermore, SAMe metabolism was identified as being perturbed due to DDC treatment. Several genes as well as some metabolites of this module show differences between A/J and C57BL/6J

Comparative analysis and modeling of the severity of steatohepatitis in DDC-treated mouse strains.

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Pandey, Vikash; Sultan, Marc; Kashofer, Karl; Ralser, Meryem; Amstislavskiy, Vyacheslav; Starmann, Julia; Osprian, Ingrid; Grimm, Christina; Hache, Hendrik; Yaspo, Marie-Laure; Sültmann, Holger; Trauner, Michael; Denk, Helmut; Zatloukal, Kurt; Lehrach, Hans; Wierling, Christoph

2014-01-01

Non-alcoholic fatty liver disease (NAFLD) has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH) showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, and fibrosis. Ultimately, steatohepatitis can result in liver cirrhosis and hepatocellular carcinoma. In this study we have analyzed three different mouse strains, A/J, C57BL/6J, and PWD/PhJ, that show different degrees of steatohepatitis when administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) containing diet. RNA-Seq gene expression analysis, protein analysis and metabolic profiling were applied to identify differentially expressed genes/proteins and perturbed metabolite levels of mouse liver samples upon DDC-treatment. Pathway analysis revealed alteration of arachidonic acid (AA) and S-adenosylmethionine (SAMe) metabolism upon other pathways. To understand metabolic changes of arachidonic acid metabolism in the light of disease expression profiles a kinetic model of this pathway was developed and optimized according to metabolite levels. Subsequently, the model was used to study in silico effects of potential drug targets for steatohepatitis. We identified AA/eicosanoid metabolism as highly perturbed in DDC-induced mice using a combination of an experimental and in silico approach. Our analysis of the AA/eicosanoid metabolic pathway suggests that 5-hydroxyeicosatetraenoic acid (5-HETE), 15-hydroxyeicosatetraenoic acid (15-HETE) and prostaglandin D2 (PGD2) are perturbed in DDC mice. We further demonstrate that a dynamic model can be used for qualitative prediction of metabolic changes based on transcriptomics data in a disease-related context. Furthermore, SAMe metabolism was identified as being perturbed due to DDC treatment. Several genes as well as some metabolites of this module show differences between A/J and C57BL/6J on the one hand and PWD/PhJ on the other.

Comparative analysis and modeling of the severity of steatohepatitis in DDC-treated mouse strains.

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Vikash Pandey

Full Text Available BACKGROUND: Non-alcoholic fatty liver disease (NAFLD has a broad spectrum of disease states ranging from mild steatosis characterized by an abnormal retention of lipids within liver cells to steatohepatitis (NASH showing fat accumulation, inflammation, ballooning and degradation of hepatocytes, and fibrosis. Ultimately, steatohepatitis can result in liver cirrhosis and hepatocellular carcinoma. METHODOLOGY AND RESULTS: In this study we have analyzed three different mouse strains, A/J, C57BL/6J, and PWD/PhJ, that show different degrees of steatohepatitis when administered a 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC containing diet. RNA-Seq gene expression analysis, protein analysis and metabolic profiling were applied to identify differentially expressed genes/proteins and perturbed metabolite levels of mouse liver samples upon DDC-treatment. Pathway analysis revealed alteration of arachidonic acid (AA and S-adenosylmethionine (SAMe metabolism upon other pathways. To understand metabolic changes of arachidonic acid metabolism in the light of disease expression profiles a kinetic model of this pathway was developed and optimized according to metabolite levels. Subsequently, the model was used to study in silico effects of potential drug targets for steatohepatitis. CONCLUSIONS: We identified AA/eicosanoid metabolism as highly perturbed in DDC-induced mice using a combination of an experimental and in silico approach. Our analysis of the AA/eicosanoid metabolic pathway suggests that 5-hydroxyeicosatetraenoic acid (5-HETE, 15-hydroxyeicosatetraenoic acid (15-HETE and prostaglandin D2 (PGD2 are perturbed in DDC mice. We further demonstrate that a dynamic model can be used for qualitative prediction of metabolic changes based on transcriptomics data in a disease-related context. Furthermore, SAMe metabolism was identified as being perturbed due to DDC treatment. Several genes as well as some metabolites of this module show differences between A

Interleukin-17 exacerbates hepatic steatosis and inflammation in non-alcoholic fatty liver disease.

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Tang, Y; Bian, Z; Zhao, L; Liu, Y; Liang, S; Wang, Q; Han, X; Peng, Y; Chen, X; Shen, L; Qiu, D; Li, Z; Ma, X

2011-11-01

Mechanisms associated with the progression of simple steatosis to non-alcoholic fatty liver disease (NAFLD) remain undefined. Regulatory T cells (T(regs)) play a critical role in regulating inflammatory processes in non-alcoholic steatohepatitis (NASH) and because T helper type 17 (Th17) functionally oppose T(reg)-mediated responses, this study focused on characterizing the role of Th17 cells using a NAFLD mouse model. C57BL/6 mice were fed either a normal diet (ND) or high fat (HF) diet for 8 weeks. Mice in the HF group had a significantly higher frequency of liver Th17 cells compared to ND-fed mice. Neutralization of interleukin (IL)-17 in HF mice ameliorated lipopolysaccharide (LPS)-induced liver injury reflected by decreased serum alanine aminotransferase (ALT) levels and reduced inflammatory cell infiltrates in the liver. In vitro, HepG2 cells cultured in the presence of free fatty acids (FFA; oleic acid and palmitic acid) for 24 h and IL-17 developed steatosis via insulin-signalling pathway interference. IL-17 and FFAs synergized to induce IL-6 production by HepG2 cells and murine primary hepatocytes which, in combination with transforming growth factor (TGF-β), expanded Th17 cells. It is likely that a similar process occurs in NASH patients, as there were significant levels of IL-17(+) cell infiltrates in NASH patient livers. The hepatic expression of Th17 cell-related genes [retinoid-related orphan receptor gamma (ROR)γt, IL-17, IL-21 and IL-23] was also increased significantly in NASH patients compared to healthy controls. Th17 cells and IL-17 were associated with hepatic steatosis and proinflammatory response in NAFLD and facilitated the transition from simple steatosis to steatohepatitis. Strategies designed to alter the balance between Th17 cells and T(regs) should be explored as a means of preventing progression to NASH and advanced liver diseases in NAFLD patients. © 2011 The Authors. Clinical and Experimental Immunology © 2011 British Society for

Medium chain triglycerides dose-dependently prevent liver pathology in a rat model of non-alcoholic fatty liver disease

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Metabolic syndrome is often accompanied by development of hepatic steatosis and less frequently by nonalcoholic fatty liver disease (NAFLD) leading to nonalcoholic steatohepatitis (NASH). Replacement of corn oil with medium chain triacylglycerols (MCT) in the diets of alcohol-fed rats has been show...

Comparison between the efficacies of curcumin and puerarin in C57BL/6 mice with steatohepatitis induced by a methionine- and choline-deficient diet.

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Wang, Yunliang; Li, Jian; Zhuge, Li; Su, Dongmei; Yang, Meijuan; Tao, Shiying; Li, Junxiang

2014-03-01

Non-alcoholic fatty liver disease (NAFLD) is a prevalent disease, which features an abnormal accumulation of lipids inside hepatocytes. Steatohepatitis plays a critical role in the process resulting in liver fibrosis and cirrhosis. Curcumin and puerarin are herbal products widely used in Asia, which are believed to have therapeutic benefits for alleviating the symptoms of steatohepatitis. In this study, mice models of steatohepatitis induced by a methionine- and choline-deficient diet (MCD) were established to compare the pharmacological actions of curcumin and puerarin. The results showed that curcumin and puerarin exerted inhibitory effects against MCD-induced steatohepatitis in mice. Briefly, curcumin and puerarin significantly downregulated the levels of tumor necrosis factor-α in the blood serum of mice (PMCD group). In addition, the levels of triglycerides, total cholesterol and low density lipoproteins in the serum were significantly reduced by puerarin treatment (PMCD group). The concentration of interleukin-6 was downregulated by curcumin only (PMCD group). Curcumin and puerarin significantly increased the levels of peroxisome proliferator-activated receptor-γ (PPARγ; PMCD group). Moreover, increased nuclear factor-κB (NF-κB) was markedly attenuated by curcumin (PMCD group). In conclusion, curcumin and puerarin appear to exert different actions against steatohepatitis. It is possible that puerarin regulated lipid metabolism in the 'first hit' stage through the PPARγ pathway, while curcumin inhibited the inflammatory response in the 'second hit' stage through the NF-κB pathway.

Novel Action of Carotenoids on Non-Alcoholic Fatty Liver Disease: Macrophage Polarization and Liver Homeostasis.

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Ni, Yinhua; Zhuge, Fen; Nagashimada, Mayumi; Ota, Tsuguhito

2016-06-24

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease. It is characterized by a wide spectrum of hepatic changes, which may progress to non-alcoholic steatohepatitis (NASH) and cirrhosis. NAFLD is considered a hepatic manifestation of metabolic syndrome; however, mechanisms underlying the onset and progression of NAFLD are still unclear. Resident and recruited macrophages are key players in the homeostatic function of the liver and in the progression of NAFLD to NASH. Progress has been made in understanding the molecular mechanisms underlying the polarized activation of macrophages. New NAFLD therapies will likely involve modification of macrophage polarization by restraining M1 activation or driving M2 activation. Carotenoids are potent antioxidants and anti-inflammatory micronutrients that have been used to prevent and treat NAFLD. In addition to their antioxidative action, carotenoids can regulate macrophage polarization and thereby halt the progression of NASH. In this review, we summarize the molecular mechanisms of macrophage polarization and the function of liver macrophages/Kupffer cells in NAFLD. From our review, we propose that dietary carotenoids, such as β-cryptoxanthin and astaxanthin, be used to prevent or treat NAFLD through the regulation of macrophage polarization and liver homeostasis.

Apnoeic-hypopnoeic episodes during obstructive sleep apnoea are associated with histological nonalcoholic steatohepatitis.

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Mishra, Poonam; Nugent, Clarke; Afendy, Arian; Bai, Chunhong; Bhatia, Priya; Afendy, Mariam; Fang, Yun; Elariny, Hazem; Goodman, Zachary; Younossi, Zobair M

2008-09-01

Nonalcoholic fatty liver disease (NAFLD) and obstructive sleep apnoea are associated with metabolic syndrome and atherosclerotic heart disease. This study evaluates the potential association between the NAFLD subtypes and a number of polysomnographical (PSG) parameters. This study included patients undergoing bariatric surgery with extensive clinical and histological data for whom complete PSG data before surgery were also available. Excess alcohol intake and other causes of liver disease were excluded. Apnoea, hypopnoea and apnoea-hypopnoea index (AHI) were calculated as described previously. In this study, a total of 101 patients [77 nonalcoholic steatohepatitis (NASH) and 22 non-NASH controls] with PSG data were included (age 42.9 +/- 11.4 years, body mass index 51.6 +/- 9.5 kg/m(2), fasting serum glucose 117.4 +/- 53.4 mg/dl, fasting serum triglycerides 171.3 +/- 82.9 mg/dl, 58% hypertension and 33% diabetes mellitus). Subjects with histological NASH had significantly lower lowest desaturation (77 vs. 85%, P=0.006), lower mean nocturnal oxygen saturation (91 vs. 93%, P=0.05), higher AHI (35 vs. 22, P=0.03), higher respiratory disturbance index (46 vs. 21, P=0.02) and higher alanine aminotransferase/aspartate aminotransferase ratio (1.4 vs. 1.3, P=0.05) compared with non-NASH controls. In multivariate analysis, the lowest desaturation (P=0.04) was independently associated with histological NASH. Lowest desaturation and mean nocturnal oxygen saturation were significantly lower in subjects with fibrosis (76 vs. 85%, P=0.004 and 90.4 vs. 93.0%, P=0.02). Our results suggest that the frequent nocturnal hypoxic episodes in NAFLD patients may be a risk factor for developing NASH. Additional studies are needed to study the effect of optimizing sleep apnoea management on the outcomes of patients with NAFLD.

Candidate proteomic biomarkers for non-alcoholic fatty liver disease (steatosis and non-alcoholic steatohepatitis) discovered with mass-spectrometry: a systematic review.

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Lădaru, Anca; Bălănescu, Paul; Stan, Mihaela; Codreanu, Ioana; Anca, Ioana Alina

2016-01-01

Non-alcoholic fatty liver disease (NAFLD) is characterized by lipid accumulation in the liver which is accompanied by a series of metabolic deregulations. There are sustained research efforts focusing upon biomarker discovery for NAFLD diagnosis and its prognosis in order investigate and follow-up patients as minimally invasive as possible. The objective of this study is to critically review proteomic studies that used mass spectrometry techniques and summarize relevant proteomic NAFLD candidate biomarkers. Medline and Embase databases were searched from inception to December 2014. A final number of 22 records were included that identified 251 candidate proteomic biomarkers. Thirty-three biomarkers were confirmed - 14 were found in liver samples, 21 in serum samples, and two from both serum and liver samples. Some of the biomarkers identified have already been extensively studied regarding their diagnostic and prognostic capacity. However, there are also more potential biomarkers that still need to be addressed in future studies.

Rising Rates of Hepatocellular Carcinoma Leading to Liver Transplantation in Baby Boomer Generation with Chronic Hepatitis C, Alcohol Liver Disease, and Nonalcoholic Steatohepatitis-Related Liver Disease.

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Cholankeril, George; Yoo, Eric R; Perumpail, Ryan B; Liu, Andy; Sandhu, Jeevin S; Nair, Satheesh; Hu, Menghan; Ahmed, Aijaz

2017-09-26

We aim to study the impact of the baby boomer (BB) generation, a birth-specific cohort (born 1945-1965) on hepatocellular carcinoma (HCC)-related liver transplantation (LT) in patients with chronic hepatitis C virus (HCV), alcoholic liver disease (ALD), and non-alcoholic steatohepatitis (NASH). We performed a retrospective analysis using the United Network for Organ Sharing (UNOS)/Organ Procurement Transplant Network (OPTN) database from 2003 to 2014 to compare HCC-related liver transplant surgery trends between two cohorts-the BB and non-BB-with a secondary diagnosis of HCV, ALD, or NASH. From 2003-2014, there were a total of 8313 liver transplant recipients for the indication of HCC secondary to HCV, ALD, or NASH. Of the total, 6658 (80.1%) HCC-related liver transplant recipients were BB. The number of liver transplant surgeries for the indication of HCC increased significantly in NASH (+1327%), HCV (+382%), and ALD (+286%) during the study period. The proportion of BB who underwent LT for HCC was the highest in HCV (84.7%), followed by NASH (70.3%) and ALD (64.7%). The recommendations for birth-cohort specific HCV screening stemmed from a greater understanding of the high prevalence of chronic HCV and HCV-related HCC within BB. The rising number of HCC-related LT among BB with ALD and NASH suggests the need for increased awareness and improved preventative screening/surveillance measures within NASH and ALD cohorts as well.

Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in Japanese patients with non-alcoholic fatty liver disease.

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Kato, Ken-Ichiro; Takeshita, Yumie; Misu, Hirofumi; Zen, Yoh; Kaneko, Shuichi; Takamura, Toshinari

2015-03-01

To examine the association between liver histological features and organ-specific insulin resistance indices calculated from 75-g oral glucose tolerance test data in patients with non-alcoholic fatty liver disease. Liver biopsy specimens were obtained from 72 patients with non-alcoholic fatty liver disease, and were scored for steatosis, grade and stage. Hepatic and skeletal muscle insulin resistance indices (hepatic insulin resistance index and Matsuda index, respectively) were calculated from 75-g oral glucose tolerance test data, and metabolic clearance rate was measured using the euglycemic hyperinsulinemic clamp method. The degree of hepatic steatosis, and grade and stage of non-alcoholic steatohepatitis were significantly correlated with Matsuda index (steatosis r = -0.45, P hepatic insulin resistance index. Multiple regression analyses adjusted for age, sex, body mass index and each histological score showed that the degree of hepatic steatosis (coefficient = -0.22, P steatosis and metabolic clearance rate (coefficient = -0.62, P = 0.059). Liver steatosis is associated with insulin resistance in skeletal muscle rather than in the liver in patients with non-alcoholic fatty liver disease, suggesting a central role of fatty liver in the development of peripheral insulin resistance and the existence of a network between the liver and skeletal muscle.

Status of antiviral immunity in patients with non-alcoholic liver fatty disease, who were Chornobyl NPP accident liquidators

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A.A. Chumak

2017-11-01

Full Text Available 34 men were examined, who after participating in the liquidation of the Chornobyl NPP accident developed non-alcoholic fatty liver disease. The state of antiviral defense was evaluated by the levels of immunoglobulin (Ig G and IgM antibodies in the blood serum. In most patients with non-alcoholic steatohepatitis, who were Chornobyl NPP accident liquidators, antibodies of the IgG, but not IgM class to the persistent mixed infection with herpes simplex virus types 1 and 2, cytomegaly and Epstein-Barr were found. A positive correlation was established between the antibody titers to the herpes simplex virus types 1 and 2 (anti-HSV-1/2 IgG and cytomegalovirus (anti-CMV IgG (rs = 0.383, p = 0.040, as well as between the antibodies titers to the nuclear antigen of Epstein-Barr virus (anti-EBV NA IgG and antibodies to core antigen of Epstein-Barr (anti-EBV VCA IgG (rs = 0.584, p = 0.002 in patients with persistent mixed infection of these herpesviruses.

Prevalence of diabetes mellitus in newly diagnosed pulmonary ...

African Journals Online (AJOL)

2017-09-03

Sep 3, 2017 ... (in particular with HIV) and non-communicable diseases, such as diabetes mellitus .... non smoking while alcohol consumption was moderate, and only 2 patients .... betes: current state and future perspectives. Trop Med Int.

Liver proteomics in progressive alcoholic steatosis

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Fernando, Harshica [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555 (United States); Wiktorowicz, John E.; Soman, Kizhake V. [Department of Biochemistry and Molecular Biology, The University of Texas Medical Branch, Galveston, TX 77555 (United States); Kaphalia, Bhupendra S.; Khan, M. Firoze [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555 (United States); Shakeel Ansari, G.A., E-mail: sansari@utmb.edu [Department of Pathology, The University of Texas Medical Branch, Galveston, TX 77555 (United States)

2013-02-01

Fatty liver is an early stage of alcoholic and nonalcoholic liver disease (ALD and NALD) that progresses to steatohepatitis and other irreversible conditions. In this study, we identified proteins that were differentially expressed in the livers of rats fed 5% ethanol in a Lieber–DeCarli diet daily for 1 and 3 months by discovery proteomics (two-dimensional gel electrophoresis and mass spectrometry) and non-parametric modeling (Multivariate Adaptive Regression Splines). Hepatic fatty infiltration was significantly higher in ethanol-fed animals as compared to controls, and more pronounced at 3 months of ethanol feeding. Discovery proteomics identified changes in the expression of proteins involved in alcohol, lipid, and amino acid metabolism after ethanol feeding. At 1 and 3 months, 12 and 15 different proteins were differentially expressed. Of the identified proteins, down regulation of alcohol dehydrogenase (− 1.6) at 1 month and up regulation of aldehyde dehydrogenase (2.1) at 3 months could be a protective/adaptive mechanism against ethanol toxicity. In addition, betaine-homocysteine S-methyltransferase 2 a protein responsible for methionine metabolism and previously implicated in fatty liver development was significantly up regulated (1.4) at ethanol-induced fatty liver stage (1 month) while peroxiredoxin-1 was down regulated (− 1.5) at late fatty liver stage (3 months). Nonparametric analysis of the protein spots yielded fewer proteins and narrowed the list of possible markers and identified D-dopachrome tautomerase (− 1.7, at 3 months) as a possible marker for ethanol-induced early steatohepatitis. The observed differential regulation of proteins have potential to serve as biomarker signature for the detection of steatosis and its progression to steatohepatitis once validated in plasma/serum. -- Graphical abstract: The figure shows the Hierarchial cluster analysis of differentially expressed protein spots obtained after ethanol feeding for 1 (1–3

Genome-based nutrition: An intervention strategy for the prevention and treatment of obesity and nonalcoholic steatohepatitis

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Roman, Sonia; Ojeda-Granados, Claudia; Ramos-Lopez, Omar; Panduro, Arturo

2015-01-01

Obesity and nonalcoholic steatohepatitis are increasing in westernized countries, regardless of their geographic location. In Latin America, most countries, including Mexico, have a heterogeneous admixture genome with Amerindian, European and African ancestries. However, certain high allelic frequencies of several nutrient-related polymorphisms may have been achieved by past gene-nutrient interactions. Such interactions may have promoted the positive selection of variants adapted to regional food sources. At present, the unbalanced diet composition of the Mexicans has led the country to a 70% prevalence rate of overweightness and obesity due to substantial changes in food habits, among other factors. International guidelines and intervention strategies may not be adequate for all populations worldwide because they do not consider disparities in genetic and environmental factors, and thus there is a need for differential prevention and management strategies. Here, we provide the rationale for an intervention strategy for the prevention and management of obesity-related diseases such as non-alcoholic steatohepatitis based on a regionalized genome-based diet. The components required to design such a diet should focus on the specific ancestry of each population around the world and the convenience of consuming traditional ethnic food. PMID:25834309

Non-Alcoholic Fatty Liver Disease (NAFLD): new challenge for general practitioners and important burden for health authorities?

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Ahmed, Mohamed H; Abu, Emmanuel O; Byrne, Christopher D

2010-10-01

Non-alcoholic fatty liver disease (NAFLD) is the most common cause of hepatic dysfunction encountered in general practice. A large proportion of individuals with type 2 diabetes and the metabolic syndrome develop NAFLD. NAFLD is associated with severe insulin resistance and increased risk of cardiovascular disease and can progress to non-alcoholic steato-hepatitis, liver cirrhosis and cancer. Currently the only known effective treatments for NAFLD are lifestyle changes including stable weight loss and a diet low in calories. General practitioners will increasingly play a key role in dealing with this evolving but serious epidemic of NAFLD and associated metabolic complications. However, success will depend on the appropriate systems and mechanisms being in place in primary care and the proper motivation, support and education of the patient. This review provides the primary care physician with: (a) a step-by step guide of how to identify NAFLD, (b) information to exclude common other causes of liver fat accumulation and (c) additional insight into relationships between NAFLD and other conditions such as obesity, cardiovascular disease and type 2 diabetes. Copyright © 2010 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

[Adiponectin in patients with metabolic syndrome and diseases of the liver, bile ducts and pancreas].

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Vašura, Adam; Blaho, Martin; Dítě, Petr; Kupka, Tomáš; Svoboda, Pavel; Martínek, Arnošt

Epidemiological data show that the metabolic syndrome can be diagnosed in up to 30 % of the population. Regarding 5 components of the metabolic syndrome, three of them, in case of positivity (visceral obesity, arterial hypertension, hypertriglyceridemia, changes of HDL-cholesterol levels and type 2 diabetes mellitus), are pathogenic factors which are the most frequently related to cardiovascular diseases, but currently they are also the focus of interest for gastroenterologists. The relationship between non-alcoholic hepatic steatosis, including non-alcoholic steatohepatitis, has been described. Less is known so far about the relation to the pancreas disease, particularly with respect to the status referred to as non-alcoholic fatty pancreas disease. The hormone selectively produced by adipose tissue is adiponectin. This protein is studied as a possible biomarker in people with metabolic syndrome, including obesity. Besides that, there is a question studied whether adiponectin can also play a significant role in the pathogenesis of diseases associated with fat building up in parenchymatous organs. Finding a reliable biomarker for patients with metabolic syndrome or diseases of the liver, biliary system and pancreas in relation to metabolic syndrome, presents a big challenge. And adiponectin is one of the promising biomarkers.Key words: adiponectin - biliary disease - metabolic syndrome - pancreatic steatosis - steatohepatitis.

Screening for non-alcoholic fatty liver disease in children and adolescents with type 1 diabetes mellitus: a cross-sectional analysis.

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Kummer, Sebastian; Klee, Dirk; Kircheis, Gerald; Friedt, Michael; Schaper, Joerg; Häussinger, Dieter; Mayatepek, Ertan; Meissner, Thomas

2017-04-01

The liver is intensely involved in glucose metabolism and is thereby closely related to diabetes pathophysiology. Adult patients with type 1 diabetes mellitus (DM) are at an increased risk for non-alcoholic fatty liver disease (NAFLD). Here, we studied the prevalence of NAFLD in a cohort of children and adolescents with type 1 DM in a tertiary care paediatric diabetes centre in Germany. We screened 93 children and adolescents with type 1 DM using ultrasound, laboratory investigations, and liver stiffness measurements (Fibroscan® [FS] and acoustic radiation force imaging [ARFI]). Of these, 82 (88.1%) had completely normal results in all examined aspects. Only one patient (1.1%) fulfilled the criteria as potential NAFLD with ALT > twice the upper limit of normal. Ten of the 93 patients (10.8%) showed any mild abnormality in at least one examined category including ALT, conventional ultrasounds and liver stiffness measurements. However, none of these ten fulfilled the NAFLD case definition criteria. Therefore, these slightly abnormal results were judged to be unspecific or at least of unknown significance in terms of NAFLD indication. Compared to data from the general population, our results do not indicate a significantly increased prevalence of NAFLD in this cohort, and advocate against the systematic screening for NAFLD in paediatric type 1 DM. What is Known: • Non-alcoholic fatty liver disease (NAFLD) is common in adults with type 1 DM, and paediatric patients with type 1 DM in Egypt and Saudi Arabia. What is New: • Our results do not indicate a significantly increased prevalence of NAFLD in a cohort of children and adolescents with type 1 DM from Germany compared to prevalence data from the general population. • This finding advocates against the systematic screening for NAFLD in paediatric type 1 DM in western countries.

Non-alcoholic fatty liver disease (NAFLD in different populations: A clinical and epidemiological study – sample of São José do Rio Preto

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Gabriel Costa de Andrade

2016-06-01

Full Text Available SUMMARY Introduction: NAFLD is an heterogeneous condition that includes steatosis and non-alcoholic steatohepatitis (NASH, in the absence of significant alcohol consumption, reaching 30% of the population. The most common risk factors are: age, gender, ethnicity, diabetes mellitus (DM, obesity, predisposition, metabolic syndrome (MS, insulin resistance (IR, drugs, and polycystic ovary syndrome. Objective: To describe the profile of patients with NAFLD seen at Hospital de Base of Rio Preto, in the state of São Paulo. Method: Patients with NAFLD were assessed, with medical and epidemiological data collected after informed consent. Results: Of the 62 patients evaluated, 76% were women, 73% Caucasians, and 71% were aged between 50 and 69 years and had no symptoms. Ultrasonography results showed steatosis in 84%. NASH was diagnosed in 61% of the sample. 21 patients underwent liver biopsy, of which 36% had cirrhosis, 1 had liver cancer, and 1 pure steatosis (5% each. Risk factors were found in 70% of patients with metabolic syndrome, 87% with increased waist circumference, 63% with dyslipidemia, 61% (n=38 with high blood pressure (HBP, 28% with DM, 52% physically inactive, and 44% with insulin resistance (IR (HOMA> 3.5. There was an association between IR and NASH (p=0.013, IR and obesity (p=0.027, IR and MS (p=0.006, and MS and steatosis on medical ultrasound (USG (p=0.014. Conclusion: The most frequent risk factors were MS and its variables: increased waist circumference, dyslipidemia and HBP. This underscores the importance of metabolic control in NAFLD and confirms its role as the hepatic component of metabolic syndrome.

CD18 deficiency improves liver injury in the MCD model of steatohepatitis.

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Pierce, Andrew A; Duwaerts, Caroline C; Siao, Kevin; Mattis, Aras N; Goodsell, Amanda; Baron, Jody L; Maher, Jacquelyn J

2017-01-01

Neutrophils and macrophages are important constituents of the hepatic inflammatory infiltrate in non-alcoholic steatohepatitis. These innate immune cells express CD18, an adhesion molecule that facilitates leukocyte activation. In the context of fatty liver, activation of infiltrated leukocytes is believed to enhance hepatocellular injury. The objective of this study was to determine the degree to which activated innate immune cells promote steatohepatitis by comparing hepatic outcomes in wild-type and CD18-mutant mice fed a methionine-choline-deficient (MCD) diet. After 3 weeks of MCD feeding, hepatocyte injury, based on serum ALT elevation, was 40% lower in CD18-mutant than wild-type mice. Leukocyte infiltration into the liver was not impaired in CD18-mutant mice, but leukocyte activation was markedly reduced, as shown by the lack of evidence of oxidant production. Despite having reduced hepatocellular injury, CD18-mutant mice developed significantly more hepatic steatosis than wild-type mice after MCD feeding. This coincided with greater hepatic induction of pro-inflammatory and lipogenic genes as well as a modest reduction in hepatic expression of adipose triglyceride lipase. Overall, the data indicate that CD18 deficiency curbs MCD-mediated liver injury by limiting the activation of innate immune cells in the liver without compromising intrahepatic cytokine activation. Reduced liver injury occurs at the expense of increased hepatic steatosis, which suggests that in addition to damaging hepatocytes, infiltrating leukocytes may influence lipid homeostasis in the liver.

Nonalcoholic steatohepatitis

NARCIS (Netherlands)

Jansen, P. L. M.

2004-01-01

Nonalcoholic steatohepatitis (NASH) is an underdiagnosed liver disease characterised by steatosis, necroinflammation and fibrosis. This disease may eventually develop into cirrhosis and hepatocellular carcinoma. NASH is highly prevalent among obese individuals and among patients with diabetes

Rat Strain Differences in Susceptibility to Alcohol-Induced Chronic Liver Injury and Hepatic Insulin Resistance

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Sarah M. DeNucci

2010-01-01

Full Text Available The finding of more severe steatohepatitis in alcohol fed Long Evans (LE compared with Sprague Dawley (SD and Fisher 344 (FS rats prompted us to determine whether host factors related to alcohol metabolism, inflammation, and insulin/IGF signaling predict proneness to alcohol-mediated liver injury. Adult FS, SD, and LE rats were fed liquid diets containing 0% or 37% (calories ethanol for 8 weeks. Among controls, LE rats had significantly higher ALT and reduced GAPDH relative to SD and FS rats. Among ethanol-fed rats, despite similar blood alcohol levels, LE rats had more pronounced steatohepatitis and fibrosis, higher levels of ALT, DNA damage, pro-inflammatory cytokines, ADH, ALDH, catalase, GFAP, desmin, and collagen expression, and reduced insulin receptor binding relative to FS rats. Ethanol-exposed SD rats had intermediate degrees of steatohepatitis, increased ALT, ADH and profibrogenesis gene expression, and suppressed insulin receptor binding and GAPDH expression, while pro-inflammatory cytokines were similarly increased as in LE rats. Ethanol feeding in FS rats only reduced IL-6, ALDH1–3, CYP2E1, and GAPDH expression in liver. In conclusion, susceptibility to chronic steatohepatitis may be driven by factors related to efficiency of ethanol metabolism and degree to which ethanol exposure causes hepatic insulin resistance and cytokine activation.

Chronic hepatitis B, nonalcoholic steatohepatitis and physical fitness of military males: CHIEF study.

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Chen, Yu-Jung; Chen, Kai-Wen; Shih, Yu-Leung; Su, Fang-Ying; Lin, Yen-Po; Meng, Fan-Chun; Lin, Felicia; Yu, Yun-Shun; Han, Chih-Lu; Wang, Chih-Hung; Lin, Jia-Wei; Hsieh, Tsai-Yuan; Li, Yi-Hwei; Lin, Gen-Min

2017-07-07

To investigate the association of chronic hepatitis B and nonalcoholic steatohepatitis with physical fitness in a Taiwanese military male cohort. We made a cross-sectional examination of this association using 3669 young adult military males according to cardiorespiratory fitness and hospitalization events recorded in the Taiwan Armed Forces study. Cases of chronic hepatitis B ( n = 121) were defined by personal history and positive detection of hepatitis B surface antigen. Cases of nonalcoholic steatohepatitis ( n = 129) were defined by alanine transaminase level > 60 U/L, liver ultrasound finding of steatosis, and absence of viral hepatitis A, B or C infection. All other study participants were defined as unaffected ( n = 3419). Physical fitness was evaluated by performance in 3000-m run, 2-min sit-ups, and 2-min push-ups exercises, with all the procedures standardized by a computerized scoring system. Multiple linear regression analysis was used to determine the relationship. Chronic hepatitis B negatively correlated with 2-min push-up numbers (β = -2.49, P = 0.019) after adjusting for age, service specialty, body mass index, systolic and diastolic blood pressures, current cigarette smoking, alcohol intake status, serum hemoglobin, and average weekly exercise times. Nonalcoholic steatohepatitis was borderline positively correlated with 3000-m running time (β = 11.96, P = 0.084) and negatively correlated with 2-min sit-up numbers (β = -1.47, P = 0.040). Chronic hepatitis B viral infection and nonalcoholic steatohepatitis affects different physical performances in young adult military males, and future study should determine the underlying mechanism.

A preliminary investigation and feature analysis of non-alcoholic fatty liver and nonalcoholic steatohepatitis in employees in an IT company

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LI Xiuchi

2017-07-01

Full Text Available ObjectiveTo investigate the incidence rates and features of non-alcoholic fatty liver (NAFL and nonalcoholic steatohepatitis (NASH, and to provide a theoretical basis for health management and development of intervention and preventive measures in the health management department. MethodsPhysical examination reports in 2016 were obtained from a large IT company to analyze the incidence rates of NAFL and NASH in different age and sex groups, as well as the correlation with the indices including overweight (or obesity, triglyceride, fasting blood glucose, blood uric acid, and blood pressure. The chi-square test was used for comparison of rates. Results In all employees, the incidence rates of NAFL and NASH were 4.51% and 17.64%, respectively, and the overall incidence rate of these two diseases was 22.15%. The NAFL-NASH group had significantly higher incidence rates of overweight (or obesity (91.20% vs 12.68%, χ2=7571.9, P＜0.001, hyperlipidemia (95.06% vs 9.27%, χ2=9373.8, P＜0.001, and hyperuricemia (40.02% vs 10.51%, χ2=1591.90, P＜0.001 than the non-NAFL-NASH group. Compared with female employees, male employees had significantly higher incidence rates of NAFL (6.78% vs 1.81%, χ2=190.35, P＜0.001 and NASH (25.04% vs 5.06%, χ2=991.90, P＜0.001, as well as significantly higher incidence rates of overweight (or obesity (40.90% vs 12.97%, χ2=1319.10, P＜0.001, hyperlipidemia (36.00% vs 16.07%, χ2=696.22, P＜0.001, hyperglycemia (2.17% vs 0.64%, χ2=53.82, P＜0.01, hyperuricemia (2676% vs 1.69%, χ2=1581.10, P＜0.001, and hypertension (6.21% vs 1.22%, χ2=170.94, P＜0.001. Compared with those aged ＜35 years, the employees aged ≥35 years had significantly higher incidence rates of NAFL (8.13% vs 4.47%, χ2=41.56, P＜0.001 and NASH (21.73% vs 16.76%, χ2=24.72, P＜0.001, as well as significantly higher incidence rates of hyperglycemia (2.79% vs 143%, χ2=17.26, P＜0.001 and hypertension (6.33% vs 4.03%, χ2=18.56, P＜0

High fat diet feeding results in gender specific steatohepatitis and inflammasome activation.

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Ganz, Michal; Csak, Timea; Szabo, Gyongyi

2014-07-14

To develop an animal model that encompasses the different facets of non-alcoholic steatohepatitis (NASH), which has been a challenge. In this study, we used a high fat diet (HFD) feeding supplemented with fructose and sucrose in the water mimicking the high-fructose corn syrup that is abundant in the diet in the United States. We used C57Bl/6 wild-type mice for short and long-term feedings of 6 and 16 wk respectively, and evaluated the extent of liver damage, steatosis, and inflammasome activation. Our methods included histopathological analysis to assess liver damage and steatosis, which involved H and E and oil-red-o staining; biochemical studies to look at ALT and triglyceride levels; RNA analysis using quantitative polymerase chain reaction; and cytokine analysis, which included the enzyme-linked immunosorbent assay method to look at interleukin (IL)-1β and tumor necrosis factor-α (TNFα) levels. Furthermore, at each length of feeding we also looked at insulin resistance and glucose tolerance using insulin tolerance tests (ITT) and glucose tolerance tests. There was no insulin resistance, steatosis, or inflammasome activation at 6 wk. In contrast, at 16 wk we found significant insulin resistance demonstrated by impaired glucose and ITT in male, but not female mice. In males, elevated alanine aminotransferase and triglyceride levels, indicated liver damage and steatosis, respectively. Increased liver TNFα and monocyte chemoattractant protein-1 mRNA and protein, correlated with steatohepatitis. The inflammasome components, adaptor molecule, Aim2, and NOD-like receptor 4, increased at the mRNA level, and functional inflammasome activation was indicated by increased caspase-1 activity and IL-1β protein levels in male mice fed a long-term HFD. Male mice on HFD had increased α-smooth muscle actin and pro-collagen-1 mRNA indicating evolving fibrosis. In contrast, female mice displayed only elevated triglyceride levels, steatosis, and no fibrosis. Our data

Histological Remission during Corticosteroid Therapy of Overlapping Nonalcoholic Steatohepatitis and Autoimmune Hepatitis: Case Report and Literature Review

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Shinichiroh Fukuda

2011-09-01

Full Text Available Concurrence of nonalcoholic steatohepatitis (NASH with autoimmune hepatitis (AIH is a rare condition that is challenging to diagnosis, due to the relatively high prevalence of autoantibodies in NASH. It is also difficult to determine the most effective treatment as corticosteroids are likely to worsen NASH despite being effective in the treatment of AIH. In this case report, we present a female diagnosed with NASH-AIH overlap with accompanying diabetes mellitus, who successfully achieved normalization of serum alanine aminotransferase levels following prednisolone therapy and weight loss. A follow-up liver biopsy performed 40 months after the initial diagnosis showed only minimal inflammatory infiltrates in the portal area without any NASH histology. Resolution of NASH, in conjunction with a reduction in hepatic fibrosis, might suggest that prednisolone itself does not aggravate steatohepatitis, but rather prevents disease progression. Appropriate immunosuppressive treatment may therefore be an important component of the optimum therapy for NASH-AIH overlap.

Therapeutic efficacy of atorvastatin in treatment of non-alcoholic fatty liver disease in patients with type Ⅱ diabetes mellitus

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FENG Mengdie

2013-07-01

Full Text Available ObjectiveTo observe the therapeutic efficacy of atorvastatin in the treatment of non-alcoholic fatty liver disease (NAFLD in patients with type Ⅱ diabetes mellitus. MethodsA total of 118 patients with type Ⅱ diabetes mellitus complicated by NAFLD, who visited the outpatient department of internal medicine or were hospitalized in our hospital from January 2010 to March 2012, were divided randomly into treatment group (n=61 and control group (n=57. Both groups received liver protection therapy and blood glucose control, and atorvastatin (20 mg/d was administered as an addition in the treatment group. The clinical symptoms, body mass index (BMI, blood levels of total cholesterol (TC, triglyceride (TG, high-density lipoprotein cholesterol (HDL-C, low-density lipoprotein cholesterol (LDL-C, alanine aminotransferase (ALT, and aspartate aminotransferase (AST, and liver B-mode ultrasound findings were evaluated before and after 6 months of treatment. The enumeration data were analysed by chi-square test, the indices before and after treatment were compared by t-test. ResultsAfter 6 months of treatment, the treatment group had a significantly decreased clinical symptom score (t=21.07, P=0.0000, significantly decreased blood levels of TC ((6.80±1.20 vs (5.24±0.67 mmol/L, t=8.87, P=0000, LDL-C ((4.38±0.75 vs (3.45±0.68 mmol/L, t=7.17, P=0.0000, TG ((2.14±0.56 vs (1.69±0.34 mmol/L, t=5.36, P=0.0000, ALT ((61±11 vs (46±9 U/L, t=8.24, P=0.0000, and AST ((53±14 vs (41±12 U/L, t=5.08, P=0.0000, and increased blood HDL-C level (t=1.95, P＞0.05, but there was no significant change in BMI (t=1.84, P=0.0683. No significant changes in these indices were found in the control group (P＞0.05. Both groups showed changes in liver density as measured by B-mode ultrasound, but there was no significant difference between them (P＞0.05. No adverse events occurred in either group. ConclusionAtorvastatin can markedly relieve clinical symptoms and lower

[Non-alcoholic fatty liver disease--new view].

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Raszeja-Wyszomirska, Joanna; Lawniczak, Małgorzata; Marlicz, Wojciech; Miezyńska-Kurtycz, Joanna; Milkiewicz, Piotr

2008-06-01

Non-alcoholic fatty liver disease (NAFLD) covers a wide spectrum of liver pathology--from steatosis alone, through the necroinflammatory disorder of non-alcoholic steatohepatitis (NASH) to cirrhosis and liver cancer. NAFLD/NASH is mostly related with visceral adiposity, obesity, type 2 diabetes melitus (DM t.2) and metabolic syndrome. Pathogenetic concepts of NAFLD include overnutrition and underactivity, insulin resistance (IR) and genetic factor. The prevalence of NAFLD has been estimated to be 17-33% in some countries, NASH may be present in about 1/3 of such cases, while 20-25% of NASH cases could progress to cirrhosis. NAFLD is now recognized as one of the most frequent reason of liver tests elevation without clinical symptoms. Insulin resistance is considering as having a central role in NAFLD pathogenesis. In hepatocytes, IR is related to hyperglycaemia and hyperinsulinaemia, formation of advanced glycation end-products, increased free fatty acids and their metabolites, oxidative stress and altered profiles of adipocytokines. Early stages of fatty liver are clinically silent and include elevation of ALT and GGTP, hyperechogenic liver in USG and/or hepatomegaly. Among clinical symptoms, abdominal discomfort is relatively common as well as chronic fatigue. NAFLD/NASH is not a benign disease, progressive liver biopsy have shown histological progression of fibrosis in 32%, the estimated rate of cirrhosis development is 20% and a liver--related death is 12% over 10 years. No treatment has scientifically proved to ameliorate NAFLD or to avoid its progression. The various therapeutic alternatives are aimed at interfering with the risk factors involved in the pathogenesis of the disorder in order to prevent the progression to end-stage liver disease. The most important therapeutic measure is increasing insulin sensitivity by an attempt to change a lifestyle mostly by dieting and physical activity in order to loose weight. The most used agent is metformin, the others

Promising therapies for treatment of nonalcoholic steatohepatitis

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Noureddin, Mazen; Zhang, Alice; Loomba, Rohit

2018-01-01

Introduction Non-alcoholic fatty liver disease (NAFLD) has become the most common etiology for abnormal aminotransferase levels and chronic liver disease. Its growing prevalence is largely linked to the presence of metabolic syndrome, particularly diabetes and insulin resistance. It is estimated that 60–80% of the type 2 diabetic population has NAFLD. NAFLD encompasses a range of conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH). A subset of patients with hepatic steatosis progress to NASH, while 15–20% of patients with NASH develop cirrhosis. This progression is thought to be multifactorial, and there are currently no FDA-approved medications for the treatment of NASH. Areas covered We review drugs currently in Phase II and III clinical trials for treatment of NAFLD and NASH, including their mechanisms of action, relationship to the pathophysiology of NASH, and rationale for their development. Expert opinion The treatment of NASH is complex and necessitates targeting a number of different pathways. Combination therapy, preferably tailored toward the disease stage and severity, will be needed to achieve maximum therapeutic effect. With multiple agents currently being developed, there may soon be an ability to effectively slow or even reverse the disease process in many NAFLD/NASH patients. PMID:27501374

Colchicine for alcoholic and non-alcoholic liver fibrosis or cirrhosis

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Rambaldi, A; Gluud, C

2001-01-01

Colchicine is an anti-inflammatory and anti-fibrotic drug. Several randomized clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic as well as non-alcoholic fibrosis and cirrhosis. The objectives were to assess the efficacy of colchicine...... evaluated in randomized trials on mortality, liver related mortality, liver related complications, liver fibrosis markers, liver histology, alcohol consumption, quality of life, and health economics in patients with alcoholic and non-alcoholic fibrosis or cirrhosis....

Serum adipokines might predict liver histology findings in non-alcoholic fatty liver disease.

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Jamali, Raika; Razavizade, Mohsen; Arj, Abbas; Aarabi, Mohammad Hossein

2016-06-07

To assess significance of serum adipokines to determine the histological severity of non-alcoholic fatty liver disease. Patients with persistent elevation in serum aminotransferase levels and well-defined characteristics of fatty liver at ultrasound were enrolled. Individuals with a history of alcohol consumption, hepatotoxic medication, viral hepatitis or known liver disease were excluded. Liver biopsy was performed to confirm non-alcoholic liver disease (NAFLD). The degrees of liver steatosis, lobular inflammation and fibrosis were determined based on the non-alcoholic fatty liver activity score (NAS) by a single expert pathologist. Patients with a NAS of five or higher were considered to have steatohepatitis. Those with a NAS of two or lower were defined as simple fatty liver. Binary logistic regression was used to determine the independent association of adipokines with histological findings. Receiver operating characteristic (ROC) analysis was employed to determine cut-off values of serum adipokines to discriminate the grades of liver steatosis, lobular inflammation and fibrosis. Fifty-four participants aged 37.02 ± 9.82 were enrolled in the study. Higher serum levels of visfatin, IL-8, TNF-α levels were associated independently with steatosis grade of more than 33% [β = 1.08 (95%CI: 1.03-1.14), 1.04 (95%CI: 1.008-1.07), 1.04 (95%CI: 1.004-1.08), P < 0.05]. Elevated serum IL-6 and IL-8 levels were associated independently with advanced lobular inflammation [β = 1.4 (95%CI: 1.09-1.8), 1.07 (95%CI: 1.003-1.15), P < 0.05]. Similarly, higher TNF-α, resistin, and hepcidin levels were associated independently with advanced fibrosis stage [β = 1.06 (95%CI: 1.002-1.12), 19.86 (95%CI: 2.79-141.19), 560.72 (95%CI: 5.98-5255.33), P < 0.05]. Serum IL-8 and TNF-α values were associated independently with the NAS score, considering a NAS score of 5 as the reference value [β = 1.05 (95%CI: 1.01-1.1), 1.13 (95%CI: 1.04-1.22), P < 0.05]. Certain adipokines may

Non-alcoholic fatty liver disease: From insulin resistance to mitochondrial dysfunction Enfermedad grasa del hígado no alcohólica: Desde la resistencia a la insulina a la disfunción mitocondrial

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J. A. Solís Herruzo

2006-11-01

Full Text Available Non-alcoholic fatty liver disease represents a set of liver lesions similar to those induced by alcohol that develop in individuals with no alcohol abuse. When lesions consist of fatty and hydropic degeneration, inflammation, and eventually fibrosis, the condition is designated non-alcoholic steatohepatitis (NASH. The pathogenesis of these lesions is not clearly understood, but they are associated with insulin resistance in most cases. As a result, abdominal fat tissue lipolysis and excessive fatty acid uptake by the liver occur. This, together with a disturbance of triglyceride export as VLDL, results in fatty liver development. Both the inflammatory and hepatocellular degenerative components of NASH are attributed to oxidative stress. Mitochondrial respiratory chain loss of activity plays a critical role in the genesis of latter stress. This may be initiated by an increase in the hepatic TNFa, iNOS induction, peroxynitrite formation, tyrosine nitration and inactivation of enzymes making up this chain. Consequences of oxidative stress include: lipid peroxidation in cell membranes, stellate cell activation in the liver, liver fibrosis, chronic inflammation, and apoptosis.

Wheat-bran autolytic peptides containing a branched-chain amino acid attenuate non-alcoholic steatohepatitis via the suppression of oxidative stress and the upregulation of AMPK/ACC in high-fat diet-fed mice.

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Kawaguchi, Takumi; Ueno, Takato; Nogata, Yoichi; Hayakawa, Masako; Koga, Hironori; Torimura, Takuji

2017-02-01

Whole-wheat intake is known to reduce the risk of metabolic syndrome. However, the active component remains unclear. Recently, we identified bioactive peptides [leucine-arginine-proline (LRP) and leucine-glutamine‑proline (LQP)] from wheat bran autolytic hydrolysate. The present study aimed to investigate the effects of LRP and LQP on non-alcoholic steatohepatitis (NASH) in a mouse model. We also evaluated the effects of these peptides on oxidative stress and on the AMP-activated protein kinase (AMPK) signaling pathway, two major pathogenic factors of NASH. Seven‑week-old male C57BL/6 mice were fed a high-fat diet for 10 weeks and administered water supplemented with 0.05% LRP, 0.20% LRP, 0.05% LQP, or 0.20% LQP (each n=5) or distilled water (control; n=5) ad libitum. Oxidative stress was evaluated by measuring the serum levels of diacron reactive oxygen metabolite (d-ROM) and biological antioxidant potential (BAP). Hepatic expression of phosphorylated AMPK and phosphorylated acetyl-CoA carboxylase (ACC) were evaluated by immunoblotting. The result showed that non‑alcoholic fatty liver disease activity score was significantly decreased in all types of treatment. Serum d-ROM levels were significantly decreased in the 0.20% LRP group, but not in the 0.05% LRP, 0.05% LQP, and 0.20% LQP groups. Serum BAP levels were significantly increased in the 0.05% LRP and 0.20% LRP groups, but not in the 0.05% LQP and 0.20% LQP groups. Immunoblotting analysis revealed that the expression of phospho-AMPK was increased whereas that of phospho-ACC was decreased in the 0.20% LQP group. In conclusion, we demonstrated that both LRP and LQP alleviated the severity of NASH in a high-fat diet-induced NASH mouse model. In addition, we showed that LRP and LQP modulated oxidative stress and upregulated AMPK/ACC, respectively. Thus, LRP and LQP may constitute clinically applicable therapeutic agents for NASH.

The Nutraceutic Silybin Counteracts Excess Lipid Accumulation and Ongoing Oxidative Stress in an In Vitro Model of Non-Alcoholic Fatty Liver Disease Progression

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Giulia Vecchione

2017-09-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is a major cause of liver-related morbidity and mortality. Oxidative stress and release of pro-inflammatory cytokines, such as tumor necrosis factor α (TNFα, are major consequences of hepatic lipid overload, which can contribute to progression of NAFLD to non-alcoholic steatohepatitis (NASH. Also, mitochondria are involved in the NAFLD pathogenesis for their role in hepatic lipid metabolism. Definitive treatments for NAFLD/NASH are lacking so far. Silybin, the extract of the milk thistle seeds, has previously shown beneficial effects in NAFLD. Sequential exposure of hepatocytes to high concentrations of fatty acids (FAs and TNFα resulted in fat overload and oxidative stress, which mimic in vitro the progression of NAFLD from simple steatosis (SS to steatohepatitis (SH. The exposure to 50 µM silybin for 24 h reduced fat accumulation in the model of NAFLD progression. The in vitro progression of NAFLD from SS to SH resulted in reduced hepatocyte viability, increased apoptosis and oxidative stress, reduction in lipid droplet size, and up-regulation of IκB kinase β-interacting protein and adipose triglyceride lipase expressions. The direct action of silybin on SS or SH cells and the underlying mechanisms were assessed. Beneficial action of silybin was sustained by changes in expression/activity of peroxisome proliferator-activated receptors and enzymes for FA oxidation. Moreover, silybin counteracted the FA-induced mitochondrial damage by acting on complementary pathways: (i increased the mitochondrial size and improved the mitochondrial cristae organization; (ii stimulated mitochondrial FA oxidation; (iii reduced basal and maximal respiration and ATP production in SH cells; (iv stimulated ATP production in SS cells; and (v rescued the FA-induced apoptotic signals and oxidative stress in SH cells. We provide new insights about the direct protective effects of the nutraceutic silybin on hepatocytes

Relevant Aspects of Nutritional and Dietary Interventions in Non-Alcoholic Fatty Liver Disease

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Maria Catalina Hernandez-Rodas

2015-10-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is the main cause of liver disease worldwide. NAFLD is linked to circumstances such as type 2 diabetes, insulin resistance, obesity, hyperlipidemia, and hypertension. Since the obesity figures and related comorbidities are increasing, NAFLD has turned into a liver problem that has become progressively more common. Currently, there is no effective drug therapy for NAFLD; therefore, interventions in lifestyles remain the first line of treatment. Bearing in mind that adherence rates to this type of treatment are poor, great efforts are currently focused on finding novel therapeutic agents for the prevention in the development of hepatic steatosis and its progression to nonalcoholic steatohepatitis and cirrhosis. This review presents a compilation of the scientific evidence found in the last years showing the results of interventions in lifestyle, diet, and behavioral therapies and research results in human, animal and cell models. Possible therapeutic agents ranging from supplementation with vitamins, amino acids, prebiotics, probiotics, symbiotics, polyunsaturated fatty acids and polyphenols to interventions with medicinal plants are analyzed.

In Vitro and in Vivo Models of Non-Alcoholic Fatty Liver Disease (NAFLD

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Ina Bergheim

2013-06-01

Full Text Available By now, non-alcoholic fatty liver disease (NAFLD is considered to be among the most common liver diseases world-wide. NAFLD encompasses a broad spectrum of pathological conditions ranging from simple steatosis to steatohepatitis, fibrosis and finally even cirrhosis; however, only a minority of patients progress to end-stages of the disease, and the course of the disease progression to the later stages seems to be slow, developing progressively over several years. Key risk factors including overweight, insulin resistance, a sedentary life-style and an altered dietary pattern, as well as genetic factors and disturbances of the intestinal barrier function have been identified in recent years. Despite intense research efforts that lead to the identification of these risk factors, knowledge about disease initiation and molecular mechanisms involved in progression is still limited. This review summarizes diet-induced and genetic animal models, as well as cell culture models commonly used in recent years to add to the understanding of the mechanisms involved in NAFLD, also referring to their advantages and disadvantages.

Stage of change and motivation to healthier lifestyle in non-alcoholic fatty liver disease.

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Centis, Elena; Moscatiello, Simona; Bugianesi, Elisabetta; Bellentani, Stefano; Fracanzani, Anna Ludovica; Calugi, Simona; Petta, Salvatore; Dalle Grave, Riccardo; Marchesini, Giulio

2013-04-01

Healthy diet and physical activity are the treatment cornerstones of non-alcoholic fatty liver disease (NAFLD); their effectiveness is however limited by difficulties in implementing lifestyle changes. We aimed at determining the stage of change and associated psychological factors as a prerequisite to refine strategies to implement behavior changes. We studied 138 consecutive NAFLD patients (73% male, age 19-73 years). The diagnosis was confirmed by liver biopsy in 64 cases (steatohepatitis, 47%). All cases completed the validated EMME-3 questionnaire, consisting of two parallel sets of instruments (for diet and physical activity, respectively) and providing stages of change according to transtheoretical model. Logistic regression analysis was used to identify factors associated with stages making behavioral changes more demanding. The individual profiles were variable; for diet, no cases had precontemplation as prevalent stage of change (highest score in individual profiles); 36% had contemplation. For physical activity, 50% were classified in either precontemplation or contemplation. Minor differences were recorded in relation to associated metabolic complications or steatohepatitis. Logistic regression identified male sex (odds ratio, 4.51; 95% confidence interval, 1.69-12.08) and age (1.70; 1.20-2.43 per decade) as the independent parameters predicting precontemplation or contemplation for diet. No predictors were identified for physical activity. NAFLD cases have scarce readiness to lifestyle changes, particularly with regard to physical activity. Defining stages of change and motivation offers the opportunity to improve clinical care of NAFLD people through individual programs exploiting the powerful potential of behavioral counseling, an issue to be tested in longitudinal studies. Copyright © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Standardized Salvia miltiorrhiza Extract Suppresses Hepatic Stellate Cell Activation and Attenuates Steatohepatitis Induced by a Methionine-Choline Deficient Diet in Mice

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Hak Sung Lee

2014-06-01

Full Text Available The aim of this study was to examine the effect of standardized extract of Salvia miltiorrhiza (SME on gene and protein expression of non-alcoholic steatohepatitis (NASH-related factors in activated human hepatic stellate cells (HSC, and in mice with steatohepatitis induced by a methionine-choline deficient (MCD diet. Male C57BL/6J mice were placed on an MCD or control diet for 8 weeks and SME (0, 0.1, 0.5 and 1 mg/kg body weight was administered orally every other day for 4 or 6 weeks. HSCs from the LX-2 cell line were treated with transforming growth factor β-1 (TGF-β1 or TGF-β1 plus SME (0.1–10 μg/mL. To investigate the effect of SME on reactive oxygen species (ROS-induced condition, LX-2 cells were treated with hydrogen peroxide (H2O2 or H2O2 plus SME (0.1–100 μg/mL. MCD administration for 12 weeks increased mRNA expression of tumor necrosis factor (TNF-α, TGF-β1, interleukin-1β (IL-1β, C-reactive protein (CRP, α-smooth muscle actin (α-SMA, type I collagen, matrix metalloproteinase-2 (MMP-2 and MMP-9. TGF-β1-induced LX-2 cells exhibited similar gene expression patterns. SME treatment significantly reduced the mRNA and protein expression of NASH-related factors in the mouse model and HSCs. Histopathological liver analysis showed improved non-alcoholic fatty liver disease (NAFLD activity and fibrosis score in SME-treated mice. The in vivo studies showed that SME had a significant effect at low doses. These results suggest that SME might be a potential therapeutic candidate for NAFLD treatment.

Non-alcoholic Fatty Liver Disease: Beneficial Effects of Flavonoids.

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Akhlaghi, Masoumeh

2016-10-01

Non-alcoholic fatty liver disease (NAFLD) has been known as the hepatic feature of metabolic syndrome. Extra fat depots, especially in visceral areas, develop insulin resistance as a result of mild oxidation and inflammation. Insulin resistance induces lipolysis and releases free fatty acids into the circulation, where they are transported to the liver. In the liver, free fatty acids are converted to triglycerides and accumulate, causing simple steatosis that, if left untreated, can lead to steatohepatitis, and subsequently liver necrosis and cirrhosis.Flavonoids, a group of plant compounds with incredible biological characteristics, have shown advantages in pathological conditions. Beneficial effects of flavonoids against NAFLD and its related disorders have been observed in both animal and human studies. Various mechanisms have been found for their protection. Flavonoids prevent hepatosteatosis by increasing fatty acid oxidation in the liver. They can also reduce caloric intake and decrease body weight and fat deposition in visceral tissues. Flavonoids are unique antioxidants that exert their beneficial effects through inhibition of nuclear factor κB, thereby attenuating release of inflammatory cytokines, which are triggers of insulin resistance. Finally, flavonoids have shown to increase adiponectin, improve insulin sensitivity and glucose tolerance, correct dyslipidemia, and reduce blood pressure in patients with NAFLD. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Procoagulant imbalance in patients with non-alcoholic fatty liver disease.

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Tripodi, Armando; Fracanzani, Anna L; Primignani, Massimo; Chantarangkul, Veena; Clerici, Marigrazia; Mannucci, Pier Mannuccio; Peyvandi, Flora; Bertelli, Cristina; Valenti, Luca; Fargion, Silvia

2014-07-01

Non-alcoholic fatty liver disease (NAFLD) is characterized by increased risk of cardiovascular events and liver-fibrosis. Both could be explained by a procoagulant-imbalance that was surmised but never directly demonstrated. We investigated 113 patients with varying histological liver damage [steatosis (n=32), steatohepatitis (n=51), metabolic-cirrhosis (n=30)], 54 with alcoholic/viral-cirrhosis and 179 controls. Plasma was evaluated for levels of pro- and anti-coagulants, and for thrombin-generation assessed as endogenous-thrombin-potential (ETP) with and without thrombomodulin or Protac® as protein C activators. The procoagulant-imbalance was defined as ETP-ratio (with-to-without thrombomodulin) or as Protac®-induced-coagulation-inhibition (PICI%). High ETP-ratios or low PICI% indicate resistance to thrombomodulin or Protac® and hence a procoagulant-imbalance. ETP-ratio increased from controls [0.57 (0.11-0.89)] to steatosis [0.72 (0.33-0.86)] and metabolic-cirrhosis [0.80 (0.57-0.95)], (pimbalance detected as ETP-ratio greater or PICI% lower than the median value of controls tended to have a higher risk of metabolic-syndrome, higher intima-media thickness, fibrosis, steatosis or lobular inflammation, all considered clinical manifestations of NAFLD. NAFLD is characterized by a procoagulant-imbalance progressing from the less severe (steatosis) to the most severe form of the disease (metabolic-cirrhosis). This imbalance appears to result from increased factor VIII and reduced protein C and might play a role in the risk of cardiovascular events and liver-fibrosis commonly observed in NAFLD. Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Metformin prevents and reverses inflammation in a non-diabetic mouse model of nonalcoholic steatohepatitis.

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Yuki Kita

Full Text Available BACKGROUND: Optimal treatment for nonalcoholic steatohepatitis (NASH has not yet been established, particularly for individuals without diabetes. We examined the effects of metformin, commonly used to treat patients with type 2 diabetes, on liver pathology in a non-diabetic NASH mouse model. METHODOLOGY/PRINCIPAL FINDINGS: Eight-week-old C57BL/6 mice were fed a methionine- and choline-deficient plus high fat (MCD+HF diet with or without 0.1% metformin for 8 weeks. Co-administration of metformin significantly decreased fasting plasma glucose levels, but did not affect glucose tolerance or peripheral insulin sensitivity. Metformin ameliorated MCD+HF diet-induced hepatic steatosis, inflammation, and fibrosis. Furthermore, metformin significantly reversed hepatic steatosis and inflammation when administered after the development of experimental NASH. CONCLUSIONS/SIGNIFICANCE: These histological changes were accompanied by reduced hepatic triglyceride content, suppressed hepatic stellate cell activation, and the downregulation of genes involved in fatty acid metabolism, inflammation, and fibrogenesis. Metformin prevented and reversed steatosis and inflammation of NASH in an experimental non-diabetic model without affecting peripheral insulin resistance.

New-Onset Diabetes Mellitus in Liver Transplant Recipients With Hepatitis C: Analysis of the National Database.

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Li, Z; Sun, F; Hu, Z; Xiang, J; Zhou, J; Yan, S; Wu, J; Zhou, L; Zheng, S

2016-01-01

New-onset diabetes mellitus (NODM) after liver transplantation (LT) occurs with increased frequency in recipients with hepatitis C virus (HCV). We compared the incidence and risk factors for NODM in HCV vs non-HCV recipients. Among 24,956 liver recipients, 18,741 without pretransplantation diabetes were identified. NODM-free survival was analyzed using Kaplan-Meier and log-rank tests, and risk factors for NODM were examined using multivariate Cox regression analysis. The overall incidence of NODM was 13.0% at 1 year after LT. At 1, 2, 3, and 5 years after LT, incidence of NODM in HCV recipients was 14.4%, 4.3%, 3.1%, and 3.5%, respectively, compared with 11.9%, 3.5%, 3.2%, and 6.4%, respectively, in non-HCV recipients. HCV recipients had a higher risk of NODM than non-HCV recipients (hazard ratio 1.17 [1.09-1.27], P diabetes mellitus. Risk factors in non-HCV recipients were male recipient, BMI, and recipients with nonalcoholic steatohepatitis diagnosis. HCV recipients have a higher incidence and more risk factors for NODM than non-HCV recipients. Early identification of modifiable risk factors will assist clinical interventions to prevent NODM complications after LT. Copyright © 2016 Elsevier Inc. All rights reserved.

PNPLA3 Expression Is Related to Liver Steatosis in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease

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Gemma Aragonès

2016-04-01

Full Text Available Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3 in the pathology of non-alcoholic fatty liver disease (NAFLD. Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present work was to evaluate the association between the liver PNPLA3 expression, key genes of lipid metabolism, and the presence of NAFLD in morbidly obese women. We used real-time polymerase chain reaction (PCR analysis to analyze the hepatic expression of PNPLA3 and lipid metabolism-related genes in 55 morbidly obese subjects with normal liver histology (NL, n = 18, simple steatosis (SS, n = 20, and non-alcoholic steatohepatitis (NASH, n = 17. Liver biopsies were collected during bariatric surgery. We observed that liver PNPLA3 expression was increased in NAFLD than in NL. It was also upregulated in SS than in NL. Interestingly, we found that the expression of PNPLA3 was significantly higher in severe than mild SS group. In addition, the expression of the transcription factors LXRα, PPARα, and SREBP2 was positively correlated with PNPLA3 liver expression. Regarding rs738409 polymorphism, GG genotype was positive correlated with the presence of NASH. In conclusion, our results show that PNPLA3 could be related to lipid accumulation in liver, mainly in the development and progression of simple steatosis.

PNPLA3 Expression Is Related to Liver Steatosis in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease.

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Aragonès, Gemma; Auguet, Teresa; Armengol, Sandra; Berlanga, Alba; Guiu-Jurado, Esther; Aguilar, Carmen; Martínez, Salomé; Sabench, Fátima; Porras, José Antonio; Ruiz, Maikel Daniel; Hernández, Mercé; Sirvent, Joan Josep; Del Castillo, Daniel; Richart, Cristóbal

2016-04-27

Recent reports suggest a role for the Patatin-like phospholipase domain-containing protein 3 (PNPLA3) in the pathology of non-alcoholic fatty liver disease (NAFLD). Lipid deposition in the liver seems to be a critical process in the pathogenesis of NAFLD. The aim of the present work was to evaluate the association between the liver PNPLA3 expression, key genes of lipid metabolism, and the presence of NAFLD in morbidly obese women. We used real-time polymerase chain reaction (PCR) analysis to analyze the hepatic expression of PNPLA3 and lipid metabolism-related genes in 55 morbidly obese subjects with normal liver histology (NL, n = 18), simple steatosis (SS, n = 20), and non-alcoholic steatohepatitis (NASH, n = 17). Liver biopsies were collected during bariatric surgery. We observed that liver PNPLA3 expression was increased in NAFLD than in NL. It was also upregulated in SS than in NL. Interestingly, we found that the expression of PNPLA3 was significantly higher in severe than mild SS group. In addition, the expression of the transcription factors LXRα, PPARα, and SREBP2 was positively correlated with PNPLA3 liver expression. Regarding rs738409 polymorphism, GG genotype was positive correlated with the presence of NASH. In conclusion, our results show that PNPLA3 could be related to lipid accumulation in liver, mainly in the development and progression of simple steatosis.

Caries in patients with non-insulin-dependent diabetes mellitus.

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Collin, H L; Uusitupa, M; Niskanen, L; Koivisto, A M; Markkanen, H; Meurman, J H

1998-06-01

The purpose of this study was to investigate the prevalence and risk factors of dental caries in patients with non-insulin-dependent diabetes mellitus and to determine whether these factors are associated with metabolic control and vascular complications of the disease. Both the occurrence of caries, acidogenic oral bacteria, and yeasts and salivary flow were studied in 25 patients with non-insulin-dependent diabetes mellitus whose diagnosis had been set 13 to 14 years earlier and in whom the metabolic evolution of the disease was well established. The patients' glycemic control was determined by means of analysis of the blood hemoglobin A1C concentration at the time of dental examination. The control group consisted of 40 nondiabetic subjects in the same age group. Decayed, missing, and filled teeth indices and numbers of surfaces with caries, filled surfaces, and root caries were determined by means of clinical dental caries examination. Stimulated salivary flow was measured, and levels of Streptococcus mutans, lactobacilli, and yeasts were analyzed. The median hemoglobin A1C concentration of the patients was 8.6%, which indicates poor metabolic control of diabetes. No association was found between the metabolic control of disease and dental caries. The occurrence of dental caries was not increased in the patients with non-insulin-dependent diabetes mellitus in comparison with the control subjects. The counts of acidogenic microbes and yeasts did not differ statistically significantly between the groups. There was no association of caries with the prevalence of coronary artery disease or hypertension in either the patients or the control subjects. In a stepwise logistic regression model, a salivary flow of at least 0.8 ml/min was related to the occurrence of dental caries in patients with non-insulin-dependent diabetes mellitus, whereas negligence with respect to dental care was the most important risk predictor in the control group. Our results showed no effect

Hepatic Encephalopathy

Medline Plus

Full Text Available ... Lipase Deficiency Liver Cancer Liver Cysts Non-Alcoholic Fatty Liver Disease Primary Biliary Cholangitis Primary Sclerosing Cholangitis What ... B & C Alcohol-related Liver Disease Non-alcoholic Fatty Liver Disease (NAFLD) & Non-alcoholic Steatohepatitis (NASH) Autoimmune Hepatitis ...

Pediatric non-alcoholic fatty liver disease: Recent solutions, unresolved issues, and future research directions

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Clemente, Maria Grazia; Mandato, Claudia; Poeta, Marco; Vajro, Pietro

2016-01-01

Non-alcoholic fatty liver disease (NAFLD) in children is becoming a major health concern. A “multiple-hit” pathogenetic model has been suggested to explain the progressive liver damage that occurs among children with NAFLD. In addition to the accumulation of fat in the liver, insulin resistance (IR) and oxidative stress due to genetic/epigenetic background, unfavorable lifestyles, gut microbiota and gut-liver axis dysfunction, and perturbations of trace element homeostasis have been shown to be critical for disease progression and the development of more severe inflammatory and fibrotic stages [non-alcoholic steatohepatitis (NASH)]. Simple clinical and laboratory parameters, such as age, history, anthropometrical data (BMI and waist circumference percentiles), blood pressure, surrogate clinical markers of IR (acanthosis nigricans), abdominal ultrasounds, and serum transaminases, lipids and glucose/insulin profiles, allow a clinician to identify children with obesity and obesity-related conditions, including NAFLD and cardiovascular and metabolic risks. A liver biopsy (the “imperfect” gold standard) is required for a definitive NAFLD/NASH diagnosis, particularly to exclude other treatable conditions or when advanced liver disease is expected on clinical and laboratory grounds and preferably prior to any controlled trial of pharmacological/surgical treatments. However, a biopsy clearly cannot represent a screening procedure. Advancements in diagnostic serum and imaging tools, especially for the non-invasive differentiation between NAFLD and NASH, have shown promising results, e.g., magnetic resonance elastography. Weight loss and physical activity should be the first option of intervention. Effective pharmacological treatments are still under development; however, drugs targeting IR, oxidative stress, proinflammatory pathways, dyslipidemia, gut microbiota and gut liver axis dysfunction are an option for patients who are unable to comply with the recommended

Effectiveness of exercise in hepatic fat mobilization in non-alcoholic fatty liver disease: Systematic review.

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Golabi, Pegah; Locklear, Cameron T; Austin, Patrick; Afdhal, Sophie; Byrns, Melinda; Gerber, Lynn; Younossi, Zobair M

2016-07-21

To investigate the efficacy of exercise interventions on hepatic fat mobilization in non-alcoholic fatty liver disease (NAFLD) patients. Ovid-Medline, PubMed, EMBASE and Cochrane database were searched for randomized trials and prospective cohort studies in adults aged ≥ 18 which investigated the effects of at least 8 wk of exercise only or combination with diet on NAFLD from 2010 to 2016. The search terms used to identify articles, in which exercise was clearly described by type, duration, intensity and frequency were: "NASH", "NAFLD", "non-alcoholic steatohepatitis", "non-alcoholic fatty liver disease", "fat", "steatosis", "diet", "exercise", "MR spectroscopy" and "liver biopsy". NAFLD diagnosis, as well as the outcome measures, was confirmed by either hydrogen-magnetic resonance spectroscopy (H-MRS) or biopsy. Trials that included dietary interventions along with exercise were accepted if they met all criteria. Eight studies met selection criteria (6 with exercise only, 2 with diet and exercise with a total of 433 adult participants). Training interventions ranged between 8 and 48 wk in duration with a prescribed exercise frequency of 3 to 7 d per week, at intensities between 45% and 75% of VO2 peak. The most commonly used imaging modality was H-MRS and one study utilized biopsy. The effect of intervention on fat mobilization was 30.2% in the exercise only group and 49.8% in diet and exercise group. There was no difference between aerobic and resistance exercise intervention, although only one study compared the two interventions. The beneficial effects of exercise on intrahepatic triglyceride (IHTG) were seen even in the absence of significant weight loss. Although combining an exercise program with dietary interventions augmented the reduction in IHTG, as well as improved measures of glucose control and/or insulin sensitivity, exercise only significantly decreased hepatic lipid contents. Prescribed exercise in subjects with NAFLD reduces IHTG independent of

Tobacco carcinogen (NNK) induces both lung cancer and non-alcoholic steatohepatitis and hepatocellular carcinomas in ferrets which can be attenuated by lycopene supplementation

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Early epidemiologic studies have reported that tobacco smoking, which is causally associated with liver cancer, is an independent risk factor for non-alcoholic fatty liver diseases (NAFLD). Lycopene from tomatoes has been shown to be a potential preventive agent against NAFLD and hepatocellular carc...

The effect of resveratrol on experimental non-alcoholic fatty liver disease depends on severity of pathology and timing of treatment

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Heebøll, Sara; El-Houri, Rime Bahij; Hellberg, Ylva Erika Kristina

2016-01-01

BACKGROUND AND AIM: Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease with few therapeutic options. RSV prevents the development of steatosis in a number of experimental fatty liver (NAFL) models but the preventive or therapeutic effects on experimental NASH.......01), while there was no effect on biochemical, histopathological, or transcriptional NASH changes. Further, RSV had no therapeutic effect on established NASH. We found RSV metabolites but no parent RSV in serum or liver tissue, confirming low bioavailability. CONCLUSIONS: These experimental findings suggest...... are not yet clarified, and clinical results on NAFLD are ambiguous. Thus, we aimed to compare the RSV-mediated preventive and therapeutic effects on experimental NAFL and NASH. METHODS: We used a high-fat (HF) diet to generate a rat NAFL model and a high-fat, high-cholesterol (HFC) diet to generate a rat NASH...

Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis

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Rambaldi, A; Gluud, C

2005-01-01

Alcohol and hepatotropic viruses cause the majority of liver cirrhosis cases in the Western World. Colchicine is an anti-inflammatory and anti-fibrotic medication. Several randomised clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic or non-alcoholic...

TO STUDY AND EVALUATE DIASTOLIC DYSFUNCTION IN PATIENTS OF ALCOHOLIC AND NON-ALCOHOLIC CIRRHOSIS

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Gaurav Sudhir

2016-04-01

Full Text Available BACKGROUND Cardiovascular dysfunction is the major component of morbidity in patients of liver cirrhosis and a cardinal prognostic indicator in patients undergoing liver transplantation. The constellation of hyperdynamic circulation, peripheral vasodilation and volume overload alters the systolic and diastolic dysfunction leading to cirrhotic cardiomyopathy (CCM. In this study, we evaluated and compared the diastolic dysfunction among alcoholic and non-alcoholic cirrhotic patients. AIMS 1 To Study the Prevalence of Diastolic Dysfunction in Alcoholic & Non-Alcoholic Cirrhotics and Controls. 2 To Compare the Diastolic functional status between alcoholic and non-alcoholic cirrhosis patients. MATERIALS AND METHODS A cross-sectional case control study was conducted in 100 male cirrhotic patients consisting of alcoholic and non-alcoholic cirrhotic subjects with age matched 50 controls in Pt. JNM Medical College & Dr. BRAM Hospital, Raipur. Left ventricular diastolic dysfunction was assessed using echocardiographic parameters. STATISTICAL ANALYSIS The range, median, standard deviation and statistical significance were calculated. Most of the data is analysed by Student Ttest, Mann Whitney U test, while the data with frequency distribution is analysed by Fisher’s exact. With p value 1. CONCLUSION Our study showed that patients with alcoholic and non-alcoholic cirrhosis have higher occurrence of DD (49% and 46% respectively than controls owing to alterations in the myocardial contractile and relaxation function. It also shows that although DD is a frequent event in cirrhosis, it is usually of mild degree and does not correlate with severity of liver dysfunction. There were no significant differences in diastolic parameters between alcoholic and non-alcoholic cirrhosis concluding that alcohol likely plays a non-significant role in cardiovascular dysfunction in cirrhotics.

Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus - insights into its mechanisms of action.

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Stefanska, B

2012-08-01

A wide variety of beneficial effects have been attributed to curcumin, a major polyphenol from the golden spice Curcuma longa known as turmeric, including amelioration of severe complications of type 2 diabetes such as hepatic fibrosis, retinopathy, neuropathy and nephropathy. In the present issue of BJP, Lin and colleagues reveal new mechanisms by which curcumin inhibits the activation of hepatic stellate cells in vitro, a hallmark of non-alcoholic steatohepatitis and hepatic fibrogenesis associated with type 2 diabetes mellitus. They demonstrated that curcumin suppresses the advanced glycation end-products (AGEs)-mediated induction of the receptor for AGEs (RAGE) gene expression by increasing PPARγ activity and stimulating de novo synthesis of glutathione. As a result, downstream elements of RAGE-activated pathways are inhibited, which prevents oxidative stress, inflammation and hepatic stellate cell activation. This report suggests that curcumin may have potential as an anti-fibrotic agent in type 2 diabetes and opens the door to the evaluation of curcumin therapeutic effects in liver conditions of different aetiology and in other disorders linked to the impairment of PPARγ activity, such as obesity and atherosclerosis. This article is a commentary on Lin et al., pp. 2212-2227 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.01910.x. © 2012 The Author. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Non-alcoholic fatty liver disease predicts type 2 diabetes mellitus, but not prediabetes, in Xi'an, China: a five-year cohort study.

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Ming, Jie; Xu, Shaoyong; Gao, Bin; Liu, Guocai; Ji, Yufei; Yang, Fan; Jia, Yunan; Fang, Yujie; Ji, Qiuhe

2015-11-01

Emerging studies have focused the association between non-alcoholic fatty liver disease (NAFLD) and the risk of type 2 diabetes mellitus (T2DM) but the results were inconsistent. In addition, few studies have put focus on the association between NAFLD and the risk of prediabetes. We aimed to investigate whether NAFLD diagnosed by ultrasonography could predict the risk of future T2DM and prediabetes in Chinese population. The population-based cohort study held in Xi'an, Northwestern China, was based on China National Diabetes and Metabolic Disorders Survey. During a follow-up of 5 years, 508 healthy subjects were included as study sample. NAFLD was determined by abdominal ultrasonography. T2DM and prediabetes were diagnosed based on oral glucose tolerance test. Of 508 subjects, 97 (19.1%) were diagnosed as NAFLD and 411 (80.9%) were as non-NAFLD; 20 (3.9%) developed diabetes and 85 (16.7%) developed prediabetes during follow-up. The incidence of diabetes and prediabetes in the NAFLD group was 20.6 and 51.6 per 1000 person-years, respectively, whereas that in non-NAFLD group was 4.9 and 29.2 per 1000 person-years respectively. Cox proportional hazard regression showed that the multivariable-adjusted relative risk (RR) of T2DM and prediabetes in the NAFLD group was 4.462 [95% confidence interval (CI): 1.855-10.734, P liver disease was a significant predictor for future diabetes, but not for prediabetes, in Xi'an, China. More cohort studies are needed to confirm our findings. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Increased Circulating Levels of Alpha-Ketoglutarate in Morbidly Obese Women with Non-Alcoholic Fatty Liver Disease.

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Gemma Aragonès

Full Text Available Non-alcoholic fatty liver disease (NAFLD causes a wide spectrum of liver damage, ranging from simple steatosis to cirrhosis. However, simple steatosis (SS and steatohepatitis (NASH cannot yet be distinguished by clinical or laboratory features. The aim of this study was to assess the relationship between alpha-ketoglutarate and the degrees of NAFLD in morbidly obese patients.We used a gas chromatography-quadruple time-of-flight-mass spectrometry analysis to quantify alpha-ketoglutarate in serum from normal-weight subjects (n = 30 and morbidly obese women (n = 97 with or without NAFLD.We found that serum levels of alpha-ketoglutarate were significantly higher in morbidly obese women than in normal-weight women. We showed that circulating levels of alpha-ketoglutarate were lower in lean controls and morbidly obese patients without NAFLD. We also found that alpha-ketoglutarate serum levels were higher in both SS and NASH than in normal liver of morbidly obese patients. However, there was no difference between SS and NASH. Moreover, we observed that circulating levels of alpha-ketoglutarate were associated with glucose metabolism parameters, lipid profile, hepatic enzymes and steatosis degree. In addition, diagnostic performance of alpha-ketoglutarate has been analyzed in NAFLD patients. The AUROC curves from patients with liver steatosis exhibited an acceptable clinical utility. Finally, we showed that the combination of biomarkers (AST, ALT and alpha-ketoglutarate had the highest accuracy in diagnosing liver steatosis.These findings suggest that alpha-ketoglutarate can determine the presence of non-alcoholic fatty liver in morbidly obese patients but it is not valid a biomarker for NASH.

Nonalcoholic Steatohepatitis: An Evolving Diagnosis

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Brent A Neuschwander-Tetri

2000-01-01

Full Text Available Nonalcoholic steatohepatitis (NASH is a histological diagnosis applied to a constellation of liver biopsy findings that develop in the absence of alcohol abuse. Steatosis, a mixed cellular inflammatory infiltrate across the lobule, evidence of hepatocyte injury and fibrosis are the findings that can be seen. This entity is often identified during evaluation of elevated aminotransferases after exclusion of viral, metabolic and other causes of liver disease. Obesity is a major risk factor for NASH. The role of diabetes is less certain, although evidence is accumulating that hyperinsulinism may play an important pathophysiological role. Patients sometimes suffer from right upper quadrant abdominal pain and fatigue; examination may reveal centripetal obesity and hepatomegaly. Although patients are often discovered because of persistent aminotransferase elevations, these enzymes can be normal in NASH. When they are elevated, the alanine aminotransferase level is typically significantly greater than the aspartate aminotransferase level. This can be particularly helpful for excluding occult alcohol abuse. Imaging studies identify hepatic steatosis when the amount of fat in the liver is significant; however, imaging does not distinguish benign steatosis from NASH. Ultimately a liver biopsy is needed to diagnose NASH. The biopsy may be useful for establishing prognosis based on the presence or absence of fibrosis and for excluding other unexpected causes of liver enzyme elevations. Weight loss is the mainstay of treatment for obese patients. About 15% to 40% of NASH patients develop fibrosis; how many of these cases progress to cirrhosis is unknown, but about 1% of liver transplants are performed with a pretransplant diagnosis of NASH.

Curcumin ameliorates hepatic fibrosis in type 2 diabetes mellitus – insights into its mechanisms of action

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Stefanska, B

2012-01-01

A wide variety of beneficial effects have been attributed to curcumin, a major polyphenol from the golden spice Curcuma longa known as turmeric, including amelioration of severe complications of type 2 diabetes such as hepatic fibrosis, retinopathy, neuropathy and nephropathy. In the present issue of BJP, Lin and colleagues reveal new mechanisms by which curcumin inhibits the activation of hepatic stellate cells in vitro, a hallmark of non-alcoholic steatohepatitis and hepatic fibrogenesis associated with type 2 diabetes mellitus. They demonstrated that curcumin suppresses the advanced glycation end-products (AGEs)-mediated induction of the receptor for AGEs (RAGE) gene expression by increasing PPARγ activity and stimulating de novo synthesis of glutathione. As a result, downstream elements of RAGE-activated pathways are inhibited, which prevents oxidative stress, inflammation and hepatic stellate cell activation. This report suggests that curcumin may have potential as an anti-fibrotic agent in type 2 diabetes and opens the door to the evaluation of curcumin therapeutic effects in liver conditions of different aetiology and in other disorders linked to the impairment of PPARγ activity, such as obesity and atherosclerosis. LINKED ARTICLE This article is a commentary on Lin et al., pp. 2212–2227 of this issue. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.01910.x PMID:22452372

Hyperuricemia Inversely Correlates with Disease Severity in Taiwanese Nonalcoholic Steatohepatitis Patients.

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Jee-Fu Huang

Full Text Available Asians are more susceptible to non-alcoholic steatohepatitis (NASH as well as metabolic disorder than other ethnicities. We aimed to assess the interaction between metabolic factors and fibrosis in Taiwanese NASH patients.A total of 130 biopsy-proven Taiwanese NASH patients (94 males, age = 43.0 ± 13.0 years were consecutively enrolled. Their demographic, metabolic profiles and histopathological manifestations were analyzed.Twenty-four (18.5% NASH patients were non-obese. Thirty-three (25.4% patients had significant fibrosis (F2 or more: 22 (16.9% patients were of F2, whilst 11 (8.5% patients were of advanced fibrosis (F3-4. The prevalence of metabolic syndrome, diabetes and hypertension were 60.8%, 39.4%, and 61.5%, respectively. There was a significant inverse correlation between hyperuricemia and fibrosis stages, ranging from 48.4% of F0-1, 33.3% of F2, and 9.1% of F3-4, respectively (P = 0.01, linear trend. Multivariate logistic regression analysis showed that a decreased serum albumin level (OR = 40.0, 95% CI = 4.5-300, P = 0.001 and normal uric acid level (OR = 5.6, 95% CI = 1.5-21.7, P = 0.01 were the significant factors associated with significant fibrosis.Hyperuricemia inversely predicts fibrosis stages. Females might carry a more disease severity than males in Taiwanese NASH patients.

Alcohol and HCV Chronic Infection Are Risk Cofactors of Type 2 Diabetes Mellitus for Hepatocellular Carcinoma in Italy

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Massimiliano Balbi

2010-03-01

Full Text Available Type 2 diabetes mellitus (DM2 has been associated with hepatocellular carcinoma (HCC development. To study this relationship, we enrolled 465 HCC patients compared with 618 Cirrhotic cases and 490 Controls. The prevalence of DM2 is significantly higher in HCC patients with an Odds Ratio of 3.12 versus Controls. In HCC cases with alcohol abuse, the frequency of DM2 is the highest. In our HCC patients, when HCV infection is associated with alcohol abuse, the liver cancer develops earlier. In addition, multivariate analysis shows that alcohol consumption is an independent risk factor for HCC more relevant than HCV infection.

Menopausal age and sex hormones in postmenopausal women with alcoholic and non-alcoholic liver disease

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Becker, U; Gluud, C; Farholt, S

1991-01-01

In order to evaluate age at menopause and serum sex hormone profiles in postmenopausal women with stable chronic liver disease, six non-cirrhotic alcoholics, 13 with alcoholic cirrhosis, eight with non-alcoholic cirrhosis, and 46 healthy controls were studied. In all three groups, patients were...... and dehydroepiandrosterone sulphate (DHAS) (p less than 0.05). The observed changes may be a consequence of liver disease since similar changes were observed in patients with alcoholic and non-alcoholic liver disease, but an additional effect of alcohol cannot be excluded....... significantly (p less than 0.05) younger at the time of natural menopause than controls. Compared to controls, non-cirrhotic alcoholic women had significantly (p less than 0.05) reduced levels of DHAS, significantly (p less than 0.05) more alcoholic cirrhotic women had detectable oestradiol concentrations...

Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease.

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Christine Bernsmeier

Full Text Available The incretins glucagon-like peptide-1 (GLP-1 and glucose-dependent insulinotropic polypeptide (GIP are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic β-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD. However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients.N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH patients and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration.Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001. In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH.Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD.

OBESITY AS A RISK FACTOR FOR NON-ALCOHOLIC FATTY LIVER DISEASE

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O. A. Pavlenko

2015-01-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is a highly prevalent disorder associated with obesity and metabolic syndrome. The main pathophysiological factor of liver steatosis is insulin resistance that may lead to development of type 2 diabetes mellitus. Overcoming of insulin resistance by means of body weight reduction and administration of insulin sensitizers is considered to be a promising approach to NAFLD treatment. In accordance with the Russian guidelines on diagnostics and treatment of NAFLD, sibutramine is the drug of choice for medical treatment of obesity. As for insulin sensitizers, metformin (biguanide class is widely used for treatment of NAFLD in everyday clinical practice. Treatment of NAFLD as a component of metabolic syndrome should be multifactorial and aimed at different aspects of the disease pathophysiology. 

Clinical utility of red cell distribution width in alcoholic and non-alcoholic liver cirrhosis.

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Milić, Sandra; Mikolasević, Ivana; Radić, Mladen; Hauser, Goran; Stimac, Davor

2011-09-01

Red blood cell distribution width (RDW) is a measure of the variation of red blood cell width that is reported as apart of standard complete blood count. Red blood cell distribution width results are often used together with mean corpuscular volume (MCV) results to figure out mixed anemia. The aim of our study was to compare the values of RDW in alcoholic and non-alcoholic liver cirrhosis and to determine if RDW follows the severity of disease according to Child-Pugh score. We retrospectively analyzed 241 patients (176 men and 65 women) with liver cirrhosis and anemia, defined as a hemoglobin value reference range is 11-15%. Alcoholic liver cirrhosis had 204 patients (85%) while non-alcoholic cirrhosis had 37 patients (15%). In group of alcoholic cirrhosis the average RDW was 16.8%. In relation to severity of disease the average RDW for Child-Pugh A was 16.80%, for Child-Pugh B was 16.92%, for Child-Pugh C was 17.10%. In the group of non-alcoholic cirrhosis the average RDW was 16.73% and in relation to severity of disease for Child-Pugh A was 16.25%, for Child-Pugh B 17.01% and for Child-Pugh C was 16.87%. We didn't find statistically significant difference of RDW between alcoholic and non alcoholic cirrhosis (p > 0.05) and we didn't proved any statistically significant increase of RDW in relation to severity of disease in group of alcoholic cirrhosis (p = 0.915) nor in group of patients with non-alcoholic cirrhosis (p = 0.697). Our study showed that RDW had not any clinical value in differentiation of anemia neither in alcoholic and non-alcoholic liver cirrhosis nor in severity of liver disease.

Assessment of treatment response in nonalcoholic steatohepatitis using advanced magnetic resonance imaging measures

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Lin, Steven C.; Heba, Elhamy; Bettencourt, Ricki; Lin, Grace Y.; Valasek, Mark A.; Lunde, Ottar; Hamilton, Gavin; Sirlin, Claude B.; Loomba, Rohit

2017-01-01

Background Magnetic resonance imaging derived measures of liver fat and volume are emerging as accurate, non-invasive imaging biomarkers in non-alcoholic steatohepatitis (NASH). Little is known about these measures in relation to histology longitudinally. Aims This study examines this relationship between MRI-derived proton-density fat-fraction (PDFF), total liver volume (TLV), total liver fat index (TLFI), vs. histology in a NASH trial. Methods This is a secondary analysis of a 24-week randomized, double-blind, placebo-controlled trial of 50 patients with biopsy-proven NASH randomized to oral ezetimibe 10mg daily (n=25) vs. placebo (n=25). Baseline and post-treatment anthropometrics, biochemical profiling, MRI, and biopsies were obtained. Results Baseline mean PDFF correlated strongly with TLFI (Spearman’s ρ=0.94, n=45, PMRI-PDFF vs. TLV indicates that 10% reduction in MRI-PDFF predicts 257 mL reduction in TLV. Conclusions MRI-PDFF and TLV strongly correlated with TLFI. Decreases in steatosis were associated with an improvement in hepatomegaly. Lower values of these measures reflect lower histologic-steatosis grades. MRI-derived measures of liver fat and volume may be used as dynamic and more responsive imaging biomarkers in a NASH trial than histology. ClinicalTrials.gov number, NCT01766713. PMID:28116801

Severe steatohepatitis in a patient with a rare neutral lipid storage disorder due to ABHD5 mutation.

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Ronchetti, Anna; Prati, Daniele; Pezzotta, Maria Grazia; Tavian, Daniela; Colombo, Roberto; Callea, Francesco; Colli, Agostino

2008-09-01

Fatty liver disease is mainly caused by alcohol consumption, excessive body weight, dyslipidemia and impaired glucose tolerance, but inherited disorders can sometimes be involved. We report the case of a 40-year-old woman with steatohepatitis and severe portal hypertension, associated with ichthyosis, cataract and hypoacusia. The clinical, pathological and genetic findings were consistent with a diagnosis of Chanarin-Dorfman syndrome (CDS), a rare autosomal recessive inherited neutral lipid storage disorder, and genetic analysis showed that a novel ABHD5 mutation is responsible.

Acquired chronic hepatocerebral degeneration due to cirrhosis from non-alcoholic steatohepatitis Síndrome hepatocerebral crónico secundario a cirrosis por esteatohepatitis no alcohólica

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A. Burgos

2009-11-01

Full Text Available Introduction and objective: acquired chronic hepatocerebral degeneration, acquired hepatolenticular degeneration or pseudo-Wilson is an infrequent disorder with a hepatic origin. Cases in the literature are scarce and it is frequently confused with hepatic encephalopathy and Wilson's disease. The aim of this essay is to report a patient suffering from this disorder due to cirrhosis from non-alcoholic steatohepatitis. Case report: we present a 54-year-old man diagnosed from cirrhosis grade B9 of the Child Pugh classification. He progressively developed a picture with bradylalia, mild postural and action tremor and spatial and temporal disorientation. Further studies demonstrated an increase of the values of hepatic transaminases and a hiperintensity in the basal nuclei in the cerebral magnetic resonance imaging. Clinical and radiological data established the diagnosis of hepatocerebral degeneration. Conclusions: acquired chronic hepatocerebral degeneration is a disorder rarely reported in the literature that it is usually confused with other diseases. We alert about the need of having this diagnosis into account with patients developing neurological symptoms after hepatic disease.Fundamento y objetivo: el síndrome hepatocerebral crónico, también denominado degeneración hepatolenticular crónica adquirida (DHCA o pseudo-Wilson, es un trastorno poco frecuente de origen hepático. Los casos recogidos en la literatura son escasos y frecuentemente es confundido con la encefalopatía hepática y con la enfermedad de Wilson. El objetivo de este artículo es presentar un paciente que sufre este trastorno de forma secundaria a una cirrosis por esteatohepatitis no alcohólica. Caso clínico: se trata de un varón de 54 años diagnosticado de cirrosis en grado funcional de Child-Pugh B9 que presentó un cuadro progresivo de bradilalia, temblor postural y de acción leve y, en ocasiones, desorientación temporoespacial. Los estudios complementarios

Antibody-Directed Glucocorticoid Targeting to CD163 in M2-type Macrophages Attenuates Fructose-Induced Liver Inflammatory Changes

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Svendsen, Pia; Graversen, Jonas Heilskov; Etzerodt, Anders

2017-01-01

Increased consumption of high-caloric carbohydrates contributes substantially to endemic non-alcoholic fatty liver disease in humans, covering a histological spectrum from fatty liver to steatohepatitis. Hypercaloric intake and lipogenetic effects of fructose and endotoxin-driven activation...... changes in rats on a high-fructose diet. The diet induced severe non-alcoholic steatohepatitis (NASH)-like changes within a few weeks but the antibody-drug conjugate strongly reduced inflammation, hepatocyte ballooning, fibrosis, and glycogen deposition. Non-conjugated dexamethasone or dexamethasone...... seems to be a promising approach for safe treatment of fructose-induced liver inflammation....

Esteato-hepatite relacionada ao vírus da hepatite C: perfil clínico-histológico Steatohepatitis related to hepatitis C virus: clinical and histological profiles

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João Eduardo Pereira

2006-04-01

aspects of steatohepatitis associated to HCV. METHODS: The study included patients with HCV without treatment. Biopsies were evaluated by METAVIR score and steatohepatitis was evaluated according to criteria of Sociedade Brasileira de Patologia (SBP. Clinical parameters included alcoholic intake history and determination of risk factors for non-alcoholic steatohepatitis (NASH. RESULTS: Steatohepatitis was observed in 42 out of 252 patients (16.6% with HCV, and 76.2% were male. Risk factors for NASH were present in 37.5% of the patients with genotype 3 and in 73% of the patients with other genotypes (p = 0.05. Obesity was present in 16.7%, diabetes in 16.7%, hyperlipidemia in 21.4%, and genotype 3 in 38.1%. Macrovacuolar steatosis presented mild intensity in 61.9% and was diffuse in 64.3%. Cirrhosis was present in 33.3% of the patients. CONCLUSIONS: Diffuse steatosis and ballooning of mild to moderate intensity characterized steatohepatitis related to HCV. Patients with genotype different from genotype 3 presented with known risk factors for NASH, whereas most of the patients with genotype 3 had only viral genotype as risk factor for steatosis. The frequency of cirrhosis was relevant and suggests that the association of steatohepatitis with HCV contribute to fibrosis progression.

Clinical Applicability of Transient Elastography for Estimating Liver Stiffness in Patients with Type 2 Diabetes Mellitus

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Van Dijk, P. R.; Landman, G. W. D.; Hoving, S.; Kleefstra, N.; Bilo, H. J. G.; Groeneveld, P. H. P.

2016-01-01

Background: Type 2 diabetes mellitus (T2DM) is a risk factor for the development of non-alcoholic fatty liver disease, which can lead to liver fibrosis and ultimately to cirrhosis. Transient elastography (TE), by using the FibroScan, and is a non-invasive ultrasonography method to measure liver

Evolution of Wernicke-Korsakoff syndrome in self-neglecting alcoholics: preliminary results of relation with Wernicke-delirium and diabetes mellitus.

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Wijnia, Jan W; van de Wetering, Ben J M; Zwart, Elles; Nieuwenhuis, K Gerrit A; Goossensen, M Anne

2012-01-01

We present a descriptive, retrospective study of initial symptoms, comorbidity, and alcohol withdrawal in 73 alcoholic patients with subsequent Korsakoff syndrome. In 25/73 (35%) of the patients the classic triad of Wernicke's encephalopathy with ocular symptoms, ataxia and confusion, was found. In at least 6/35 (17%) of the initial deliria (95% confidence interval: 10-25%) we observed no other underlying causes, thus excluding other somatic causes, medication, (recent) alcohol withdrawal, or intoxication. We suggest that these deliria may have been representing Wernicke's encephalopathy. A high frequency (15%) of diabetics may reflect a contributing factor of diabetes mellitus in the evolution of the Wernicke-Korsakoff syndrome. Copyright © American Academy of Addiction Psychiatry.

Lower levels of insulin-like growth factor-1 standard deviation score are associated with histological severity of non-alcoholic fatty liver disease.

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Sumida, Yoshio; Yonei, Yoshikazu; Tanaka, Saiyu; Mori, Kojiroh; Kanemasa, Kazuyuki; Imai, Shunsuke; Taketani, Hiroyoshi; Hara, Tasuku; Seko, Yuya; Ishiba, Hiroshi; Okajima, Akira; Yamaguchi, Kanji; Moriguchi, Michihisa; Mitsuyoshi, Hironori; Yasui, Kohichiroh; Minami, Masahito; Itoh, Yoshito

2015-07-01

Growth hormone (GH) deficiency may be associated with histological progression of non-alcoholic fatty liver disease (NAFLD) which includes non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH). Insulin-like growth factor 1 (IGF-1) is mainly produced by hepatocytes and its secretion is stimulated by GH. Our aim was to determine whether more histologically advanced NAFLD is associated with low circulating levels of IGF-1 in Japanese patients. Serum samples were obtained in 199 Japanese patients with biopsy-proven NAFLD and in 2911 sex- and age-matched healthy people undergoing health checkups. The serum levels of IGF-1 were measured using a commercially available immunoradiometric assay. The standard deviation scores (SDS) of IGF-1 according to age and sex were also calculated in NAFLD patients. The serum IGF-1 levels in NAFLD patients were significantly lower (median, 112 ng/mL) compared with the control population (median, 121 ng/mL, P < 0.0001). IGF-1 SDS less than -2.0 SD from median were found in 11.6% of 199 patients. NASH patients exhibited significantly lower levels of IGF-1 SDS (n = 130; median, -0.7) compared with NAFL patients (n = 69; median, -0.3; P = 0.026). The IGF-1 SDS values decreased significantly with increasing lobular inflammation (P < 0.001) and fibrosis (P < 0.001). In multiple regressions, the association between the IGF-1 SDS values and the severity of NAFLD persisted after adjusting for age, sex and insulin resistance. Low levels of circulating IGF-1 may have a role in the development of advanced NAFLD, independent of insulin resistance. Supplementation with GH/IGF-1 may be a candidate for the treatment of NASH. © 2014 The Japan Society of Hepatology.

Positive association between high-sensitivity C-reactive protein level and diabetes mellitus among US non-Hispanic black adults.

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Shankar, A; Li, J

2008-08-01

Previous epidemiologic studies have demonstrated a positive association between serum C-reactive protein (CRP) level and diabetes mellitus. However among US race-ethnicities, the putative association between CRP and diabetes mellitus in non-Hispanic Blacks is not clear. We specifically examined the association between high-sensitivity CRP level and diabetes mellitus in a representative sample of US non-Hispanic blacks. Cross-sectional study among 1,479 National Health and Nutrition Examination Survey 1999-2002 non-Hispanic black participants aged > or = 20 years. Main outcome-of-interest was the presence of diabetes mellitus (fasting plasma glucose > or = 126 mg/dL, non-fasting plasma glucose > or = 200 mg/dL, or self-reported current use of oral hypoglycemic medication or insulin) (n=204). Higher CRP levels were positively associated with diabetes mellitus, independent of smoking, waist circumference, hypertension, and other confounders. Multivariable odds ratio (OR) [95% confidence intervals (CI)] comparing elevated CRP level (>3 mg/L) to low CRP level (diabetes mellitus appeared to be present across the full range of CRP, without any threshold effect. Higher serum high-sensitivity CRP levels are positively associated with diabetes mellitus in a sample of US non-Hispanic blacks. Inflammatory processes previously shown to be related to diabetes mellitus in other race-ethnicities may be involved in non-Hispanic blacks also.

Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals.

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Salgado, Ana Lúcia Farias de Azevedo; Carvalho, Luciana de; Oliveira, Ana Claudia; Santos, Virgínia Nascimento dos; Vieira, Jose Gilberto; Parise, Edison Roberto

2010-01-01

Due to its good correlation to glycemic clamp, HOMA-IR has been widely utilized as insulin resistance index in clinical and epidemiological studies involving non-alcoholic fatty liver disease carriers. However, values used for this parameter have shown large variability. To identify the HOMA-IR cut value that best distinguishes non-diabetic non-alcoholic fatty liver disease patients from a control group. One hundred sixteen non-alcoholic fatty liver disease patients were studied, diagnosed by clinical, biochemical, and liver image or biopsy criteria, and 88 healthy individuals, without any liver disease and testing for oral glucose tolerance within normality. These groups did not differ in age and gender. All were submitted to oral glucose tolerance test and blood samples were collected for glucose and insulin measurements by immunofluorometric method. HOMA-IR was calculated according to the formula: fasting insulin (microU/L) x fasting glucose (nmol/L)/22.5. NAFLD patients showed higher insulin, glycemia, and HOMA-IR values than control group, even when excluding glucose intolerant and diabetes mellitus patients by their glycemic curves. HOMA-IR 75th percentile for control group was 1.78 and the best area under the curve index was obtained for HOMA-IR values of 2.0 [AUC= 0.840 (0.781-0.899 CI 95%), sensitivity (Se): 85%, specificity (Sp): 83%] while value 2.5 showed best specificity without important loss in sensitivity [AUC=0,831 (0.773-0.888) Se = 72%, Sp = 94%]. HOMA-IR values above or equal to 2.0 or 2.5 show enhanced diagnostic value in distinguishing non-alcoholic fatty liver disease carriers from control group individuals.

Pharmacokinetics in patients with chronic liver disease and hepatic safety of incretin-based therapies for the management of type 2 diabetes mellitus.

Science.gov (United States)

Scheen, André J

2014-09-01

Patients with type 2 diabetes mellitus have an increased risk of chronic liver disease (CLD) such as non-alcoholic fatty liver disease and steatohepatitis, and about one-third of cirrhotic patients have diabetes. However, the use of several antidiabetic agents, such as metformin and sulphonylureas, may be a concern in case of hepatic impairment (HI). New glucose-lowering agents targeting the incretin system are increasingly used for the management of type 2 diabetes. Incretin-based therapies comprise oral inhibitors of dipeptidyl peptidase-4 (DPP-4) (gliptins) or injectable glucagon-like peptide-1 (GLP-1) receptor agonists. This narrative review summarises the available data regarding the use of both incretin-based therapies in patients with HI. In contrast to old glucose-lowering agents, they were evaluated in specifically designed acute pharmacokinetic studies in patients with various degrees of HI and their hepatic safety was carefully analysed in large clinical trials. Only mild changes in pharmacokinetic characteristics of DPP-4 inhibitors were observed in patients with different degrees of HI, presumably without major clinical relevance. GLP-1 receptor agonists have a renal excretion rather than liver metabolism. Specific pharmacokinetic data in patients with HI are only available for liraglutide. No significant changes in liver enzymes were reported with DPP-4 inhibitors or GLP-1 receptor agonists, alone or in combination with various other glucose-lowering agents, in clinical trials up to 2 years in length. On the contrary, preliminary data suggested that incretin-based therapies may be beneficial in patients with CLD, more particularly in the presence of non-alcoholic fatty liver disease. Nevertheless, caution should be recommended, especially in patients with advanced cirrhosis, because of a lack of clinical experience with incretin-based therapies in these vulnerable patients.

High-fat but not sucrose intake is essential for induction of dyslipidemia and non-alcoholic steatohepatitis in guinea pigs

DEFF Research Database (Denmark)

Ipsen, David Højland; Tveden-Nyborg, Pernille; Rolin, Bidda

2016-01-01

Background Non-alcoholic fatty liver disease (NAFLD) and dyslipidemia are closely related. Diet plays an important role in the progression of these diseases, but the role of specific dietary components is not completely understood. Therefore, we investigated the role of dietary sucrose and fat....../cholesterol on the development of dyslipidemia and NAFLD. Methods Seventy female guinea pigs were block-randomized (based on weight) into five groups and fed a normal chow diet (control: 4 % fat), a very high-sucrose diet (vHS: 4 % fat, 25 % sucrose), a high-fat diet (HF: 20 % fat, 0.35 % cholesterol), a high......-fat/high-sucrose diet (HFHS: 20 % fat, 15 % sucrose, 0.35 % cholesterol) or a high-fat/very high-sucrose diet (HFvHS: 20 % fat, 25 % sucrose, 0.35 % cholesterol) for 16 and 25 weeks. Results All three high-fat diets induced dyslipidemia with increased concentrations of plasma cholesterol (p 

Serum phospholipid omega-3 polyunsaturated fatty acids and insulin resistance in type 2 diabetes mellitus and non-alcoholic fatty liver disease.

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Lou, Da-Jun; Zhu, Qi-Qian; Si, Xu-Wei; Guan, Li-Li; You, Qiao-Ying; Yu, Zhong-Ming; Zhang, Ai-Zhen

2014-01-01

To investigate the relationship between serum phospholipid omega-3 polyunsaturated fatty acids (ω-3 PUFAs) and insulin resistance (IR) in patients with type 2 diabetes mellitus (T2DM) and non-alcoholic fatty liver disease (NAFLD). 51 patients with T2DM and NAFLD (T2DM+NAFLD group), 50 with T2DM alone (T2DM group), 45 with NAFLD alone (NAFLD group), and 42 healthy control subjects (NC group) were studied. Serum ω-3 PUFA profiles were analyzed by gas chromatography, and alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and serum lipid concentrations were measured. Insulin resistance was assessed by the homeostasis model assessment method (HOMA-IR). HOMA-IR levels were higher in the T2DM+NAFLD group than in the T2DM, NAFLD and NC groups (p<0.05), as were ALT, AST, GGT, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) concentrations (p<0.05). Conversely, serum ω-3 PUFA levels were significantly lower in the T2DM+NAFLD group than in the other groups (p<0.05). The ω-3 PUFA level was negatively correlated with HOMA-IR, TC, LDL-C and TG. Serum phospholipid ω-3 PUFA levels were significantly decreased in patients with T2DM and NAFLD, and were negatively related with insulin resistance. Thus, reduced ω-3 PUFAs may play an important role in the development of T2DM and NAFLD. Copyright © 2014 Elsevier Inc. All rights reserved.

Rising Rate of Liver Transplantation in the Baby Boomer Generation with Non-alcoholic Steatohepatitis in the United States.

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Siddique, Osama; Joseph-Talreja, Mairin; Yoo, Eric R; Perumpail, Ryan B; Cholankeril, George; Harrison, Stephen A; Younossi, Zobair M; Wong, Robert J; Ahmed, Aijaz

2017-09-28

Background and Aims: Nonalcoholic steatohepatitis (NASH) is the most rapidly growing indication for liver transplantation (LT) in the United States and is on a trajectory to become the leading indication for LT in the next decade. We aimed to study the trends in NASH-related LT among persons born between 1945 and 1965, the baby boomer (BB) generation. Methods: We performed a retrospective cohort analysis using population-based data from the United Network for Organ Sharing/Organ Procurement and Transplantation Network registry from 2004-2015 to evaluate the birth cohort-specific trends in liver transplant waitlist registrations and liver transplant surgeries in patients with NASH. We stratified our study population into three birth cohorts: 1) birth before 1945, 2) birth between 1945 and 1965, and 3) birth after 1965. Results: The overall rates of NASH-related waitlist registrations and liver transplant surgeries steadily increased from 2004 to 2015 and were reflective of a sharp rise noted in the NASH BB sub-group. From 2004 to 2015, the proportion of BB patients with NASH added to LT waitlist demonstrated an incremental growth, 60.6% in 2004 versus 83.2% in 2015 ( p < 0.01). Among the liver transplant recipients with NASH, the proportion represented by the BB cohort increased from 56.3% in 2004 to 80.0% in 2015 ( p < 0.01). Conclusions: We report rising rates of waitlist registration and LT for the indication of NASH. More importantly, the BB sub-cohort was mainly responsible for these alarming trends.

Non-laboratory-based self-assessment screening score for non-alcoholic fatty liver disease: development, validation and comparison with other scores.

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Yong-ho Lee

Full Text Available Non-alcoholic fatty liver disease (NAFLD is a prevalent and rapidly increasing disease worldwide; however, no widely accepted screening models to assess the risk of NAFLD are available. Therefore, we aimed to develop and validate a self-assessment score for NAFLD in the general population using two independent cohorts.The development cohort comprised 15676 subjects (8313 males and 7363 females who visited the National Health Insurance Service Ilsan Hospital in Korea in 2008-2010. Anthropometric, clinical, and laboratory data were examined during regular health check-ups and fatty liver diagnosed by abdominal ultrasound. Logistic regression analysis was conducted to determine predictors of prevalent NAFLD and to derive risk scores/models. We validated our models and compared them with other existing methods using an external cohort (N = 66868.The simple self-assessment score consists of age, sex, waist circumference, body mass index, history of diabetes and dyslipidemia, alcohol intake, physical activity and menopause status, which are independently associated with NAFLD, and has a value of 0-15. A cut-off point of ≥ 8 defined 58% of males and 36% of females as being at high-risk of NAFLD, and yielded a sensitivity of 80% in men (77% in women, a specificity of 67% (81%, a positive predictive value of 72% (63%, a negative predictive value of 76% (89% and an AUC of 0.82 (0.88. Comparable results were obtained using the validation dataset. The comprehensive NAFLD score, which includes additional laboratory parameters, has enhanced discrimination ability, with an AUC of 0.86 for males and 0.91 for females. Both simple and comprehensive NAFLD scores were significantly increased in subjects with higher fatty liver grades or severity of liver conditions (e.g., simple steatosis, steatohepatitis.The new non-laboratory-based self-assessment score may be useful for identifying individuals at high-risk of NAFLD. Further studies are warranted to evaluate

PKCδ as a regulator for TGFβ1-induced α-SMA production in a murine nonalcoholic steatohepatitis model.

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Su Jin Lee

Full Text Available The precise mechanism of TGFβ1 signaling in the progression of non-alcoholic steatohepatitis (NASH has remained unclear. In particular, a potential regulatory mechanism by which PKCδ affects profibrogenic gene expression had never been explored. In this study, therefore, the role of PKCδ in TGFβ1 mediated α-SMA expression was investigated using NASH model mice. In preparation of the NASH model, male C57BL6/J mice were fed a methionine-choline-deficient (MCD diet for 3 weeks, after which time they were intraperitoneally injected with lipopolysaccharide (LPS. In addition, Tlr4(Lps-d (CH3/HeJ mice were used to demonstrate the TGFβ1 signaling's dependency on TLR4 induction. Liver histology and hepatic hepatitis markers were investigated, and hepatic gene expression levels were determined by real-time PCR. Acute liver injury by LPS injection specifically elevated not only α-SMA expression but also phospho-PKCδ in this model. In contrast, Tlr4(Lps-d (CH3/HeJ and blockade of TGFβ1 receptor by SB431542 resulted in a significant reduction of PKCδ activation and α-SMA expression. Moreover, the TGFβ1-induced α-SMA production was significantly reduced by a specific PKCδ inhibitor. These findings suggested that PKCδ plays a critical role in TGFβ1-induced α-SMA production in a NASH model. Thus, this was the first demonstration of the involvement of PKCδ in the regulation of α-SMA expression in NASH liver tissues, and the impaired induction of PKCδ phosphorylation by LPS in a steatohepatitis condition. Interestingly, treatment by PKCδ inhibitor caused dramatic reduction of myofibroblast activation, indicating that PKCδ represents a promising target for treating NASH.

Pharmacological inhibition of the chemokine CXCL16 diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury.

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Alexander Wehr

Full Text Available Non-alcoholic fatty liver disease (NAFLD is a major cause of morbidity and mortality in developed countries, resulting in steatohepatitis (NASH, fibrosis and eventually cirrhosis. Modulating inflammatory mediators such as chemokines may represent a novel therapeutic strategy for NAFLD. We recently demonstrated that the chemokine receptor CXCR6 promotes hepatic NKT cell accumulation, thereby controlling inflammation in experimental NAFLD. In this study, we first investigated human biopsies (n = 20, confirming that accumulation of inflammatory cells such as macrophages is a hallmark of progressive NAFLD. Moreover, CXCR6 gene expression correlated with the inflammatory activity (ALT levels in human NAFLD. We then tested the hypothesis that pharmacological inhibition of CXCL16 might hold therapeutic potential in NAFLD, using mouse models of acute carbon tetrachloride (CCl4- and chronic methionine-choline-deficient (MCD diet-induced hepatic injury. Neutralizing CXCL16 by i.p. injection of anti-CXCL16 antibody inhibited the early intrahepatic NKT cell accumulation upon acute toxic injury in vivo. Weekly therapeutic anti-CXCL16 administrations during the last 3 weeks of 6 weeks MCD diet significantly decreased the infiltration of inflammatory macrophages into the liver and intrahepatic levels of inflammatory cytokines like TNF or MCP-1. Importantly, anti-CXCL16 treatment significantly reduced fatty liver degeneration upon MCD diet, as assessed by hepatic triglyceride levels, histological steatosis scoring and quantification of lipid droplets. Moreover, injured hepatocytes up-regulated CXCL16 expression, indicating that scavenging functions of CXCL16 might be additionally involved in the pathogenesis of NAFLD. Targeting CXCL16 might therefore represent a promising novel therapeutic approach for liver inflammation and steatohepatitis.

The Relationship between Type 2 Diabetes Mellitus and Non-Alcoholic Fatty Liver Disease Measured by Controlled Attenuation Parameter.

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Chon, Young Eun; Kim, Kwang Joon; Jung, Kyu Sik; Kim, Seung Up; Park, Jun Yong; Kim, Do Young; Ahn, Sang Hoon; Chon, Chae Yoon; Chung, Jae Bock; Park, Kyeong Hye; Bae, Ji Cheol; Han, Kwang Hyub

2016-07-01

The severity of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) population compared with that in normal glucose tolerance (NGT) individuals has not yet been quantitatively assessed. We investigated the prevalence and the severity of NAFLD in a T2DM population using controlled attenuation parameter (CAP). Subjects who underwent testing for biomarkers related to T2DM and CAP using Fibroscan® during a regular health check-up were enrolled. CAP values of 250 dB/m and 300 dB/m were selected as the cutoffs for the presence of NAFLD and for moderate to severe NAFLD, respectively. Biomarkers related to T2DM included fasting glucose/insulin, fasting C-peptide, hemoglobin A1c (HbA1c), glycoalbumin, and homeostasis model assessment of insulin resistance of insulin resistance (HOMA-IR). Among 340 study participants (T2DM, n=66; pre-diabetes, n=202; NGT, n=72), the proportion of subjects with NAFLD increased according to the glucose tolerance status (31.9% in NGT; 47.0% in pre-diabetes; 57.6% in T2DM). The median CAP value was significantly higher in subjects with T2DM (265 dB/m) than in those with pre-diabetes (245 dB/m) or NGT (231 dB/m) (all p<0.05). Logistic regression analysis showed that subjects with moderate to severe NAFLD had a 2.8-fold (odds ratio) higher risk of having T2DM than those without NAFLD (p=0.02; 95% confidence interval, 1.21-6.64), and positive correlations between the CAP value and HOMA-IR (ρ0.407) or fasting C-peptide (ρ0.402) were demonstrated. Subjects with T2DM had a higher prevalence of severe NAFLD than those with NGT. Increased hepatic steatosis was significantly associated with the presence of T2DM, and insulin resistance induced by hepatic fat may be an important mechanistic connection.

Glucagon-like peptide-1 analogue prevents nonalcoholic steatohepatitis in non-obese mice.

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Yamamoto, Takaya; Nakade, Yukiomi; Yamauchi, Taeko; Kobayashi, Yuji; Ishii, Norimitsu; Ohashi, Tomohiko; Ito, Kiyoaki; Sato, Ken; Fukuzawa, Yoshitaka; Yoneda, Masashi

2016-02-28

To investigate whether a glucagon-like peptide-1 (GLP-1) analogue inhibits nonalcoholic steatohepatitis (NASH), which is being increasingly recognized in Asia, in non-obese mice. A methionine-choline-deficient diet (MCD) along with exendin-4 (20 μg/kg per day, ip), a GLP-1 analogue, or saline was administered to male db/db mice (non-obese NASH model). Four or eight weeks after commencement of the diet, the mice were sacrificed and their livers were excised. The excised livers were examined by histochemistry for evidence of hepatic steatosis and inflammation. Hepatic triglyceride (TG) and free fatty acid (FFA) content was measured, and the expression of hepatic fat metabolism- and inflammation-related genes was evaluated. Oxidative stress-related parameters and macrophage recruitment were also examined using immunohistochemistry. Four weeks of MCD feeding induced hepatic steatosis and inflammation and increased the hepatic TG and FFA content. The expression of fatty acid transport protein 4 (FATP4), a hepatic FFA influx-related gene; macrophage recruitment; and the level of malondialdehyde (MDA), an oxidative stress marker, were significantly augmented by a 4-wk MCD. The levels of hepatic sterol regulatory element-binding protein-1c (SREBP-1c) mRNA (lipogenesis-related gene) and acyl-coenzyme A oxidase 1 (ACOX1) mRNA (β-oxidation-related gene) had decreased at 4 wk and further decreased at 8 wk. However, the level of microsomal triglyceride transfer protein mRNA (a lipid excretion-related gene) remained unchanged. The administration of exendin-4 significantly attenuated the MCD-induced increase in hepatic steatosis, hepatic TG and FFA content, and FATP4 expression as well as the MCD-induced augmentation of hepatic inflammation, macrophage recruitment, and MDA levels. Additionally, it further decreased the hepatic SREBP-1c level and alleviated the MCD-mediated inhibition of the ACOX1 mRNA level. These results suggest that GLP-1 inhibits hepatic steatosis and

Usefulness of T1 mapping on Gd-EOB-DTPA-enhanced MR imaging in assessment of non-alcoholic fatty liver disease

International Nuclear Information System (INIS)

Ding, Ying; Rao, Sheng-Xiang; Meng, Tao; Chen, Caizhong; Li, Renchen; Zeng, Meng-Su

2014-01-01

This study evaluates the value of Gd-EOB-DTPA-enhanced MRI for diagnosis and staging of non-alcoholic fatty liver disease (NAFLD) in an animal model by T 1 relaxation time measurement. Thirty-four rabbits were divided into the control group (n = 10) and NAFLD group, which was split into four groups (n = 6) with a high-fat diet for an interval of 3 weeks. A dual flip angle was performed before and at the hepatobiliary phase (HBP). T 1 relaxation times of the liver parenchyma and the decrease rate (∇%) were calculated. Histological findings according to semi-quantitative scoring of steatosis, activity and fibrosis were the standard of reference. HBP and ∇% T 1 relaxation time measurement showed significant differences between normal and NAFLD groups, between non-alcoholic steatohepatitis (NASH) and NAFLD without NASH (p = 0.000-0.049), between fibrosis groups (p = 0.000-0.019), but no difference between F1 and F2 (p = 0.834). The areas under the receiver operating characteristic curves (AUCs) of T 1 relaxation time for HBP and ∇% were 0.86-0.93 for the selection of NASH and activity score ≥2, and 0.86-0.95 for the selection of F ≥ 1, 2, 3. No significant difference was found for diagnostic performance between HBP and ∇% T 1 relaxation time. HBP T 1 relaxation time measurement of Gd-EOB-DTPA-enhanced MRI was useful to evaluate NAFLD according to the SAF score. HBP T 1 relaxation time measurement was as accurate as ∇% T 1 relaxation time. (orig.)

Genetic ancestry analysis in non-alcoholic fatty liver disease patients from Brazil and Portugal

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Cavalcante, Lourianne Nascimento; Stefano, Jose Tadeu; Machado, Mariana V; Mazo, Daniel F; Rabelo, Fabiola; Sandes, Kiyoko Abe; Carrilho, Flair José; Cortez-Pinto, Helena; Lyra, Andre Castro; de Oliveira, Claudia P

2015-01-01

AIM: To study the association between genetic ancestry, non-alcoholic fatty liver disease (NAFLD) metabolic characteristics in two cohorts of patients, from Brazil and Portugal. METHODS: We included 131 subjects from Brazil [(n = 45 with simple steatosis (S. Steatosis) and n = 86 with nonalcoholic steatohepatitis (NASH)] and 90 patients from Portugal (n = 66, S. Steatosis; n = 24, NASH). All patients had biopsy-proven NAFLD. In histologic evaluation NAFLD activity score was used to assess histology and more than 5 points defined NASH in this study. Patients were divided into two groups according to histology diagnosis: simple steatosis or non-alcoholic statohepatitis. Genetic ancestry was assessed using real-time polymerase chain reaction. Seven ancestry informative markers (AT3-I/D, LPL, Sb19.3, APO, FY-Null, PV92, and CKMM) with the greatest ethnic-geographical differential frequencies (≥ 48%) were used to define genetic ancestry. Data were analyzed using R PROJECTS software. Ancestry allele frequencies between groups were analyzed by GENEPOP online and the estimation of genetic ancestry contribution was evaluated by ADMIX-95 software. The 5% alpha-error was considered as significant (P 2.5 [NASH 5.3 (70.8%) vs S. Steatosis 4.6 (29.2%) P = 0.04]. In the Portuguese study population, dyslipidemia was present in all patients with NASH (P = 0.03) and hypertension was present in a larger percentage of subjects in the S. Steatosis group (P = 0.003, respectively). The genetic ancestry contribution among Brazilian and Portuguese individuals with NASH was similar to those with S. Steatosis from each cohort (Brazilian cohort: P = 0.75; Portuguese cohort: P = 0.97). Nonetheless, the genetic ancestry contribution of the Brazilian and Portuguese population were different, and a greater European and Amerindian ancestry contribution was detected in the Portuguese population while a higher African genetic ancestry contribution was observed in Brazilian population of both NASH

Genetic ancestry analysis in non-alcoholic fatty liver disease patients from Brazil and Portugal.

Science.gov (United States)

Cavalcante, Lourianne Nascimento; Stefano, Jose Tadeu; Machado, Mariana V; Mazo, Daniel F; Rabelo, Fabiola; Sandes, Kiyoko Abe; Carrilho, Flair José; Cortez-Pinto, Helena; Lyra, Andre Castro; de Oliveira, Claudia P

2015-06-08

To study the association between genetic ancestry, non-alcoholic fatty liver disease (NAFLD) metabolic characteristics in two cohorts of patients, from Brazil and Portugal. We included 131 subjects from Brazil [(n = 45 with simple steatosis (S. Steatosis) and n = 86 with nonalcoholic steatohepatitis (NASH)] and 90 patients from Portugal (n = 66, S. Steatosis; n = 24, NASH). All patients had biopsy-proven NAFLD. In histologic evaluation NAFLD activity score was used to assess histology and more than 5 points defined NASH in this study. Patients were divided into two groups according to histology diagnosis: simple steatosis or non-alcoholic statohepatitis. Genetic ancestry was assessed using real-time polymerase chain reaction. Seven ancestry informative markers (AT3-I/D, LPL, Sb19.3, APO, FY-Null, PV92, and CKMM) with the greatest ethnic-geographical differential frequencies (≥ 48%) were used to define genetic ancestry. Data were analyzed using R PROJECTS software. Ancestry allele frequencies between groups were analyzed by GENEPOP online and the estimation of genetic ancestry contribution was evaluated by ADMIX-95 software. The 5% alpha-error was considered as significant (P 2.5 [NASH 5.3 (70.8%) vs S. Steatosis 4.6 (29.2%) P = 0.04]. In the Portuguese study population, dyslipidemia was present in all patients with NASH (P = 0.03) and hypertension was present in a larger percentage of subjects in the S. Steatosis group (P = 0.003, respectively). The genetic ancestry contribution among Brazilian and Portuguese individuals with NASH was similar to those with S. Steatosis from each cohort (Brazilian cohort: P = 0.75; Portuguese cohort: P = 0.97). Nonetheless, the genetic ancestry contribution of the Brazilian and Portuguese population were different, and a greater European and Amerindian ancestry contribution was detected in the Portuguese population while a higher African genetic ancestry contribution was observed in Brazilian population of both NASH and S

Carboxylesterase 1 Is Regulated by Hepatocyte Nuclear Factor 4α and Protects Against Alcohol- and MCD diet-induced Liver Injury.

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Xu, Jiesi; Xu, Yang; Li, Yuanyuan; Jadhav, Kavita; You, Min; Yin, Liya; Zhang, Yanqiao

2016-04-14

The liver is a major organ that controls hepatic and systemic homeostasis. Dysregulation of liver metabolism may cause liver injury. Previous studies have demonstrated that carboxylesterase 1 (CES1) regulates hepatic triglyceride metabolism and protects against liver steatosis. In the present study, we investigated whether CES1 played a role in the development of alcoholic liver disease (ALD) and methionine and choline-deficient (MCD) diet-induced liver injury. Both hepatocyte nuclear factor 4α (HNF4α) and CES1 were markedly reduced in patients with alcoholic steatohepatitis. Alcohol repressed both HNF4α and CES1 expression in primary hepatocytes. HNF4α regulated CES1 expression by directly binding to the proximal promoter of CES1. Global inactivation of CES1 aggravated alcohol- or MCD diet-induced liver inflammation and liver injury, likely as a result of increased production of acetaldehyde and reactive oxygen species and mitochondrial dysfunctions. Knockdown of hepatic CES1 exacerbated ethanol-induced steatohepatitis. These data indicate that CES1 plays a crucial role in protection against alcohol- or MCD diet-induced liver injury.

ORIGINAL ARTICLE Non-Alcoholic Fatty Liver Disease and ...

African Journals Online (AJOL)

2018-01-01

Jan 1, 2018 ... ABSTRACT. BACKGROUND: Non-alcoholic Fatty Liver Disease (NAFLD) among type 2 diabetic patients is completely ignored in developing regions like Africa paving the way for public health and economic burden in the region. Therefore, the main objective of this research was to evaluate non-alcoholic ...

Measurement of the total antioxidant response using a novel automated method in subjects with nonalcoholic steatohepatitis

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Sarifakiogullari Serpil

2005-11-01

Full Text Available Abstract Background Oxidative stress, an increase in oxidants and/or a decrease in antioxidant capacity, is one of the potential biochemical mechanisms involved in the pathogenesis of nonalcoholic steatohepatitis. We aimed to investigate the total antioxidant response using a novel automated method in nonalcoholic steatohepatitis subjects. As a reciprocal measure, we also aimed to determine total peroxide level in the same plasma samples. Methods Twenty-two subjects with biopsy proven nonalcoholic steatohepatitis and 22 healthy controls were enrolled. Total antioxidant response and total peroxide level measurements were done in all participants. The ratio percentage of total peroxide level to total antioxidant response was regarded as oxidative stress index. Results Total antioxidant response of subjects with nonalcoholic steatohepatitis was significantly lower than controls (p In subjects with nonalcoholic steatohepatitis, fibrosis score was significantly correlated with total peroxide level, total antioxidant response and oxidative stress index (p 0.05. Conclusion Nonalcoholic steatohepatitis is associated with increased oxidant capacity, especially in the presence of liver fibrosis. The novel automated assay is a reliable and easily applicable method for total plasma antioxidant response measurement in nonalcoholic steatohepatitis.

[Acrodystrophic neuropathy in an alcoholic].

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Yamamura, Y; Hironaka, M; Shimoyama, M; Toyota, Y; Kurokawa, M; Kohriyama, T; Nakamura, S

1993-01-01

The patient was a 48-year-old alcoholic man with no contributory family history. At age 36 he had developed sensory dominant polyneuropathy with highly impaired temperature sensation and deep sensation in the lower extremities, recurrent ulcers of the toes, and sexual impotence. A sural nerve biopsy at this time revealed marked loss of myelinated fibers with relative preservation of the population of unmyelinated fibers. Subsequently, he developed muscle atrophy of the lower thighs, urinary incontinence, and Wernicke's encephalopathy, and became non-ambulatory at age 44. The peripheral nerve conduction findings suggested predominantly axonal degeneration. The entire course was characterized by alternative progression and partial recovery influenced by his alcohol intake and nutritional state. Alcoholic neuropathy is a major cause of solitary acrodystrophic neuropathy (ADN). Manifestations of autonomic and motor neuropathy are more marked in alcoholic ADN than in HSAN-I, and central nervous system involvement is the hallmark of alcoholic ADN. In the treatment of patients with alcoholic ADN, attention should be paid to diabetes mellitus, malnutritional state, and vitamin deficiency, which frequently complicate alcoholism.

The association of vitamin D deficiency with non-alcoholic fatty liver disease

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Küçükazman, Metin; Ata, Naim; Dal, Kürşat; Yeniova, Abdullah Özgür; Kefeli, Ayşe; Basyigit, Sebahat; Aktas, Bora; Akin, Kadir Okhan; Ağladioğlu, Kadir; Üre, Öznur Sari; Topal, Firdes; Nazligül, Yaşar; Beyan, Esin; Ertugrul, Derun Taner

2014-01-01

OBJECTIVE: Vitamin D deficiency has been related to diabetes, hypertension, hyperlipidemia and peripheral vascular disease. In this study, we aimed to investigate the role of vitamin D status in non-alcoholic fatty liver disease. METHODS: We included 211 consecutive subjects to examine the presence of non-alcoholic fatty liver disease. Of these subjects, 57 did not have non-alcoholic fatty liver disease and 154 had non-alcoholic fatty liver disease. RESULTS: The non-alcoholic fatty liver ...

The biomechanics of simple steatosis and steatohepatitis

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Parker, K. J.; Ormachea, J.; Drage, M. G.; Kim, H.; Hah, Z.

2018-05-01

Magnetic resonance and ultrasound elastography techniques are now important tools for staging high-grade fibrosis in patients with chronic liver disease. However, uncertainty remains about the effects of simple accumulation of fat (steatosis) and inflammation (steatohepatitis) on the parameters that can be measured using different elastographic techniques. To address this, we examine the rheological models that are capable of capturing the dominant viscoelastic behaviors associated with fat and inflammation in the liver, and quantify the resulting changes in shear wave speed and viscoelastic parameters. Theoretical results are shown to match measurements in phantoms and animal studies reported in the literature. These results are useful for better design of elastographic studies of fatty liver disease and steatohepatitis, potentially leading to improved diagnosis of these conditions.

Evidence that non-alcoholic fatty liver disease and polycystic ovary syndrome are associated by necessity rather than chance: a novel hepato-ovarian axis?

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Targher, Giovanni; Rossini, Maurizio; Lonardo, Amedeo

2016-02-01

Increasing evidence suggests that non-alcoholic fatty liver disease (NAFLD) and polycystic ovary syndrome (PCOS) are associated with obesity, insulin resistance, metabolic syndrome, cardiovascular disease, cirrhosis, and liver tumors. On these grounds, we have hypothesized that NAFLD and PCOS occur more frequently than expected by chance alone. We have tested this hypothesis by reviewing the clinical and biological evidence that supports a significant association between NAFLD and PCOS. PubMed was extensively searched for articles published through March 2015 using the keywords "nonalcoholic fatty liver disease" or "fatty liver" combined with "PCOS." Several cross-sectional and case-control studies have consistently demonstrated that the prevalence of NAFLD is remarkably increased in young women with PCOS, independent of overweight/obesity and other coexisting metabolic syndrome features, and that these women are more likely to have the more severe forms of NAFLD (non-alcoholic steatohepatitis, advanced fibrosis, and cirrhosis). Accumulating evidence suggests that NAFLD, especially its necro-inflammatory form, may exacerbate hepatic and systemic insulin resistance and releases multiple pro-inflammatory, pro-coagulant, and pro-fibrogenic mediators that may play important roles in the pathophysiology of PCOS. These findings call for more active and systematic search for NAFLD among women with PCOS. Conversely, gastroenterologists/hepatologists need to be aware of the presence of PCOS among female patients with NAFLD and compatible clinical features. Finally, all these patients should undergo regular follow-up not only for liver-related complications but also for cardio-metabolic diseases.

Serum Matrix Metalloproteinase-9 and Tissue Inhibitor of Metalloproteinase-1 Expression in Patients with Non-alcoholic Fatty Liver Disease

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Taner Akyol

2015-06-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD is the most common chronic liver disease in developed countries. NAFLD may progress to non-alcoholic steatohepatitis (NASH and cirrhosis. Emerging evidence suggests that NAFLD is the hepatic manifestation of metabolic syndrome (MetS. NAFLD is closely linked to MetS, with a significant increase in cardiovascular risk. Several matrix metalloproteinases (MMPs and tissue inhibitors of MMPs (TIMPs play important roles in the pathophysiology of atherosclerosis and liver fibrosis. In this study we investigated the usefulness of serum metalloproteinases as noninvasive markers of NAFLD. Forty-six patients with NAFLD and twenty-six healthy controls were enrolled into the study, in Gulhane Military Medical Academy, Haydarpasa Training Hospital. Liver biopsies were performed on all patients with NAFLD and histopathological evaluations were made by an experienced pathologist. All NAFLD patients were divided into 2 subgroups according to MetS status using ATP III criteria. MMP-9 and TIMP-1 were studied in serum samples of all groups. Results were compared between both groups and subgroups. In this study, the NAFLD and control groups did not differ significantly on MMP-9, TIMP-1 and TIMP-1/MMP-9 ratio (p > 0.05. However, we found a significant relationship between the HOMA and TIMP-1 (p<0.05. Moreover, MMP-9 and TIMP-1/MMP-9 levels were significantly correlated with waist circumference (p<0.05. Our findings are not sufficient to suggest that MMP-9, TIMP-1 and TIMP-1/MMP-9 ratio might be used as noninvasive biochemical diagnostic tests among NAFLD patients. [Dis Mol Med 2015; 3(2.000: 11-17

A Probable Case of Burn-out NASH Caused by Panhypopituitarism

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Terawaki, Yuichi; Murase, Kunitaka; Motonaga, Ryoko; Tanabe, Makito; Nomiyama, Takashi; Shakado, Satoshi; Mizoguchi, Mikiro; Sakisaka, Shotaro; Yanase, Toshihiko

2016-03-01

A 38-year-old man diagnosed with craniopharyngioma at 8 years old underwent repeated surgery and radiation therapy. Complications included panhypopituitarism including growth hormone deficiency and hypogonadism at 13 years old. At 26 years of age, a slight fatty liver was found, which finally developed into liver cirrhosis (LC) at 35 years old. Viral infection or other etiologies causing LC were negative on serum examinations. Liver biopsy suggested a possibility of burn-out non-alcoholic steatohepatitis. This case indicates that a long-standing growth hormone deficiency and hypogonadism may lead to LC as a type of burn-out non-alcoholic steatohepatitis.

Expression of genes for microRNA-processing enzymes is altered in advanced non-alcoholic fatty liver disease.

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Sharma, Haveesh; Estep, Michael; Birerdinc, Aybike; Afendy, Arian; Moazzez, Amir; Elariny, Hazem; Goodman, Zachary; Chandhoke, Vikas; Baranova, Ancha; Younossi, Zobair M

2013-08-01

Recently, microRNAs (miRNA) have been linked to the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH). First transcribed as pri-miRNA, these molecules are further processed by a complex of endonuclear and cytosolic RNA binding molecules to form mature miRNAs. The aim of this study is to investigate mechanisms of miRNA regulation in the visceral adipose of obese NAFLD patients via measuring expression of miRNA processing enzymes and pri-miRNA. Total RNAs were extracted from visceral adipose tissue (VAT) samples collected from patients undergoing bariatric surgery. All patients had biopsy-proven NAFLD (NASH patients [n = 12] and non-NASH NAFLD [n = 12]). For each patient, we profiled mRNA levels for three miRNA processing elements (Drosha, DGCR8, and Dicer1) and seven pri-miRNAs (pri-miR-125b-2, pri-miR-16-2, pri-miR-26a-1, pri-miR-26a-2, pri-miR-7-1, pri-miR-7-2, and pri-miR-7-3). Expression of Dicer1, Drosha and DGCR8 was significantly increased within the NASH cohort along with expression of pri-miR-7-1. The presence of focal necrosis on the liver biopsy correlated significantly with levels of Dicer1 and DGRC8. Both NASH and ballooning degeneration of hepatocytes correlated negatively with the expression levels of hsa-miR-125b. Histologic NASH correlated positively with the expression levels of pri-miR-16-2 and pri-miR-7-1. The presence of the hepatocyte's ballooning degeneration in the liver biopsy correlated positively with pri-miR-26a-1 and pri-miR-7-1. The expression profile of pri-miR-125b-2 also correlated positively with body mass index. Our findings support the hypothesis that VAT-derived miRNA may contribute to the pathogenesis of NASH in obese patients. © 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.

Measurement of the total antioxidant response using a novel automated method in subjects with nonalcoholic steatohepatitis.

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Horoz, Mehmet; Bolukbas, Cengiz; Bolukbas, Fusun F; Sabuncu, Tevfik; Aslan, Mehmet; Sarifakiogullari, Serpil; Gunaydin, Necla; Erel, Ozcan

2005-11-11

Oxidative stress, an increase in oxidants and/or a decrease in antioxidant capacity, is one of the potential biochemical mechanisms involved in the pathogenesis of nonalcoholic steatohepatitis. We aimed to investigate the total antioxidant response using a novel automated method in nonalcoholic steatohepatitis subjects. As a reciprocal measure, we also aimed to determine total peroxide level in the same plasma samples. Twenty-two subjects with biopsy proven nonalcoholic steatohepatitis and 22 healthy controls were enrolled. Total antioxidant response and total peroxide level measurements were done in all participants. The ratio percentage of total peroxide level to total antioxidant response was regarded as oxidative stress index. Total antioxidant response of subjects with nonalcoholic steatohepatitis was significantly lower than controls (p total peroxide level and mean oxidative stress index were higher (all p total peroxide level, total antioxidant response and oxidative stress index (p 0.05). Nonalcoholic steatohepatitis is associated with increased oxidant capacity, especially in the presence of liver fibrosis. The novel automated assay is a reliable and easily applicable method for total plasma antioxidant response measurement in nonalcoholic steatohepatitis.

A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease.

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Adeeba Ahmed

Full Text Available Non alcoholic fatty liver disease (NAFLD is the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of liver disease ranging from reversible hepatic steatosis, to non alcoholic steato-hepatitis (NASH and cirrhosis. The potential role of glucocorticoids (GC in the pathogenesis of NAFLD is highlighted in patients with GC excess, Cushing's syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, hepatic cortisol availability is controlled by enzymes that regenerate cortisol (F from inactive cortisone (E (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1, or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR.In vitro studies defined 11β-HSD1 expression in normal and NASH liver samples. We then characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD compared to 32 obese controls using gas chromatographic analysis of 24 hour urine collection and plasma cortisol generation profile following oral cortisone.In patients with steatosis 5αR activity was increased, with a decrease in hepatic 11β-HSD1 activity. Total cortisol metabolites were increased in this group consistent with increased GC production rate. In contrast, in patients with NASH, 11β-HSD1 activity was increased both in comparison to patients with steatosis, and controls. Endorsing these findings, 11β-HSD1 mRNA and immunostaining was markedly increased in NASH patients in peri septal hepatocytes and within CD68 positive macrophages within inflamed cirrhotic septa.Patients with hepatic steatosis have increased clearance and decreased hepatic regeneration of cortisol and we propose that this may represent a protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11β-HSD1 activity and consequent cortisol regeneration may

A switch in hepatic cortisol metabolism across the spectrum of non alcoholic fatty liver disease.

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Ahmed, Adeeba; Rabbitt, Elizabeth; Brady, Theresa; Brown, Claire; Guest, Peter; Bujalska, Iwona J; Doig, Craig; Newsome, Philip N; Hubscher, Stefan; Elias, Elwyn; Adams, David H; Tomlinson, Jeremy W; Stewart, Paul M

2012-01-01

Non alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of the metabolic syndrome. NAFLD represents a spectrum of liver disease ranging from reversible hepatic steatosis, to non alcoholic steato-hepatitis (NASH) and cirrhosis. The potential role of glucocorticoids (GC) in the pathogenesis of NAFLD is highlighted in patients with GC excess, Cushing's syndrome, who develop central adiposity, insulin resistance and in 20% of cases, NAFLD. Although in most cases of NAFLD, circulating cortisol levels are normal, hepatic cortisol availability is controlled by enzymes that regenerate cortisol (F) from inactive cortisone (E) (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1), or inactivate cortisol through A-ring metabolism (5α- and 5β-reductase, 5αR and 5βR). In vitro studies defined 11β-HSD1 expression in normal and NASH liver samples. We then characterised hepatic cortisol metabolism in 16 patients with histologically proven NAFLD compared to 32 obese controls using gas chromatographic analysis of 24 hour urine collection and plasma cortisol generation profile following oral cortisone. In patients with steatosis 5αR activity was increased, with a decrease in hepatic 11β-HSD1 activity. Total cortisol metabolites were increased in this group consistent with increased GC production rate. In contrast, in patients with NASH, 11β-HSD1 activity was increased both in comparison to patients with steatosis, and controls. Endorsing these findings, 11β-HSD1 mRNA and immunostaining was markedly increased in NASH patients in peri septal hepatocytes and within CD68 positive macrophages within inflamed cirrhotic septa. Patients with hepatic steatosis have increased clearance and decreased hepatic regeneration of cortisol and we propose that this may represent a protective mechanism to decrease local GC availability to preserve hepatic metabolic phenotype. With progression to NASH, increased 11β-HSD1 activity and consequent cortisol regeneration may serve to

Disturbed Vitamin A Metabolism in Non-Alcoholic Fatty Liver Disease (NAFLD

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Ali Saeed

2017-12-01

Full Text Available Vitamin A is required for important physiological processes, including embryogenesis, vision, cell proliferation and differentiation, immune regulation, and glucose and lipid metabolism. Many of vitamin A’s functions are executed through retinoic acids that activate transcriptional networks controlled by retinoic acid receptors (RARs and retinoid X receptors (RXRs.The liver plays a central role in vitamin A metabolism: (1 it produces bile supporting efficient intestinal absorption of fat-soluble nutrients like vitamin A; (2 it produces retinol binding protein 4 (RBP4 that distributes vitamin A, as retinol, to peripheral tissues; and (3 it harbors the largest body supply of vitamin A, mostly as retinyl esters, in hepatic stellate cells (HSCs. In times of inadequate dietary intake, the liver maintains stable circulating retinol levels of approximately 2 μmol/L, sufficient to provide the body with this vitamin for months. Liver diseases, in particular those leading to fibrosis and cirrhosis, are associated with impaired vitamin A homeostasis and may lead to vitamin A deficiency. Liver injury triggers HSCs to transdifferentiate to myofibroblasts that produce excessive amounts of extracellular matrix, leading to fibrosis. HSCs lose the retinyl ester stores in this process, ultimately leading to vitamin A deficiency. Non-alcoholic fatty liver disease (NAFLD is the hepatic manifestation of metabolic syndrome and is a spectrum of conditions ranging from benign hepatic steatosis to non-alcoholic steatohepatitis (NASH; it may progress to cirrhosis and liver cancer. NASH is projected to be the main cause of liver failure in the near future. Retinoic acids are key regulators of glucose and lipid metabolism in the liver and adipose tissue, but it is unknown whether impaired vitamin A homeostasis contributes to or suppresses the development of NAFLD. A genetic variant of patatin-like phospholipase domain-containing 3 (PNPLA3-I148M is the most prominent

Systems-level organization of non-alcoholic fatty liver disease progression network

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K. Shubham

2017-10-01

Full Text Available Non-Alcoholic Fatty Liver Disease (NAFLD is a hepatic metabolic disorder that is commonly associated with sedentary lifestyle and high fat diets. NAFLD is prevalent in individuals with obesity, insulin resistance and Type 2 Diabetes (T2D. The clinical spectrum of NAFLD ranges from simple steatosis to Non-Alcoholic Steatohepatitis (NASH with fibrosis, which can progress to cirrhosis and hepatocellular carcinoma.The pathogenesis of NAFLD is complex, involving crosstalk between multiple organs, cell-types, and environmental and genetic factors. Dysfunction of White Adipose Tissue (WAT plays a central role in the development of NAFLD and other metabolic disorders. WAT is an active endocrine organ that regulates whole-body energy homeostasis, lipid metabolism, insulin sensitivity and food intake by secreting biologically active molecules (lipokines, adipokines and cytokines. WAT dynamically reacts to nutrient excess or deprivation by remodelling the number (called hyperplasia and/or size (called hypertrophy of adipocytes to store fat or supply nutrients to other tissues by lipolysis, respectively. Adipose tissue remodelling is also accompanied by changes in the composition or function of stromal vascular cells and ECM. The major objective of our study was to identify and characterize the metabolic and signaling modules associated with the progression of NAFLD in the VAT. We performed Weighted Gene Co-expression Network Analysis (WGCNA to organize microarray data obtained from the VAT of patients at different stages of NAFLD into functional modules. In order to obtain insights into the metabolism and its regulation at the genome scale, a co-expression network of metabolic genes in the Human Metabolic Network (HMR2 was constructed and compared with the co-expression network constructed based on all the varying genes. We also used the prior network information on adipocyte metabolism (GEM to verify and extract reporter metabolites. Our analysis revealed

Notch signaling and progenitor/ductular reaction in steatohepatitis.

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Carola M Morell

Full Text Available Persistent hepatic progenitor cells (HPC activation resulting in ductular reaction (DR is responsible for pathologic liver repair in cholangiopathies. Also, HPC/DR expansion correlates with fibrosis in several chronic liver diseases, including steatohepatitis. Increasing evidence indicates Notch signaling as a key regulator of HPC/DR response in biliary and more in general liver injuries. Therefore, we aimed to investigate the role of Notch during HPC/DR activation in a mouse model of steatohepatitis.Steatohepatitis was generated using methionine-choline deficient (MCD diet. For hepatocyte lineage tracing, R26R-YFP mice were infected with AAV8-TBG-Cre.MCD diet promoted a strong HPC/DR response that progressively diffused in the lobule, and correlated with increased fibrosis and TGF-β1 expression. Notch signaling was unchanged in laser-capture microdissected HPC/DR, whereas Notch receptors were down regulated in hepatocytes. However, in-vivo lineage tracing experiments identified discrete hepatocytes showing Notch-1 activation and expressing (the Notch-dependent Sox9. Stimulation of AML-12 hepatocyte-cell line with immobilized Jag1 induced Sox9 and down-regulated albumin and BSEP expression. TGF-β1 treatment in primary hepatic stellate cells (HSC induced Jag1 expression. In MCD diet-fed mice, αSMA-positive HSC were localized around Sox9 expressing hepatocytes, suggesting that Notch activation in hepatocytes was promoted by TGF-β1 stimulated HSC. In-vivo Notch inhibition reduced HPC response and fibrosis progression.Our data suggest that Notch signaling is an important regulator of DR and that in steatohepatitis, hepatocytes exposed to Jag1-positive HSC, contribute to pathologic DR by undergoing Notch-mediated differentiation towards an HPC-like phenotype. Given the roles of Notch in fibrosis and liver cancer, these data suggest mesenchymal expression of Jag1 as an alternative therapeutic target.

Homicide in Chicago from 1890 to 1930: prohibition and its impact on alcohol- and non-alcohol-related homicides.

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Asbridge, Mark; Weerasinghe, Swarna

2009-03-01

The aim of the current paper is to examine the impact of the enactment of constitutional prohibition in the United States in 1920 on total homicides, alcohol-related homicides and non-alcohol-related homicides in Chicago. Data are drawn from the Chicago Historical Homicide Project, a data set chronicling 11 018 homicides in Chicago between 1870 and 1930. Interrupted time-series and autoregression integrated moving average (ARIMA) models are employed to examine the impact of prohibition on three separate population-adjusted homicide series. All models control for potential confounding from World War I demobilization and from trend data drawn from Wesley Skogan's Time-Series Data from Chicago. Total and non-alcohol-related homicide rates increased during prohibition by 21% and 11%, respectively, while alcohol-related homicides remained unchanged. For other covariates, alcohol-related homicides were related negatively to the size of the Chicago police force and positively to police expenditures and to the proportion of the Chicago population aged 21 years and younger. Non-alcohol-related homicides were related positively to police expenditures and negatively to the size of the Chicago police force. While total and non-alcohol-related homicides in the United States continued to rise during prohibition, a finding consistent with other studies, the rate of alcohol-related homicides remained unchanged. The divergent impact of prohibition on alcohol- and non-alcohol-related homicides is discussed in relation to previous studies of homicide in this era.

Fatty liver disease--a practical guide for GPs.

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Iser, David; Ryan, Marno

2013-07-01

Non-alcoholic fatty liver disease (NAFLD), encompassing both simple steatosis and non-alcoholic steato-hepatitis (NASH), is the most common cause of liver disease in Australia. Non-alcoholic fatty liver disease needs to be considered in the context of the metabolic syndrome, as cardiovascular disease will account for much of the mortality associated with NAFLD. To provide an approach to the identification of NAFLD in general practice, the distinction between simple steatosis and NASH, and the management of these two conditions. Non-alcoholic steato-hepatitis is more common in the presence of diabetes, obesity, older age and increased inflammation, and is more likely to progress to cirrhosis. Cirrhosis may be complicated by hepatocellular carcinoma or liver failure. Hepatocellular carcinoma has also been described in NASH without cirrhosis. Assessment and treatment of features of the metabolic syndrome may reduce associated cardiovascular mortality. Numerous agents have been evaluated, but weight loss remains the only effective treatment for NAFLD.

Serum Adipokine and Ghrelin Levels in Nonalcoholic Steatohepatitis

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Mehmet Yalniz

2006-01-01

Full Text Available Adipokines and ghrelin play role in insulin resistance, the key pathophysiological abnormality in patients with nonalcoholic fatty liver diseases. In the present study, relationship between nonalcoholic steatohepatitis (NASH and serum adipokine and ghrelin levels was investigated. Thirty seven patients with biopsy-proven NASH and 25 age- and sex-matched controls were enrolled. Ten of NASH patients (27% had diabetes mellitus (n=5 or impaired glucose tolerance (n=5. Body mass index (BMI was less than 30 kg/m2 in 67.6% of patients, while in the remaining 32.4% it was more than 30 kg/m2. Serum adiponectin, leptin, TNF-α, and ghrelin were determined. Serum leptin (15.49±4.84 vs 10.31±2.53 and TNF-α (12.1±2.7 vs 10.31±2.56 levels were significantly higher in the NASH group compared to in the control group (P30 or glucose tolerance was impaired or not (P>.05. Additionally, neither adipokines nor ghrelin was correlated with histopathological grade and stage (P>.05. In conclusion; there is a significant relationship between NASH and adipokines and ghrelin independent from BMI and status of the glucose metabolism. These cytokines that appear to have role in the pathogenesis of NASH, however, do not have any effect upon the severity of the histopathology.

Usefulness of T1 mapping on Gd-EOB-DTPA-enhanced MR imaging in assessment of non-alcoholic fatty liver disease

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Ding, Ying; Rao, Sheng-Xiang; Meng, Tao; Chen, Caizhong; Li, Renchen; Zeng, Meng-Su [Zhongshan/Hospital of Fudan University, Department of Radiology, Shanghai (China)

2014-04-15

This study evaluates the value of Gd-EOB-DTPA-enhanced MRI for diagnosis and staging of non-alcoholic fatty liver disease (NAFLD) in an animal model by T{sub 1} relaxation time measurement. Thirty-four rabbits were divided into the control group (n = 10) and NAFLD group, which was split into four groups (n = 6) with a high-fat diet for an interval of 3 weeks. A dual flip angle was performed before and at the hepatobiliary phase (HBP). T{sub 1} relaxation times of the liver parenchyma and the decrease rate (∇%) were calculated. Histological findings according to semi-quantitative scoring of steatosis, activity and fibrosis were the standard of reference. HBP and ∇% T{sub 1} relaxation time measurement showed significant differences between normal and NAFLD groups, between non-alcoholic steatohepatitis (NASH) and NAFLD without NASH (p = 0.000-0.049), between fibrosis groups (p = 0.000-0.019), but no difference between F1 and F2 (p = 0.834). The areas under the receiver operating characteristic curves (AUCs) of T{sub 1} relaxation time for HBP and ∇% were 0.86-0.93 for the selection of NASH and activity score ≥2, and 0.86-0.95 for the selection of F ≥ 1, 2, 3. No significant difference was found for diagnostic performance between HBP and ∇% T{sub 1} relaxation time. HBP T{sub 1} relaxation time measurement of Gd-EOB-DTPA-enhanced MRI was useful to evaluate NAFLD according to the SAF score. HBP T{sub 1} relaxation time measurement was as accurate as ∇% T{sub 1} relaxation time. (orig.)

Motor performance during and following acute alcohol intoxication in healthy non-alcoholic subjects

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Poulsen, Mette Buch; Jakobsen, Johannes Klitgaard; Andersen, Henning

2007-01-01

Chronic alcohol abuse has adverse effects on skeletal muscle, and reduced muscle strength is frequently seen in chronic alcoholics. In this study the acute effects of moderate alcohol intoxication on motor performance was evaluated in 19 non-alcoholic healthy subjects (10 women, 9 men......). A randomised double-blinded placebo controlled design was applied to subjects receiving alcohol in juice and pure juice at two separate test periods. Isokinetic and isometric muscle strength and endurance were determined before, during, 24 and 48 h after the ingestion of alcohol in juice and juice (placebo......). To detect a reduced activation of the central motor pathways superimposed external electrical stimulations during voluntary contractions were applied. Creatine kinase (CK) was measured to detect any alcohol-induced changes in sarcolemmal integrity. No change was seen in isokinetic as well as in isometric...

Mouse Models of Diet-Induced Nonalcoholic Steatohepatitis Reproduce the Heterogeneity of the Human Disease

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Machado, Mariana Verdelho; Michelotti, Gregory Alexander; Xie, Guanhua; de Almeida, Thiago Pereira; Boursier, Jerome; Bohnic, Brittany; Guy, Cynthia D.; Diehl, Anna Mae

2015-01-01

Background and aims Non-alcoholic steatohepatitis (NASH), the potentially progressive form of nonalcoholic fatty liver disease (NAFLD), is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD) diet and Western diet. Methods Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose) for 16 weeks. Liver pathology and metabolic profile were compared. Results The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation) was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation. Conclusion Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH. PMID:26017539

Mouse models of diet-induced nonalcoholic steatohepatitis reproduce the heterogeneity of the human disease.

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Mariana Verdelho Machado

Full Text Available Non-alcoholic steatohepatitis (NASH, the potentially progressive form of nonalcoholic fatty liver disease (NAFLD, is the pandemic liver disease of our time. Although there are several animal models of NASH, consensus regarding the optimal model is lacking. We aimed to compare features of NASH in the two most widely-used mouse models: methionine-choline deficient (MCD diet and Western diet.Mice were fed standard chow, MCD diet for 8 weeks, or Western diet (45% energy from fat, predominantly saturated fat, with 0.2% cholesterol, plus drinking water supplemented with fructose and glucose for 16 weeks. Liver pathology and metabolic profile were compared.The metabolic profile associated with human NASH was better mimicked by Western diet. Although hepatic steatosis (i.e., triglyceride accumulation was also more severe, liver non-esterified fatty acid content was lower than in the MCD diet group. NASH was also less severe and less reproducible in the Western diet model, as evidenced by less liver cell death/apoptosis, inflammation, ductular reaction, and fibrosis. Various mechanisms implicated in human NASH pathogenesis/progression were also less robust in the Western diet model, including oxidative stress, ER stress, autophagy deregulation, and hedgehog pathway activation.Feeding mice a Western diet models metabolic perturbations that are common in humans with mild NASH, whereas administration of a MCD diet better models the pathobiological mechanisms that cause human NAFLD to progress to advanced NASH.

Acetaldehyde Adducts in Alcoholic Liver Disease

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Mashiko Setshedi

2010-01-01

Full Text Available Chronic alcohol abuse causes liver disease that progresses from simple steatosis through stages of steatohepatitis, fibrosis, cirrhosis, and eventually hepatic failure. In addition, chronic alcoholic liver disease (ALD, with or without cirrhosis, increases risk for hepatocellular carcinoma (HCC. Acetaldehyde, a major toxic metabolite, is one of the principal culprits mediating fibrogenic and mutagenic effects of alcohol in the liver. Mechanistically, acetaldehyde promotes adduct formation, leading to functional impairments of key proteins, including enzymes, as well as DNA damage, which promotes mutagenesis. Why certain individuals who heavily abuse alcohol, develop HCC (7.2–15% versus cirrhosis (15–20% is not known, but genetics and co-existing viral infection are considered pathogenic factors. Moreover, adverse effects of acetaldehyde on the cardiovascular and hematologic systems leading to ischemia, heart failure, and coagulation disorders, can exacerbate hepatic injury and increase risk for liver failure. Herein, we review the role of acetaldehyde adducts in the pathogenesis of chronic ALD and HCC.

The association of vitamin D deficiency with non-alcoholic fatty liver disease

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Metin Küçükazman

2014-08-01

Full Text Available OBJECTIVE: Vitamin D deficiency has been related to diabetes, hypertension, hyperlipidemia and peripheral vascular disease. In this study, we aimed to investigate the role of vitamin D status in non-alcoholic fatty liver disease. METHODS: We included 211 consecutive subjects to examine the presence of non-alcoholic fatty liver disease. Of these subjects, 57 did not have non-alcoholic fatty liver disease and 154 had non-alcoholic fatty liver disease. RESULTS: The non-alcoholic fatty liver disease group had significantly higher fasting blood glucose (p = 0.005, uric acid (p = 0.001, aspartate aminotransferase (p<0.001, alanine aminotransferase (p<0.001, γ-glutamyltransferase (p<0.0001, alkaline phosphatase (p = 0.028, HbA1c (p<0.001, ferritin (p<0.001, insulin (p = 0.016, C-peptide (p = 0.001, HOMA-IR (p = 0.003, total cholesterol (p = 0.001, triglyceride (p = 0.001 and white blood cell (p = 0.04 levels. In contrast, the non-alcoholic fatty liver disease group had significantly lower 25(OHD levels (12.3±8.9 ng/dl, p<0.001 compared with those of the control group (20±13.6 ng/dl. CONCLUSIONS: In this study, we found lower serum 25(OHD levels in patients with non-alcoholic fatty liver disease than in subjects without non-alcoholic fatty liver disease. To establish causality between vitamin D and non-alcoholic fatty liver disease, further interventional studies with a long-term follow-up are needed.

Epidemiology of Diabetes Mellitus in the United Arab Emirates.

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Razzak, Hira Abdul; Harbi, Alya; Shelpai, Wael; Qawas, Ahmad

2017-09-20

Background/ Objective: Diabetes mellitus is a non-communicable disease which has become a major global public health issue. This systematic review summarized epidemiological studies related to the prevalence, risk factors, complications, incidence, knowledge, attitude and practices of Diabetes Mellitus (DM) among Arab population in the United Arab Emirates (UAE). PubMed, Scopus databases, Science direct, Wiley online library, and other local journals were searched to identify relevant literature using appropriate keywords to retrieve studies conducted in the UAE. Search limits were restricted to studies in English language, between 2007 and 2016, and on UAE population (both citizens and expatriates). Electronic database search yielded 24 studies about the prevalence, incidence, complications, risk factors, knowledge, attitudes and practices of diabetes, including cross sectional studies (n =18), population-based survey (n = 1), retrospective cohort studies (n = 3), qualitative (n=1), and randomized controlled trial (n = 1). Countrywide prevalence estimates of Diabetes Mellitus were reported to be high. The major determinants of Diabetes Mellitus involved hypertension, physical inactivity, sedentary lifestyle, and unhealthy diet. Even though past evidences have promulgated the role of numerous causative factors, the epidemiological implications of some of the risk factors including family history, educational level, and the use of alcohol remains elusive. This systematic review signifies epidemiology of Diabetes Mellitus in the United Arab Emirates and suggests that extra efforts are needed for preventive and curative strategies in order to decrease the burden of this non-communicable disease. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Relationship between intestinal flora and inflammatory factors in patients with nonalcoholic steatohepatitis.

Science.gov (United States)

Zhang, Jian; Wang, Chunying; Wang, Ji; Zhang, Fengchi

2018-01-01

This study was conducted to analyze the change in intestinal flora of patients with nonalcoholic steatohepatitis and its correlation to the levels of the inflammatory cytokines interleukin-10 (IL-10) and IL-17. We selected 90 patients that were diagnosed with and treated for nonalcoholic steatohepatitis as the patient group and 80 healthy cases as the control group. We then compared the intestinal flora in the subject feces and the intestinal colonization resistance (B/E, Bifidobacterium to Enterobacter ) of both groups. Using RT-PCR, we also detected IL-10 and IL-17 mRNA levels in the peripheral blood mononuclear cells of both groups. Furthermore, we used the ELISA method to determine serum IL-10 and IL-17 levels in order to explore the correlation between IL-10, IL-17 and B/E. The number of Bifidobacterium and Lactobacillus were significantly lower in the patient group than the control group (Pflora in the patients group were negatively correlated with serum IL-10 (r=-0.546, Pflora in patients with nonalcoholic steatohepatitis are closely related to the changes of serum IL-10 and IL-17 levels, and they are involved in the development of nonalcoholic steatohepatitis.

Long-Term Pioglitazone Treatment for Patients With Nonalcoholic Steatohepatitis and Prediabetes or Type 2 Diabetes Mellitus: A Randomized Trial.

Science.gov (United States)

Cusi, Kenneth; Orsak, Beverly; Bril, Fernando; Lomonaco, Romina; Hecht, Joan; Ortiz-Lopez, Carolina; Tio, Fermin; Hardies, Jean; Darland, Celia; Musi, Nicolas; Webb, Amy; Portillo-Sanchez, Paola

2016-09-06

The metabolic defects of nonalcoholic steatohepatitis (NASH) and prediabetes or type 2 diabetes mellitus (T2DM) seem to be specifically targeted by pioglitazone. However, information about its long-term use in this population is limited. To determine the efficacy and safety of long-term pioglitazone treatment in patients with NASH and prediabetes or T2DM. Randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT00994682). University hospital. Patients (n = 101) with prediabetes or T2DM and biopsy-proven NASH were recruited from the general population and outpatient clinics. All patients were prescribed a hypocaloric diet (500-kcal/d deficit from weight-maintaining caloric intake) and then randomly assigned to pioglitazone, 45 mg/d, or placebo for 18 months, followed by an 18-month open-label phase with pioglitazone treatment. The primary outcome was a reduction of at least 2 points in the nonalcoholic fatty liver disease activity score in 2 histologic categories without worsening of fibrosis. Secondary outcomes included other histologic outcomes, hepatic triglyceride content measured by magnetic resonance and proton spectroscopy, and metabolic parameters. Among patients randomly assigned to pioglitazone, 58% achieved the primary outcome (treatment difference, 41 percentage points [95% CI, 23 to 59 percentage points]) and 51% had resolution of NASH (treatment difference, 32 percentage points [CI, 13 to 51 percentage points]) (P < 0.001 for each). Pioglitazone treatment also was associated with improvement in individual histologic scores, including the fibrosis score (treatment difference, -0.5 [CI, -0.9 to 0.0]; P = 0.039); reduced hepatic triglyceride content from 19% to 7% (treatment difference, -7 percentage points [CI, -10 to -4 percentage points]; P < 0.001); and improved adipose tissue, hepatic, and muscle insulin sensitivity (P < 0.001 vs. placebo for all). All 18-month metabolic and histologic improvements persisted over 36 months of

The role of bile acids in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis.

Science.gov (United States)

Chow, Monica D; Lee, Yi-Horng; Guo, Grace L

2017-08-01

Nonalcoholic fatty liver disease is growing in prevalence worldwide. It is marked by the presence of macrosteatosis on liver histology but is often clinically asymptomatic. However, it can progress into nonalcoholic steatohepatitis which is a more severe form of liver disease characterized by inflammation and fibrosis. Further progression leads to cirrhosis, which predisposes patients to hepatocellular carcinoma or liver failure. The mechanism by which simple steatosis progresses to steatohepatitis is not entirely clear. However, multiple pathways have been proposed. A common link amongst many of these pathways is disruption of the homeostasis of bile acids. Other than aiding in the absorption of lipids and lipid-soluble vitamins, bile acids act as ligands. For example, they bind to farnesoid X receptor, which is critically involved in many of the pathways responsible for maintaining bile acid, glucose, and lipid homeostasis. Alterations to these pathways can lead to dysregulation of energy balance and increased inflammation and fibrosis. Repeated insults over time may be the key to development of steatohepatitis. For this reason, current drug therapies target aspects of these pathways to try to reduce and halt inflammation and fibrosis. This review will focus on the role of bile acids in these various pathways and how changes in these pathways may result in steatohepatitis. While there is no approved pharmaceutical treatment for either hepatic steatosis or steatohepatitis, this review will also touch upon the multitude of potential therapies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Branched-chain amino acids prevent hepatic fibrosis and development of hepatocellular carcinoma in a non-alcoholic steatohepatitis mouse model.

Science.gov (United States)

Takegoshi, Kai; Honda, Masao; Okada, Hikari; Takabatake, Riuta; Matsuzawa-Nagata, Naoto; Campbell, Jean S; Nishikawa, Masashi; Shimakami, Tetsuro; Shirasaki, Takayoshi; Sakai, Yoshio; Yamashita, Taro; Takamura, Toshinari; Tanaka, Takuji; Kaneko, Shuichi

2017-03-14

Oral supplementation with branched-chain amino acids (BCAA; leucine, isoleucine, and valine) in patients with liver cirrhosis potentially suppresses the incidence of hepatocellular carcinoma (HCC) and improves event-free survival. However, the detailed mechanisms of BCAA action have not been fully elucidated. BCAA were administered to atherogenic and high-fat (Ath+HF) diet-induced nonalcoholic steatohepatitis (NASH) model mice. Liver histology, tumor incidence, and gene expression profiles were evaluated. Ath+HF diet mice developed hepatic tumors at a high frequency at 68 weeks. BCAA supplementation significantly improved hepatic steatosis, inflammation, fibrosis, and tumors in Ath+HF mice at 68 weeks. GeneChip analysis demonstrated the significant resolution of pro-fibrotic gene expression by BCAA supplementation. The anti-fibrotic effect of BCAA was confirmed further using platelet-derived growth factor C transgenic mice, which develop hepatic fibrosis and tumors. In vitro, BCAA restored the transforming growth factor (TGF)-β1-stimulated expression of pro-fibrotic genes in hepatic stellate cells (HSC). In hepatocytes, BCAA restored TGF-β1-induced apoptosis, lipogenesis, and Wnt/β-Catenin signaling, and inhibited the transformation of WB-F344 rat liver epithelial stem-like cells. BCAA repressed the promoter activity of TGFβ1R1 by inhibiting the expression of the transcription factor NFY and histone acetyltransferase p300. Interestingly, the inhibitory effect of BCAA on TGF-β1 signaling was mTORC1 activity-dependent, suggesting the presence of negative feedback regulation from mTORC1 to TGF-β1 signaling. Thus, BCAA induce an anti-fibrotic effect in HSC, prevent apoptosis in hepatocytes, and decrease the incidence of HCC; therefore, BCAA supplementation would be beneficial for patients with advanced liver fibrosis with a high risk of HCC.

A biomarker panel for non-alcoholic steatohepatitis (NASH) and NASH-related fibrosis.

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Younossi, Zobair M; Page, Sandra; Rafiq, Nila; Birerdinc, Aybike; Stepanova, Maria; Hossain, Noreen; Afendy, Arian; Younoszai, Zahra; Goodman, Zachary; Baranova, Ancha

2011-04-01

Patients with biopsy-proven NASH and especially those with fibrosis are at risk for progressive liver disease, emphasizing the clinical importance of developing non-invasive biomarkers for NASH and NASH-related fibrosis. This study examines the performance of a new biomarker panel for NASH and NASH-related fibrosis with a combination of clinical and laboratory variables. Enrolled patients had biopsy-proven NAFLD. Clinical data, laboratory data, and serum samples were collected at the time of biopsy. Fasting serum was assayed for adiponectin, resistin, glucose, M30, M65, Tissue inhibitor of metalloproteinases-1 (Timp-1), ProCollagen 3 N-terminal peptide (PIIINP), and hyaluronic acid (HA). Regression models predictive of NASH, NASH-related fibrosis, and NASH-related advanced fibrosis were designed and cross-validated. Of the 79 enrolled NAFLD patients, 40 had biopsy-proven NASH and 39 had non-NASH NAFLD. Clinical and laboratory data were from this cohort were used to develop a NAFLD Diagnostic Panel that includes three models (models for NASH, NASH-related fibrosis, and NASH-related advanced fibrosis). The model for predicting NASH includes diabetes, gender, BMI, triglycerides, M30 (apoptosis), and M65-M30 (necrosis) [AUC: 0.81, 95% CI, 0.70-0.89, 300 p value <9E 301 (-06)]. The NASH-related fibrosis prediction model includes the same predictors [AUC: 0.80, 95% CI 0.68-0.88, 307 p value <0.00014]. Finally, the NASH-related advanced fibrosis model includes type 2 diabetes, serum triglycerides, Timp-1, and AST [AUC: 0.81, 95% CI, 0.70-0.89; p value, 0.000062]. This NAFLD Diagnostic Panel based on a clinical and laboratory data has good performance characteristics and is easy to use. This biomarker panel could become useful in the management of patients with NAFLD.

Non-invasive markers of atherosclerosis and their correlation with ...

African Journals Online (AJOL)

McRoy

2014-07-26

Jul 26, 2014 ... Study of non- invasive markers in patients with type 2 diabetes mellitus. Int J Med Biomed Res ... hypertension, smoking, and alcohol intake were documented for .... The risk of general CVD and hard CVD was significantly ...

Ursodeoxycholic acid for nonalcoholic steatohepatitis.

Science.gov (United States)

Wu, Sheng-di; Li, Lei; Wang, Ji-yao

2012-11-01

The aim of this study was to evaluate the effects of ursodeoxycholic acid on patients with nonalcoholic steatohepatitis using meta-analysis. PubMed, EMBASE, Web of Science, Cochrane Library, Chinese Biomedical Databases, and article references were searched. We included randomized controlled trials using liver biopsy as a reference standard. We identified three eligible studies. Among histological responses, only lobular inflammation improved in the high-dose ursodeoxycholic acid subgroup compared with the control group [mean deviation (MD): -0.23 (-0.40, -0.06), P=0.008]. However, fibrosis may tend to increase [MD: 0.08 (-0.04, 0.20), P=0.17]. Among biochemical responses, γ-glutamyl transpeptidase reduction was significantly greater in the ursodeoxycholic acid group than in the placebo group, and the reduction tendency was only shown in the high-dose subgroup [MD: -35.58 (-52.60, -18.56), Pursodeoxycholic acid subgroup compared with the control group [MD: 0.43 (0.14, 0.72), P=0.004]. Ursodeoxycholic acid-treated patients did not differ significantly from control patients with regard to alanine transaminase, aspartate aminotransferase, and alkaline phosphatase activities. Adverse events were nonspecific and considered of no major clinical relevance. Ursodeoxycholic acid in monotherapy has no substantial positive effect on nonalcoholic steatohepatitis.

AFP, PIVKAII, GP3, SCCA-1 and follisatin as surveillance biomarkers for hepatocellular cancer in non-alcoholic and alcoholic fatty liver disease

International Nuclear Information System (INIS)

Beale, Gary; Reeves, Helen; Chattopadhyay, Dipankar; Gray, Joe; Stewart, Stephen; Hudson, Mark; Day, Christopher; Trerotoli, Paolo; Giannelli, Gianluigi; Manas, Derek

2008-01-01

The incidence and mortality of hepatocellular cancer (HCC) complicating alcoholic and non-alcoholic fatty liver diseases (ALD and NAFLD) is rising in western societies. Despite knowing the at risk populations for HCC development, the lack of sensitive and specific means of surveillance hampers disease detection at curable stages. The most widely used serum HCC marker is alpha-fetoprotein (AFP), while PIVKA-II, glypican-3 (GP3) and Squamous Cell Carcinoma Antigen -1 (SCCA-1) have been proposed as new biomarkers. Assessment of these HCC biomarkers has largely been performed in patients with viral hepatitis. We conducted a cross sectional study assessing the value of these serum proteins, as well a novel candidate biomarker -follistatin – in patients with HCC arising on a background of ALD or NAFLD. Pre-treatment serum samples from 50 patients with HCC arising on a background of ALD (n = 31) or NAFLD (n = 19) were assessed by specific ELISA assay for PIVKAII, Glypican-3, SCCA-1 and Follistatin. Results were compared and contrasted with a control patient group with biopsy proven steatohepatitis-related cirrhosis (n = 41). The diagnostic accuracy of each of the candidate biomarkers was evaluated using receiver operating characteristic (ROC) curve analysis, reporting the area under the curve (AUC) and its 95% confidence interval (CI). Performance was compared to that of the established biomarker, AFP. Serum levels of all proteins were assessed by specific ELISA assays. GP3, SCCA-1 and follistatin had no HCC surveillance benefit in these patients. AFP and PIVKAII were superior to the other markers, particularly in combination. We conclude that while novel means of surveillance are urgently required, the combination of AFP and PIVKAII for HCC is an improvement on AFP alone in ALD/NAFLD patients. Furthermore, our data in this homogenous subset of patients- particularly that confirming no role for SCCA-1 – suggests that the choice of optimal biomarkers for HCC

Prevalence of diabetes mellitus among obese and non-obese patients with coronary artery disease

International Nuclear Information System (INIS)

Khan, S.B.; Rehman, H.U.; Hafeezullah, M.; Gul, A.M.

2010-01-01

Background: Globally, obesity is now recognised as an epidemic. The degree of obesity is proportional to the rate of development of cardiovascular diseases, hence, resulting in a dramatic increase in morbidity and mortality. Apart from obesity, diabetes mellitus is another well recognised risk factor contributing to coronary artery disease. The precise prevalence of obesity-related diabetes varies with age, race and gender; and is yet unknown in our population. We therefore, carried out study with the aim to determine the prevalence of diabetes mellitus in obese and non-obese patients with diagnosed coronary artery disease. Methods: This hospital based cross-sectional comparative study was conducted in Cardiology Department of Postgraduate Medical Institute, Lady Reading Hospital, Peshawar, from March 15, 2005 to May 30, 2006. A total of 200 patients with diagnosed coronary artery disease were enrolled, 100 were classified as obese and 100 as non-obese. Results: Among these, 139 patients were male and 61 female. A total of 88 were found to be diabetic, 54 of these were obese and 34 non-obese (p =0.004). Conclusion: Diabetes mellitus was significantly more frequent among obese patients with coronary artery disease as compared to non obese patients with coronary artery disease. (author)

[Non-alcoholic fatty liver: 10 years' experience at the Insituto Nacional de la Nutrición Salvador Zubirán].

Science.gov (United States)

de la Mora, G; Olivera, M; de la Cerda, R; Arista, J; Kershenobich, D; Uribe, M

1994-01-01

To describe the characteristics of non-alcoholic steatohepatitis (NASH) at the Instituto Nacional de la Nutricion Salvador Zubiran. We reviewed all liver biopsy reports from January 1982 to December 1991. From patient records we obtained the following data: clinical, biochemical, imaging studies and we reviewed the histological material. We correlated clinical, biochemical and histological data. From 2963 biopsies reviewed we obtained 16 cases of NASH. We found a 7:1 female/male ratio. Median age was 30 years and six patients were obese. Eleven patients had concomitant disease (diabetes in seven) and nine were using drugs. All had been studied for biochemical abnormalities and were asymptomatic. Ten patients had hepatomegaly and six splenomegaly. Ultrasound suggested the diagnosis in 50% of the cases. All had steatosis, inflammatory infiltrate, necrosis, fibrosis and Mallory bodies at different stages. One case had cirrhosis on initial biopsy and two developed cirrhosis on follow-up (one and eight years later). We did not find any correlation between clinical, biochemical or imaging characteristics and histological findings. When we compared these findings between obese and non obese patients and primary and secondary NASH we did not find any differences between groups. NASH is infrequent in our institution. The underlying pathogenesis seems to be multifactorial. There is no biochemical-histological correlation. Cirrhosis can develop in some cases.

Non-alcoholic fatty liver disease is associated with left ventricular diastolic dysfunction in essential hypertension.

Science.gov (United States)

Fallo, F; Dalla Pozza, A; Sonino, N; Lupia, M; Tona, F; Federspil, G; Ermani, M; Catena, C; Soardo, G; Di Piazza, L; Bernardi, S; Bertolotto, M; Pinamonti, B; Fabris, B; Sechi, L A

2009-11-01

Insulin resistance is recognized as the pathophysiological hallmark of non-alcoholic fatty liver disease (NAFLD). A relation between insulin sensitivity and left ventricular morphology and function has been reported in essential hypertension, where a high prevalence of NAFLD has been recently found. We investigated the inter-relationship between left ventricular morphology/function, metabolic parameters and NAFLD in 86 never-treated essential hypertensive patients subdivided in two subgroups according to the presence (n = 48) or absence (n = 38) of NAFLD at ultrasonography. The two groups were similar as to sex, age and blood pressure levels. No patient had diabetes mellitus, obesity, hyperlipidemia, or other risk factors for liver disease. Body mass index, waist circumference, triglycerides, glucose, insulin, homeostasis model of assessment index for insulin resistance (HOMA-IR), aspartate aminotransferase and alanine aminotransferase were higher and adiponectin levels were lower in patients with NAFLD than in patients without NAFLD, and were associated with NAFLD at univariate analysis. Patients with NAFLD had similar prevalence of left ventricular hypertrophy compared to patients without NAFLD, but a higher prevalence of diastolic dysfunction (62.5 vs 21.1%, P 220 ms. Diastolic dysfunction (P = 0.040) and HOMA-IR (P = 0.012) remained independently associated with NAFLD at backward multivariate analysis. Non-alcoholic fatty liver disease was associated with insulin resistance and abnormalities of left ventricular diastolic function in a cohort of patients with essential hypertension, suggesting a concomitant increase of metabolic and cardiac risk in this condition.

Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

International Nuclear Information System (INIS)

Wu, Weibin; Liu, Xijun; Peng, Xiaomin; Xue, Ruyi; Ji, Lingling; Shen, Xizhong; Chen, She; Gu, Jianxin; Zhang, Si

2014-01-01

Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR −/− ) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR −/− mice fed MCD diet (FXR −/− /MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR −/− /MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR −/− /MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR −/− /MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection

Bile acids override steatosis in farnesoid X receptor deficient mice in a model of non-alcoholic steatohepatitis

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Wu, Weibin; Liu, Xijun; Peng, Xiaomin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Xue, Ruyi [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Ji, Lingling [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Shen, Xizhong [Department of Gastroenterology and Hepatology, Zhongshan Hospital, Shanghai Institute of Liver Disease, Fudan University, Shanghai 200032 (China); Chen, She, E-mail: shechen@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhang, Si, E-mail: zhangsi@fudan.edu.cn [Gene Research Center, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China)

2014-05-23

Highlights: • FXR deficiency enhanced MCD diet-induced hepatic fibrosis. • FXR deficiency attenuated MCD diet-induced hepatic steatosis. • FXR deficiency repressed genes involved in fatty acid uptake and triglyceride accumulation. - Abstract: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases, and the pathogenesis is still not well known. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily and plays an essential role in maintaining bile acid and lipid homeostasis. In this study, we study the role of FXR in the pathogenesis of NFALD. We found that FXR deficient (FXR{sup −/−}) mice fed methionine- and choline-deficient (MCD) diet had higher serum ALT and AST activities and lower hepatic triglyceride levels than wild-type (WT) mice fed MCD diet. Expression of genes involved in inflammation (VCAM-1) and fibrosis (α-SMA) was increased in FXR{sup −/−} mice fed MCD diet (FXR{sup −/−}/MCD) compared to WT mice fed MCD diet (WT/MCD). Although MCD diet significantly induced hepatic fibrosis in terms of liver histology, FXR{sup −/−}/MCD mice showed less degree of hepatic steatosis than WT/MCD mice. Moreover, FXR deficiency synergistically potentiated the elevation effects of MCD diet on serum and hepatic bile acids levels. The super-physiological concentrations of hepatic bile acids in FXR{sup −/−}/MCD mice inhibited the expression of genes involved in fatty acid uptake and triglyceride accumulation, which may be an explanation for less steatosis in FXR{sup −/−}/MCD mice in contrast to WT/MCD mice. These results suggest that hepatic bile acids accumulation could override simple steatosis in hepatic injury during the progression of NAFLD and further emphasize the role of FXR in maintaining hepatic bile acid homeostasis in liver disorders and in hepatic protection.

Chronic hepatitis

African Journals Online (AJOL)

infection by four diagnostic systems: first generation and second generation. ELlSA, second generation recombinant immunoblot assay and nested polymerase chain reaction analysis. HepatoJogy 1992; 16: 300-305. 14. Van der Poel CL, ... Alpha-1-antitrypsin deficiency. Alcoholic hepatitis. Non-alcoholic steatohepatitis.

Efficacy of Probiotics and Smectite in Rats with Non-Alcoholic Fatty Liver Disease.

Science.gov (United States)

Kobyliak, Nazarii; Abenavoli, Ludovico; Falalyeyeva, Tetyana; Beregova, Tetyana

2018-01-01

Today probiotics have been suggested as a treatment for the prevention of non-alcoholic fatty liver disease (NAFLD). Smectite is a natural silicate that binds to digestive mucous and has the ability to bind endo- and exotoxins. The present study was designed to determine whether probiotics plus smectite is superior to probiotic alone on the monosodium glutamate (MSG) induced NAFLD model in rats. We included 60 rats divided into 4 groups 15 animals in each. Rats of group I were intact. Newborns rats of groups II-IV were injected with MSG. The III (Symbiter) group received 2.5 ml/kg of multiprobiotic "Symbiter" containing concentrated biomass of 14 probiotic bacteria genera. The IV (Symbiter+Smectite) groups received "Symbiter Forte" combination of probiotic biomass with smectite gel (250 mg). In both interventional groups reduction of total NAS score as compared to MSG-obesity was observed. Indeed similar values of steatosis score (0.93 ± 0.22 vs. 0.87 ± 0.16) in both treatment groups, we observed that lower total score for Symbiter+ Smectite are associated with more pronounced reduction of lobular inflammation (0.13 ± 0.09 vs. 0.33 ± 0.15) as compared to administration of probiotic alone. This data accompanied with significant reduction of IL-1 and restoration of IL-10 between these 2 groups. Additional to alive probiotic administration of smectite gel due to his absorbent activity and mucus layer stabilization properties can impact on synergistic enhancement of single effect which manifested with reduction of lobular inflammation and at list partly steatohepatitis prevention.

Ursodeoxycholic Acid in Treatment of Non-cholestatic Liver Diseases: A Systematic Review.

Science.gov (United States)

Reardon, Jillian; Hussaini, Trana; Alsahafi, Majid; Azalgara, Vladimir Marquez; Erb, Siegfried R; Partovi, Nilufar; Yoshida, Eric M

2016-09-28

Aims: To systematically evaluate the literature for evidence to support the use of bile acids in non-cholestatic liver conditions. Methods: Searches were conducted on the databases of Medline (1948-March 31, 2015), Embase (1980-March 31, 2015) and the Cochrane Central Register of Controlled Trials, and on Google and Google Scholar to identify articles describing ursodeoxycholic acid (UDCA) and its derivatives for non-cholestatic hepatic indications. Combinations of the following search terms were used: ursodeoxycholic acid, ursodiol, bile acids and/or salts, non alcoholic fatty liver, non alcoholic steatohepatitis, fatty liver, alcoholic hepatitis, alcohol, liver disease, autoimmune, autoimmune hepatitis, liver transplant, liver graft, transplant rejection, graft rejection, ischemic reperfusion injury, reperfusion injury, hepatitis B, hepatitis C, viral hepatitis, chronic hepatitis, acute hepatitis, transaminases, alanine transaminase, liver enzymes, aspartate aminotransferase, gamma-glutamyl transferase, gamma-glutamyl transpeptidase, bilirubin, alkaline phosphatase. No search limits were applied. Additionally, references of the included studies were reviewed to identify additional articles. Results: The literature search yielded articles meeting inclusion criteria for the following indications: non-alcoholic fatty liver disease (n = 5); alcoholic liver disease (n = 2); autoimmune hepatitis (n = 6), liver transplant (n = 2) and viral hepatitis (n = 9). Bile acid use was associated with improved normalization of liver biochemistry in non-alcoholic fatty liver disease, autoimmune hepatitis and hepatitis B and C infections. In contrast, liver biochemistry normalization was inconsistent in alcoholic liver disease and liver transplantation. The majority of studies reviewed showed that normalization of liver biochemistry did not correlate to improvement in histologic disease. In the prospective trials reviewed, adverse effects associated with the bile acids were limited

The contribution of chemical shift imaging with digital subtracting images to the diagnosis of steatohepatitis

International Nuclear Information System (INIS)

Guo Xinghua; Wang Juanping; Zhang Chongjie; Zheng Guofang; Fan Ruiqiang; Zhu Sumei; Liu Qiwang

2006-01-01

Objective: To investigate the diagnosis value of chemical shift imaging with digital subtracting in steatohepatitis. Methods: The in-phase images were subtracted by the out-phase ones in 34 cases of steatohepatitis, and the CNR were measured on these subtracted images to estimate the steatosis of the liver. The relationship of CT grade of steatohepatitis and CNR from the subtracted images was analyzed to evaluate the relationship between CNR and the degree of hepatic steatosis. The sensitivity and specificity of the subtracting and eyeballing methods were compared with chi-square test. Results: On the subtracted images, the liver and spleen were seen nearly the same aspects as low signals, CNR=0.98±0.06, meanwhile the spongy vertebra and the subcutaneous or abdominal lipid were seen as obvious higher signals in 52 normal cases. On the 34 steatohepatitis, scattered high signals were seen in the liver, which made the signal of liver higher than that of spleen, CNR=3.25±0.91--14.35±6.10. There was positive correlation between CNR and CT grade in the 34 cases of steatohepatitis, r=0.893, P<0.01. The sensitivity and specificity of the subtracting method were 88.24% and 94. 23%, significantly higher than that of the eyeballing results, 32.35% and 80.77%, P<0.01 and P<0.05. Conclusion: Chemical shift imaging with digital subtracting is a sensitive, specific, objective method to diagnose steatohepatitis and it is of potential ability for quantitative diagnosis. (authors)

Monitoring food and non-alcoholic beverage promotions to children.

Science.gov (United States)

Kelly, B; King, L; Baur, L; Rayner, M; Lobstein, T; Monteiro, C; Macmullan, J; Mohan, S; Barquera, S; Friel, S; Hawkes, C; Kumanyika, S; L'Abbé, M; Lee, A; Ma, J; Neal, B; Sacks, G; Sanders, D; Snowdon, W; Swinburn, B; Vandevijvere, S; Walker, C

2013-10-01

Food and non-alcoholic beverage marketing is recognized as an important factor influencing food choices related to non-communicable diseases. The monitoring of populations' exposure to food and non-alcoholic beverage promotions, and the content of these promotions, is necessary to generate evidence to understand the extent of the problem, and to determine appropriate and effective policy responses. A review of studies measuring the nature and extent of exposure to food promotions was conducted to identify approaches to monitoring food promotions via dominant media platforms. A step-wise approach, comprising 'minimal', 'expanded' and 'optimal' monitoring activities, was designed. This approach can be used to assess the frequency and level of exposure of population groups (especially children) to food promotions, the persuasive power of techniques used in promotional communications (power of promotions) and the nutritional composition of promoted food products. Detailed procedures for data sampling, data collection and data analysis for a range of media types are presented, as well as quantifiable measurement indicators for assessing exposure to and power of food and non-alcoholic beverage promotions. The proposed framework supports the development of a consistent system for monitoring food and non-alcoholic beverage promotions for comparison between countries and over time. © 2013 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of the International Association for the Study of Obesity.

Genome-Wide Association Studies Candidate Gene to Dual Modifier of Nonalcoholic Steatohepatitis and Atherosclerosis

Directory of Open Access Journals (Sweden)

Clint L. Miller, PhD

2016-12-01

Full Text Available Nonalcoholic steatohepatitis is a common disease involving chronic accumulation of fat and inflammation in the liver, often leading to advanced fibrosis, cirrhosis, and cancer. It is known that nonalcoholic steatohepatitis shares many features with atherosclerosis; however, there are still no effective therapeutics. In a recent study published in Nature, investigators demonstrated that mice lacking a high-density lipoprotein–associated gene were surprisingly protected from both steatohepatitis and atherosclerosis through the stabilization of the liver X receptor. This work reveals a timely candidate target for 2 highly prevalent cardiovascular diseases.

Glycemic Allostasis during Mental Activities on Fasting in Non-alcohol Users and Alcohol Users with Different Durations of Abstinence.

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Welcome, Mo; Pereverzev, Va

2014-09-01

Glycemic allostasis is the process by which blood glucose stabilization is achieved through the balancing of glucose consumption rate and release into the blood stream under a variety of stressors. This paper reviews findings on the dynamics of glycemic levels during mental activities on fasting in non-alcohol users and alcohol users with different periods of abstinence. Referred articles for this review were searched in the databases of PubMed, Scopus, DOAJ and AJOL. The search was conducted in 2013 between January 20 and July 31. The following keywords were used in the search: alcohol action on glycemia OR brain glucose OR cognitive functions; dynamics of glycemia, dynamics of glycemia during mental activities; dynamics of glycemia on fasting; dynamics of glycemia in non-alcohol users OR alcohol users; glycemic regulation during sobriety. Analysis of the selected articles showed that glycemic allostasis during mental activities on fasting is poorly regulated in alcohol users even after a long duration of sobriety (1-4 weeks after alcohol consumption), compared to non-alcohol users. The major contributor to the maintenance of euglycemia during mental activities after the night's rest (during continuing fast) is gluconeogenesis.

Ethanol concentration in breastmilk after the consumption of non-alcoholic beer.

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Schneider, Claudia; Thierauf, Annette; Kempf, Jürgen; Auwärter, Volker

2013-06-01

During lactation, the consumption of ethanol is discussed controversially. After women drink alcoholic beverages, ethanol can be found in breastmilk with a time lag. To abstain from ethanol, but not from the taste of alcoholic beverages, in particular, non-alcoholic beer has become popular in recent years. According to regulations in the United States and most European countries, these "alcohol-free" beverages may still contain ethanol up to 1.2% by volume. To determine how much of this ethanol may reach the breastfed child, a drinking experiment with non-alcoholic beer was performed. Fifteen healthy breastfeeding women participated in the study. After at least 5 days of abstinence from ethanol and the donation of a void breastmilk sample, they were asked to drink 1.5 L of non-alcoholic beer within 1 hour. Breastmilk samples were collected using electronic breast pumps immediately after the end of drinking as well as 1 and 3 hours later. The milk was analyzed for ethanol by headspace-gas chromatography-flame ionization detection using a fully validated method. In two women, trace amounts of ethanol (up to 0.0021 g/L) were found in the samples gained immediately after the drinking period. In the other samples ethanol could not be detected (limit of detection=0.0006 g/L). The mother's consumption of non-alcoholic beer is likely innocuous for the breastfed infant.

Lack of ClC-2 Alleviates High Fat Diet-Induced Insulin Resistance and Non-Alcoholic Fatty Liver Disease

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Dongxia Fu

2018-03-01

Full Text Available Background/Aims: Non-alcoholic fatty liver disease (NAFLD is the most common cause of chronic liver disease. This study aims to investigate whether chloride channel 2 (ClC-2 is involved in high fat diet (HFD-induced NAFLD and possible molecular mechanisms. Methods: ClC-2 expression was liver-specifically downregulated using adeno-associated virus in C57BL/6 mice treated with a chow diet or HFD for 12 weeks. Peripheral blood and liver tissues were collected for biochemical and pathological estimation respectively. Western blotting was applied to detect the protein expressions of lipid synthesis-related enzymes and the phosphorylated level of IRS-1, Akt and mTOR. Results: ClC-2 mRNA level was significantly increased in patients with non-alcoholic steatohepatitis, which positively correlated with the plasma levels of alanine transaminase (ALT, aspartate transaminase (AST and insulin. Knockdown of ClC-2 in liver attenuated HFD-induced weight gain, obesity, hepatocellular ballooning, and liver lipid accumulation and fibrosis, accompanied by reduced plasma free fatty acid (FFA, triglyceride (TG, total cholesterol (TC, ALT, AST, glucose and insulin levels and homeostasis model of insulin resistance (HOMA-IR value. Moreover, HFD-treated mice lacking ClC-2 showed inhibited hepatic lipid accumulation via regulating lipid metabolism through decreasing sterol regulatory element binding protein (SREBP-1c expression and its downstream targeting enzymes such as fatty acid synthase (FAS, HMG-CoA reductase (HMGCR and acetyl-Coenzyme A carboxylase (ACCα. In addition, in vivo and in vitro results demonstrated that ClC-2 downregulation in HFD-treated mice or HepG2 cells increased the sensitivity to insulin via activation of IRS-1/Akt/mTOR signaling pathway. Conclusion: Our present study reveals a critical role of ClC-2 in regulating metabolic diseases. Mice lacking ClC-2 are associated with a remarkably beneficial metabolic phenotype, suggesting that decreasing Cl

Reduced impact of renal failure on the outcome of patients with alcoholic liver disease undergoing liver transplantation.

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Cheong, Jaeyoun; Galanko, Joseph A; Arora, Sumant; Cabezas, Joaquin; Ndugga, Nambi J; Lucey, Michael R; Hayashi, Paul H; Barritt, Alfred Sidney; Bataller, Ramon

2017-02-01

Pretransplant renal failure is commonly reported to be a poor prognostic indicator affecting survival after liver transplantation (LT). However, whether the impact of renal failure on patient outcome varies according to the aetiology of the underlying liver disease is largely unknown. We investigated the association between renal failure at the time of LT and patient outcome in patients with alcoholic liver disease (ALD) (n = 6920), non-alcoholic steatohepatitis (NASH) (n = 2956) and hepatitis C (HCV) (n = 14 922) using the United Network for Organ Sharing (UNOS) database between February 2002 and December 2013. A total of 24 798 transplant recipients were included. The presence of renal failure was more frequently seen in patients with ALD (23.95%) and NASH (23.27%) compared to patients with HCV (19.38%) (P renal failure was an independent predictor of poor survival. Renal failure showed detrimental effect on patient survival in the overall series (HR = 1.466, P renal failure was less marked in patients with ALD (HR = 1.31, P renal failure had better long-term prognosis than non-ALD patients. Renal failure at the time of LT conferred a lower patient and graft survival post-LT. However, renal failure has less impact on the outcome of patients with ALD than that of patients with non-alcoholic liver disease after LT. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Screening for nonalcoholic steatohepatitis by using cytokeratin 18 and transient elastography in HIV mono-infection.

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Amine Benmassaoud

Full Text Available HIV-infected individuals are at high risk of developing nonalcoholic steatohepatitis (NASH, a leading cause of end-stage liver disease in Western countries. Nonetheless, due to the invasiveness of liver biopsy, NASH remains poorly understood in HIV mono-infection. We aimed to characterize the prevalence and predictors of NASH in unselected HIV mono-infected patients by means of non-invasive diagnostic tools.HIV-infected adults without significant alcohol intake or co-infection with hepatitis B or C underwent a routine screening program employing transient elastography (TE with controlled attenuation parameter (CAP and the serum biomarker cytokeratin-18 (CK-18. NASH was diagnosed non-invasively as the coexistence of fatty liver (CAP ≥248 dB/m and CK-18 >246 U/L. Identified cases of NASH were offered a diagnostic liver biopsy. Predictors of NASH were determined by multivariate logistic regression analysis.202 consecutive HIV mono-infected patients were included. NASH was non-invasively diagnosed in 23 cases (11.4%. Among them, 17 underwent a liver biopsy, and histology confirmed NASH in all cases. The prevalence of NASH was higher in patients with hypertriglyceridemia (17.1%, insulin resistance defined by homeostasis model for assessment of insulin resistance (HOMA-IR (25%, those with detectable HIV viral load (42.9% and those with elevated ALT (53.6%. After adjustment, higher HOMA-IR (adjusted odds ratio [aOR] = 1.20, 95% CI 1.01-1.43; p = 0.03 and ALT (aOR = 2.39, 95% CI 1.50-3.79; p<0.001 were independent predictors of NASH.NASH, diagnosed by a non-invasive diagnostic approach employing CK-18 and TE with CAP, is common in unselected HIV mono-infected individuals, particularly in the presence of insulin resistance and elevated ALT.

Fructose, high fructose corn syrup, sucrose, and non-alcoholic liver disease

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Nonalcoholic fatty liver disease (NAFLD), formerly called nonalcoholic steatohepatitis, is characterized by hepatic steatosis and abnormal triglyceride accumulation in liver cells. Its etiology, pathophysiology, and pathogenesis are still poorly understood. Some have suggested that the increased in...

Fasting and nonfasting triglycerides in cardiovascular and other diseases.

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Piťha, J; Kovář, J; Blahová, T

2015-01-01

Moderately elevated plasma/serum triglycerides (2-10 mmol/l) signalize increased risk for cardiovascular disease or presence of non-alcoholic steatohepatitis. Extremely elevated triglycerides (more than 10 mmol/l) signalize increased risk for pancreatitis and lipemia retinalis. The concentration of triglycerides is regulated by many genetic and nongenetic factors. Extremely elevated triglycerides not provoked by nutritional factors, especially inappropriate alcohol intake are more likely to have a monogenic cause. On the contrary, mildly to moderately elevated triglycerides are often caused by polygenic disorders; these could be also associated with central obesity, insulin resistance, and diabetes mellitus. Concentration of triglycerides is also closely interconnected with presence of atherogenic remnant lipoproteins, impaired reverse cholesterol transport and more atherogenic small LDL particles. In general, there is tight association between triglycerides and many other metabolic factors including intermediate products of lipoprotein metabolism which are frequently atherogenic. Therefore, reliable evaluation of the independent role of triglycerides especially in atherosclerosis and cardiovascular disease is difficult. In individual cases values of HDL cholesterol, non-HDL cholesterol (total minus HDL cholesterol), non-HDL/nonLDL cholesterol (total minus HDL minus LDL cholesterol, especially in nonfasting status), atherogenic index of plasma and/or apolipoprotein B could help in decisions regarding aggressiveness of treatment.

Gene expression profile associated with superimposed non-alcoholic fatty liver disease and hepatic fibrosis in patients with chronic hepatitis C.

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Younossi, Zobair M; Afendy, Arian; Stepanova, Maria; Hossain, Noreen; Younossi, Issah; Ankrah, Kathy; Gramlich, Terry; Baranova, Ancha

2009-10-01

Hepatic steatosis occurs in 40-70% of patients chronically infected with hepatitis C virus [chronic hepatitis C (CH-C)]. Hepatic steatosis in CH-C is associated with progressive liver disease and a low response rate to antiviral therapy. Gene expression profiles were examined in CH-C patients with and without hepatic steatosis, non-alcoholic steatohepatitis (NASH) and fibrosis. This study included 65 CH-C patients who were not receiving antiviral treatment. Total RNA was extracted from peripheral blood mononuclear cells, quantified and used for one-step reverse transcriptase-polymerase chain reaction to profile 153 mRNAs that were normalized with six 'housekeeping' genes and a reference RNA. Multiple regression and stepwise selection assessed differences in gene expression and the models' performances were evaluated. Models predicting the grade of hepatic steatosis in patients with CH-C genotype 3 involved two genes: SOCS1 and IFITM1, which progressively changed their expression level with the increasing grade of steatosis. On the other hand, models predicting hepatic steatosis in non-genotype 3 patients highlighted MIP-1 cytokine encoding genes: CCL3 and CCL4 as well as IFNAR and PRKRIR. Expression levels of PRKRIR and SMAD3 differentiated patients with and without superimposed NASH only in the non-genotype 3 cohort (area under the receiver operating characteristic curve=0.822, P-value 0.006]. Gene expression signatures related to hepatic fibrosis were not genotype specific. Gene expression might predict moderate to severe hepatic steatosis, NASH and fibrosis in patients with CH-C, providing potential insights into the pathogenesis of hepatic steatosis and fibrosis in these patients.

Sales impact of displaying alcoholic and non-alcoholic beverages in end-of-aisle locations: an observational study.

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Nakamura, Ryota; Pechey, Rachel; Suhrcke, Marc; Jebb, Susan A; Marteau, Theresa M

2014-05-01

In-store product placement is perceived to be a factor underpinning impulsive food purchasing but empirical evidence is limited. In this study we present the first in-depth estimate of the effect of end-of-aisle display on sales, focussing on alcohol. Data on store layout and product-level sales during 2010-11 were obtained for one UK grocery store, comprising detailed information on shelf space, price, price promotion and weekly sales volume in three alcohol categories (beer, wine, spirits) and three non-alcohol categories (carbonated drinks, coffee, tea). Multiple regression techniques were used to estimate the effect of end-of-aisle display on sales, controlling for price, price promotion, and the number of display locations for each product. End-of-aisle display increased sales volumes in all three alcohol categories: by 23.2% (p = 0.005) for beer, 33.6% (p sales of alcohol and non-alcoholic beverages. Restricting the use of aisle ends for alcohol and other less healthy products might be a promising option to encourage healthier in-store purchases, without affecting availability or cost of products. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Type 2 Diabetes Mellitus and Simple Glucose Metabolism Parameters may Reliably Predict Nonalcoholic Fatty Liver Disease Features.

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Cazzo, Everton; Jimenez, Laísa Simakawa; Gestic, Martinho Antonio; Utrini, Murillo Pimentel; Chaim, Fábio Henrique Mendonça; Chaim, Felipe David Mendonça; Pareja, José Carlos; Chaim, Elinton Adami

2018-01-01

This study aims to investigate the correlation between features of NAFLD among individuals with morbid obesity and the surrogate IR markers homeostasis model assessment (HOMA), product of triglycerides and glucose (TyG), and triglyceride-to-high-density-lipoprotein ratio (TG/HDL-c). A cross-sectional study, which enrolled 89 individuals who consecutively underwent bariatric surgery from February through December 2015, was conducted. NAFLD was assessed through histological examination of liver biopsies and correlated with the values of HOMA, TyG, and TG/HDL-c and their respective cutoff points for insulin resistance (IR). xThe prevalence of liver steatosis was 68.5%; the affected individuals presented significantly higher fasting glucose levels (p diabetes mellitus (T2DM) (p < 0.001). Fibrosis occurred in 66.3% of the individuals and was significantly associated with higher levels of HbA1c (p < 0.05) and a higher prevalence of T2DM (p < 0.05). Steatohepatitis was present in 64% of the individuals and was significantly associated with older age (p < 0.05), higher levels of fasting glucose (p < 0.05), and a higher prevalence of T2DM (p < 0.001). After Bonferroni's adjustment, T2DM was significantly correlated with fibrosis (p < 0.01) and steatohepatitis (p < 0.001) and older age was significantly correlated with fibrosis (p < 0.05). T2DM was the only variable independently associated with fibrosis and steatohepatitis (p < 0.05 in both cases). T2DM was a significant predictor of NAFLD features among individuals undergoing bariatric surgery; higher Hb A1c was correlated with fibrosis. T2DM was independently associated with fibrosis and steatohepatitis. HOMA, TyG, and TG/HDL-c ratio did not present significant associations with NAFLD.

Correlation of blood glucose, serum chemerin and insulin resistance with NAFLD in patients with type 2 diabetes mellitus.

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Zhang, Zhengjun; Wang, Jijun; Wang, Hongmei

2018-03-01

Non-alcoholic fatty liver disease (NAFLD) is a form of clinical syndrome characterized by the fatty degeneration in liver histology and should be further investigated. The aim of the study was to investigate the effects of blood glucose, serum chemerin and insulin resistance on non-alcoholic fatty liver disease (NAFLD) in patients with type 2 diabetes mellitus to provide a basis for the prevention and treatment thereof. In total, 300 patients with type 2 diabetes mellitus treated and admitted into the Endocrinology Department of our hospital from June 2015 to June 2017 were enrolled and divided into the simple type 2 diabetes mellitus (group A) and concurrent NAFLD (group B) groups. The sex, age, body mass index (BMI), blood pressure, blood biochemical indexes and chemerin level were compared between the two groups. The patients in group B were further divided into the mild fatty liver (group B1), moderate fatty liver (group B2) and severe fatty liver (group B3) groups. The sex, age, BMI blood pressure, blood biochemical indexes and chemerin level were also compared among the three groups. Finally, the risk factors of type 2 diabetes mellitus complicated by NAFLD were analyzed via logistic regression. The BMI, fasting plasma glucose (FPG), 2 h post-prandial plasma glucose (2hPG), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), alanine aminotransferase (ALT), fasting insulin (FINS), homeostasis model assessment of insulin resistance (HOMA-IR) and HOMA-β indexes and serum chemerin level in group B were significantly higher than those in group A (Pdiabetes mellitus complicated by NAFLD is closely associated with severe glucose-lipid metabolism disorder and insulin resistance, and BMI, FPG, TC, LDL-c, FINS, HOMA-IR and chemerin constitute risk factors of concurrent NAFLD.

Metabolically induced liver inflammation leads to NASH and differs from LPS-or IL-1β-induced chronic inflammation

NARCIS (Netherlands)

Liang, W.; Lindeman, J.H.; Menke, A.L.; Koonen, D.P.; Morrison, M.; Havekes, L.M.; Hoek, A.M. van den; Kleemann, R.

2014-01-01

The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1β

Metabolically induced liver inflammation leads to NASH and differs from LPS- or IL-1 beta-induced chronic inflammation

NARCIS (Netherlands)

Liang, Wen; Lindeman, Jan H.; Menke, Aswin L.; Koonen, Debby P.; Morrison, Martine; Havekes, Louis M.; van den Hoek, Anita M.; Kleemann, Robert

The nature of the chronic inflammatory component that drives the development of non-alcoholic steatohepatitis (NASH) is unclear and possible inflammatory triggers have not been investigated systematically. We examined the effect of non-metabolic triggers (lipopolysaccharide (LPS), interleukin-1 beta

Antidepressant sales and the risk for alcohol-related and non-alcohol-related suicide in Finland--an individual-level population study.

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Moustgaard, Heta; Joutsenniemi, Kaisla; Myrskylä, Mikko; Martikainen, Pekka

2014-01-01

A marked decline in suicide rates has co-occurred with increased antidepressant sales in several countries but the causal connection between the trends remains debated. Most previous studies have focused on overall suicide rates and neglected differential effects in population subgroups. Our objective was to investigate whether increasing sales of non-tricyclic antidepressants have reduced alcohol- and non-alcohol-related suicide risk in different population subgroups. We followed a nationally representative sample of 950,158 Finnish adults in 1995-2007 for alcohol-related (n = 2,859) and non-alcohol-related (n = 8,632) suicides. We assessed suicide risk by gender and social group according to regional sales of non-tricyclic antidepressants, measured by sold doses per capita, prevalence of antidepressant users, and proportion of antidepressant users with doses reflecting minimally adequate treatment. Fixed-effects Poisson regression models controlled for regional differences and time trends that may influence suicide risk irrespective of antidepressant sales. The number of sold antidepressant doses per capita and the prevalence of antidepressant users were unrelated to male suicide risk. However, one percentage point increase in the proportion of antidepressant users receiving minimally adequate treatment reduced non-alcohol-related male suicide risk by one percent (relative risk 0.987, 95% confidence interval 0.976-0.998). This beneficial effect only emerged among men with high education, high income, and employment, among men without a partner, and men not owning their home. Alcohol-related suicides and female suicides were unrelated to all measures of antidepressant sales. We found little evidence that increase in overall sales or in the prevalence of non-tricyclic antidepressant users would have caused the fall in suicide rates in Finland in 1995-2007. However, the rise in the proportion of antidepressant users receiving minimally adequate treatment, possibly

Failure of carnitine in improving hepatic nitrogen content in alcoholic and non-alcoholic malnourished rats

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Luciana P. Rodrigues

2010-01-01

Full Text Available AIMS: To investigate the effect of carnitine supplementation on alcoholic malnourished rats' hepatic nitrogen content. METHODS: Malnourished rats, on 50% protein-calorie restriction with free access to water (malnutrition group and malnourished rats under the same conditions with free access to a 20% alcohol/water solution (alcohol group were studied. After the undernourishment period (4 weeks with or without alcohol, both groups were randomly divided into two subgroups, one of them nutritionally recovered for 28 days with free access to a normal diet and water (recovery groups and the other re-fed with free access to diet and water plus carnitine (0.1 g/g body weight/day by gavage (carnitine groups. No alcohol intake was allowed during the recovery period. RESULTS: The results showed: i no difference between the alcohol/no alcohol groups, with or without carnitine, regarding body weight gain, diet consumption, urinary nitrogen excretion, plasma free fatty acids, lysine, methionine, and glycine. ii Liver nitrogen content was highest in the carnitine recovery non-alcoholic group (from 1.7 to 3.3 g/100 g, P.05 was highest in the alcoholic animals. CONCLUSION: Carnitine supplementation did not induce better nutritional recovery.

Comparison of optic disc topography in non-glaucomatous eyes of children with juvenile diabetes mellitus and normal children.

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Elgin, Ufuk; Cankaya, Bülent; Simsek, Tulay; Batman, Aygen

2010-01-01

To compare the optic disc topography parameters of children with juvenile diabetes mellitus and normal children using the Heidelberg Retinal Tomograph (HRT III) (Heidelberg Engineering, Heidelberg, Germany). The topographic optic disc parameters (cup volume, cup area, rim volume, rim area, disc area, mean cup-to-disc ratio, and mean cup depth) of 28 non-glaucomatous eyes of 28 children with type 1 diabetes mellitus and 28 eyes of 28 age-matched healthy children were compared using the nonparametric Mann-Whitney U test. No statistically significant differences were found between cup volume (P = .782), cup area (P = .878), rim volume (P = .853), disc area (P = .452), mean cup-to-disc ratio (P = .852), and mean cup depth (P = .711) of eyes of cases with diabetes mellitus and normal subjects. This result suggests that non-glaucomatous eyes of children with type 1 diabetes mellitus and healthy subjects have similar topographic optic disc characteristics. Copyright 2010, SLACK Incorporated.

Controlled attenuation parameter using the FibroScan® XL probe for quantification of hepatic steatosis for non-alcoholic fatty liver disease in an Asian population.

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Chan, Wah-Kheong; Nik Mustapha, Nik Raihan; Wong, Grace Lai-Hung; Wong, Vincent Wai-Sun; Mahadeva, Sanjiv

2017-02-01

The FibroScan® XL probe reduces failure of liver stiffness measurement (LSM) and unreliable results in obese patients. The objective of this article is to evaluate the accuracy of controlled attenuation parameter (CAP) obtained using the XL probe for the estimation of hepatic steatosis in patients with non-alcoholic fatty liver disease (NAFLD). Adult NAFLD patients with a liver biopsy within six months were included and were examined with the FibroScan® M and XL probes. Histopathological findings were reported according to the Non-Alcoholic Steatohepatitis Clinical Research Network Scoring System. Participants who did not have fatty liver on ultrasonography were recruited as controls. A total of 57 NAFLD patients and 22 controls were included. The mean age of the NAFLD patients and controls was 50.1 ± 10.4 years and 20.2 ± 1.3 years, respectively ( p  = 0.000). The mean body mass index was 30.2 ± 5.0 kg per m 2 and 20.5 ± 2.4 kg per m 2 , respectively ( p  = 0.000). The distribution of steatosis grades were: S0, 29%; S1, 17%; S2, 35%; S3, 19%. The AUROC for estimation of steatosis grade ≥ S1, S2 and S3 was 0.94, 0.80 and 0.69, respectively, using the M probe, and 0.97, 0.81 and 0.67, respectively, using the XL probe. CAP obtained using the XL probe had similar accuracy as the M probe for the estimation of hepatic steatosis in NAFLD patients.

Chronic alcohol consumption, type 2 diabetes mellitus, insulin-like growth factor-I (IGF-I), and growth hormone (GH) in ethanol-treated diabetic rats.

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Kim, Soo-Jeong; Ju, Anes; Lim, Seul-Gi; Kim, Dai-Jin

2013-11-13

Alcohol has deleterious influences on glucose metabolism which may contribute to the development of type 2 diabetes mellitus (T2DM). Insulin-like growth factor I (IGF-I) and growth hormone (GH), which interact with insulin to modulate metabolic control, have been shown to be related to impaired glucose tolerance. This study was conducted to assess the possibility that altered circulating IGF-I and GH levels contribute to the exacerbation of T2DM by alcohol use in type 2 diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats and non-diabetic Long-Evans Tokushima Otsuka (LETO) rats. OLETF rats were pair-fed a Lieber-DeCarli Regular Ethanol diet and LETO rats were pair-fed a control diet for 6 weeks. At 6 weeks, an Intraperitoneal Glucose Tolerance Test (IP-GTT) was performed and IGF-I and GH levels were evaluated. Prior to an IP-GTT, OLETF-Ethanol (O-E) group had significantly a decrease in the mean glucose levels compared to OLETF-Control (O-C) group. At 120 min post IP-GTT, the O-E group had significantly an increase in the mean glucose levels compared to O-C group. The serum IGF-I levels were significantly lower and the serum GH levels were significantly higher in the O-E group than in L-C group. These results suggest that IGF-I and GH are prominent in defining the risk and development of T2DM, and may be adversely affected by heavy alcohol use, possibly mediating its diabetogenic effects. Thus, the overall glucose intolerance in the setting of alcoholism may be attributable to inappropriate alteration of IGF-I and GH levels. © 2013. Published by Elsevier Inc. All rights reserved.

Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus

DEFF Research Database (Denmark)

Almind, K; Bjørbaek, C; Vestergaard, H

1993-01-01

Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate...

Hepatic NAD(+) deficiency as a therapeutic target for non-alcoholic fatty liver disease in ageing.

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Zhou, Can-Can; Yang, Xi; Hua, Xia; Liu, Jian; Fan, Mao-Bing; Li, Guo-Qiang; Song, Jie; Xu, Tian-Ying; Li, Zhi-Yong; Guan, Yun-Feng; Wang, Pei; Miao, Chao-Yu

2016-08-01

Ageing is an important risk factor of non-alcoholic fatty liver disease (NAFLD). Here, we investigated whether the deficiency of nicotinamide adenine dinucleotide (NAD(+) ), a ubiquitous coenzyme, links ageing with NAFLD. Hepatic concentrations of NAD(+) , protein levels of nicotinamide phosphoribosyltransferase (NAMPT) and several other critical enzymes regulating NAD(+) biosynthesis, were compared in middle-aged and aged mice or patients. The influences of NAD(+) decline on the steatosis and steatohepatitis were evaluated in wild-type and H247A dominant-negative, enzymically-inactive NAMPT transgenic mice (DN-NAMPT) given normal or high-fat diet (HFD). Hepatic NAD(+) level decreased in aged mice and humans. NAMPT-controlled NAD(+) salvage, but not de novo biosynthesis pathway, was compromised in liver of elderly mice and humans. Given normal chow, middle-age DN-NAMPT mice displayed systemic NAD(+) reduction and had moderate NAFLD phenotypes, including lipid accumulation, enhanced oxidative stress, triggered inflammation and impaired insulin sensitivity in liver. All these NAFLD phenotypes, especially release of pro-inflammatory factors, Kupffer cell accumulation, monocytes infiltration, NLRP3 inflammasome pathway and hepatic fibrosis (Masson's staining and α-SMA staining), deteriorated further under HFD challenge. Oral administration of nicotinamide riboside, a natural NAD(+) precursor, completely corrected these NAFLD phenotypes induced by NAD(+) deficiency alone or HFD, whereas adenovirus-mediated SIRT1 overexpression only partially rescued these phenotypes. These results provide the first evidence that ageing-associated NAD(+) deficiency is a critical risk factor for NAFLD, and suggest that supplementation with NAD(+) substrates may be a promising therapeutic strategy to prevent and treat NAFLD. © 2016 The British Pharmacological Society.

Comparisons of Korsakoff and Non-Korsakoff Alcoholics on Neuropsychological Tests of Prefrontal Brain Functioning

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Oscar-Berman, Marlene; Kirkley, Shalene M.; Gansler, David A.; Couture, Ashley

2014-01-01

Background Evidence suggests that alcoholics exhibit particular deficits in brain systems involving the prefrontal cortex, but few studies have directly compared patients with and without Korsakoff’s syndrome on measures of prefrontal integrity. Methods Neuropsychological tasks sensitive to dysfunction of frontal brain systems were administered, along with standard tests of memory, intelligence, and visuospatial abilities, to 50 healthy, abstinent, nonamnesic alcoholics, 6 patients with alcohol-induced persisting amnestic disorder (Korsakoff’s syndrome), 6 brain-damaged controls with right hemisphere lesions, and 82 healthy nonalcoholic controls. Results Korsakoff patients were impaired on tests of memory, fluency, cognitive flexibility, and perseveration. Non-Korsakoff alcoholics showed some frontal system deficits as well, but these were mild. Cognitive deficits in non-Korsakoff alcoholics were related to age, duration of abstinence (less than 5 years), duration of abuse (more than 20 years), and amount of alcohol intake. Conclusions Abnormalities of frontal system functioning are most apparent in alcoholics with Korsakoff’s syndrome. In non-Korsakoff alcoholics, factors contributing to cognitive performance are age, duration of abstinence, duration of alcoholism, and amount of alcohol consumed. PMID:15100620

Male non-insulin users with type 2 diabetes mellitus are predisposed to gastric corpus-predominant inflammation after H. pylori infection.

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Yang, Yao-Jong; Wu, Chung-Tai; Ou, Horng-Yih; Lin, Chin-Han; Cheng, Hsiu-Chi; Chang, Wei-Lun; Chen, Wei-Ying; Yang, Hsiao-Bai; Lu, Cheng-Chan; Sheu, Bor-Shyang

2017-10-30

Both H. pylori infection and diabetes increase the risk of gastric cancer. This study investigated whether patients with type 2 diabetes mellitus (T2DM) and H. pylori infection had more severe corpus gastric inflammation and higher prevalence of precancerous lesions than non-diabetic controls. A total of 797 patients with type 2 diabetes mellitus were screened for H. pylori, of whom 264 had H. pylori infection. Of these patients, 129 received esophagogastroduodenoscopy to obtain topographic gastric specimens for gastric histology according to the modified Updated Sydney System, corpus-predominant gastritis index (CGI), Operative Link on Gastritis Assessment, and Operative Link on Gastric Intestinal Metaplasia Assessment. Non-diabetic dyspeptic patients who had H. pylori infection confirmed by esophagogastroduodenoscopy were enrolled as controls. The male as well as total T2DM patients had higher acute/chronic inflammatory and lymphoid follicle scores in the corpus than non-diabetic controls (p H. pylori-infected patients with type 2 diabetes mellitus. Patients with type 2 diabetes mellitus and H. pylori infection had more severe corpus gastric inflammation than non-diabetic controls. Moreover, male gender and non-insulin users of T2DM patients were predisposed to have corpus-predominant gastritis after H. pylori infection. ClinicalTrial: NCT02466919 , retrospectively registered may 17, 2015.

Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease

International Nuclear Information System (INIS)

Wahlang, Banrida; Song, Ming; Beier, Juliane I.; Cameron Falkner, K.; Al-Eryani, Laila; Clair, Heather B.; Prough, Russell A.; Osborne, Tanasa S.; Malarkey, David E.; Christopher States, J.; Cave, Matthew C.

2014-01-01

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20 mg/kg or 200 mg/kg in corn oil) for 12 weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260 + HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNFα were increased only at 20 mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200 mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200 mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant “second hit” in the transformation of steatosis to steatohepatitis. - Highlights: • Aroclor 1260 exposure decreased adiposity in mice fed with high fat diet • Aroclor 1260 exposure induced steatohepatitis in diet-induced obese mice • Aroclor 1260 (20 and 200 mg/kg) induced

Evaluation of Aroclor 1260 exposure in a mouse model of diet-induced obesity and non-alcoholic fatty liver disease

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Wahlang, Banrida [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Song, Ming [Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Beier, Juliane I. [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Cameron Falkner, K. [Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Al-Eryani, Laila [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Clair, Heather B.; Prough, Russell A. [Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Osborne, Tanasa S.; Malarkey, David E. [Cellular and Molecular Pathology Branch, National Toxicology Program, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (United States); Christopher States, J. [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Cave, Matthew C., E-mail: matt.cave@louisville.edu [Department of Pharmacology and Toxicology, University of Louisville School of Medicine, Louisville, KY 40202 (United States); Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, University of Louisville School of Medicine, Louisville, KY 40202 (United States); The Robley Rex Veterans Affairs Medical Center, Louisville, KY 40206 (United States)

2014-09-15

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD) in epidemiologic studies. The purpose of this study was to evaluate the hepatic effects of a PCB mixture, Aroclor 1260, whose composition mimics human bioaccumulation patterns, in a mouse model of diet-induced obesity (DIO). Male C57Bl/6J mice were fed control diet or 42% high fat diet (HFD) and exposed to Aroclor 1260 (20 mg/kg or 200 mg/kg in corn oil) for 12 weeks. A glucose tolerance test was performed; plasma/tissues were obtained at necropsy for measurements of adipocytokine levels, histology, and gene expression. Aroclor 1260 exposure was associated with decreased body fat in HFD-fed mice but had no effect on blood glucose/lipid levels. Paradoxically, Aroclor 1260 + HFD co-exposed mice demonstrated increased hepatic inflammatory foci at both doses while the degree of steatosis did not change. Serum cytokines, ALT levels and hepatic expression of IL-6 and TNFα were increased only at 20 mg/kg, suggesting an inhibition of pro-inflammatory cytokine production at the 200 mg/kg exposure. Aroclor 1260 induced hepatic expression of cytochrome P450s including Cyp3a11 (Pregnane-Xenobiotic Receptor target) and Cyp2b10 (constitutive androstane receptor target) but Cyp2b10 inducibility was diminished with HFD-feeding. Cyp1a2 (aryl hydrocarbon Receptor target) was induced only at 200 mg/kg. In summary, Aroclor 1260 worsened hepatic and systemic inflammation in DIO. The results indicated a bimodal response of PCB-diet interactions in the context of inflammation which could potentially be explained by xenobiotic receptor activation. Thus, PCB exposure may be a relevant “second hit” in the transformation of steatosis to steatohepatitis. - Highlights: • Aroclor 1260 exposure decreased adiposity in mice fed with high fat diet • Aroclor 1260 exposure induced steatohepatitis in diet-induced obese mice • Aroclor 1260 (20 and 200 mg/kg) induced

Hemochromatosis and diabetes mellitus: case report and literature review

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Karina Biavatti

2008-12-01

Full Text Available Hemochromatosis is a disorder characterized by iron storage amended. The acquired form of the disease can be caused by iron overload, alcoholism, infection by  C virus hepatitis, non-alcoholic hepatitis and chronic liver disease. The hereditary form can be caused by different mutations, being the C282Y and H63D the most frequent, 83% of cases are homozigotous for C282Y and 4% are compound heterozygous (C282Y/H63D. Hemochromatosis is a condition that can affect several organs, including: heart, joints, liver, hypothalamus, pituitary, pancreas and gonads. The aim of this study was to report a case of hemochromatosis and review the literature, with special attention to the association of hemochromatosis and diabetes mellitus. Patient 53 years, male presented to the doctor with arthralgia metacarpophalangeal, ankles, knees, coxofemoral right, and cervical and lumbar, complaints of fatigue and weight loss. Between 3 brothers, one of them had a diagnosis of hereditary hemochromatosis, with PCR demonstrating homozygous for C282Y. Labs: GOT 128 U/L, ALT 231 U/L, alkaline phosphatase 258 U/L, abdominal ultrasound with hepatomegaly and spleen at the upper limit of normal. Liver biopsy demonstrated portal fibrosis extension with hemosiderosis intense. It also made the diagnosis of diabetes mellitus. The research confirmed the same mutation of the changing family: homozygous for C282Y

Light to Moderate Alcohol Consumption Is Protective for Type 2 Diabetes Mellitus in Normal Weight and Overweight Individuals but Not the Obese

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Patricia A. Metcalf

2014-01-01

Full Text Available Objective. To examine the association between alcohol consumption and risk of type 2 diabetes mellitus (T2DM overall and by body mass index. Methods. Cross-sectional study of employed individuals. Daily alcohol intakes were calculated from a self-administered food frequency questionnaire by 5,512 Maori, Pacific Island, and European workers (3,992 men, 1520 women aged 40 years and above. Results. There were 170 new cases of T2DM. Compared to the group with no alcohol consumption and adjusting for age, sex, and ethnicity, the group consuming alcohol had relative risks of T2DM of 0.23 (95% CI: 0.08, 0.65 in normal weight individuals, 0.38 (0.18, 0.81 in overweight individuals, and 0.99 (0.59, 1.67 in obese individuals. After further adjusting for total cholesterol, HDL-cholesterol, triglycerides, smoking habit, physical activity, socioeconomic status, body mass index, and hypertension, the relative risks of T2DM were 0.16 (0.05, 0.50 in normal weight individuals, 0.43 (0.19, 0.97 in overweight individuals, and 0.92 (0.52, 1.60 in overweight individuals. Across the categories of alcohol consumption, there was an approximate U-shaped relationship for new cases of T2DM. There was no significant association between alcohol consumption and IGT. Conclusions. Alcohol consumption was protective against diagnosis of T2DM in normal and overweight individuals but not in the obese.

Prevalence of metabolic risk factors in non-alcoholic fatty liver disease

International Nuclear Information System (INIS)

Ashraf, N.; Sarfraz, T.; Mumtaz, Z.; Rizwan, M.

2017-01-01

Objective: To determine the frequency of factors leading to metabolic syndrome among non-alcoholic fatty liver disease (NAFLD) patients at a tertiary care hospital. Study Design: Descriptive cross sectional study. Place and Duration of Study: Department of Medicine, Combined Military Hospital, Kharian. Study was carried out over a period of six months from Jan 2015 to Jun 2015. Material and Methods: A total of 110 patients were included in this study. Past history was taken to rule out alcohol intake, viral and drug induced etiology, to determine the presence of co-morbidities like obesity, type 2 diabetes mellitus, arterial hypertension and dyslipidemia. Physical examination was carried to determine the arterial blood pressure and to determine anthropometric data that is weight, height, body mass index (BMI) and abdominal obesity by measuring waist circumference. Results: Mean age of the patients was 49.95 +- 8.86 years. There were 72 male patients (65.5%) while 38 (34.5%) patients were female. Different metabolic factors were central obesity in 82 patients (74.5%), raised high density lipoprotein (HDL) in 19 patients (17.3%), raised cholesterol in 87 patients (79.1%), raised blood pressure in 65 patients (59.1%) and raised fasting plasma glucose in 82 patients (74.5%). Mean BMI was 26.31 kg/m2 +- 2.68, mean waist circumference was 109.82 cm +- 18.41, mean cholesterol was 237.50 +- 48.47mg/dl, mean systolic blood pressure was 148.88mmHg +- 22.10, mean diastolic blood pressure was 90.41mmHg +- 12.25 and mean fasting plasma glucose was 113.28mg/dl +- 22.80. Stratification with regard to age was carried out. Conclusion: A considerable number of patients with NAFLD had metabolic syndrome. There was a close correlation between NAFLD and metabolic syndrome. (author)

Antidepressant Sales and the Risk for Alcohol-Related and Non-Alcohol-Related Suicide in Finland—An Individual-Level Population Study

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Moustgaard, Heta; Joutsenniemi, Kaisla; Myrskylä, Mikko; Martikainen, Pekka

2014-01-01

Objectives A marked decline in suicide rates has co-occurred with increased antidepressant sales in several countries but the causal connection between the trends remains debated. Most previous studies have focused on overall suicide rates and neglected differential effects in population subgroups. Our objective was to investigate whether increasing sales of non-tricyclic antidepressants have reduced alcohol- and non-alcohol-related suicide risk in different population subgroups. Methods We followed a nationally representative sample of 950,158 Finnish adults in 1995–2007 for alcohol-related (n = 2,859) and non-alcohol-related (n = 8,632) suicides. We assessed suicide risk by gender and social group according to regional sales of non-tricyclic antidepressants, measured by sold doses per capita, prevalence of antidepressant users, and proportion of antidepressant users with doses reflecting minimally adequate treatment. Fixed-effects Poisson regression models controlled for regional differences and time trends that may influence suicide risk irrespective of antidepressant sales. Results The number of sold antidepressant doses per capita and the prevalence of antidepressant users were unrelated to male suicide risk. However, one percentage point increase in the proportion of antidepressant users receiving minimally adequate treatment reduced non-alcohol-related male suicide risk by one percent (relative risk 0.987, 95% confidence interval 0.976–0.998). This beneficial effect only emerged among men with high education, high income, and employment, among men without a partner, and men not owning their home. Alcohol-related suicides and female suicides were unrelated to all measures of antidepressant sales. Conclusion We found little evidence that increase in overall sales or in the prevalence of non-tricyclic antidepressant users would have caused the fall in suicide rates in Finland in 1995–2007. However, the rise in the proportion of antidepressant

Alcohol Advertising in Sport and Non-Sport TV in Australia, during Children's Viewing Times.

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Kerry S O'Brien

Full Text Available Estimate the amount of alcohol advertising in sport vs. non-sport programming in Australian free-to-air TV and identify children's viewing audience composition at different times of the day. Alcohol advertising and TV viewing audience data were purchased for free-to-air sport and non-sport TV in Australia for 2012. We counted alcohol advertisements in sport and non-sport TV in daytime (6 am-8.29 pm and evening periods (8.30 pm-11.59 pm and estimated viewing audiences for children and young adults (0-4 years, 5-13 years, 14-17 years, 18-29 years. During the daytime, most of the alcohol advertising (87% was on sport TV. In the evening, most alcohol advertising (86% was in non-sport TV. There was little difference in the mean number of children (0-17 years viewing TV in the evening (N = 273,989, compared with the daytime (N = 235,233. In programs containing alcohol advertising, sport TV had a greater mean number of alcohol adverts per hour (mean 1.74, SD = 1.1 than non-sport TV (mean 1.35, SD = .94. Alcohol advertising during the daytime, when large numbers of children are watching TV, is predominantly in free-to-air sport TV. By permitting day-time advertising in sport programs and in any programs from 8.30 pm when many children are still watching TV, current regulations are not protecting children from exposure to alcohol advertising.

Alcohol Advertising in Sport and Non-Sport TV in Australia, during Children's Viewing Times.

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O'Brien, Kerry S; Carr, Sherilene; Ferris, Jason; Room, Robin; Miller, Peter; Livingston, Michael; Kypri, Kypros; Lynott, Dermot

2015-01-01

Estimate the amount of alcohol advertising in sport vs. non-sport programming in Australian free-to-air TV and identify children's viewing audience composition at different times of the day. Alcohol advertising and TV viewing audience data were purchased for free-to-air sport and non-sport TV in Australia for 2012. We counted alcohol advertisements in sport and non-sport TV in daytime (6 am-8.29 pm) and evening periods (8.30 pm-11.59 pm) and estimated viewing audiences for children and young adults (0-4 years, 5-13 years, 14-17 years, 18-29 years). During the daytime, most of the alcohol advertising (87%) was on sport TV. In the evening, most alcohol advertising (86%) was in non-sport TV. There was little difference in the mean number of children (0-17 years) viewing TV in the evening (N = 273,989), compared with the daytime (N = 235,233). In programs containing alcohol advertising, sport TV had a greater mean number of alcohol adverts per hour (mean 1.74, SD = 1.1) than non-sport TV (mean 1.35, SD = .94). Alcohol advertising during the daytime, when large numbers of children are watching TV, is predominantly in free-to-air sport TV. By permitting day-time advertising in sport programs and in any programs from 8.30 pm when many children are still watching TV, current regulations are not protecting children from exposure to alcohol advertising.

Pathomorphology of liver fibrosis in trepanobioptates of patients with steatohepatitis: main types, sources of development, features of progression

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V. A. Tumanskiy

2017-12-01

Full Text Available Until recently, among the pathologists, hepatologists and gastroenterologists, a discussion continues on the morphogenesis and gradation of liver fibrosis in non-alcoholic patients (NASH and alcoholic steatohepatitis (ASH. Purpose of the study. Studying the main types and sources of liver fibrosis in patients with nonalcoholic and alcoholic steatohepatitis, justifying the gradation of its severity, taking into account the quantitative dynamics of fibrogenic producer cells, the relative area of fibrosis and the deposition of type I, III and IV collagen in the liver. Material and methods. Histological and histochemical examination of liver fibrosis was performed in 198 patients with NASH of 18-79 years and in 79 patients with ASH of 47-63 years. Immunohistochemical study with measurement of the area of expression of activated αSMA + perisinusoidal stellate cells and αSMA + portal myofibroblasts with F1 (mild, F2 (moderate, F3 (severe fibrosis and F4 fibrosis / cirrhosis was performed in 80 trepanobioptates of patients with NASH (20 cases in each group, electron microscopic examination of the liver – in 10 deceased patients suffering from NASH. Results. In patients with NASH and ASH, there are two major types of liver fibrosis progress: the perisinusoidal pericellular and portal-Z3 perisinusoidal fibrosis, the development of which is the new generation of αSMA + star cells and αSMA + portal myofibroblasts of the fibrogenic immunophenotype, with co-expression of fascin and vimentin and absence of desmine expression. As the perisinusoidal pericellular fibrosis progresses from the mild F1 degree, to the severe F3 fibrosis and to the extremely severe F4 fibrosis / cirrhosis of the pericellular type, the area of the Masson-positive extracellular molecular-fibrous matrix (H = 88,70 р = 0,05 and the area of αSMA + collagen-producing stellate cells of perisinusoidal-pericellular localization (H = 45,12, p = 0,05. According to the data of

Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches

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Antonella Borrelli

2018-05-01

Full Text Available Non-alcoholic fatty liver disease (NAFLD represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC. Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the “Two Hit Theory” to the “Multiple Hit Theory”. However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS. The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first “Achilles’ heel” of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor. Recently, a new isoform of human manganese superoxide dismutase (MnSOD was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel

Age, Sex and Atherogenic Risk in Type 2 Diabetes Mellitus and Non ...

African Journals Online (AJOL)

The objective of this study was to assess the degree of atherogenic risk in type 2 DM and non-DM patients and to relate age and sex with atherogenic risk of the patients. A total of 192 participants, consisting of one hundred (100) type 2 diabetes mellitus patients and ninety-two (92) healthy controls were randomly selected ...

Rapid MRI using a modified Dixon technique: a non-invasive and effective method for detection and monitoring of fatty metamorphosis of the liver

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Fishbein, M.H. [Pediatric Gastroenterology, Dept. of Pediatrics, Springfield, IL (United States); Stevens, W.R. [St. John' s Hospital, Department of Radiology, Springfield, IL (United States)

2001-11-01

Fatty liver and non-alcoholic steatohepatitis are frequently associated with obesity. Weight loss is the mainstay of therapy for these conditions. In this case report, we used a modification of the Dixon method to demonstrate normalization of hepatic fat content in an obese individual with fatty liver following weight reduction. This technique involves fast gradient echo instead of spin echo, which has been utilized previously, as the former provides an accurate and more rapid means of assessing hepatic fat content. This technique is recommended for the assessment of hepatic steatosis in at-risk subjects. (orig.)

Rapid MRI using a modified Dixon technique: a non-invasive and effective method for detection and monitoring of fatty metamorphosis of the liver

International Nuclear Information System (INIS)

Fishbein, M.H.; Stevens, W.R.

2001-01-01

Fatty liver and non-alcoholic steatohepatitis are frequently associated with obesity. Weight loss is the mainstay of therapy for these conditions. In this case report, we used a modification of the Dixon method to demonstrate normalization of hepatic fat content in an obese individual with fatty liver following weight reduction. This technique involves fast gradient echo instead of spin echo, which has been utilized previously, as the former provides an accurate and more rapid means of assessing hepatic fat content. This technique is recommended for the assessment of hepatic steatosis in at-risk subjects. (orig.)

Myths about diabetes mellitus among non-diabetic individuals attending primary health care centers of karachi suburbs

International Nuclear Information System (INIS)

Nisar, N.; Khan, I.A.; Qadri, M.H.; Sher, A.

2007-01-01

To determine the myths and misconception about diabetes mellitus among non-diabetics attending primary health care centers of Gadap town, Karachi. Data was collected from four primary health care centers, located at Gadap Town, Karachi, and about 198 non-diabetic patients, above 18 years of age, and resident of Gadap Town, coming consecutively during the month of July 2005, were interviewed after taking the informed consent by using a semi-structured pre-tested questionnaire regarding prevailing myths about diabetes mellitus. The data collected was entered and analyzed by using a statistical package SPSS 11.0. Myths are defined as stories shared by a group, as part of the cultural identity. There were 198 participants in the study. Mean age of study participants was 40 years with standard deviation of 13, while approximately two thirds, 62.6%, were females. About 39% had history of type II diabetes mellitus in family. Overall myths related to diabetes mellitus were common among the individuals, males reported myths pre-dominantly contagiousness of diabetes (p= <0.03), diabetics becoming more ill (p=<0.009) and belief in spiritual treatment for permanent cure of diabetes (p=<0.006). People having 5- 16 years of education were less misconceived as compared to illiterates. The variables that showed significant difference were overeating, causing diabetes (p= <0.006), diabetics falling ill more than others (p=<0.04), eating less starch (p=< 0.0006) and alternative treatment like spiritual treatment (p=<0.00001). Family history of diabetes was also found significantly associated with reporting myths. Frequency of reporting myths was significantly high in this study with preponderance of males, family history of diabetes mellitus and educational status. Education serves as protective factor, hence efforts should be made to promote education and health awareness regarding the disease, with more emphasis on addressing myths regarding diabetes mellitus. (author)

Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

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Nancy Magee

2016-01-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL to nonalcoholic steatohepatitis (NASH and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning, inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future.

[Sugar content in non-alcoholic beverages and dietary recemmendations for children and adolescents].

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Bilek, Maciej; Rybakowa, Maria

2015-01-01

Increase the intake of sugars among the inhabitants of developed countries is related to, among others, increasing consumption of non-alcoholic beverages, for which the relationship with the epidemic of obesity, particularly among children and adolescents, has been proven. The most frequently cited are non-alcoholic beverages, sweetened glucose-fructose syrup, ie. colas, tonics, ice teas, lemonades. Fruit drinks, fruit juices and nectars are commonly cited as a healthy alternative to non-alcoholic beverages and, however, we do not pay attention to the high content of sugars in these products. Determine the content of sugars in non-alcohollic beverages popular among children and adolescents. 80 non-alcoholic beverages such as cola, tonic, lemonade, ice tea, flavored waters, fruit juices, fruit nectars and fruit drinks. Evaluation of the content of monosaccharides and sucrose was performed by high performance liquid chromatography method (HPLC). In the tested non-alcohollic beverages, monosaccharides ie. glucose and fructose and the disaccharide sucrose were detected in different proportions. The product with the lowest content of the total sugars content was flavored water with lemon flavor based on the mineral water (2.72 g/100 ml). In the group of fruit juices, fruit nectars and fruit drinks highest sugars content have been reported (12.94 g/100 ml for aronia nectar and 12.76 g/100ml for the juice of pomegranate and grapes). Significant monosaccharides and sucrose content in the tested non-alcohollic beverages tends to claim that their manufacturers should be obliged to place warnings on the labels addressed to patients suffering from disorders of carbohydrate metabolism. Educational programs for children and adolescents with diabetes should include information about the content of a large amount of sugars in fruit products: fruit juices, fruit drinks and fruit nectar. © Polish Society for Pediatric Endocrinology and Diabetology.

Hypolactasia is associated with insulin resistance in nonalcoholic steatohepatitis

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de Campos Mazo, Daniel Ferraz; Mattar, Rejane; Stefano, José Tadeu; da Silva-Etto, Joyce Matie Kinoshita; Diniz, Márcio Augusto; Duarte, Sebastião Mauro Bezerra; Rabelo, Fabíola; Lima, Rodrigo Vieira Costa; de Campos, Priscila Brizolla; Carrilho, Flair José; Oliveira, Claudia P

2016-01-01

AIM To assess lactase gene (LCT)-13910C>T polymorphisms in Brazilian non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) patients in comparison with healthy controls. METHODS This was a transverse observational clinical study with NAFLD patients who were followed at the Hepatology Outpatient Unit of the Hospital das Clínicas, São Paulo, Brazil. The polymorphism of lactase non-persistence/lactase persistence (LCT-13910C>T) was examined by PCR-restriction fragment length polymorphism technique in 102 liver biopsy-proven NAFLD patients (steatosis in 9 and NASH in 93) and compared to those of 501 unrelated healthy volunteers. Anthropometric, clinical, biochemical and liver histology data were analyzed. Continuous variables were compared using the t or Mann-Whitney tests, and categorical data were compared with the Fisher’s exact test. Univariate logistic regression and multivariate logistic regression adjusted for gender and age were performed. RESULTS No differences in the LCT-13910 genotype frequencies were noted between the NAFLD patients (66.67% of the patients with steatosis were CC, 33.33% were CT, and none were TT; 55.91% of the patients with NASH were CC, 39.78% were CT, and 4.3% were TT; P = 0.941) and the healthy controls (59.12% were CC, 35.67% were CT, and 5.21% were TT) or between the steatosis and NASH patients. That is, the distribution of the lactase non-persistence/lactase persistence polymorphism (LCT-13910C>T) in the patients with NAFLD was equal to that in the general population. In the NASH patients, the univariate analysis revealed that the lactase non-persistence (low lactase activity or hypolactasia) phenotype was associated with higher insulin levels (23.47 ± 15.94 μU/mL vs 15.8 ± 8.33 μU/mL, P = 0.027) and a higher frequency of insulin resistance (91.84% vs 72.22%, P = 0.02) compared with the lactase persistence phenotype. There were no associations between the LCT genotypes and diabetes (P = 0

Formulation for Effective Screening and Management of Nonalcoholic Steatohepatitis: Noninvasive NAFLD Management Strategy

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Kanae Hirose

2016-01-01

Full Text Available To establish a versatile means for screening and management of nonalcoholic steatohepatitis (NASH, shear wave velocity was measured in 20 normal controls and 138 consecutive nonalcoholic fatty liver disease (NAFLD cases. Referencing biochemical properties in 679 healthy volunteers, a formula to distinguish NASH suspects was established and validated in another cohort of 138 histologically proven NAFLD cases. NASH and simple steatosis (SS suspects were selected based on a plot of shear wave velocity against age. A formula consisting of five factors (γ-glutamyl transpeptidase, alkaline phosphatase, platelet counts, body mass index, and presence/absence of type 2 diabetes mellitus distinguished NASH suspects from SS suspects with area under the receiver operating characteristic curve values of 86% and 84% in the development and validation cohorts. Among 25 NAFLD cases in which shear wave velocity was repeatedly measured, 8 and 9 cases revealed an increase or decrease, respectively, of shear wave velocity in the entire liver, and the corresponding change in shear wave velocity was primarily observed in the right lobe or the left lateral segment, respectively. These results suggest that the new formula and sequential shear wave velocity measurements at each segment enable high throughput screening of NASH suspects and noninvasive assessment of pathophysiological alleviation/aggravation in cases of NASH.

Association of grade of non-alcoholic fatty liver disease and glycated albumin to glycated hemoglobin ratio in patients with type 2 diabetes mellitus.

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Jung, Chan-Hee; Lee, Bora; Choi, Dug-Hyun; Jung, Sang-Hee; Kim, Bo-Yeon; Kim, Chul-Hee; Kang, Sung-Koo; Mok, Ji-Oh

2017-03-01

The aim of this study was to investigate the association between the glycated albumin (GA) to glycated hemoglobin (HbA1c) (GA/HbA1c) ratio and grade of non-alcoholic fatty liver disease (NAFLD) on ultrasonography (US) in patients with type 2 diabetes mellitus (T2DM). This retrospective, cross-sectional study was performed with data obtained from 186 T2DM patients. Participants were assessed for serum GA/HbA1c ratio and fatty liver using US. NAFLD was defined as ultrasonographically detected fatty liver and was graded as normal, mild, moderate, and severe fatty liver. A total of 98 subjects (53%) were diagnosed with NAFLD on US, of which 47 (48%) had moderate-to-severe grade of NAFLD. The mean GA level and GA/HbA1c ratio significantly decreased across increasing NAFLD stages (34% vs. 29% vs. 27% vs. 28%, p=0.023 for trend; 3.1vs. 2.9vs. 2.6vs. 2.7, p=0.001 for trend, respectively), whereas there was no significant difference in HbA1c level among groups (p=0.714 for trend). There was a significant decrease in prevalence of NAFLD across GA/HbA1c ratio tertiles (67% vs. 58% vs. 41%, p for trend=0.007). Multivariate logistic regression analysis showed that individuals with the lowest GA/HbA1c ratio had an odds ratio (OR) of 2.75 (95% CI=1.06-7.13) for having any grade of NAFLD and an OR of 4.48 [1.20-16.74] for moderate-to-severe grade NAFLD compared with the highest GA/HbA1c ratio even after adjustment for confounding factors (p=0.038, p=0.026, respectively). The present study showed that GA/HbA1c ratio was significantly inversely associated with the presence and severity of NAFLD on US. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Association of non-alcoholic fatty liver disease with chronic kidney disease: a systematic review and meta-analysis.

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Giovanni Musso

2014-07-01

Full Text Available BACKGROUND: Chronic kidney disease (CKD is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD. METHODS AND FINDINGS: English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR, and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants, we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69-2.66 and incident (hazard ratio [HR] 1.79, 95% CI 1.65-1.95 CKD. Non-alcoholic steatohepatitis (NASH was associated with a higher prevalence (OR 2.53, 95% CI 1.58-4.05 and incidence (HR 2.12, 95% CI 1.42-3.17 of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3

Food Purchase Decision-Making Typologies of Women with Non-Insulin-Dependent Diabetes Mellitus.

Science.gov (United States)

Miller, Carla; Warland, Rex; Achterberg, Cheryl

1997-01-01

Food selection is a key factor in the nutritional management of diabetes. Criteria that influence point-of-purchase decision making in women with non-insulin-dependent diabetes mellitus were identified. Four types of shoppers were distinguished from interviews; cluster analysis was used to confirm the analysis. Usefulness in patient education is…

NON-ALCOHOLIC FATTY LIVER DISEASE IN CHILDREN

Directory of Open Access Journals (Sweden)

L.V. Chistova

2010-01-01

Full Text Available Metabolic syndrome that represents a totality of interrelated carbohydrate metabolism and lipid disorders, as well as a mechanism regulating arterial tension and endothelium function is one of the critical issues in pediatrics. In recent years, children with metabolic syndrome are increasingly diagnosed with liver injuries symptoms that are associated with a fatty transformation of the liver [1–3]. In this case, non-alcoholic fatty liver disease (NAFLD, a liver manifestation of metabolic syndrome is diagnosed. The diagnosis is confirmed in the absence of alcohol abuse in the past medical history, virus and autoimmune liver disease markers, elimination of toxic and drug influence, as wells as disorders of copper and iron exchange in the patient’s system. One of the key risk factors for developing NAFLD in children is overeating and reduced physical activities. It was believed in the past that NAFLD is relatively benign, however, there is evidence in current literature that this is a pathological condition that may develop and result in extreme fibrotic alterations in the liver parenchymatous tissue all the way to cirrhosis and hepatocellular carcinoma [4]. Early-stage identification and timely launch of therapy for NAFLD in children represents one of the most important objectives in modern healthcare. Key words: metabolic syndrome, non-alcoholic fatty liver disease, children, steatohepatosis. (Pediatric Pharmacology. – 2010; 7(6:68-72

Bach1 gene ablation reduces steatohepatitis in mouse MCD diet model.

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Inoue, Motoki; Tazuma, Susumu; Kanno, Keishi; Hyogo, Hideyuki; Igarashi, Kazuhiko; Chayama, Kazuaki

2011-03-01

Bach1 is a transcriptional repressor of heme oxygenase-1 (HO-1, a.k.a. HSP-32), which is an inducible enzyme and has anti-oxidation/anti-inflammatory properties shown in various models of organ injuries. Since oxidative stress plays a pivotal role in the pathogenesis of nonalcoholic steatohepatitis (NASH), HO-1 induction would be expected to prevent the development of NASH. In this study, we investigated the influence of Bach1 ablation in mice on the progression of NASH in methionine-choline deficient (MCD) diet model. Bach1 ablation resulted in significant induction of HO-1 mRNA and its activity in the liver. When fed MCD diet, Bach1(-/-) mice exhibited negligible hepatic steatosis compared to pronounced steatohepatitis in wild type mice with 6-fold increase in hepatic triglyceride content. Whereas feeding of MCD diet decreased mRNA expressions of peroxisome proliferator-activated receptor (PPAR) α and microsomal triglyceride transfer protein (MTP) in wild type mice, there were no change in Bach1(-/-) mice. In addition, hepatic concentration of malondialdehyde (MDA), a biomarker for oxidative stress as well as plasma alanine aminotransferase (ALT) was significantly lower in Bach1(-/-) mice. These findings suggest that Bach1 ablation exerts hepatoprotective effect against steatohepatitis presumably via HO-1 induction and may be a potential therapeutic target.

Clinical Utility of Red Cell Distribution Width in Alcoholic and Non-alcoholic Liver Cirrhosis

OpenAIRE

Milić, Sandra; Mikolašević, Ivana; Radić, Mladen; Hauser, Goran; Štimac, Davor

2011-01-01

Red blood cell distribution width (RDW) is a measure of the variation of red blood cell width that is reported as a part of standard complete blood count. Red blood cell distribution width results are often used together with mean corpuscular volume (MCV) results to figure out mixed anemia. The aim of our study was to compare the values of RDW in alcoholic and non-alcoholic liver cirrhosis and to determine if RDW follows the severity of disease according to Child-Pugh score. We re...

Free testosterone concentration is inversely associated with markers of liver fibrosis in men with type 2 diabetes mellitus.

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Miyauchi, Shozo; Miyake, Teruki; Miyazaki, Masumi; Eguchi, Toru; Niiya, Tetsuji; Yamamoto, Shin; Senba, Hidenori; Furukawa, Shinya; Matsuura, Bunzo; Hiasa, Yoichi

2017-12-28

The association between serum testosterone level and liver fibrosis in patients with non-alcoholic fatty liver disease is unclear. To clarify this association, we investigated the relationship between serum free testosterone concentration and markers of liver fibrosis in men with type 2 diabetes mellitus but no obvious features of alcohol consumption. This retrospective observational cross-sectional study enrolled 248 men with type 2 diabetes mellitus. The FIB-4 index was measured as a marker of liver fibrosis, and multiple linear regression analysis was performed to examine its association with serum free testosterone concentration. In addition, the 7S domain of type IV collagen (IV-7S) was examined in 140 of the 248 patients. The mean free testosterone concentration was 10.6 ± 6.8 pg/mL and the means of the FIB-4 index and IV-7S were 1.64 ± 1.19 and 4.02 ± 1.11 ng/mL, respectively. After adjusting for all relevant variables, serum free testosterone concentrations were inversely associated with both the FIB-4 index and IV-7S (β; -0.28, P diabetes mellitus may help to predict progression to advanced liver disease. Identifying patients at risk may help to prevent the development of cirrhosis and hepatocellular carcinoma.

Hepatic Encephalopathy

Medline Plus

Full Text Available ... Disease (NAFLD) & Non-alcoholic Steatohepatitis (NASH) Autoimmune Hepatitis Bile duct disease such as Primary Biliary Cirrhosis (PBC) ... spleen (splenomegaly) Stone-like particles in gallbladder and bile duct (gallstones) Liver cancer (hepatocellular carcinoma) Chronic liver ...

Measurement of the total antioxidant response using a novel automated method in subjects with nonalcoholic steatohepatitis

OpenAIRE

Horoz, Mehmet; Bolukbas, Cengiz; Bolukbas, Fusun F; Sabuncu, Tevfik; Aslan, Mehmet; Sarifakiogullari, Serpil; Gunaydin, Necla; Erel, Ozcan

2005-01-01

Abstract Background Oxidative stress, an increase in oxidants and/or a decrease in antioxidant capacity, is one of the potential biochemical mechanisms involved in the pathogenesis of nonalcoholic steatohepatitis. We aimed to investigate the total antioxidant response using a novel automated method in nonalcoholic steatohepatitis subjects. As a reciprocal measure, we also aimed to determine total peroxide level in the same plasma samples. Methods Twenty-two subjects with biopsy proven nonalco...

Nor-ursodeoxycholic acid reverses hepatocyte-specific nemo-dependent steatohepatitis.

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Beraza, Naiara; Ofner-Ziegenfuss, Lisa; Ehedego, Haksier; Boekschoten, Mark; Bischoff, Stephan C; Mueller, Michael; Trauner, Michael; Trautwein, Christian

2011-03-01

Hepatocyte-specific NEMO/NF-κB deleted mice (NEMO(Δhepa)) develop spontaneous non-alcoholic steatohepatitis (NASH). Free fatty acids and bile acids promote DR5 expression. TRAIL/NK cell-mediated activation of TRAIL-R2/DR5 plays an important role during acute injury in NEMO(Δhepa) mice. To inhibit the progression of NASH in the absence of hepatocyte-NEMO/NF-kB signaling. NEMOf/f and NEMO(Δhepa) mice were fed with a low-fat diet, and with two anticholestatic diets; UDCA and NorUDCA. The impact of these treatments on the progression of NASH was evaluated. We show that high expression of DR5 in livers from NEMO(Δhepa) mice is accompanied by an abundant presence of bile acids (BAs), misregulation of BA transporters and significant alteration of lipid metabolism-related genes. Additionally, mice lacking NEMO in hepatocytes spontaneously showed ductular response at young age. Unexpectedly, feeding of NEMO(Δhepa) mice with low-fat diet failed to improve chronic liver injury. Conversely, anti-cholestatic treatment with nor-ursodeoxycholic acid (NorUDCA), but not with ursodeoxycholic acid (UDCA), led to a significant attenuation of liver damage in NEMO(Δhepa) mice. The strong therapeutic effect of NorUDCA relied on a significant downregulation of LXR-dependent lipogenesis and the normalisation of BA metabolism through mechanisms involving cross-talk between Cyp7a1 and SHP. This was associated with the significant improvement of liver histology, NEMO(Δhepa)/NorUDCA-treated mice showed lower apoptosis and reduced CyclinD1 expression, indicating attenuation of the compensatory proliferative response to hepatocellular damage. Finally, fibrosis and ductular reaction markers were significantly reduced in NorUDCA-treated NEMO(Δhepa) mice. Overall, our work demonstrates the contribution of bile acids metabolism to the progression of NASH in the absence of hepatocyte-NF-kB through mechanisms involving DR5-apoptosis, inflammation and fibrosis. Our work suggests a potential

Alcohol Advertising in Sport and Non-Sport TV in Australia, during Children’s Viewing Times

Science.gov (United States)

O’Brien, Kerry S.; Carr, Sherilene; Ferris, Jason; Room, Robin; Miller, Peter; Livingston, Michael; Kypri, Kypros; Lynott, Dermot

2015-01-01

Estimate the amount of alcohol advertising in sport vs. non-sport programming in Australian free-to-air TV and identify children’s viewing audience composition at different times of the day. Alcohol advertising and TV viewing audience data were purchased for free-to-air sport and non-sport TV in Australia for 2012. We counted alcohol advertisements in sport and non-sport TV in daytime (6am-8.29pm) and evening periods (8.30pm-11.59pm) and estimated viewing audiences for children and young adults (0–4 years, 5–13 years, 14–17 years, 18–29 years). During the daytime, most of the alcohol advertising (87%) was on sport TV. In the evening, most alcohol advertising (86%) was in non-sport TV. There was little difference in the mean number of children (0–17 years) viewing TV in the evening (N = 273,989), compared with the daytime (N = 235,233). In programs containing alcohol advertising, sport TV had a greater mean number of alcohol adverts per hour (mean 1.74, SD = 1.1) than non-sport TV (mean 1.35, SD = .94). Alcohol advertising during the daytime, when large numbers of children are watching TV, is predominantly in free-to-air sport TV. By permitting day-time advertising in sport programs and in any programs from 8.30pm when many children are still watching TV, current regulations are not protecting children from exposure to alcohol advertising. PMID:26263170

Alcoholism and diabetes mellitus: Case report | Otieno | East African ...

African Journals Online (AJOL)

He was an alcoholic receiving psychiatric care for alcoholism. They both presented separately at different hospitals with decompensated diabetes following heavy alcohol consumption. The history and clinico-laboratory picture of both patients are presented and brief management programme and outcome are also given.

Impulsive and non-impulsive suicide attempts in patients treated for alcohol dependence.

Science.gov (United States)

Wojnar, Marcin; Ilgen, Mark A; Czyz, Ewa; Strobbe, Stephen; Klimkiewicz, Anna; Jakubczyk, Andrzej; Glass, Jennifer; Brower, Kirk J

2009-05-01

Suicidal behavior has been recognized as an increasing problem among alcohol-dependent subjects. The aim of the study was to identify correlates of impulsive and non-impulsive suicide attempts among a treated population of alcohol-dependent patients. A total of 154 patients with alcohol dependence consecutively admitted for addiction treatment participated in the study. Suicidal behavior was assessed together with severity of alcohol dependence, childhood abuse, impulsivity, and family history. A stop-signal procedure was used as a behavioral measure of impulsivity. Lifetime suicide attempts were reported by 43% of patients in alcohol treatment; of which 62% were impulsive. Compared to patients without a suicide attempt, those with a non-impulsive attempt were more likely to have a history of sexual abuse (OR=7.17), a family history of suicide (OR=4.09), and higher scores on a personality measure of impulsiveness (OR=2.27). The only significant factor that distinguished patients with impulsive suicide attempts from patients without a suicide attempt and from patients with a non-impulsive suicide attempt was a higher level of behavioral impulsivity (OR=1.84-2.42). Retrospective self-report of suicide attempts and family history. Lack of diagnostic measure.

Behaviors Predicting Foot Lesions in Patients with Non-Insulin-Dependent Diabetes Mellitus

OpenAIRE

Suico, Jeffrey G; Marriott, Deanna J; Vinicor, Frank; Litzelman, Debra K

1998-01-01

Associations between specific foot-care behaviors and foot lesions in patients with non-insulin-dependent diabetes mellitus were prospectively investigated. Data from a randomized controlled trial for preventing diabetic foot lesions were analyzed as a prospective cohort using logistic regression. Independent variables included foot-care behaviors, patient self-foot examination, going barefoot, availability of foot-care assistance, and visits to health-care providers. The dependent variable w...

Liver transplantation for NASH cirrhosis is not performed at the expense of major post-operative morbidity

NARCIS (Netherlands)

van den Berg, Eline H.; Douwes, Rianne M.; de Meijer, Vincent E.; Schreuder, Tim C. M. A.; Blokzijl, Hans

Background: Non-alcoholic steatohepatitis (NASH) is an emerging indication for liver transplantation (LT) and coexists with multiple comorbidities. Obese and cirrhotic patients experience more perioperative complications. Limited data exist about short-term complications after LT for NASH cirrhosis.

Yao et al., Afr J Tradit Complement Altern Med. (2014) 11(1):222-227

African Journals Online (AJOL)

cadewumi

. HIGH-FAT-DIET-INDUCING NON-ALCOHOLIC STEATOHEPATITIS IN RATS. Zheng Yao1, Xiao-Chen Liu 2, Ying-Er Gu 3*. 1Zhejiang Cancer Hospital, Hangzhou, [310022], P.R. China. 2Affiliated Hospital of Stomatology, School of Medicine ...

Hyperthyroidism Improves the Pathological Condition of Nonalcoholic Steatohepatitis: A Case of Nonalcoholic Steatohepatitis with Graves' Disease.

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Miyake, Teruki; Matsuura, Bunzo; Furukawa, Shinya; Todo, Yasuhiko; Yamamoto, Shin; Yoshida, Osamu; Imai, Yusuke; Watanabe, Takao; Yamamoto, Yasunori; Hirooka, Masashi; Tokumoto, Yoshio; Kumagi, Teru; Abe, Masanori; Seike, Hirotaka; Miyauchi, Shozo; Hiasa, Yoichi

2016-01-01

3,5,3'-triiodo-L-thyronine regulates the glucose metabolism, lipid metabolism, and hepatic steatosis. Several groups have shown the relationships between hypothyroidism and nonalcoholic fatty liver and hypothyroidism and nonalcoholic steatohepatitis (NASH). However, the effect of hyperthyroidism on NASH has not yet been investigated. We herein report effects of thyroid hormone on the pathological condition of NASH in a patient with NASH complicated by Graves' disease. In our case, the liver enzyme level improved with the increasing thyroid hormone level; however, the liver enzyme level was aggravated with the improving thyroid hormone level. Therefore, hyperthyroidism may improve the pathological condition of NASH.

Yellow Tongue Coating is Associated With Diabetes Mellitus Among Japanese Non-smoking Men and Women: The Toon Health Study.

Science.gov (United States)

Tomooka, Kiyohide; Saito, Isao; Furukawa, Shinya; Maruyama, Koutatsu; Eguchi, Eri; Iso, Hiroyasu; Tanigawa, Takeshi

2017-12-28

Yellow tongue coating is one of the clinical signs for diabetes mellitus according to traditional East Asian medicine. Few reports have been available on the association between yellow tongue coating and the prevalence of type 2 diabetes in the general population. We examined that association among population samples of non-smoking men and women. The study subjects were Japanese non-smoking men (n = 315) and women (n = 654) aged 30-79 years who resided in Toon city and participated in the Toon Health Study from July 2011 through November 2014. Tongue coating was assessed by a nationally licensed acupuncturist and classified into three categories of white (normal), light yellow, and yellow. We performed an oral glucose tolerance test to confirm the presence of diabetes mellitus and prediabetes. The associations between yellow tongue coating and the prevalence of diabetes mellitus and prediabetes were examined using multivariable logistic regression analyses, adjusting for age, sex, body mass index, drinking status, and physical activity. The multivariable odds ratios of diabetes mellitus were 1.39 (95% confidence interval [CI], 0.72-2.67) for light yellow tongue coating and 2.23 (95% CI, 1.16-4.30) for yellow tongue coating compared with white tongue coating. The respective multivariable odds ratios of prediabetes were 1.13 (95% CI, 0.80-1.61) and 1.43 (95% CI, 0.96-2.12). Yellow tongue coating was associated with higher prevalence of diabetes mellitus and tended to be associated with that of prediabetes among Japanese non-smoking men and women.

Human leukocyte antigen class II susceptibility conferring alleles among non-insulin dependent diabetes mellitus patients

International Nuclear Information System (INIS)

Tipu, H.N.; Ahmed, T.A.; Bashir, M.M.

2010-01-01

To determine the frequency of Human Leukocyte Antigen (HLA) class II susceptibility conferring alleles among type 2 Diabetes mellitus patients, in comparison with healthy controls. Cross-sectional comparative study. Patients with non-insulin dependent Diabetes mellitus meeting World Health Organization criteria were studied. These were compared with age and gender matched healthy control subjects. For each subject (patients as well as controls), DNA was extracted from ethylene diamine tetra-acetate sample and HLA class II DRB1 typing was carried out at allele group level (DRB1*01-DRB1*16) by sequence specific primers. Human leukocyte antigen DRB1 type was determined by agarose gel electrophoresis and results were recorded. Frequencies were determined as number of an allele divided by total number of alleles per group; p-value was computed using Pearson's chi-square test. Among the 100 patients, there were 63 males and 37 females with 68 controls. A total of 13 different HLA DRB1 alleles were detected, with DRB1*15 being the commonest in both the groups. The allele DRB1*13 had statistically significant higher frequency in patient group as compared to controls (p 0.005). HLA DRB1*13 was found with a significantly increased frequency in non-insulin dependent Diabetes mellitus. (author)

Obstructive Sleep Apnea and Non-alcoholic Fatty Liver Disease: Is the Liver Another Target?

Directory of Open Access Journals (Sweden)

Aibek eMirrakhimov

2012-10-01

Full Text Available Obstructive sleep apnea (OSA is recurrent obstruction of the upper airway during sleep leading to intermittent hypoxia (IH. OSA has been associated with all components of the metabolic syndrome as well as with non-alcoholic fatty liver disease (NAFLD. NAFLD is a common condition ranging in severity from uncomplicated hepatic steatosis to steatohepatitis (NASH, liver fibrosis and cirrhosis. The gold standard for the diagnosis and staging of NAFLD is liver biopsy. Obesity and insulin resistance lead to liver steatosis, but the causes of the progression to NASH are not known. Emerging evidence suggests that OSA may play a role in the progression of hepatic steatosis and the development of NASH. Several cross-sectional studies showed that the severity of IH in patients with OSA predicted the severity of NAFLD on liver biopsy. However, neither prospective nor interventional studies with continuous positive airway pressure (CPAP treatment have been performed. Studies in a mouse model showed that IH causes triglyceride accumulation in the liver and liver injury as well as hepatic inflammation. The mouse model provided insight in the pathogenesis of liver injury showing that (1 IH accelerates the progression of hepatic steatosis by inducing adipose tissue lipolysis and increasing free fatty acids (FFA flux into the liver; (2 IH up-regulates lipid biosynthetic pathways in the liver; (3 IH induces oxidative stress in the liver; (4 IH up-regulates hypoxia inducible factor 1 alpha and possibly HIF-2 alpha, which may increase hepatic steatosis and induce liver inflammation and fibrosis. However, the role of FFA and different transcription factors in the pathogenesis of IH-induced NAFLD is yet to be established. Thus, multiple lines of evidence suggest that IH of OSA may contribute to the progression of NAFLD but definitive clinical studies and experiments in the mouse model have yet to be done.

LPSF/GQ-02 inhibits the development of hepatic steatosis and inflammation in a mouse model of non-alcoholic fatty liver disease (NAFLD).

Science.gov (United States)

Soares e Silva, Amanda Karolina; de Oliveira Cipriano Torres, Dilênia; dos Santos Gomes, Fabiana Oliveira; dos Santos Silva, Bruna; Lima Ribeiro, Edlene; Costa Oliveira, Amanda; dos Santos, Laise Aline Martins; de Lima, Maria do Carmo Alves; Pitta, Ivan da Rocha; Peixoto, Christina Alves

2015-01-01

Non-alcoholic fatty liver disease (NAFLD) defines a wide spectrum of liver diseases that extends from simple steatosis to non-alcoholic steatohepatitis. Although the pathogenesis of NAFLD remains undefined, it is recognized that insulin resistance is present in almost all patients who develop this disease. Thiazolidinediones (TZDs) act as an insulin sensitizer and have been used in the treatment of patients with type 2 diabetes and other insulin-resistant conditions, including NAFLD. Hence, therapy of NAFLD with insulin-sensitizing drugs should ideally improve the key hepatic histological changes, while also reducing cardiometabolic and cancer risks. Controversially, TZDs are associated with the development of cardiovascular events and liver problems. Therefore, there is a need for the development of new therapeutic strategies to improve liver function in patients with chronic liver diseases. The aim of the present study was to assess the therapeutic effects of LPSF/GQ-02 on the liver of LDLR-/- mice after a high-fat diet. Eighty male mice were divided into 4 groups and two different experiments: 1-received a standard diet; 2-fed with a high-fat diet (HFD); 3-HFD+pioglitazone; 4-HFD+LPSF/GQ-02. The experiments were conducted for 10 or 12 weeks and in the last two or four weeks respectively, the drugs were administered daily by gavage. The results obtained with an NAFLD murine model indicated that LPSF/GQ-02 was effective in improving the hepatic architecture, decreasing fat accumulation, reducing the amount of collagen, decreasing inflammation by reducing IL-6, iNOS, COX-2 and F4 / 80, and increasing the protein expression of IκBα, cytoplasmic NFκB-65, eNOS and IRS-1 in mice LDLR -/-. These results suggest a direct action by LPSF/GQ-02 on the factors that affect inflammation, insulin resistance and fat accumulation in the liver of these animals. Further studies are being conducted in our laboratory to investigate the possible mechanism of action of LPSF/GQ-02 on

Health and economic benefits of reducing sugar intake in the USA, including effects via non-alcoholic fatty liver disease: a microsimulation model

Science.gov (United States)

Vreman, Rick A; Goodell, Alex J; Rodriguez, Luis A; Porco, Travis C; Lustig, Robert H; Kahn, James G

2017-01-01

Objectives Excessive consumption of added sugars in the human diet has been associated with obesity, type 2 diabetes (T2D), coronary heart disease (CHD) and other elements of the metabolic syndrome. Recent studies have shown that non-alcoholic fatty liver disease (NAFLD) is a critical pathway to metabolic syndrome. This model assesses the health and economic benefits of interventions aimed at reducing intake of added sugars. Methods Using data from US National Health Surveys and current literature, we simulated an open cohort, for the period 2015–2035. We constructed a microsimulation model with Markov chains for NAFLD (including steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC)), body mass index, T2D and CHD. We assessed reductions in population disease prevalence, disease-attributable disability-adjusted life years (DALYs) and costs, with interventions that reduce added sugars consumption by either 20% or 50%. Findings The model estimated that a 20% reduction in added sugars intake will reduce prevalence of hepatic steatosis, NASH, cirrhosis, HCC, obesity, T2D and CHD. Incidence of T2D and CHD would be expected to decrease by 19.9 (95% CI 12.8 to 27.0) and 9.4 (95% CI 3.1 to 15.8) cases per 100 000 people after 20 years, respectively. A 20% reduction in consumption is also projected to annually avert 0.767 million (M) DALYs (95% CI 0.757M to 0.777M) and a total of US$10.3 billion (B) (95% CI 10.2B to 10.4B) in discounted direct medical costs by 2035. These effects increased proportionally when added sugars intake were reduced by 50%. Conclusions The decrease in incidence and prevalence of disease is similar to results in other models, but averted costs and DALYs were higher, mainly due to inclusion of NAFLD and CHD. The model suggests that efforts to reduce consumption of added sugars may result in significant public health and economic benefits. PMID:28775179

Macrophage Stimulating Protein Enhances Hepatic Inflammation in a NASH Model

NARCIS (Netherlands)

Li, Jieyi; Chanda, Dipanjan; van Gorp, Patrick J.; Jeurissen, Mike L. J.; Houben, Tom; Walenbergh, Sofie M. A.; Debets, Jacques; Oligschlaeger, Yvonne; Gijbels, Marion J. J.; Neumann, Dietbert; Shiri-Sverdlov, Ronit

2016-01-01

Non-alcoholic steatohepatitis (NASH) is a common liver disease characterized by hepatic lipid accumulation (steatosis) and inflammation. Currently, therapeutic options are poor and the long-term burden to society is constantly increasing. Previously, macrophage stimulating protein (MSP)-a serum

Non-viral causes of liver cancer: does obesity led inflammation play a role?

Science.gov (United States)

Alzahrani, Badr; Iseli, Tristan J; Hebbard, Lionel W

2014-04-10

Liver cancer is the fifth most common cancer worldwide and the third most common cause of cancer mortality. Hepatocellular carcinoma (HCC) accounts for around 90% of primary liver cancers. Chronic infection with hepatitis B and hepatitis C viruses are two of most common causes of liver cancer. However, there are non-viral factors that are associated with liver cancer development. Numerous population studies have revealed strong links between obesity and the development of liver cancer. Obesity can alter hepatic pathology, metabolism and promote inflammation, leading to nonalcoholic fatty liver disease (NAFLD) and the progression to the more severe form, non-alcoholic steatohepatitis (NASH). NASH is characterised by prominent steatosis and inflammation, and can lead to HCC. Here, we discuss the role of obesity in inflammation and the principal signalling mechanisms involved in HCC formation. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Non-invasive separation of alcoholic and non-alcoholic liver disease with predictive modeling.

Directory of Open Access Journals (Sweden)

Jan-Peter Sowa

Full Text Available BACKGROUND & OBJECTIVE: Currently, a major clinical challenge is to distinguish between chronic liver disease caused by metabolic syndrome (non-alcoholic fatty liver disease, NAFLD from that caused by long term or excessive alcohol consumption (ALD. The etiology of severe liver disease affects treatment options and priorities for liver transplantation and organ allocation. Thus we compared physiologically similar NAFLD and ALD patients to detect biochemical differences for improved separation of these mechanistically overlapping etiologies. METHODS: In a cohort of 31 NAFLD patients with BMI below 30 and a cohort of ALD patient with (ALDC n = 51 or without cirrhosis (ALDNC n = 51 serum transaminases, cell death markers and (adipo-cytokines were assessed. Groups were compared with One-way ANOVA and Tukey's correction. Predictive models were built by machine learning techniques. RESULTS: NAFLD, ALDNC or ALDC patients did not differ in demographic parameters. The ratio of alanine aminotransferase/aspartate aminotransferase--common serum parameters for liver damage--was significantly higher in the NAFLD group compared to both ALD groups (each p<0.0001. Adiponectin and tumor necrosis factor(TNF-alpha were significantly lower in NAFLD than in ALDNC (p<0.05 or ALDC patients (p<0.0001. Significantly higher serum concentrations of cell death markers, hyaluronic acid, adiponectin, and TNF-alpha (each p<0.0001 were found in ALDC compared to ALDNC. Using machine learning techniques we were able to discern NAFLD and ALDNC (up to an AUC of 0.9118±0.0056 or ALDC and ALDNC (up to an AUC of 0.9846±0.0018, respectively. CONCLUSIONS: Machine learning techniques relying on ALT/AST ratio, adipokines and cytokines distinguish NAFLD and ALD. In addition, severity of ALD may be non-invasively diagnosed via serum cytokine concentrations.

Development and Quality Evaluation of a Non-Alcoholic Beverage ...

African Journals Online (AJOL)

Development and Quality Evaluation of a Non-Alcoholic Beverage from Cocoyam ( Xanthosoma sagittifolium and Colocasia esculenta ) ... Nigerian Food Journal ... evaluation were conducted on the products to assess the highest preference.

Identifying non-pharmacological risk factors for falling in older adults with type 2 diabetes mellitus: a systematic review.

Science.gov (United States)

Gravesande, Janelle; Richardson, Julie

2017-07-01

To identify the non-pharmacological risk factors for falling in older adults with type 2 diabetes mellitus (DM2). A systematic review of randomized controlled trials, prospective cohort studies, cross-sectional studies and before/after studies was conducted. Eligible studies identified non-pharmacological risk factors for falling in older adults with DM2. Medline, Embase, Pubmed and CINAHL were searched for relevant studies published through December 2015. Reference lists were also searched for relevant studies. Search terms were DM2, risk factors, falls and falling, older adults, aging, non-insulin dependent diabetes mellitus, accidental falls and trip. Publication language was restricted to English. Thirteen studies met the inclusion criteria: four cross-sectional, six prospective cohorts, two randomized controlled trials and one before/after study. These studies included a total of 13,104 participants, ≥50 years. The most common risk factors for falling were impaired balance, reduced walking velocity, peripheral neuropathy and comorbid conditions. However, lower extremity pain, being overweight and comorbid conditions had the greatest impact on fall risk. Interventions to reduce falling in older adults with type 2 diabetes mellitus should focus on reducing lower extremity pain, reducing body weight and managing comorbid conditions. Implications for Rehabilitation    Diabetes mellitus:   • Older adults with type 2 diabetes mellitus (DM2) have a higher risk for falling than older adults without.   • Older adults with DM2 are more likely to suffer serious injuries when they fall.   • Comprehensive risk factor identification is necessary for rehabilitation professionals to accurately determine whether their clients are at risk for falling.   • Rehabilitation professionals also need to tailor interventions based on the client's risk factors in order to effectively reduce falls and fall-related injuries.

Impact of alcohol and alcohol mixed with energy drinks on non-medical prescription stimulant use in a nationally representative sample of 12th-grade students.

Science.gov (United States)

Housman, Jeff M; Williams, Ronald D; Woolsey, Conrad L

2016-08-01

Approximately 30% of high school students use energy drinks. Alcohol use and alcohol mixed with energy drink use (AmED) is associated with risky behavior, including non-medical prescription stimulant use. We assessed alcohol-only, AmED and non-medical prescription stimulant use among 12th grade students in the U.S. using a nationally representative secondary data from the 2012 Monitoring the Future Study. Wilcoxon-Mann-Whitney tests and logistic regression analyses were used to determine differences in non-medical prescription stimulant use by students who used alcohol-only versus AmED and to identify covariates of non-medical prescription stimulant use. Pearson-product moment coefficients were used to determine strength of variable relationships. Significant differences were found in frequency of Ritalin (p energy drink and AmED use, as the combined effects of stimulants contained in energy drinks and the depressant effects of alcohol appear to be associated with increased non-medical prescription stimulant use. Research on the influential factors related to energy drinks, alcohol, and non-medical prescription stimulants will help practitioners to more appropriately design prevention and intervention strategies addressing these high-risk behaviors. (Am J Addict 2016;25:378-384). © 2016 American Academy of Addiction Psychiatry.

Trapping of oxidized LDL in lysosomes of Kupffer cells is a trigger for hepatic inflammation

NARCIS (Netherlands)

Bieghs, Veerle; Walenbergh, Sofie M. A.; Hendrikx, Tim; van Gorp, Patrick J.; Verheyen, Fons; Olde Damink, Steven W.; Masclee, Ad A.; Koek, Ger H.; Hofker, Marten H.; Binder, Christoph J.; Shiri-Sverdlov, Ronit

Background & Aims: Non-alcoholic steatohepatitis (NASH) is characterized by steatosis and inflammation. The transition from steatosis towards NASH represents a key step in pathogenesis, as it will set the stage for further severe liver damage. Under normal conditions, lipoproteins that are

The changes in levels of C-P and insulin in glucose tolerance test in rats with experimental non-insulin dependent diabetes mellitus

International Nuclear Information System (INIS)

Liu Xinqiu; Lei Ming

2001-01-01

The changes in levels of C-P and insulin were investigated in the GT test in rats with non-insulin dependent diabetes mellitus. In order to establish a model of non-insulin dependent diabetes mellitus (NIDDM), the authors injected rats with small dose streptozocoi (i.v.). Two weeks after the injection, the rats developed impaired glucose tolerance (IGT). Then, they were fed with high energy diet for eight weeks to form NIDDM. The results showed that the highest peak time of C-P and insulin in NIDDM was remarkably later than that in normal subjects, the highest peak time was in two hours (P < 0.05). The data suggest that level of C-P could accurately respond to level of insulin, and this experimental non-insulin dependent diabetes mellitus model is ideal

Hepatocyte caspase-8 is an essential modulator of steatohepatitis in rodents

NARCIS (Netherlands)

Hatting, M.; Zhao, G.; Schumacher, F.; Sellge, G.; Masaoudi, Al M.; Gaßler, N.; Boekschoten, M.V.; Müller, M.R.; Liedtke, C.; Cubero, F.J.; Trautwein, C.

2013-01-01

In human and murine models of nonalcoholic steatohepatitis (NASH), increased hepatocyte apoptosis is a critical mechanism contributing to inflammation and fibrogenesis. Caspase 8 (Casp8) is essential for death-receptor-mediated apoptosis activity and therefore its modulation might be critical for

New clinical score to diagnose nonalcoholic steatohepatitis in obese patients

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Pulzi Fernanda BU

2011-02-01

Full Text Available Abstract Background Nonalcoholic fatty liver disease (NAFLD is the most frequent disease associated with abnormal liver tests that is characterized by a wide spectrum of liver damage, ranging from simple macro vesicular steatosis to steatohepatitis (NASH, cirrhosis or liver carcinoma. Liver biopsy is the most precise test to differentiate NASH from other stages of NAFLD, but it is an invasive and expensive method. This study aimed to create a clinical laboratory score capable of identify individual with NASH in severely obese patients submitted to bariatric surgery. Methods The medical records from 66 patients submitted to gastroplasty were reviewed. Their chemistry profile, abdominal ultrasound (US and liver biopsy done during the surgical procedure were analyzed. Patients were classified into 2 groups according to liver biopsy: Non-NASH group - those patients without NAFLD or with grade I, II or III steatosis; and NASH group - those with steatohepatitis or fibrosis. The t-test was used to compare each variable with normal distribution between NASH and Non-NASH groups. When comparing proportions of categorical variables, we used chi-square or z-test, where appropriate. A p-value Results 83% of patients with obesity grades II or III showed NAFLD, and the majority was asymptomatic. Total Cholesterol (TC≥200 mg/dL, alanine aminotransferase (ALT ≥30, AST/ALT ratio (AAR≤ 1, gammaglutaril-transferase (γGT≥30 U/L and abdominal US, compatible with steatosis, showed association with NASH group. We proposed 2 scores: Complete score (TC, ALT, AAR, γGT and US and the simplified score, where US was not included. The combination of biochemical and imaging results improved accuracy to 84.4% the recognition of NASH (sensitivity 70%, specificity 88.6%, NPV 91.2%, PPV 63. 6%. Conclusion Alterations in TC, ALT, AAR, γGT and US are related to the most risk for NASH. The combination of biochemical and imaging results improved accuracy to 84.4% the

Non-alcoholic Korsakoff syndrome in psychiatric patients with a history of undiagnosed Wernicke's encephalopathy.

Science.gov (United States)

Nikolakaros, Georgios; Ilonen, Tuula; Kurki, Timo; Paju, Janina; Papageorgiou, Sokratis G; Vataja, Risto

2016-11-15

Wernicke's encephalopathy is often undiagnosed, particularly in non-alcoholics. There are very few reports of non-alcoholic patients diagnosed with Korsakoff syndrome in the absence of a prior diagnosis of Wernicke's encephalopathy and no studies of diffusion tensor imaging in non-alcoholic Korsakoff syndrome. We report on three non-alcoholic psychiatric patients (all women) with long-term non-progressive memory impairment that developed after malnutrition accompanied by at least one of the three Wernicke's encephalopathy manifestations: ocular abnormalities, ataxia or unsteadiness, and an altered mental state or mild memory impairment. In neuropsychological examination, all patients had memory impairment, including intrusions. One patient had mild cerebellar vermis atrophy in MRI taken after the second episode of Wernicke's encephalopathy. The same patient had mild hypometabolism in the lateral cortex of the temporal lobes. Another patient had mild symmetrical atrophy and hypometabolism of the superior frontal lobes. Two patients were examined with diffusion tensor imaging. Reduced fractional anisotropy values were found in the corona radiata in two patients, and the uncinate fasciculus and the inferior longitudinal fasciculus in one patient. Our results suggest that non-alcoholic Korsakoff syndrome is underdiagnosed. Psychiatric patients with long-term memory impairment may have Korsakoff syndrome and, therefore, they should be evaluated for a history of previously undiagnosed Wernicke's encephalopathy. Copyright © 2016 Elsevier B.V. All rights reserved.

Probiotics and Alcoholic Liver Disease: Treatment and Potential Mechanisms

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Fengyuan Li

2016-01-01

Full Text Available Despite extensive research, alcohol remains one of the most common causes of liver disease in the United States. Alcoholic liver disease (ALD encompasses a broad spectrum of disorders, including steatosis, steatohepatitis, and cirrhosis. Although many agents and approaches have been tested in patients with ALD and in animals with experimental ALD in the past, there is still no FDA (Food and Drug Administration approved therapy for any stage of ALD. With the increasing recognition of the importance of gut microbiota in the onset and development of a variety of diseases, the potential use of probiotics in ALD is receiving increasing investigative and clinical attention. In this review, we summarize recent studies on probiotic intervention in the prevention and treatment of ALD in experimental animal models and patients. Potential mechanisms underlying the probiotic function are also discussed.

Diabetes mellitus, pulmonary tuberculosis and chronic calcific ...

African Journals Online (AJOL)

The prevalence of chronic calcific pancreatitis (CCP) was determined in 25 successive patients with both diabetes mellitus and newly diagnosed pulmonary tuberculosis. Twenty patients (80%) were alcoholics and all were black. Of these, 9 (45%) had CCP. In only 3 of these 9 patients was the history compatible with the ...

Diabetes mellitus, pulmonary tuberculosis and chronic calcific ...

African Journals Online (AJOL)

The prevalence of chronic calcific pancreatitis (CCP) was determined in 25 successive patients with both diabetes mellitus and newly diagnosed pulmonary tuberculosis. Twenty patients (80%) were alcoholics and all were black. Of these, 9. (45%) had CCP. In only 3 of these 9 patients was the history compatible with the ...

Non-alcoholic fatty liver disease - histological scoring systems: a large cohort single-center, evaluation study.

Science.gov (United States)

Rastogi, Archana; Shasthry, Saggere Muralikrishna; Agarwal, Ayushi; Bihari, Chhagan; Jain, Priyanka; Jindal, Ankur; Sarin, Shiv

2017-11-01

Non-alcoholic fatty liver disease (NAFLD) is an increasingly common cause of chronic liver disease. Till date, liver biopsy remains the gold standard for identification and quantification of the wide histological spectra of NAFLD. Histological scorings are very useful and widely applied for the diagnosis and management in clinical trials and follow-up studies of non-alcoholic steatohepatitis (NASH). However, in view of scarce published literature, there is a need to evaluate them in large cohort of NAFLD. This study was aimed to evaluate the two histological scoring systems (NAS-CRN, SAF) in the diagnosis of NAFLD and to assess the role of histological characteristics as injury markers in NAFLD. Retrospective histological study of liver biopsies of 1000 patients diagnosed as NAFLD, between 2010 and 2016, was conducted. Histopathologic evaluation and semiquantiative scoring based on NAS-CRN and SAF algorithm and their correlation with serum aminotransferase and fibrosis were performed. Liver biopsies were classified according to the NAS-CRN scoring, as NAS <3 (not NASH) in 72 (7.2%), NAS 3-4 (borderline NASH) in 310 (31%), and NAS ≥5 (definite NASH) in 618 (61.8%), and SAF classified 117 (11.7%) not NASH and 883 (88.3%) definite NASH. There was excellent concordance for definite NASH and not NASH; however, 88.06% of borderline NASH was classified as NASH by SAF. 76.39% by NAS and 78.63% by SAF algorithm who were diagnosed as not NASH showed the presence of fibrosis; however, higher stages of fibrosis were significantly more prevalent in definite NASH, excluding burnt-out cirrhosis. Serum ALT was significantly associated with increasing stages of fibrosis (p < 0.001) and the three categories (not NASH, borderline NASH, and definite NASH) when classified as with/without fibrosis (p < 0.001). Steatosis of higher grades, more ballooned cells, and more foci of Lobular Inflammation were found in significantly higher proportion of patients with NASH (p < 0

Altered Parietal Activation during Non-symbolic Number Comparison in Children with Prenatal Alcohol Exposure

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Keri J. Woods

2018-01-01

Full Text Available Number processing is a cognitive domain particularly sensitive to prenatal alcohol exposure, which relies on intact parietal functioning. Alcohol-related alterations in brain activation have been found in the parietal lobe during symbolic number processing. However, the effects of prenatal alcohol exposure on the neural correlates of non-symbolic number comparison and the numerical distance effect have not been investigated. Using functional magnetic resonance imaging (fMRI, we examined differences in brain activation associated with prenatal alcohol exposure in five parietal regions involved in number processing during a non-symbolic number comparison task with varying degrees of difficulty. fMRI results are presented for 27 Cape Colored children (6 fetal alcohol syndome (FAS/partial FAS, 5 heavily exposed (HE non-sydromal, 16 controls; mean age ± SD = 11.7 ± 1.1 years. Fetal alcohol exposure was assessed by interviewing mothers using a timeline follow-back approach. Separate subject analyses were performed in each of five regions of interest, bilateral horizontal intraparietal sulci (IPS, bilateral posterior superior parietal lobules (PSPL, and left angular gyrus (left AG, using the general linear model with predictors for number comparison and difficulty level. Mean percent signal change for each predictor was extracted for each subject for each region to examine group differences and associations with continuous measures of alcohol exposure. Although groups did not differ in performance, controls activated the right PSPL more during non-symbolic number comparison than exposed children, but this was not significant after controlling for maternal smoking, and the right IPS more than children with fetal alcohol syndrome (FAS or partial FAS. More heavily exposed children recruited the left AG to a greater extent as task difficulty increased, possibly to compensate, in part, for impairments in function in the PSPL and IPS. Notably, in non

Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid

NARCIS (Netherlands)

IJssennagger, Noortje; Janssen, A.W.F.; Milona, Alexandra; Ramos Pittol, J.M.; Hollman, D.A.A.; Mokry, Michal; Betzel, Bark; Berends, F.J.; Janssen, I.M.; Mil, van S.W.C.; Kersten, Sander

2016-01-01

Background & Aims: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse

Gene expression profiling in human precision cut liver slices in response to the FXR agonist obeticholic acid

NARCIS (Netherlands)

Ijssennagger, Noortje; Janssen, Aafke W F; Milona, Alexandra; Ramos Pittol, José M; Hollman, Danielle A A; Mokry, Michal; Betzel, Bark; Berends, Frits J; Janssen, Ignace M; van Mil, Saskia W C; Kersten, Sander

2016-01-01

BACKGROUND & AIMS: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH) and type 2 diabetes, activates FXR. Mouse studies

Effect of non-alcoholic fatty liver disease on carotid artery intima-media thickness as a risk factor for atherosclerosis

Science.gov (United States)

Nahandi, Maryam Zaare; Ramazanzadeh, Elham; Abbaszadeh, Leili; Javadrashid, Reza; Shirazi, Koorosh Masnadi; Gholami, Nasrin

2014-01-01

Aim This study aimed to evaluate the effect of NAFLD on CIMT as a risk factor for atherosclerosis. Background The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide due to rise of obesity and diabetes mellitus (DM) prevalence. Non-invasive assessment of carotid intima-media thickness (CIMT) by high-resolution carotid B-mode ultrasonography is widely used for determining the atherosclerosis. Patients and methods In this case-control setting, 151 subjects were categorized in three groups: group I including 49 patients with NAFLD and DM; group II including 50 non-diabetic NAFLD patients; and the control including 52 normal subjects as group III. The right and left CIMTs and its maximum reading (CIMTmax) were measured by a skilled sonographist blind to the groups. The sonographic grading of the NAFLD was determined in group I and II. Results Median CIMTmax was significantly higher in group I comparing with group II and control group (pliver enzymes (in both groups, 0.6 mm, p= 0.402). Conclusion Based on our findings, there is a significant association between the presence of NAFLD and atherosclerosis. This association was independent to the DM presence. The grade of NAFLD and elevated liver function tests had no effect on severity of atherosclerosis. PMID:25436098

Prognostic Value of Non-Invasive Fibrosis and Steatosis Tools, Hepatic Venous Pressure Gradient (HVPG and Histology in Nonalcoholic Steatohepatitis.

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Giada Sebastiani

Full Text Available Non-invasive diagnostic methods for liver fibrosis predict clinical outcomes in viral hepatitis and nonalcoholic fatty liver disease (NAFLD. We specifically evaluated prognostic value of non-invasive fibrosis methods in nonalcoholic steatohepatitis (NASH against hepatic venous pressure gradient (HVPG and liver histology.This was a retrospective cohort study of 148 consecutive patients who met the following criteria: transjugular liver biopsy with HVPG measurement; biopsy-proven NASH; absence of decompensation; AST-to-Platelets Ratio Index (APRI, fibrosis-4 (FIB-4, NAFLD fibrosis score, ultrasound, hepatic steatosis index and Xenon-133 scan available within 6 months from biopsy; a minimum follow-up of 1 year. Outcomes were defined by death, liver transplantation, cirrhosis complications. Kaplan-Meier and Cox regression analyses were employed to estimate incidence and predictors of outcomes, respectively. Prognostic value was expressed as area under the curve (AUC.During a median follow-up of 5 years (interquartile range 3-8, 16.2% developed outcomes, including 7.4% who died or underwent liver transplantation. After adjustment for age, sex, diabetes, the following fibrosis tools predicted outcomes: HVPG >10mmHg (HR=9.60; 95% confidence interval [CI] 3.07-30.12, histologic fibrosis F3-F4 (HR=3.14; 1.41-6.95, APRI >1.5 (HR=5.02; 1.6-15.7, FIB-4 >3.25 (HR=6.33; 1.98-20.2, NAFLD fibrosis score >0.676 (HR=11.9; 3.79-37.4. Prognostic value was as follows: histologic fibrosis stage, AUC=0.85 (95% CI 0.76-0.93; HVPG, AUC=0.81 (0.70-0.91; APRI, AUC=0.89 (0.82-0.96; FIB-4, AUC=0.89 (0.83-0.95; NAFLD fibrosis score, AUC=0.79 (0.69-0.91. Neither histologic steatosis nor non-invasive steatosis methods predicted outcomes (AUC<0.50.Non-invasive methods for liver fibrosis predict outcomes of patients with NASH. They could be used for serial monitoring, risk stratification and targeted interventions.

Effects of exercise training on glucose control, lipid metabolism, and insulin sensitivity in hypertriglyceridemia and non-insulin dependent diabetes mellitus.

Science.gov (United States)

Lampman, R M; Schteingart, D E

1991-06-01

Exercise training has potential benefits for patients with hyperlipidemia and/or non-insulin dependent diabetes mellitus. In nondiabetic, nonobese subjects with hypertriglyceridemia, exercise training alone increased insulin sensitivity, improved glucose tolerance, and lowered serum triglyceride and cholesterol levels. These improvements did not occur when exercise training alone was given to similar patients with impaired glucose tolerance. In severely obese (X = 125 kg) subjects without diabetes melitus, a 600 calorie diet alone decreased glucose and insulin concentrations and improved glucose tolerance but did not increase insulin sensitivity. The addition of exercise training improved insulin sensitivity. Obese, non-insulin dependent diabetes mellitus subjects on sulfonylurea therapy alone increased insulin levels but failed to improve insulin sensitivity or glucose levels. In contrast, the addition of exercise training to this medication resulted in improved insulin sensitivity and lowered glucose levels. We conclude that exercise training has major effects on lowering triglyceride levels in hyperlipidemic subjects and can potentiate the effect of diet or drug therapy on glucose metabolism in patients with non-insulin dependent diabetes mellitus.

49 CFR 40.13 - How do DOT drug and alcohol tests relate to non-DOT tests?

Science.gov (United States)

2010-10-01

... 49 Transportation 1 2010-10-01 2010-10-01 false How do DOT drug and alcohol tests relate to non... TRANSPORTATION WORKPLACE DRUG AND ALCOHOL TESTING PROGRAMS Employer Responsibilities § 40.13 How do DOT drug and... non-DOT drug and alcohol testing programs. This prohibition includes the use of the DOT forms with...

The Interleukin-20 Cytokine Family in Liver Disease

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Esther Caparrós

2018-05-01

Full Text Available The three main causes of inflammation and chronic injury in the liver are viral hepatitis, alcohol consumption, and non-alcoholic steatohepatitis, all of which can lead to liver fibrosis, cirrhosis, and hepatocellular carcinoma, which in turn may prompt the need for liver transplant. The interleukin (IL-20 is a subfamily part of the IL-10 family of cytokines that helps the liver respond to damage and disease, they participate in the control of tissue homeostasis, and in the immunological responses developed in this organ. The best-studied member of the family in inflammatory balance of the liver is the IL-22 cytokine, which on the one hand may have a protective role in fibrosis progression but on the other may induce liver tissue susceptibility in hepatocellular carcinoma development. Other members of the family might also carry out this dual function, as some of them share IL receptor subunits and signal through common intracellular pathways. Investigators are starting to consider the potential for targeting IL-20 subfamily members in liver disease. The recently explored role of miRNA in the transcriptional regulation of IL-22 and IL-24 opens the door to promising new approaches for controlling the local immune response and limiting organ injury. The IL-20RA cytokine receptor has also been classified as being under miRNA control in non-alcoholic steatohepatitis. Moreover, researchers have proposed combining anti-inflammatory drugs with IL-22 as a hepatoprotective IL for alcoholic liver disease (ALD treatment, and clinical trials of ILs for managing severe alcoholic-derived liver degeneration are ongoing. In this review, we focus on exploring the role of the IL-20 subfamily of cytokines in viral hepatitis, ALD, non-alcoholic steatohepatitis, and hepatocellular carcinoma, as well as delineating the main strategies explored so far in terms of therapeutic possibilities of the IL-20 subfamily of cytokines in liver disease.

Attitudes toward Tobacco, Alcohol, and Non-Alcoholic Beverage Advertisement Themes among Adolescent Boys.

Science.gov (United States)

Friedman, Katherine L; Roberts, Megan E; Keller-Hamilton, Brittney; Yates, Katherine A; Paskett, Electra D; Berman, Micah L; Slater, Michael D; Lu, Bo; Ferketich, Amy K

2018-02-13

Previous studies have examined what adolescents find appealing in tobacco and alcohol advertisements and how different themes in advertisements are used to manipulate consumer behaviors. Yet, we know little about the relationship between the themes portrayed in advertisements and youth attitudes towards those themes. This study compared attitudes towards advertisements for different consumer products in a sample of urban and rural adolescent boys in order to examine how key marketing themes impact adolescent attitudes towards those advertisements. Participants were 11- to 16-year-old boys (N = 1220) residing in either urban or rural Ohio Appalachian counties. Each participant viewed five print advertisements (one each for cigarettes, electronic cigarettes (e-cigarettes), smokeless tobacco (SLT), non-alcoholic beverages, and alcohol), presented in a random order, for eight seconds each. All advertisements had appeared in magazines that adolescent males commonly read. Attitudes towards each of the five advertisements were assessed. The advertisements were then coded for the presence of various themes, including social acceptance and masculinity. Analyses were conducted to determine associations between advertisement type and the attitude measure, and between the presence of a theme and the attitude measure. Overall, participants preferred non-tobacco advertisements to tobacco advertisements, rural participants had less positive attitudes and participants who had peers who used tobacco had more positive attitudes. Social acceptance and entertainment themes increased the appeal of SLT advertisements, and sex appeal increased the appeal of e-cigarette advertisements. Conclusions/Importance: Findings suggest that advertisements that promote the social nature of use in SLT advertisements may be of particular concern for their influence on adolescent boys.

Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection—Liver: The “Musketeer” in the Spotlight

Science.gov (United States)

Ballestri, Stefano; Nascimbeni, Fabio; Romagnoli, Dante; Baldelli, Enrica; Targher, Giovanni; Lonardo, Amedeo

2016-01-01

The pathogenesis of type 2 diabetes (T2D) involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR), which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of fatty (simple steatosis and steatohepatitis) and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC)) that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity, IR and T2D. Hepatitis C virus (HCV) infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of IR and T2D has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links T2D with NAFLD and HCV infection. For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a “vicious circle”, eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved. PMID:27005620

Type 2 Diabetes in Non-Alcoholic Fatty Liver Disease and Hepatitis C Virus Infection—Liver: The “Musketeer” in the Spotlight

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Stefano Ballestri

2016-03-01

Full Text Available The pathogenesis of type 2 diabetes (T2D involves chronic hyperinsulinemia due to systemic and hepatic insulin resistance (IR, which if uncorrected, will lead to progressive pancreatic beta cell failure in predisposed individuals. Non-alcoholic fatty liver disease (NAFLD encompasses a spectrum of fatty (simple steatosis and steatohepatitis and non-fatty liver changes (NASH-cirrhosis with or without hepatocellular carcinoma (HCC that are commonly observed among individuals with multiple metabolic derangements, notably including visceral obesity, IR and T2D. Hepatitis C virus (HCV infection is also often associated with both hepatic steatosis and features of a specific HCV-associated dysmetabolic syndrome. In recent years, the key role of the steatotic liver in the development of IR and T2D has been increasingly recognized. Thus, in this comprehensive review we summarize the rapidly expanding body of evidence that links T2D with NAFLD and HCV infection. For each of these two liver diseases with systemic manifestations, we discuss the epidemiological burden, the pathophysiologic mechanisms and the clinical implications. To date, substantial evidence suggests that NAFLD and HCV play a key role in T2D development and that the interaction of T2D with liver disease may result in a “vicious circle”, eventually leading to an increased risk of all-cause mortality and liver-related and cardiovascular complications. Preliminary evidence also suggests that improvement of NAFLD is associated with a decreased incidence of T2D. Similarly, the prevention of T2D following HCV eradication in the era of direct-acting antiviral agents is a biologically plausible result. However, additional studies are required for further clarification of mechanisms involved.

The Ossabaw pig as a model for diet induced atherosclerosis and statin responsiveness

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Background and Objectives: The Ossabaw pig has been established as a model for obesity, metabolic syndrome, atherosclerosis and non-alcoholic steatohepatitis, when fed an extreme diet (high trans fat and fructose) in caloric excess. To increase the translational nature of this model, we determined i...

Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid [human

NARCIS (Netherlands)

IJssennagger, Noortje; Janssen, Aafke; Mil, van Saskia; Kersten, Sander

2016-01-01

Background: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6α-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH)

Gene expression profiling in human precision-cut liver slices upon treatment with the FXR agonist obeticholic acid [mouse

NARCIS (Netherlands)

IJssennagger, Noortje; Janssen, Aafke; Kersten, Sander; Mil, van S.W.C.

2016-01-01

Background: The bile acid-activated farnesoid X receptor (FXR) is a nuclear receptor regulating bile acid, glucose and cholesterol homeostasis. Obeticholic acid (OCA; also known as INT-747 or 6α-ethyl-chenodeoxycholic acid), a promising drug for the treatment of non-alcoholic steatohepatitis (NASH)

NASH and atherosclerosis are two aspects of a shared disease : Central role for macrophages

NARCIS (Netherlands)

Bieghs, Veerle; Rensen, Patrick C. N.; Hofker, Marten H.; Shiri-Sverdlov, Ronit

Macrophage infiltration into the atherosclerotic lesion is known to play a central role in the initiation of atherosclerosis. In contrast, the role of macrophages during the etiology of non-alcoholic steatohepatitis (NASH) has been considered to be merely a late consequence of steatosis. However,

Cardiovascular consequences of diabetes mellitus

NARCIS (Netherlands)

C.A. Baan (Caroline)

1999-01-01

textabstractDiabetes mellitus comprises a clinically and genetically heterogeneous group of disorders that have one common feature: abnormally high levels of glucose in the blood. The most common form is non-insulin dependent diabetes mellitus (NlDDM); about 80-90% of all diabetic patients has

Fructose Consumption, Lipogenesis, and Non-Alcoholic Fatty Liver Disease

NARCIS (Netherlands)

ter Horst, Kasper W.; Serlie, Mireille J.

2017-01-01

Increased fructose consumption has been suggested to contribute to non-alcoholic fatty liver disease (NAFLD), dyslipidemia, and insulin resistance, but a causal role of fructose in these metabolic diseases remains debated. Mechanistically, hepatic fructose metabolism yields precursors that can be

Gender differences in alcohol-related non-consensual sex; cross-sectional analysis of a student population

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Gunby Clare

2012-03-01

Full Text Available Abstract Background Sexual offences are a global public health concern. Recent changes in the law in England and Wales have dramatically altered the legal landscape of sexual offences, but sexual assaults where the victim is voluntarily intoxicated by alcohol continue to have low conviction rates. Worldwide, students are high consumers of alcohol. This research aimed to compare male and female students in relation to their knowledge and attitudes about alcohol and sexual activity and to identify factors associated with being the victim of alcohol-related non-consensual sex. Methods 1,110 students completed an online questionnaire. Drinking levels were measured using the Alcohol Use Disorder Identification Test. Non-consensual sexual experiences were measured using the Sexual Experience Survey. Univariate and multivariate analyses were undertaken using chi square and backwards stepwise logistic regression respectively. Results A third of respondents had experienced alcohol-related non-consensual sex. Male and female students differed in the importance they gave to cues in deciding if a person wished to have sex with them and their understanding of the law of consent. 82.2% of women who had experienced alcohol-related non-consensual sex were hazardous drinkers compared to 62.9% who drank at lower levels (P Conclusions Alcohol-related coerced sexual activity is a significant occurrence among students; attitudinal and knowledge differences between males and females may explain this. Educational messages that focus upon what is deemed acceptable sexual behaviour, the law and rape myths are needed but are set against a backdrop where drunkenness is commonplace.

Ursodeoxycholic Acid and Atorvastatin in the Treatment of Nonalcoholic Steatohepatitis

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Murat Kiyici

2003-01-01

Full Text Available BACKGROUND/AIMS: Nonalcoholic steatohepatitis (NASH is a serious disorder with the potential to gradually progress to cirrhosis. It is generally associated with obesity, diabetes and hyperlipidemia. Currently, there is no established therapy for NASH. The aim of the present study was to evaluate the effectiveness of atorvastatin and ursodeoxycholic acid (UDCA in the treatment of NASH.

Motives for mixing alcohol with energy drinks and other non-alcoholic beverages and its effects on overall alcohol consumption among UK students.

Science.gov (United States)

Johnson, Sean J; Alford, Chris; Verster, Joris C; Stewart, Karina

2016-01-01

A UK student survey examined the motivations for consuming energy drinks alone and mixed with alcohol, and aimed to determine whether the type of motive had a differential effect on overall alcohol consumption. The online survey (N = 1873) assessed alcohol consumption and motivations for consumption when mixed with energy drinks (AMED) and mixed with other non-alcoholic beverages (AMOB) using a within-subject design. The most frequent neutral motives reported for AMED consumption included "I like the taste" (66.5%), and "to celebrate a special occasion" (35.2%). 52.6% of AMED consumers reported consuming AMED for at least one of five negative motives, primarily "to get drunk" (45.6%). Despite these negative motives those students reported consuming significantly less alcohol and fewer negative alcohol-related consequences on AMED occasions compared to alcohol-only (AO) occasions. Although the motives for consuming AMED and AMOB were comparable, more participants reported consuming AMED "to celebrate a special occasion", "to get drunk", because they "received the drink from someone else" or "because others drink it as well". However, significantly more students reported consuming AMOB than AMED because "It feels like I can drink more alcohol". Alcohol consumption was significantly less on AMED occasions compared to AMOB occasions, and both occasions significantly less than AO occasions. The majority of reasons for consuming AMED relate to neutral motives. Although 52.6% of students reported one or more negative motives for AMED consumption (predominantly "to get drunk") this had no differential effect on total alcohol consumption. The differences in motives suggest AMED is consumed more to enjoy special occasions and as a group-bonding experience, however alcohol consumption is significantly lower on such occasions in comparison to when AMOB or AO are consumed. Copyright © 2015. Published by Elsevier Ltd.

Dietary Iron Supplementation Alters Hepatic Inflammation in a Rat Model of Nonalcoholic Steatohepatitis

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Machi Atarashi

2018-02-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD is now the most common liver disease in the world. NAFLD can progress to nonalcoholic steatohepatitis (NASH, cirrhosis and eventually hepatocellular carcinoma. Acquired hepatic iron overload is seen in a number of patients with NAFLD; however, its significance in the pathology of NAFLD is still debated. Here, we investigated the role of dietary iron supplementation in experimental steatohepatitis in rats. Rats were fed a control, high-fat (HF, high-fat high-iron (HFHI and high-iron (HI diet for 30 weeks. Blood biochemical, histopathological and gut microbiota analyses were performed. Rats in HF and HFHI groups showed an ALT-dominant elevation of serum transaminases, hepatic steatosis, hepatic inflammation, and upregulation of proinflammatory cytokines. The number of large inflammatory foci, corresponding to lobular inflammation in NASH patients, was significantly higher in HFHI than in HF group; within the lesion, macrophages with intense iron staining were observed. Hepatic expression of TNFα was higher in HFHI than that in HF group. There was no significant change in hepatic oxidative stress, gut microbiota or serum endotoxin levels between HF and HFHI groups. These results suggested that dietary iron supplementation enhances experimental steatohepatitis induced by long-term high-fat diet feeding in rats. Iron-laden macrophages can play an important role in the enhancement of hepatic inflammation.

Striatal activation and frontostriatal connectivity during non-drug reward anticipation in alcohol dependence.

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Becker, Alena; Kirsch, Martina; Gerchen, Martin Fungisai; Kiefer, Falk; Kirsch, Peter

2017-05-01

According to prevailing neurobiological theories of addiction, altered function in neural reward circuitry is a central mechanism of alcohol dependence. Growing evidence postulates that the ventral striatum (VS), as well as areas of the prefrontal cortex, contribute to the increased incentive salience of alcohol-associated cues, diminished motivation to pursue non-drug rewards and weakened strength of inhibitory cognitive control, which are central to addiction. The present study aims to investigate the neural response and functional connectivity underlying monetary, non-drug reward processing in alcohol dependence. We utilized a reward paradigm to investigate the anticipation of monetary reward in 32 alcohol-dependent inpatients and 35 healthy controls. Functional magnetic resonance imaging was used to measure task-related brain activation and connectivity. Alcohol-dependent patients showed increased activation of the VS during anticipation of monetary gain compared with healthy controls. Generalized psychophysiological interaction analyses revealed decreased functional connectivity between the VS and the dorsolateral prefrontal cortex in alcohol dependent patients relative to controls. Increased activation of the VS and reduced frontostriatal connectivity were associated with increased craving. These findings provide evidence that alcohol dependence is rather associated with disrupted integration of striatal and prefrontal processes than with a global reward anticipation deficit. © 2016 Society for the Study of Addiction.

The impact of cereal grain consumption on the development and severity of non-alcoholic fatty liver disease.

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Georgoulis, Michael; Kontogianni, Meropi D; Tileli, Nafsika; Margariti, Aikaterini; Fragopoulou, Elisabeth; Tiniakos, Dina; Zafiropoulou, Rodessa; Papatheodoridis, George

2014-12-01

There is evidence that dietary habits contribute to the presence and severity of non-alcoholic fatty liver disease (NAFLD). The aim of the present study was to explore any associations between consumption of grains and the development and severity of NAFLD. Seventy-three consecutive NAFLD patients were enrolled. Additionally, 58 controls matched for age, sex and body mass index with 58 patients were also included. Consumption of grains was estimated through a semi-quantitative food frequency questionnaire. Medical history, anthropometric indices, body composition analysis, physical activity data, biochemical and inflammatory markers were available for all the participants. Liver stiffness measurement by transient elastography was performed in 58 and liver biopsy in 34 patients. In patients, consumption of whole grains was associated with lower abdominal fat level (β = -0.24, p = 0.02) and lower levels of insulin resistance index (β = -0.28, p = 0.009), while it also correlated inversely with interleukin-6 levels (ρ = -0.23, p = 0.05). Consumption of whole grains was associated with lower likelihood of having histological steatohepatitis (OR 0.97, 95% CI 0.94-1.000), after adjusting for sex and energy intake, but the association became weaker after further adjusting for abdominal fat or interleukin-6 levels. In the case-control analysis, consumption of refined grains was associated with higher odds of having NAFLD (OR 1.021, 95% CI 1.001-1.042), after adjusting for age, sex, energy intake, abdominal fat level, HOMA-IR, LDL, adiponectin and TNF-α. Although refined grain consumption increased the likelihood of having NAFLD, whole-grain consumption favorably affected clinical characteristics of patients with NAFLD and tended to be associated with less severe disease.

Craving as a DSM-5 Symptom of Alcohol Use Disorder in Non-Treatment Seekers.

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Hartwell, Emily E; Ray, Lara A

2018-05-01

DSM-5 has added craving as a new criterion and changed the diagnostic structure of alcohol use disorder (AUD). Though craving has long been a target of intervention, less is known about the impact this addition will have on prevalence and factor structure of AUD, particularly in non-treatment seeker with alcohol problems. Non-treatment seeking individuals reporting alcohol-related problems (N = 296) completed a structured clinical interview and the Penn Alcohol Craving Scale (PACS). PACS scores greater than 20 were considered to meet diagnostic criteria for the alcohol craving symptom. This study examined DSM-IV to DSM-5 diagnostic conversion and conducted an exploratory factor analysis to test the factor structure of the DSM-5 symptoms, including craving. The mean PACS score was 13.1 and alcohol craving was strongly correlated with other measures of alcohol use. Using the proposed cut-off score of PACS > 20, 46 participants (16.2%) met criteria for alcohol craving. Craving loaded moderately (0.47) onto the retained DSM symptoms and produced a unidimensional factor structure. The majority of participants who met for a DSM-IV AUD also met for a DSM-5 AUD (98.8%). Craving prevalence using the PACS was relatively low compared to the remaining 10 DSM-5 symptoms, possibly due to the non-treatment seeking nature of the sample. Conversion of DSM-IV to DSM-5 in this sample led to a small increase in overall AUD prevalence. Craving loaded well onto a single factor structure for AUD.

A Series of microRNA in the Chromosome 14q32.2 Maternally Imprinted Region Related to Progression of Non-Alcoholic Fatty Liver Disease in a Mouse Model.

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Kinya Okamoto

Full Text Available Simple steatosis (SS and non-alcoholic steatohepatitis (NASH are subtypes of non-alcoholic fatty liver disease (NAFLD, and the pathogenic differences between SS and NASH remain unclear. MicroRNAs (miRNAs are endogenous, non-coding, short RNAs that regulate gene expression. The aim of this study was to use animal models and human samples to examine the relationship between miRNA expression profiles and each type of NAFLD (SS and NASH.DD Shionogi, Fatty Liver Shionogi (FLS and FLS ob/ob mice were used as models for normal control, SS and NASH, respectively. Microarray analysis and real-time PCR were used to identify candidate NAFLD-related miRNAs. Human serum samples were used to examine the expression profiles of these candidate miRNAs in control subjects and patients with SS or NASH.Fourteen miRNAs showed clear expression differences among liver tissues from SS, NASH, and control mice with good reproducibility. Among these NAFLD candidate miRNAs, seven showed similar expression patterns and were upregulated in both SS and NASH tissues; these seven candidate miRNAs mapped to an miRNA cluster in the 14q32.2 maternally imprinted region delineated by delta-like homolog 1 and type III iodothyronine deiodinase (Dlk1-Dio3 mat. Software-based predictions indicated that the transforming growth factor-β pathway, insulin like growth factor-1 and 5' adenosine monophosphate activated protein kinase were potential targets of theses Dlk1-Dio3 mat NAFLD candidate miRNAs. In addition, serum samples from patients with SS or NASH differed markedly with regard to expression of the putative Dlk1-Dio3 mat miRNAs, and these differences accurately corresponded with NAFLD diagnosis.The expression profiles of seven miRNAs in 14q32.2 mat have high potential as biomarkers for NAFLD and for improving future research on the pathogenesis and treatment of NASH.

Hazardous alcohol consumption in non-aboriginal male inmates in New South Wales.

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Field, Courtney

2018-03-12

Purpose The purpose of this paper is to examine correlates and predictors of hazardous drinking behaviour, that may be considered evidence of generalised strain, in a sample of incarcerated non-Aboriginal males in New South Wales, Australia. Design/methodology/approach Data were collected from 283 non-Aboriginal male inmates as part of a larger epidemiological survey of inmates in NSW undertaken in 2015 by the Justice Health and Forensic Mental Health Network. Data relating to a range of social factors were selected with reference to relevant literature and assessed with regards their predictive value for scores from the Alcohol Use Disorders Identification Test (AUDIT). To facilitate regression analysis, variables were logically organised into historical factors or adult factors. Findings Almost all participants reported some history of alcohol consumption. Hazardous drinking was common among participants. While parental alcohol problems and adult drug use were the only correlates of AUDIT scores, parental misuse of alcohol was shown to be an important predictor of AUDIT scores in regression analysis. The role of parent gender was inconclusive. Previous incarceration as an adult, employment status, and drug use as an adult also predicted AUDIT scores. Originality/value Alcohol abuse is common among inmates and the use of alcohol is implicated in the commission of many offences. A better understanding of its genesis may inspire novel approaches to treatment, leading to improved health outcomes for inmates.

Alcohol use, sexual activity, and perceived risk in high school athletes and non-athletes.

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Wetherill, Reagan R; Fromme, Kim

2007-09-01

The current study examined one's sense of personal invincibility as a contributing factor to high school athletes' more frequent behavioral risks compared to those of non-athletes. Perceived risk was assessed as a mediator of sports participation and alcohol use, and sports participation and sexual activity among high school athletes. Prior to leaving home, college-bound high school graduates (n = 2,247) completed web-based surveys assessing alcohol use, sexual activity, sports participation, and perceived risk. The mediational models were analyzed using generalized linear modeling and the procedures of Baron and Kenny (1986). Relative to non-athletes, athletes reported greater alcohol use, more sexual partners, and lower perceived risk. Perceived risk mediated the association between sports participation and alcohol use for both young men and women. Perceived risk also mediated the association between sports participation and number of sexual partners for women and partially mediated this association for men. Perceived risk partially mediated the association between sports participation and episodes of unsafe sexual activity in both men and women. These findings suggest a potential cognitive mechanism which may account for differences in alcohol use and sexual activity between athletes and non-athletes during late adolescence.

Treatment of Nonalcoholic Steatohepatitis in Adults: Present and Future

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S. Gitto

2015-01-01

Full Text Available Nonalcoholic steatohepatitis has become one of the most common liver-related health problems. This condition has been linked to an unhealthy diet and weight gain, but it can also be observed in nonobese people. The standard of care is represented by the lifestyle intervention. However, because this approach has several limitations, such as a lack of compliance, the use of many drugs has been proposed. The first-line pharmacological choices are vitamin E and pioglitazone, both showing a positive effect on transaminases, fat accumulation, and inflammation. Nevertheless, vitamin E has no proven effect on fibrosis and on long-term morbidity and mortality and pioglitazone has a negative impact on weight. Other drugs have been studied such as metformin, ursodeoxycholic acid, statins, pentoxiphylline, and orlistat with only partially positive results. Among the emerging treatments, telmisartan is particularly interesting as it seems to have an impact on insulin resistance, liver steatosis, inflammation, and fibrosis. However, the pathogenesis of steatohepatitis is highly complex and is determined by different parallel hits; indeed, the association of different drugs that act on various levels has been suggested. In conclusion, lifestyle intervention should be optimised and the associations of different drugs should be tested in large studies with long-term outcomes.

Hepatic fat quantification magnetic resonance for monitoring treatment response in pediatric nonalcoholic steatohepatitis.

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Koh, Hong; Kim, Seung; Kim, Myung-Joon; Kim, Hyun Gi; Shin, Hyun Joo; Lee, Mi-Jung

2015-09-07

To evaluate the possibility of treatment effect monitoring using hepatic fat quantification magnetic resonance (MR) in pediatric nonalcoholic steatohepatitis (NASH). We retrospectively reviewed the medical records of patients who received educational recommendations and vitamin E for NASH and underwent hepatic fat quantification MR from 2011 to 2013. Hepatic fat fraction (%) was measured using dual- and triple-echo gradient-recalled-echo sequences at 3T. The compliant and non-compliant groups were compared clinically, biochemically, and radiologically. Twenty seven patients (M:F = 24:3; mean age: 12 ± 2.3 years) were included (compliant group = 22, non-compliant = 5). None of the baseline findings differed between the 2 groups, except for triglyceride level (compliant vs non-compliant, 167.7 mg/dL vs 74.2 mg/dL, P = 0.001). In the compliant group, high-density lipoprotein increased and all other parameters decreased after 1-year follow-up. However, there were various changes in the non-compliant group. Dual-echo fat fraction (-19.2% vs 4.6, P fat fraction (-13.4% vs 3.5, P fat fraction showed a positive correlation (ρ = 0.418, P = 0.030). Hepatic fat quantification MR can be a non-invasive, quantitative and useful tool for monitoring treatment effects in pediatric NASH.

Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis

OpenAIRE

Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

2014-01-01

Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant ...

Drug Induced Steatohepatitis: An Uncommon Culprit of a Common Disease

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Liane Rabinowich

2015-01-01

Full Text Available Nonalcoholic fatty liver disease (NAFLD is a leading cause of liver disease in developed countries. Its frequency is increasing in the general population mostly due to the widespread occurrence of obesity and the metabolic syndrome. Although drugs and dietary supplements are viewed as a major cause of acute liver injury, drug induced steatosis and steatohepatitis are considered a rare form of drug induced liver injury (DILI. The complex mechanism leading to hepatic steatosis caused by commonly used drugs such as amiodarone, methotrexate, tamoxifen, valproic acid, glucocorticoids, and others is not fully understood. It relates not only to induction of the metabolic syndrome by some drugs but also to their impact on important molecular pathways including increased hepatocytes lipogenesis, decreased secretion of fatty acids, and interruption of mitochondrial β-oxidation as well as altered expression of genes responsible for drug metabolism. Better familiarity with this type of liver injury is important for early recognition of drug hepatotoxicity and crucial for preventing severe forms of liver injury and cirrhosis. Moreover, understanding the mechanisms leading to drug induced hepatic steatosis may provide much needed clues to the mechanism and potential prevention of the more common form of metabolic steatohepatitis.

Alcohol consumption patterns in Thailand and their relationship with non-communicable disease.

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Wakabayashi, Mami; McKetin, Rebecca; Banwell, Cathy; Yiengprugsawan, Vasoontara; Kelly, Matthew; Seubsman, Sam-ang; Iso, Hiroyasu; Sleigh, Adrian

2015-12-24

Heavy alcohol consumption is an established risk factor for non-communicable diseases (NCDs) but few studies have investigated drinking and disease risk in middle income, non-western countries. We report on the relationship between alcohol consumption and NCDs in Thailand. A nationwide cross sectional survey was conducted of 87,151 Thai adult open university students aged 15 to 87 years (mean age 30.5 years) who were recruited into the Thai Cohort Study. Participants were categorized as never having drunk alcohol (n = 22,527), as being occasional drinkers who drank infrequently but heavily (4+ glasses/occasion - occasional heavy drinkers, n = 24,152) or drank infrequently and less heavily (migration and other recognized risks for NCDs (sedentary lifestyle and poor diet). After adjustment for these factors the odds ratios (ORs) for several NCDs outcomes - high cholesterol, hypertension, and liver disease - were significantly elevated among both occasional heavy drinkers (1.2 to 1.5) and regular heavy drinkers (1.5 to 2.0) relative to never drinkers. Heavy alcohol consumption of 4 or more glasses per occasion, even if the occasions were infrequent, was associated with elevated risk of NCDs in Thailand. These results highlight the need for strategies in Thailand to reduce the quantity of alcohol consumed to prevent alcohol-related disease. Thailand is fortunate that most of the female population is culturally protected from drinking and this national public good should be endorsed and supported.

Health and economic benefits of reducing sugar intake in the USA, including effects via non-alcoholic fatty liver disease: a microsimulation model.

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Vreman, Rick A; Goodell, Alex J; Rodriguez, Luis A; Porco, Travis C; Lustig, Robert H; Kahn, James G

2017-08-03

Excessive consumption of added sugars in the human diet has been associated with obesity, type 2 diabetes (T2D), coronary heart disease (CHD) and other elements of the metabolic syndrome. Recent studies have shown that non-alcoholic fatty liver disease (NAFLD) is a critical pathway to metabolic syndrome. This model assesses the health and economic benefits of interventions aimed at reducing intake of added sugars. Using data from US National Health Surveys and current literature, we simulated an open cohort, for the period 2015-2035. We constructed a microsimulation model with Markov chains for NAFLD (including steatosis, non-alcoholic steatohepatitis (NASH), cirrhosis and hepatocellular carcinoma (HCC)), body mass index, T2D and CHD. We assessed reductions in population disease prevalence, disease-attributable disability-adjusted life years (DALYs) and costs, with interventions that reduce added sugars consumption by either 20% or 50%. The model estimated that a 20% reduction in added sugars intake will reduce prevalence of hepatic steatosis, NASH, cirrhosis, HCC, obesity, T2D and CHD. Incidence of T2D and CHD would be expected to decrease by 19.9 (95% CI 12.8 to 27.0) and 9.4 (95% CI 3.1 to 15.8) cases per 100 000 people after 20 years, respectively. A 20% reduction in consumption is also projected to annually avert 0.767 million (M) DALYs (95% CI 0.757M to 0.777M) and a total of US$10.3 billion (B) (95% CI 10.2B to 10.4B) in discounted direct medical costs by 2035. These effects increased proportionally when added sugars intake were reduced by 50%. The decrease in incidence and prevalence of disease is similar to results in other models, but averted costs and DALYs were higher, mainly due to inclusion of NAFLD and CHD. The model suggests that efforts to reduce consumption of added sugars may result in significant public health and economic benefits. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All

Impaired activity and gene expression of hexokinase II in muscle from non-insulin-dependent diabetes mellitus patients

DEFF Research Database (Denmark)

Vestergaard, H; Bjørbaek, C; Hansen, T

1995-01-01

-phosphate concentrations in muscle have been found in non-insulin-dependent diabetes mellitus (NIDDM) patients when examined during a hyperglycemic hyperinsulinemic clamp. These findings [correction of finding] are consistent with a defect in glucose transport and/or phosphorylation. In the present study...

Peroxisomal enzymes in the liver of rats with experimental diabetes mellitus type 2.

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Turecký, L; Kupčová, V; Uhlíková, E; Mojto, V

2014-01-01

Diabetes mellitus is relatively frequently associated with fatty liver disease. Increased oxidative stress probably plays an important role in the development of this hepatopathy. One of possible sources of reactive oxygen species in liver is peroxisomal system. There are several reports about changes of peroxisomal enzymes in experimental diabetes, mainly enzymes of fatty acid oxidation. The aim of our study was to investigate the possible changes of activities of liver peroxisomal enzymes, other than enzymes of beta-oxidation, in experimental diabetes mellitus type 2. Biochemical changes in liver of experimental animals suggest the presence of liver steatosis. The changes of serum parameters in experimental group are similar to changes in serum of patients with non-alcoholic fatty liver disease. We have shown that diabetes mellitus influenced peroxisomal enzymes by the different way. Despite of well-known induction of peroxisomal beta-oxidation, the activities of catalase, aminoacid oxidase and NADH-cytochrome b(5) reductase were not significantly changed and the activities of glycolate oxidase and NADP-isocitrate dehydrogenase were significantly decreased. The effect of diabetes on liver peroxisomes is probably due to the increased supply of fatty acids to liver in diabetic state and also due to increased oxidative stress. The changes of metabolic activity of peroxisomal compartment may participate on the development of diabetic hepatopathy.

Global deletion of glutathione S-Transferase A4 exacerbates developmental nonalcoholic steatohepatitis

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We established a mouse model of developmental nonalcoholic steatohepatitis (NASH) by feeding a high polyunsaturated fat liquid diet to female glutathione-S-transferase 4-4 (Gsta4-/-)/peroxisome proliferator activated receptor a (Ppara-/-) double knockout 129/SvJ mice for 12 weeks from weaning. We us...

Estimated intake of intense sweeteners from non-alcoholic beverages in Denmark, 2005

DEFF Research Database (Denmark)

Leth, Torben; Jensen, U.; Fagt, Sisse

2008-01-01

In 2005, 76 out of 177 analysed samples of non-alcoholic beverages were found to contain the intense sweeteners cyclamate, acesulfame-K, aspartame, and saccharin. The content of cyclamate did not exceed the now permitted maximum level in the European Union of 250 mg l(-1) in soft drinks. The esti......In 2005, 76 out of 177 analysed samples of non-alcoholic beverages were found to contain the intense sweeteners cyclamate, acesulfame-K, aspartame, and saccharin. The content of cyclamate did not exceed the now permitted maximum level in the European Union of 250 mg l(-1) in soft drinks...

MCD-induced steatohepatitis is associated with hepatic adiponectin resistance and adipogenic transformation of hepatocytes.

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Larter, Claire Z; Yeh, Matthew M; Williams, Jacqueline; Bell-Anderson, Kim S; Farrell, Geoffrey C

2008-09-01

In these studies, we tested the hypothesis that increased lipid intake would exacerbate the severity of nutritional steatohepatitis. C57Bl/6J mice were fed methionine-and-choline deficient (MCD) diets containing 20% (high) or 5% (low) fat by weight for 3 weeks and compared to lipid-matched controls. MCD feeding increased serum ALT levels and induced hepatic steatosis, lobular inflammation and ballooning degeneration of hepatocytes, irrespective of dietary fat content. Hepatic triglyceride accumulation was similar between high and low-fat MCD-fed mice, but lipoperoxide levels were approximately 3-fold higher in the high-fat MCD-fed animals. Serum adiponectin levels increased in MCD-fed mice, although to a lesser extent in high-fat fed animals. AMPK phosphorylation was correspondingly increased in muscle of MCD-fed mice, but hepatic AMPK phosphorylation decreased, and there was little evidence of PPAR alpha activation, suggesting impaired adiponectin action in the livers of MCD-fed animals. Hepatocyte PPAR gamma mRNA levels increased in MCD-fed mice, and were associated with increased aP2 expression, indicating adipogenic transformation of hepatocytes. Increased dietary lipid intake did not alter steatohepatitis severity in MCD-fed mice despite increased lipoperoxide accumulation. Instead, steatohepatitis was associated with impaired hepatic adiponectin action, and adipogenic transformation of hepatocytes in both low and high-fat MCD-fed mice.

Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

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Smith, G D; Amos, T A; Mahler, R; Peters, T J

1987-01-01

Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes mellitus showed a significant improvement in their glucose tolerance, which paralleled the severity of their diabetes. This response seems to reflect decreased degradation of insulin rather than increased pancreatic output. These observations suggest that treatment with chloroquine or suitable analogues may be a new approach to the management of diabetes. PMID:3103729

A case of insulinoma with non-alcoholic fatty liver disease: Roles of hyperphagia and hyperinsulinemia in pathogenesis of the disease.

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Rokutan, Mariyo; Yabe, Daisuke; Komoto, Izumi; Kurose, Takeshi; Kawai, Jun; Nakamura, Takefumi; Imamura, Masayuki; Seino, Yutaka

2015-01-01

Nonalcoholic fatty liver disease (NAFLD) is a serious health-related condition all over the world; the number of patients is increasing in Asian countries including Japan. Better understanding of its pathophysiology is required to develop effective therapeutics, as patients may go on to develop non-alcoholic steatohepatitis and hepatocellular carcinomas. While NAFLD is believed to be associated with metabolic risk factors such as obesity, diabetes, and dyslipidemia, its etiology remains largely unknown and the development or co-existence of NAFLD in patients with insulinoma has not been investigated. A 33-year-old male with an insulinoma, who had been hypoglycemic during the previous four years, developed abnormally elevated levels of liver enzymes and histological fatty liver characteristic of NAFLD by the time of admission to our hospital for resection of an insulinoma. His medical records for the previous eight years revealed that his bodyweight had increased gradually from 60 kg to 71 kg for seven years and then acutely increased to 79 kg in the latest one-year period. This sudden increase was thought to be due to the patient's self-described overeating of fruits to forestall hypoglycemia. Fresh fruits are rich in fructose, and the patient's triglycerides, alanine and aspartate transaminases showed an acute increase in the previous one-year period. After resection of the insulinoma, the levels of these parameters all were mostly restored, which suggests that hyperinsulinemia and subsequent hyperphagia played a role in the development of NAFLD in this case. This is the first report of patient with NAFLD and an insulinoma.

The Combination of Blueberry Juice and Probiotics Ameliorate Non-Alcoholic Steatohepatitis (NASH) by Affecting SREBP-1c/PNPLA-3 Pathway via PPAR-α

Science.gov (United States)

Ren, Tingting; Zhu, Juanjuan; Zhu, Lili; Cheng, Mingliang

2017-01-01

Nonalcoholic steatohepatitis (NASH) is liver inflammation and a major threat to public health. Several pharmaceutical agents have been used for NASH therapy but their high-rate side effects limit the use. Blueberry juice and probiotics (BP) have anti-inflammation and antibacterial properties, and may be potential candidates for NASH therapy. To understand the molecular mechanism, Sprague Dawley rats were used to create NASH models and received different treatments. Liver tissues were examined using HE (hematoxylin and eosin) and ORO (Oil Red O) stain, and serum biochemical indices were measured. The levels of peroxisome proliferators-activated receptor (PPAR)-α, sterol regulatory element binding protein-1c (SREBP-1c), Patatin-like phospholipase domain-containing protein 3 (PNPLA-3), inflammatory cytokines and apoptosis biomarkers in liver tissues were measured by qRT-PCR and Western blot. HE and ORO analysis indicated that the hepatocytes were seriously damaged with more and larger lipid droplets in NASH models while BP reduced the number and size of lipid droplets (p < 0.05). Meanwhile, BP increased the levels of SOD (superoxide dismutase), GSH (reduced glutathione) and HDL-C (high-density lipoprotein cholesterol), and reduced the levels of AST (aspartate aminotransferase), ALT (alanine aminotransferase), TG (triglycerides), LDL-C (low-density lipoprotein cholesterol) and MDA (malondialdehyde) in NASH models (p < 0.05). BP increased the level of PPAR-α (Peroxisome proliferator-activated receptor α), and reduced the levels of SREBP-1c (sterol regulatory element binding protein-1c) and PNPLA-3 (Patatin-like phospholipase domain-containing protein 3) (p < 0.05). BP reduced hepatic inflammation and apoptosis by affecting IL-6 (interleukin 6), TNF-α (Tumor necrosis factor α), caspase-3 and Bcl-2 in NASH models. Furthermore, PPAR-α inhibitor increased the level of SREBP-1c and PNPLA-3. Therefore, BP prevents NASH progression by affecting SREBP-1c/PNPLA-3 pathway

Dietary lycopene and tomato extract supplementations inhibit nonalcoholic steatohepatitis-promoted hepatocarcinogenesis in rats

Science.gov (United States)

Epidemiological and experimental studies provide supportive evidence that lycopene (LY), a major carotenoid from tomatoes and tomato products, may act as a chemopreventive agent against certain types of cancers. We recently showed that high-fat diet (HFD)-induced nonalcoholic steatohepatitis (NASH) ...

Do pre-drinkers consume more alcohol than non-pre-drinkers on an event-specific night out?

DEFF Research Database (Denmark)

Østergaard, Jeanette; Skov, Peter Rohde

2014-01-01

Introduction and Aims Young people drinking heavily before going out to bars and clubs is associated with alcohol-related harm and therefore of great public concern. This study examines whether pre-drinkers consume more alcohol than non-pre-drinkers on an event-specific night out in England...... demographics, socioeconomic status, frequency of intoxication and alcohol unit intake before and during the young people's night out. Results A mixed linear model performed on the panel mobile survey shows that pre-drinkers in England and Denmark consume 9.185 (P ..., respectively, more than the non-pre-drinkers. However, in both countries pre-drinkers consume 3.430 (P alcohol on-premises than the non-pre-drinkers. Discussion and Conclusion Pre-drinking is a widespread phenomenon in England and Denmark, with more than half of young...

Circulating dipeptidyl peptidase-4 activity correlates with measures of hepatocyte apoptosis and fibrosis in non-alcoholic fatty liver disease in type 2 diabetes mellitus and obesity: A dual cohort cross-sectional study.

Science.gov (United States)

Williams, Kathryn H; Vieira De Ribeiro, Ana Júlia; Prakoso, Emilia; Veillard, Anne-Sophie; Shackel, Nicholas A; Brooks, Belinda; Bu, Yangmin; Cavanagh, Erika; Raleigh, Jim; McLennan, Susan V; McCaughan, Geoffrey W; Keane, Fiona M; Zekry, Amany; Gorrell, Mark D; Twigg, Stephen M

2015-11-01

Intrahepatic expression of dipeptidyl peptidase-4 (DPP4), and circulating DPP4 (cDPP4) levels and its enzymatic activity, are increased in non-alcoholic fatty liver disease (NAFLD) and in type 2 diabetes mellitus and/or obesity. DPP4 has been implicated as a causative factor in NAFLD progression but few studies have examined associations between cDPP4 activity and NAFLD severity in humans. This study aimed to examine the relationship of cDPP4 activity with measures of liver disease severity in NAFLD in subjects with diabetes and/or obesity. cDPP4 was measured in 106 individuals with type 2 diabetes who had transient elastography (Cohort 1) and 145 individuals with morbid obesity who had liver biopsy (Cohort 2). Both cohorts had caspase-cleaved keratin-18 (ccK18) measured as a marker of apoptosis. Natural log increases in cDPP4 activity were associated with increasing quartiles of ccK18 (Cohorts 1 and 2) and with median liver stiffness ≥10.3 kPa (Cohort 1) and significant fibrosis (F ≥ 2) on liver biopsy (Cohort 2). In diabetes and/or obesity, cDPP4 activity is associated with current apoptosis and liver fibrosis. Given the pathogenic mechanisms by which DPP4 may progress NAFLD, measurement of cDPP4 activity may have utility to predict disease progression and DPP4 inhibition may improve liver histology over time. © 2014 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

A Novel Role of SIRT1/ FGF-21 in Taurine Protection Against Cafeteria Diet-Induced Steatohepatitis in Rats

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Azza H. Abd Elwahab

2017-09-01

Full Text Available Background: Non-alcoholic fatty liver disease (NAFLD is one of the alarmingly rising clinical problems in the 21st century with no effective drug treatment until now. Taurine is an essential amino acid in humans that proved efficacy as a non-pharmacological therapy in a plethora of diseases; however, its impact on NAFLD remains elusive. The aim of the current study is to evaluate the protective mechanism of taurine in experimental steatohepatitis induced by junk food given as cafeteria-diet (CAF-D in male albino rats. Methods: Forty adult male albino rats of local strain between 8-10 weeks old, weighing 150 ± 20 g, were divided into four equal groups: Group I (control group, Group II (Taurine group, Group III (CAF-D for 12 weeks and Group IV (CAF-D +Taurine. CAF-D was given in addition to the standard chow for 12 weeks, where each rat was given one piece of beef burger fried in 15 g of sunflower oil, one teaspoonful of mayonnaise, and one piece of petit pan bread, weighing 60g/ piece. In the serum, liver function tests; ALT, AST, ALP, GGT and the lipid profile; TG, TC, HDL-C added to reduced glutathione (GSH were assessed colorimetrically, while fibroblast growth factor (FGF-21, adiponectin & interleukin (IL-6 via ELISA. The same technique was used for the assays of the hepatic levels of FGF-21, silent information regulator (SIRT1, malondialdehyde (MDA,IL-10, tumor necrosis factor-α (TNF-α as well as the apoptotic markers; caspase-3 and B-cell lymphoma (Bcl-2. Results: The cafeteria-diet induced steatohepatitis was reflected by significantly increased body and liver weight gain, elevation of liver enzymes; ALT, AST, ALP and GGT added to the dyslipidemic panel, presented as increased TC, TG, LDL-C and decreased HDL-C levels. The steatosis-induced inflammatory milieu, marked by elevated serum levels of FGF-21, IL-6, hepatic TNF-α, as well as reduced IL-10 and adiponectin, was associated with steatosis- induced hepatic oxidative stress

A Novel Role of SIRT1/ FGF-21 in Taurine Protection Against Cafeteria Diet-Induced Steatohepatitis in Rats.

Science.gov (United States)

Abd Elwahab, Azza H; Ramadan, Basma K; Schaalan, Mona F; Tolba, Amina M

2017-01-01

Non-alcoholic fatty liver disease (NAFLD) is one of the alarmingly rising clinical problems in the 21st century with no effective drug treatment until now. Taurine is an essential amino acid in humans that proved efficacy as a non-pharmacological therapy in a plethora of diseases; however, its impact on NAFLD remains elusive. The aim of the current study is to evaluate the protective mechanism of taurine in experimental steatohepatitis induced by junk food given as cafeteria-diet (CAF-D) in male albino rats. Forty adult male albino rats of local strain between 8-10 weeks old, weighing 150 ± 20 g, were divided into four equal groups: Group I (control group), Group II (Taurine group), Group III (CAF-D for 12 weeks) and Group IV (CAF-D +Taurine). CAF-D was given in addition to the standard chow for 12 weeks, where each rat was given one piece of beef burger fried in 15 g of sunflower oil, one teaspoonful of mayonnaise, and one piece of petit pan bread, weighing 60g/ piece. In the serum, liver function tests; ALT, AST, ALP, GGT and the lipid profile; TG, TC, HDL-C added to reduced glutathione (GSH) were assessed colorimetrically, while fibroblast growth factor (FGF)-21, adiponectin & interleukin (IL)-6 via ELISA. The same technique was used for the assays of the hepatic levels of FGF-21, silent information regulator (SIRT1), malondialdehyde (MDA),IL-10, tumor necrosis factor-α (TNF-α) as well as the apoptotic markers; caspase-3 and B-cell lymphoma (Bcl-2). The cafeteria-diet induced steatohepatitis was reflected by significantly increased body and liver weight gain, elevation of liver enzymes; ALT, AST, ALP and GGT added to the dyslipidemic panel, presented as increased TC, TG, LDL-C and decreased HDL-C levels. The steatosis-induced inflammatory milieu, marked by elevated serum levels of FGF-21, IL-6, hepatic TNF-α, as well as reduced IL-10 and adiponectin, was associated with steatosis- induced hepatic oxidative stress, reflected by increased hepatic MDA and

Aggravation of nonalcoholic steatohepatitis by moderate alcohol consumption is associated with decreased SIRT1 activity in rats

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Chronic alcohol intake decreases adiponectin and sirtuin 1 (SIRT1) expressions, both of which have been implicated in various biological processes including inflammation, apoptosis and metabolism. We have previously shown that moderate consumption of alcohol aggravates liver inflammation and apoptos...

Effects of glycemic control on saliva flow rates and protein composition in non-insulin-dependent diabetes mellitus.

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Dodds, M W; Dodds, A P

1997-04-01

The objective of this study was to determine whether improvements in the level of diabetic control in a group of subjects with poorly controlled non-insulin-dependent diabetes mellitus influence salivary output and composition. Repeated whole unstimulated and stimulated parotid saliva samples were collected from diabetic patients attending an outpatient diabetes education program and a matched nondiabetic control group. Saliva was analyzed for flow rates, parotid protein concentration and composition, and amylase activity. Subjective responses to questions about salivary hypofunction were tested. There were no significant differences in whole unstimulated and stimulated parotid flow rates or stimulated parotid protein concentration and composition between diabetics and the control group. Amylase activity was higher in diabetics and decreased with improved glycemic control. Subjects reporting taste alterations had higher mean blood glucose levels than subjects with normal taste sensation. Poorly controlled non-insulin-dependent diabetes mellitus has no influence on saliva output, although amylase activity may be elevated, and there may be taste alterations.

Salivary alterations in type 2 (non-insulin-dependent) diabetes mellitus and hypertension.

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Dodds, M W; Yeh, C K; Johnson, D A

2000-10-01

The aim of this study was to determine whether saliva output and composition are altered in type 2 diabetes mellitus by comparison with a healthy, non-medicated control group, and also a group of hypertensives. From a community-dwelling cohort of Mexican American and European American subjects enrolled in the OH:SALSA oral aging study, we identified 233 subjects with type 2 diabetes mellitus, 227 with hypertension, and 240 healthy control subjects. We collected unstimulated whole (UW) and submandibular/ sublingual (US) saliva, as well as stimulated parotid (SP) and submandibular/ sublingual (SS) saliva. Flow rates were determined, yeast carriage was assayed in UW saliva, and SP and SS saliva samples were analyzed for protein composition. ELISA was used to determine concentrations of an array of specific protein components, with both antimicrobial and other activities. Both diabetic and hypertensive subjects had reduced output of both stimulated and unstimulated submandibular/sublingual saliva. 30% of the diabetic subjects had high oral yeast counts (> or =1000 cfu/mL) compared with 17% of the healthy subjects and 20% of the hypertensives. Significant increases in the concentrations of a number of the protein components were found in the diabetic subjects, specifically, SP lactoferrin, myeloperoxidase (MPO), and salivary peroxidase (SPO), as well as SS total protein, albumin, lactoferrin and secretory IgA. The pattern of decreased flow rates and increased protein concentrations were similar, but consistently greater in diabetics than hypertensives, suggesting that disease-specific mechanisms may be responsible. Diabetics may be more prone to oral dryness and infections than non-diabetics.

[Non-alcoholic fatty liver disease (NAFLD) in patients with metabolic syndrome and type 2 diabetes mellitus. Pathomechanism, new diagnostic markers].

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Kieć-Wilk, Beata; Klupa, Tomasz; Dembińska-Kieć, Aldona

2010-01-01

Non-alcoholic fatty liver disease (NAFLD) is a complex of a wide spectrum of liver pathology--from steatosis alone, to cirrhosis and liver cancer. The pathogenic concept of NAFLD covers overnutrition with fatty acids, underactivity. Insulin resistance is believed to play the main role in this process. NAFLD is mostly related to visceral adiposity, metabolic syndrome and type 2 diabetes melitus. The presented work is a review of in vitro and in vivo modern studies, as well as clinical observations on molecular mechanisms leading to development and progress of NAFLD. Up till today their is no treatment od NAFLD, and this pathology is not benign--it may lead to patients' death in 10 years. The clinical approach to NAFLD is prevention of it's development. The manuscript is a review of new biochemical markers allowing for early detection of metabolic disorders leading to NAFLD development, thus to sufficient prevention of this pathology in patients.

Korsakoff Syndrome in Non-alcoholic Psychiatric Patients. Variable Cognitive Presentation and Impaired Frontotemporal Connectivity

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Georgios Nikolakaros

2018-05-01

Full Text Available Background: Non-alcoholic Wernicke's encephalopathy and Korsakoff syndrome are greatly underdiagnosed. There are very few reported cases of neuropsychologically documented non-alcoholic Korsakoff syndrome, and diffusion tensor imaging (DTI data are scarce.Methods: We report clinical characteristics and neuropsychological as well as radiological findings from three psychiatric patients (one woman and two men with a history of probable undiagnosed non-alcoholic Wernicke's encephalopathy and subsequent chronic memory problems.Results: All patients had abnormal neuropsychological test results, predominantly in memory. Thus, the neuropsychological findings were compatible with Korsakoff syndrome. However, the neuropsychological findings were not uniform. The impairment of delayed verbal memory of the first patient was evident only when the results of the memory tests were compared to her general cognitive level. In addition, the logical memory test and the verbal working memory test were abnormal, but the word list memory test was normal. The second patient had impaired attention and psychomotor speed in addition to impaired memory. In the third patient, the word list memory test was abnormal, but the logical memory test was normal. All patients had intrusions in the neuropsychological examination. Executive functions were preserved, except for planning and foresight, which were impaired in two patients. Conventional MRI examination was normal. DTI showed reduced fractional anisotropy values in the uncinate fasciculus in two patients, and in the corpus callosum and in the subgenual cingulum in one patient.Conclusions: Non-alcoholic Korsakoff syndrome can have diverse neuropsychological findings. This may partly explain its marked underdiagnosis. Therefore, a strong index of suspicion is needed. The presence of intrusions in the neuropsychological examination supports the diagnosis. Damage in frontotemporal white matter tracts, particularly in the

Korsakoff Syndrome in Non-alcoholic Psychiatric Patients. Variable Cognitive Presentation and Impaired Frontotemporal Connectivity.

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Nikolakaros, Georgios; Kurki, Timo; Paju, Janina; Papageorgiou, Sokratis G; Vataja, Risto; Ilonen, Tuula

2018-01-01

Background: Non-alcoholic Wernicke's encephalopathy and Korsakoff syndrome are greatly underdiagnosed. There are very few reported cases of neuropsychologically documented non-alcoholic Korsakoff syndrome, and diffusion tensor imaging (DTI) data are scarce. Methods: We report clinical characteristics and neuropsychological as well as radiological findings from three psychiatric patients (one woman and two men) with a history of probable undiagnosed non-alcoholic Wernicke's encephalopathy and subsequent chronic memory problems. Results: All patients had abnormal neuropsychological test results, predominantly in memory. Thus, the neuropsychological findings were compatible with Korsakoff syndrome. However, the neuropsychological findings were not uniform. The impairment of delayed verbal memory of the first patient was evident only when the results of the memory tests were compared to her general cognitive level. In addition, the logical memory test and the verbal working memory test were abnormal, but the word list memory test was normal. The second patient had impaired attention and psychomotor speed in addition to impaired memory. In the third patient, the word list memory test was abnormal, but the logical memory test was normal. All patients had intrusions in the neuropsychological examination. Executive functions were preserved, except for planning and foresight, which were impaired in two patients. Conventional MRI examination was normal. DTI showed reduced fractional anisotropy values in the uncinate fasciculus in two patients, and in the corpus callosum and in the subgenual cingulum in one patient. Conclusions: Non-alcoholic Korsakoff syndrome can have diverse neuropsychological findings. This may partly explain its marked underdiagnosis. Therefore, a strong index of suspicion is needed. The presence of intrusions in the neuropsychological examination supports the diagnosis. Damage in frontotemporal white matter tracts, particularly in the uncinate

Non-alcoholic fatty liver disease is associated with high prevalence of gastro-oesophageal reflux symptoms.

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Miele, Luca; Cammarota, Giovanni; Vero, Vittoria; Racco, Simona; Cefalo, Consuelo; Marrone, Giuseppe; Pompili, Maurizio; Rapaccini, Gianlodovico; Bianco, Alessandro; Landolfi, Raffaele; Gasbarrini, Antonio; Grieco, Antonio

2012-12-01

Gastro-oesophageal reflux symptoms are usually reported by patients with obesity and metabolic syndrome. Aim of this study was to assess the prevalence and clinical characteristics of gastro-oesophageal reflux symptoms in subjects with non-alcoholic fatty liver disease. Cross-sectional, case-control study of 185 consecutive patients with non-alcoholic fatty liver disease and an age- and sex-matched control group of 112 healthy volunteers. Participants were interviewed with the aid of a previously validated questionnaire to assess lifestyle and reflux symptoms in the 3 months preceding enrolment. Odds ratios were determined before and after adjustment for body mass index, increased waist circumference, physical activity, metabolic syndrome and proton pump inhibitors and/or antiacid medication. The prevalence of heartburn and/or regurgitation and of at least one of gastro-oesophageal reflux symptoms was significantly higher in the non-alcoholic fatty liver disease group. Non-alcoholic fatty liver disease subjects were associated to higher prevalence of heartburn (adjusted odds ratios: 2.17, 95% confidence intervals: 1.16-4.04), regurgitation (adjusted odds ratios: 2.61, 95% confidence intervals: 1.24-5.48) and belching (adjusted odds ratios: 2.01, 95% confidence intervals: 1.12-3.59) and had higher prevalence of at least one GER symptom (adjusted odds ratios: 3.34, 95% confidence intervals: 1.76-6.36). Non-alcoholic fatty liver disease is associated with a higher prevalence of gastro-oesophageal reflux symptoms. Copyright © 2012 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Correlation analysis between bone density measured by quantitative CT and blood sugar level of aged patients with non-insulin-dependent diabetes mellitus

International Nuclear Information System (INIS)

Wang Guizhi; Liang Ping; Qiao Junhua; Liu Chunyan

2008-01-01

Objective: To approach the correlation between the bone density measured by quantitative CT and the blood sugar level of the aged patients with non-insulin-dependent diabetes mellitus, and observe the effects of the blood sugar level on the bone density. Methods: The lumbar bone densities and the blood sugar levels of 160 aged patients with non-insulin-dependent diabetes mellitus (hyperglycemia group 80 cases, euglycemia group 80 cases ) and the healthy aged people (80 cases) were detected by quantitative CT and serum biochemical detection; the correlation between the blood sugar level and the bone density and the osteoporosis occurrence status of aged people in various groups were analyzed. Results: The bone density in the non-insulin-dependent diabetes and hyperglycemia group was lower than those in normal (control) group and non-insulin-dependent diabetes and euglycemia group (P<0.05); the morbility of osteoporosis in the non-insulin-dependent diabetes and hyperglycemia group was higher than those in normal (control) group and non-insulin-dependent diabetes and euglycemia group (P<0.05); negative correlation was found between the bone density and the blood sugar level (aged male group: r=-0.7382, P=0.0013; aged female group: r=-0.8343, P=0.0007). Conclusion: The blood sugar level affects the bone density of the aged patients with non-insulin-dependent diabetes mellitus; the higher the blood sugar level, the lower the bone density. The non-insulin-dependent diabetes aged patients with hyperglycemia have the liability of osteoporosis. (authors)

Circulating adiponectin levels in type 2 diabetes mellitus patients with or without non-alcoholic fatty liver disease: Results of a small, open-label, randomized controlled intervention trial in a subgroup receiving short-term exenatide.

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Savvidou, Savvoula; Karatzidou, Kyparissia; Tsakiri, Kalliopi; Gagalis, Asterios; Hytiroglou, Prodromos; Goulis, John

2016-03-01

Diabetes mellitus type 2 (DMT2) and non-alcoholic fatty liver disease (NAFLD) are both characterized by decreased circulating adiponectin. Recently, glucagon-like peptide-1 receptor agonists have been shown to induce adiponectin's expression. However, their interaction on clinical grounds needs to be further elucidated. DMT2 patients with abnormal aminotransferases were screened for NAFLD and subjected to liver biopsy (group A, n=17). A subgroup of patients (n=110), after assessed for eligibility criteria, was blindly randomized to receive either 6-month exenatide supplementation on glargine insulin (group B) or intense, self-regulated, insulin therapy alone (group C). Baseline patient characteristics: 49(38.6%) males, aged 63.1 ± 7.5 years-old, BMI 32.9 ± 4.9 kg/m(2), HbA1c 8.1 ± 1.2% (65 ± 14 mmol/mol), median ALT 23 U/L (range 5-126), AST 20 U/L (7-72). Group A had biopsy-proven NAFLD with a median Activity Score of 5 and fibrosis stage 3. Presence of NAFLD was accompanied by a significant decline in adiponectin (p<0.001), which was negatively correlated with the degree of ALT in all groups (Spearman's correlation, rs=-0.644, p<0.001). In the subgroup intervention trial, adiponectin was significantly raised in both groups B and C (t-Student for paired samples, p=0.001) by Δ=+24.2% (interquartile range 14.8-53.2%). This elevation was not associated with the type of intervention but with weight loss, glycemic control and reduction of C-reactive protein (one-way ANCOVA). Supplementation of exenatide to glargine insulin compared to standard insulin was: (i) effective in inducing weight loss, (ii) non-inferior in lowering HbA1c and (iii) non-inferior in increasing circulating adiponectin. Higher adiponectin was associated with lower ALT, suggesting a hepato-protective role for this cytokine. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Taking care: Creating a non-alcoholic cocktail for Generation X

African Journals Online (AJOL)

word “elegant” refers to the presentation of the cocktail, as defined in the choice of .... a thin layer in the mouth and is perceived as less fresh. For example ... be used in marketing non-alcoholic cocktails, because they are. Table 1: The basic ...

Determination of Caffeine Content in Non-Alcoholic Beverages and ...

African Journals Online (AJOL)

It was found that Burn®, XL energy drink® and Red Bull® had the highest amount of caffeine. It was however noted that though most of the non-alcoholic beverages had high caffeine content they had no label claim. Key Words: Reverse Phase High Performance Liquid chromatography (HPLC), Ultra violet visible (UV/VIS), ...

Skin cell isolation and expansion for cell transplantation is limited in patients using tobacco, alcohol, or are exhibiting diabetes mellitus.

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Johnen, Christa; Hartmann, Bernd; Steffen, Ingo; Bräutigam, Kirsten; Witascheck, Tom; Toman, Nidal; Küntscher, Markus V; Gerlach, Jörg C

2006-03-01

The aim of this exploratory study was to investigate the isolation and expansion of keratinocytes and fibroblasts from donors with certain medical histories. Biopsies were taken from donors (N=32) falling into one or more of the following categories: a history of heavy smoking and/or alcohol abuse, drug abuse, diabetes mellitus or steroid treatment. Cells from donors who did not fall into any of the above-mentioned categories were used as controls. Proliferation and growth behaviour of cells were analyzed by measurement of passage duration, absorbance (MTT-assay) and light microscopy. Donors with a specific medical history required larger biopsy areas than the control group for isolating a sufficient number of fibroblasts and keratinocytes. Times to confluence were significantly prolonged and absorbances (MTT) were significantly reduced in several donor groups when compared to control cultures. Biopsies from donors with steroid treatment, drug abuse and combined nicotine and alcohol abuse could not be established beyond passage 0 degrees or 1 degree, respectively. We conclude that isolation and expansion of skin cells from donors with certain medical histories may require larger biopsies, prolonged expansion times or may even result in failure. These findings may therefore be of clinical importance in the field of autologous skin cell transplantation.

Factors Associated with Alcohol Consumption: A Survey of Women ...

African Journals Online (AJOL)

AJRH Managing Editor

intellectual deficiency in childhood7,11 and fetal alcohol exposure .... learning disabilities, behavioural problems and attention deficit ..... angry (24.1%). The intensity of feelings were high .... mellitus20. Through risky behaviour such as unsafe.

The Effect of Alcohol on Postprandial and Fasting Triglycerides

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Albert Van de Wiel

2012-01-01

Full Text Available Alcohol has a significant additive effect on the postprandial triglyceride peak when it accompanies a meal containing fat, especially saturated fat. This results from a decrease in the breakdown of chylomicrons and VLDL remnants due to an acute inhibitory effect of alcohol on lipoprotein lipase activity. Furthermore, alcohol increases the synthesis of large VLDL particles in the liver, which is the main source of triglycerides in the hypertriglyceridemia associated with chronic excessive alcohol intake. In case of chronic consumption, lipoprotein lipase activity seems to adapt itself. The effect of alcohol on adipose tissues is less clear. Sometimes, a severe hypertriglyceridemia induced by alcohol (SHIBA can be observed, especially in patients with type 2 diabetes mellitus and/or obesity increasing the risk of pancreatitis.

Further evidence for GHB naturally occurring in common non-alcoholic beverages.

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Elliott, Simon P; Fais, Paolo

2017-08-01

GHB has been implicated in many cases of suspected surreptitious administration with the purpose of increasing victim vulnerability to sexual assault. Low amounts of endogenous (or naturally occurring) GHB, which do not reach pharmacologically active levels, have been detected in alcoholic and non-alcoholic beverages. Due to the continued requirement to obtain data on the presence of endogenous GHB in various beverage types, GHB concentrations were measured in a series of non-alcoholic beverages. Tonic water and lemon flavoured tonic water beverages were analysed at 0, 24 and 96h after the bottle opening using gas chromatography coupled to tandem mass spectrometry (GC-MS/MS) on an Agilent 6890/7000C Triple Quadrupole. GHB was detected in all beverages at very low amounts ranging from 89 to 145ng/mL (0.089-0.145mg/L) and did not demonstrate a general trend of variation for concentration along the tested time span (96h). The presented data provide additional evidence for the endogenous nature of GHB in non-alcoholic beverages at very low concentrations, which are many orders of magnitude lower than those described to produce any pharmacological effect on the subject. However, when considering a case of alleged drug-facilitated sexual assault, a low level of GHB detected in a drink may be related both to a surreptitiously GHB administration with subsequent dilution for concealment or to the presence of endogenous GHB. On this basis, a comprehensive analysis of all the available information, including circumstantial data demonstrating possible attempts to conceal GHB administration and an assessment of levels of endogenous GHB in the suspected beverage type, is of the utmost importance for a proper interpretation of the toxicological results. Copyright © 2017 Elsevier B.V. All rights reserved.

The sedative effect of non-alcoholic beer in healthy female nurses.

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Lourdes Franco

Full Text Available INTRODUCTION: The hop (Humulus lupulus L., a component of beer, is a sedative plant whose pharmacological activity is principally due to its bitter resins, in particular to the α-acid degradation product 2-methyl-3-buten-2-ol. The mechanism of action of hop resin consists of raising the levels of the neurotransmitter γ-aminobutyric acid (GABA, an inhibitory neurotransmitter acting in the central nervous system (CNS. OBJECTIVES: To analyze the sedative effect of hops as a component of non-alcoholic beer on the sleep/wake rhythm in a work-stressed population. METHODS: The experiment was conducted with healthy female nurses (n = 17 working rotating and/or night shifts. Overnight sleep and chronobiological parameters were assessed by actigraphy (Actiwatch® after moderate ingestion of non-alcoholic beer containing hops (333 ml with 0.0% alcohol with supper for 14 days (treatment. Data were obtained in comparison with her own control group without consumption of beer during supper. RESULTS: Actigraphy results demonstrated improvement of night sleep quality as regards the most important parameters: Sleep Latency diminished (p≤0.05 in the Treatment group (12.01±1.19 min when compared to the Control group (20.50±4.21 min, as also did Total Activity (p≤0.05; Treatment group = 5284.78±836.99 activity pulses vs Control = 7258.78±898.89 activity pulses. In addition, anxiety as indexed by the State-Trait Anxiety Inventory (STAI decreased in the Treatment group (State Anxiety 18.09±3.8 vs Control 20.69±2.14. CONCLUSION: The moderate consumption of non-alcoholic beer will favour night-time rest, due in particular to its hop components, in addition to its other confirmed benefits for the organism.

The Sedative Effect of Non-Alcoholic Beer in Healthy Female Nurses

Science.gov (United States)

Franco, Lourdes; Sánchez, Cristina; Bravo, Rafael; Rodríguez, Ana B.; Barriga, Carmen; Romero, Eulalia; Cubero, Javier

2012-01-01

Introduction The hop (Humulus lupulus L.), a component of beer, is a sedative plant whose pharmacological activity is principally due to its bitter resins, in particular to the α-acid degradation product 2-methyl-3-buten-2-ol. The mechanism of action of hop resin consists of raising the levels of the neurotransmitter γ-aminobutyric acid (GABA), an inhibitory neurotransmitter acting in the central nervous system (CNS). Objectives To analyze the sedative effect of hops as a component of non-alcoholic beer on the sleep/wake rhythm in a work-stressed population. Methods The experiment was conducted with healthy female nurses (n = 17) working rotating and/or night shifts. Overnight sleep and chronobiological parameters were assessed by actigraphy (Actiwatch®) after moderate ingestion of non-alcoholic beer containing hops (333 ml with 0,0% alcohol) with supper for 14 days (treatment). Data were obtained in comparison with her own control group without consumption of beer during supper. Results Actigraphy results demonstrated improvement of night sleep quality as regards the most important parameters: Sleep Latency diminished (p≤0.05) in the Treatment group (12.01±1.19 min) when compared to the Control group (20.50±4.21 min), as also did Total Activity (p≤0.05; Treatment group = 5284.78±836.99 activity pulses vs Control = 7258.78±898.89 activity pulses). In addition, anxiety as indexed by the State-Trait Anxiety Inventory (STAI) decreased in the Treatment group (State Anxiety 18.09±3.8 vs Control 20.69±2.14). Conclusion The moderate consumption of non-alcoholic beer will favour night-time rest, due in particular to its hop components, in addition to its other confirmed benefits for the organism. PMID:22815680

[The prevalence of type 2 diabetes mellitus and prediabetes in children].

Science.gov (United States)

Jin, Yan-Yan; Liang, Li; Fu, Jun-Fen; Wang, Xiu-Min

2011-02-01

To investigate the incident and prevalence of type 2 diabetes mellitus (T2DM) and prediabetes in obese children in the last ten years. The clinical data of hospitalized children with newly diagnosed diabetes mellitus (DM) or obesity between October 2000 and September 2011 were retrospectively studied. A total of 503 newly onset cases were diagnosed as DM in the past ten years, of which 31 were diagnosed as T2DM. The prevalence of T2DM in the second five-year duration increased significantly compared with that in the first five-year duration (0.18‰ vs 0.05‰; P1). The number of cases of type 1 diabetes mellitus (T1DM) and T2DM increased by 1.35 fold and 4.20 fold, respectively in the second five-year duration. A total of 1301 obese patients received oral glucose tolerance tests, and 29 cases were diagnosed with T2DM and 255 cases with prediabetes. Of the 255 cases of prediabetes, 133 had dyslipidemia, 138 had non-alcoholic fatty liver disease and 53 had hypertension. The prevalence rates of T1DM and T2DM increased significantly in the last 5 years. The prevalence of T2DM increased more significantly than T1DM. There was a higher prevalence of prediabetes in obese children. Childhood obesity predicts a higher risk of T2DM and cardiovascular disease in the future.

Abnormal Metabolite in Alcoholic Subjects,

Science.gov (United States)

1982-01-01

this study included alcoholic hepatitis or cirrhosis of the liver in 29. of the alcoholic subjects; diabetes mellitus in 8 and Korsakoff’s syndrome in 6...evidence of -7- Korsakoff’s syndrome and the presence or absence of 2,3-butanediol. There was, however, a suggestive correlation with independently...Gamma GT 193, SGPT 29 b 0 0.023 0.05 51a F.B. 22 M 28 0.029 0.14 b 0 ɘ.01 0.12 77 J.N.S. 52 M 0 0.027 0.11 57 JJ.S 45 m 4. 0.25 .35 Korsakoff ’s

Research of Household Expenditure for Food and Non-Alcoholic Beverages in the Republic of Croatia

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Krsto Kero

2011-12-01

Full Text Available The aim of this paper is to investigate household spending by income deciles. Only the most important one among the expenditure categories was considered, food and non-alcoholic beverages. Research and analysis were based on the results of the Questionnaire on Household Expenditure in the Republic of Croatia. Adequate mathematical and statistical models of expenditure for food and non-alcoholic beverages by income deciles were established. The defined models were used in further research to calculate the coefficient of elasticity. The research showed that expenditure for food and non-alcoholic beverages is non-elastic, thus confirming the first Engel’s law. The obtained results can be used in planning household expenditure also in future periods, considering the fact that the model of expenditure by income deciles referring to the period 200 – 2009 was developed. A model for measuring elasticity was constructed as well. It refers to a 10-year period and can be used to forecast future coefficients of elasticity.

Non-alcoholic acute Wernicke's encephalopathy: Role of MRI in non typical cases

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Elefante, Andrea, E-mail: aelefant@unina.it [Department of Neuroradiology, University of Naples “Federico II”, Naples (Italy); Puoti, Gianfranco [I Division of Neurology, General Medicine Department, Second University of Naples, Naples (Italy); Senese, Rossana [Department of Neuroradiology, University of Naples “Federico II”, Naples (Italy); Coppola, Cinzia [I Division of Neurology, General Medicine Department, Second University of Naples, Naples (Italy); Russo, Carmela [Department of Neuroradiology, University of Naples “Federico II”, Naples (Italy); Tortora, Fabio [Department of Neuroradiology, Second University of Naples, Naples (Italy); Divitiis, Oreste de [Department of Neurosurgery, University of Naples “Federico II”, Naples (Italy); Brunetti, Arturo [Department of Neuroradiology, University of Naples “Federico II”, Naples (Italy)

2012-12-15

Aim: Acute Wernicke's encephalopathy (WE) is a severe neurological disorder caused by thiamine deficiency, most commonly found in chronic alcoholics. It is not so easy to suspect acute WE when the clinical picture does not include all the typical symptoms and alcohol abuse is not reported. Three rare cases of Wernicke's encephalopathy (WE) in non-alcoholic patients are reported. Cases presentation: Two patients developed the disease following prolonged intravenous feeding, the third was carrying a gastric lymphoma. None of them presented with the classic clinical triad of WE (ophtalmoplegia/nystagmus, ataxia and consciousness disturbance), showing just one or two of the typical symptoms. Brain Magnetic Resonance Imaging (MRI) represented the key tool to suspect and define WE diagnosis, showing a picture characterized by bilaterally altered signal of the thalamic pulvinar, mesencephalic cup, mammillary bodies, periaqueductal grey matter and floor of fourth ventricle. All patients dramatically improved within 48 h after administration of thiamine. Conclusion: We emphasize that WE should be suspected in all patients showing typical MRI features presenting with at least one of the clinical triad of WE.

Non-Alcoholic Beverages from Fermented Cereals with Increased Oligosaccharide Content

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Grazina Juodeikiene

2016-01-01

Full Text Available The aim of this study is to develop a new technology for making traditional Lithuanian non-alcoholic beverage kvass from fermented cereals by extending the spectrum of raw materials (extruded rye and applying new biotechnological resources (xylanolytic enzymes and lactic acid bacteria (LAB to improve its functional properties. Arabinoxylans in extruded rye were very efficiently hydrolysed into oligosaccharides by xylanolytic complex Ceremix Plus MG. Using Ceremix Plus MG and LAB fermentation, the yield of arabinoxylooligosaccharides and xylooligosaccharides in beverage was increased to 300 and 1100 mg/L, respectively. Beverages fermented by LAB had lower pH values and ethanol volume fraction compared to the yeast-fermented beverage. The acceptability of the beverage fermented by Lactobacillus sakei was higher than of Pediococcus pentosaceus- or yeast-fermented beverages and similar to the acceptability of commercial kvass made from malt extract. The results showed that extruded rye, xylanolytic enzymes and LAB can be used for production of novel and safe high-value non-alcoholic beverages.

Hepatic unsaturated fatty acids in patients with non-alcoholic fatty liver disease assessed by 3.0 T MR spectroscopy

International Nuclear Information System (INIS)

Werven, J.R. van; Schreuder, T.C.M.A.; Nederveen, A.J.; Lavini, C.; Jansen, P.L.M.; Stoker, J.

2010-01-01

Rationale and objective: Non-alcoholic fatty liver disease (NAFLD) is related to the metabolic syndrome and obesity. Proton magnetic resonance spectroscopy ( 1 H MRS) is a non-invasive technique to assess hepatic triglyceride content (HTGC) and allows assessment of unsaturated fatty acids (UFA). There is increasing evidence that hepatic UFA are associated with the development of NAFLD. Therefore the objective of this study was to assess hepatic UFA in patients with NAFLD using 1 H MRS. Materials and methods: We included 26 consecutive patients with deranged liver enzymes, with and without type 2 diabetes mellitus (DM2), suspected for NAFLD. Liver function and metabolic parameters were assessed. 1 H MRS measurements were performed at 3.0 T. From the 1 H MR spectra two ratios were calculated: ratio 1 (UFA); unsaturated fatty acid peak vs. reference water peak and ratio 2 (HTGC); total fatty acid peak vs. reference water peak. Results: Twenty-six patients were included. In these patients hepatic UFA (ratio 1) correlated with AST/ALT ratio (r = -0.46, p = 0.02), glucose levels (r = 0.46, p = 0.018), HOMA-IR (r = 0.59, p = 0.004) and HTGC (r = 0.81, p 1 H MRS. 1 H MRS determined hepatic UFA correlate with clinical and metabolic parameters associated with NAFLD. Hepatic UFA are increased in patients with DM2. This study provides evidence for the use of non-invasive 1 H MRS to assess hepatic UFA in vivo.

Aminoacid polymorphisms of insulin receptor substrate-1 in non-insulin-dependent diabetes mellitus

DEFF Research Database (Denmark)

Almind, K; Bjørbaek, C; Vestergaard, H

1993-01-01

Since relative or absolute insulin deficiency and insulin insensitivity are involved in the aetiology of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether patients with NIDDM exhibit genetic variability in the coding region of insulin receptor substrate-1 (IRS-1), a candidate...... with NIDDM and 3 of the controls were heterozygous at codon 972 for a polymorphism in which glycine was substituted with arginine. Moreover, at codon 513, 6 patients with NIDDM and 2 controls had a heterozygous polymorphism with a transition from alanine to proline. None of the polymorphism carriers had both...

Verbal learning and memory in adolescent cannabis users, alcohol users and non-users.

Science.gov (United States)

Solowij, Nadia; Jones, Katy A; Rozman, Megan E; Davis, Sasha M; Ciarrochi, Joseph; Heaven, Patrick C L; Lubman, Dan I; Yücel, Murat

2011-07-01

Long-term heavy cannabis use can result in memory impairment. Adolescent users may be especially vulnerable to the adverse neurocognitive effects of cannabis. In a cross-sectional and prospective neuropsychological study of 181 adolescents aged 16-20 (mean 18.3 years), we compared performance indices from one of the most widely used measures of learning and memory--the Rey Auditory Verbal Learning Test--between cannabis users (n=52; mean 2.4 years of use, 14 days/month, median abstinence 20.3 h), alcohol users (n=67) and non-user controls (n=62) matched for age, education and premorbid intellectual ability (assessed prospectively), and alcohol consumption for cannabis and alcohol users. Cannabis users performed significantly worse than alcohol users and non-users on all performance indices. They recalled significantly fewer words overall (pmemory performance after controlling for extent of exposure to cannabis. Despite relatively brief exposure, adolescent cannabis users relative to their age-matched counterparts demonstrated similar memory deficits to those reported in adult long-term heavy users. The results indicate that cannabis adversely affects the developing brain and reinforce concerns regarding the impact of early exposure.

Effects of nitrendipine and enalapril on left ventricular mass in patients with non-insulin-dependent diabetes mellitus and hypertension

NARCIS (Netherlands)

Gerritsen, TA; Bak, AAA; Stolk, RP; Jonker, JJC; Grobbee, DE

Objective To compare the effects of a calcium antagonist (nitrendipine) and an angiotensin converting enzyme inhibitor (enalapril) with those of placebo on left ventricular mass in patients with non-insulin-dependent diabetes mellitus and hypertension, Design A double-blind randomized,

Thyroid hormone stimulated glucose uptake in human mononuclear blood cells from normal persons and from patients with non-insulin-dependent diabetes mellitus

DEFF Research Database (Denmark)

Kvetny, J; Matzen, L

1989-01-01

Thyroxine and T3 induced oxygen consumption and glucose uptake were studied in vitro in mononuclear blood cells isolated from patients with non-insulin-dependent diabetes mellitus (NIDDM) and from non-diabetic control persons. Cellular oxygen consumption and glucose uptake were promptly increased...

Evaluating the Efficiency of Hepatoprotector Hepa Veda in Patients with Liver Pathology

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Yu.M. Stepanov

2015-04-01

Full Text Available The article presents the results of efficiency of monotherapy with hepatoprotector Hepa veda in patients with liver pathology. There were found a significant decrease of aminotransferase level in patients with non-alcoholic steatohepatitis and a tendency to decrease in patients with chronic viral hepatitis C that showed the efficiency of this hepatoprotector.

Association patterns of volatile metabolites in urinary excretions among Type-2 Non-Insulin dependent diabetes patients

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Muhammad Saqib Shahzad

2016-05-01

Full Text Available Background: Patterns of volatile metabolites in urine are important to detect abnormalities associated with diabetes. Present study was conducted to find out the excretion patterns of endogenously produced alcohols in urine for type 2 (Non-Insulin Dependent diabetes mellitus. A cross sectional analytical study was conducted with duration extended from Jan to Mar 2015. Methods: The current study included 40 patients with chronic type 2 diabetes mellitus. In total, 10 sex and age matched subjects with no history of any disease were considered as controls. Blood sugar was estimated by autoanalyzer using standard kit of Merck following manufacturer`s instructions. Urine sugar was quantitatively detected by biuret reagent using titration technique. Urinary alcohol was identified and estimated by gas chromatography. Urinary ketone bodies were estimated by urinary strip. Results: It was observed that level of fasting blood sugar was significantly increased (P<0.001 in patients as compared to their controls. The blood sugar and urinary alcohol in patients were 3.0% and 6.0% respectively. Urinary ketone bodies were found to be 2+. On the other hand urine sugar, alcohol and ketone bodies were not detected in the negative control subjects. Conclusions: It is concluded that urinary alcohol is endogenously produced in patients with type 2 diabetes due to uncontrolled hyperglycemia. However further work is needed to find out the ratio of urinary and blood alcohol which may confirm the present findings.

Father and son attachment styles in alcoholic and non-alcoholic families

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Mythili Hazarika

2017-12-01

Full Text Available Background: The theory of attachment is important to understand a lot of human behaviour. Styles of attachment could be important predictors in developing dependence on alcoholism. Insecure attachment patterns could be significant risk factors for future alcohol use. Methods: Participants for this study consist of fathers with alcohol dependence syndrome (ADS from treatment centres and fathers from the community with no dependency on alcohol, and their sons (n=200. The Michigan Alcoholism Screening Test (MAST, socioeconomic status scale were administered, and attachment styles were derived by the Attachment Style Questionnaire (ASQ. We hypothesised a prior concept reflecting theoretical predictions for the association between attachment styles and alcohol in both the generations. Results: Statistics on SPSS-16 was used to test our hypotheses. As predicted, fathers with ADS had insecure attachments styles in comparison to the control group. Substance abuse/dependence and treatment participation were at an all-time low for the secure group. Conclusion: The findings from this study identify attachment styles as an influential factor in understanding the divergence between alcohol dependence in treatment seekers. The findings further imply that differential treatment may need to be provided taking into account one’s attachment representation to promote successful recovery. It also highlights the need to develop secure ties in children of alcoholic parents to protect them from use of substances as a coping and a learned mechanism. Limitations of the study and suggestions for further research are highlighted and implications for diagnosis and treatment are discussed.

Clinical relevance of the bile acid receptor TGR5 in metabolism

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van Nierop, F Samuel; Scheltema, Matthijs J; Eggink, Hannah M

2017-01-01

The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex enterohep......The bile acid receptor TGR5 (also known as GPBAR1) is a promising target for the development of pharmacological interventions in metabolic diseases, including type 2 diabetes, obesity, and non-alcoholic steatohepatitis. TGR5 is expressed in many metabolically active tissues, but complex...... enterohepatic bile acid cycling limits the exposure of some of these tissues to the receptor ligand. Profound interspecies differences in the biology of bile acids and their receptors in different cells and tissues exist. Data from preclinical studies show promising effects of targeting TGR5 on outcomes...... such as weight loss, glucose metabolism, energy expenditure, and suppression of inflammation. However, clinical studies are scarce. We give a summary of key concepts in bile acid metabolism; outline different downstream effects of TGR5 activation; and review available data on TGR5 activation, with a focus...

Living in the shadow of terrorism: psychological distress and alcohol use among religious and non-religious adolescents in Jerusalem.

Science.gov (United States)

Schiff, Miriam

2006-05-01

This study examines the effects of prolonged exposure to terrorism in 600 religious and non-religious Jewish adolescents living in Jerusalem, particularly post-traumatic stress (PTS) symptoms, depressive symptoms, alcohol use, coping strategies and social support. The youth in Jerusalem reported high exposure to terrorist acts. This exposure was associated with high PTS, depressive symptoms and alcohol use. Despite an apparently greater exposure to terrorism, religious adolescents reported lower levels of PTS and alcohol consumption, but similar levels of depressive symptoms to non-religious adolescents. Problem-solving coping predicted higher depressive symptoms for religious adolescents exposed to terrorism but not for similarly exposed non-religious adolescents. In contrast, emotion-focused coping predicted more alcohol consumption among highly exposed non-religious adolescents, while emotion-focused coping predicted more alcohol consumption among religious adolescents with low exposure. The overall findings suggest that religiosity may buffer the negative consequences of exposure in other ways than through coping or support.

Potential for alcohol and drug interactions in older adults: evidence from the Irish longitudinal study on ageing

Science.gov (United States)

2014-01-01

Background Older adults are susceptible to adverse effects from the concomitant use of prescription medications and alcohol. This study estimates the prevalence of exposure to alcohol interactive (AI) medications and concomitant alcohol use by therapeutic class in a large, nationally representative sample of older adults. Methods Cross-sectional analysis of a population based sample of older Irish adults aged ≥60 years using data from The Irish Longitudinal Study on Ageing (TILDA) (N = 3,815). AI medications were identified using Stockley’s Drug Interactions, the British National Formulary and the Irish Medicines Formulary. An in-home inventory of medications was used to characterise AI drug exposure by therapeutic class. Self-reported alcohol use was classified as non-drinker, light/moderate and heavy drinking. Comorbidities known to be exacerbated by alcohol were also recorded (diabetes mellitus, hypertension, peptic ulcer disease, liver disease, depression, gout or breast cancer), as well as sociodemographic and health factors. Results Seventy-two per cent of participants were exposed to AI medications, with greatest exposure to cardiovascular and CNS agents. Overall, 60% of participants exposed to AI medications reported concomitant alcohol use, compared with 69.5% of non-AI exposed people (p alcohol consumption (both light/moderate and heavier) and AI medications. Current smokers and people with increasing co-morbidities were also at greatest risk for heavy drinking in combination with AI medications. Conclusions The concurrent use of alcohol with AI medications, or with conditions known to be exacerbated by alcohol, is common among older Irish adults. Prescribers should be aware of potential interactions, and screen patients for alcohol use and provide warnings to minimize patient risk. PMID:24766969

Expresión génica en pacientes obesos con enfermedad hepática por depósito de grasa Gene expression in obese patients with non-alcoholic steatohepatitis

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A. Cayón

2008-04-01

pacientes con EHNA.Although the molecular basis for the pathophysiology of non-alcoholic steatohepatitis (NASH is poorly understood, we evaluate the hepatic gene expression of cytokines, chemokines, cell receptors, growth factors, intracellular transducers and extracellular communication proteins in liver tissue of obese patients (with and without NASH, and we determine the specific intrahepatic gene expression profiles associated with histological severe NASH. Thirty-eight obese patients with BMI > 35 were analyzed, who underwent bariatric surgery. Biopsy specimen samples were snap-frozen in liquid nitrogen. Hepatic gene expression was determined in liver biopsy specimens from 3 groups: a obese patients without NASH (n = 12; b patients with NASH without fibrosis (n = 13; and c patients with NASH and fibrosis (n = 13. Genes were considered to be expressed differentially in NASH only if there was a greater than 2-fold difference in abundance of mRNA when compared with each of the control group. These results were confirmed by real-time PCR. Fourteen genes were differentially expressed (10 overexpressed and 4 underexpressed in patients with NASH. Genes that were significantly overexpressed included prohibitin, TNF, TNF RI (p55, MCSF, R2-TRAIL, b1-CTGF, FGF, VEGF, and BIGH3OBR. Insulin growth factor-1, insulin growth factor-2, interleukin-2 and tyrosine-receptor were underexpressed in NASH patients. In conclusion: 1. The obese patients with NASH without fibrosis show an overexpression of proinflammatory and proapoptotic genes. Also, the NASH patients with fibrosis show an overexpression of fibrogenic genes, including the leptin receptor Ob-Rb. 2. The up-regulated gene expression of prohibitin suggests mitochondrial dysfunction in NASH patients.

Intestinal CYP2E1: A mediator of alcohol-induced gut leakiness

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Christopher B. Forsyth

2014-01-01

Full Text Available Chronic alcohol use can result in many pathological effects including alcoholic liver disease (ALD. While alcohol is necessary for the development of ALD, only 20–30% of alcoholics develop alcoholic steatohepatitis (ASH with progressive liver disease leading to cirrhosis and liver failure (ALD. This suggests that while chronic alcohol consumption is necessary it is not sufficient to induce clinically relevant liver damage in the absence of a secondary risk factor. Studies in rodent models and alcoholic patients show that increased intestinal permeability to microbial products like endotoxin play a critical role in promoting liver inflammation in ALD pathogenesis. Therefore identifying mechanisms of alcohol-induced intestinal permeability is important in identifying mechanisms of ALD and for designing new avenues for therapy. Cyp2e1 is a cytochrome P450 enzyme that metabolizes alcohol has been shown to be upregulated by chronic alcohol use and to be a major source of oxidative stress and liver injury in alcoholics and in animal and in vitro models of chronic alcohol use. Because Cyp2e1 is also expressed in the intestine and is upregulated by chronic alcohol use, we hypothesized it could play a role in alcohol-induced intestinal hyperpermeability. Our in vitro studies with intestinal Caco-2 cells and in mice fed alcohol showed that circadian clock proteins CLOCK and PER2 are required for alcohol-induced permeability. We also showed that alcohol increases Cyp2e1 protein and activity but not mRNA in Caco-2 cells and that an inhibitor of oxidative stress or siRNA knockdown of Cyp2e1 prevents the increase in CLOCK or PER2 proteins and prevents alcohol-induced hyperpermeability. With our collaborators we have also shown that Cyp2e1 knockout mice are resistant to alcohol-induced gut leakiness and liver inflammation. Taken together our data support a novel Cyp2e1-circadian clock protein mechanism for alcohol-induced gut leakiness that could provide new

MICROBIOTA AND GUT-LIVER AXIS: A MINI-REVIEW ON THEIR INFLUENCES ON OBESITY AND OBESITY RELATED LIVER DISEASE

OpenAIRE

Vajro, Pietro; Paolella, Giulia; Fasano, Alessio

2013-01-01

A specific bacterial gut microbiota profile with increased extraction of calories has recently been associated with obesity, which has been shown to be a transmissible phenotype by microbiota transplantation. At the same time, there is now increasing evidence that gut microbiota plays a role in the development of hepatic steatosis and its progression to non-alcoholic steatohepatitis, as well.

Questionnaire survey on lifestyle of patients with nonalcoholic steatohepatitis.

Science.gov (United States)

Noto, Haruka; Tokushige, Katsutoshi; Hashimoto, Etsuko; Taniai, Makiko; Shiratori, Keiko

2014-11-01

Lack of exercise and excessive food intake are known to be the important causes of nonalcoholic steatohepatitis (NASH). To elucidate the relationship between lifestyle and NASH, we surveyed exercise and dietary habits, comparing them among 171 biopsy-proven NASH patients, 29 nonalcoholic fatty liver (NAFL) patients and 49 normal subjects. Dietary habits including the duration of dinner time, amount of rice at dinner, and weekly frequencies of meat, fries, Chinese noodles, sweets, and instant food consumption were significantly different in male NASH patients compared to normal male subjects. In women, differences were seen in the amount of rice at dinner, frequency of eating out, and proclivity for sweets. In male NASH patients, the frequency of physical exercise was significantly lower. The lifestyle tendencies of NASH were almost similar to those of NAFL. In the comparison between obese NASH and non-obese NASH, no clear lifestyle differences were found. In conclusion, the most striking result of this survey was that the lifestyle of males contributed significantly to the development of NASH. These results point to treatment of NASH in males. In female NASH patients, lifestyle differences were minimal, and the effects of other factors such as genetic background will need to be investigated.

Effects of alcohol intake on brain structure and function in non-alcohol-dependent drinkers

OpenAIRE

Bruin, Eveline Astrid de

2005-01-01

About 85% of the adult population in the Netherlands regularly drinks alcohol. Chronic excessive alcohol intake in alcohol-dependent individuals is known to have damaging effects on brain structure and function. Relatives of alcohol-dependent individuals display differences in brain function that are similar to those found in alcoholics, even if they have never been drinking alcohol. This suggests that brain damage in alcohol-dependent individuals is at least partly related to genetic factors...

The relative incidence of diabetes mellitus in abo/rhesus blood ...

African Journals Online (AJOL)

A total of 224 diabetics and 221 non-diabetics (control) were involved in this study, to determine the relative incidence of diabetes mellitus in ABO/Rhesus blood group. The current criteria for the diagnosis f diabetes mellitus were applied in differentiating the diabetics from the non-diabetics. Blood group, fasting blood sugar ...

Gingival crevicular blood: As a non-invasive screening tool for diabetes mellitus in dental clinics

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Neema Shetty

2013-01-01

Full Text Available Background: A high number of patients with periodontitis may have undiagnosed diabetes. Self-monitoring devices provide a simple method for rapid monitoring of the glucose level in the blood by utilizing a blood sample from the finger, but this method requires a needle puncture to obtain blood. It is possible that gingival crevicular blood (GCB from routine periodontal probing may be a source of blood for glucose measurements. Aim: To establish whether GCB can be used as a non-invasive diagnostic aid in screening for diabetes mellitus during routine periodontal examination. Materials and Methods: The study involved 50 diabetics and 50 non-diabetics, with an age range of 26-66 years. Both diabetic and non-diabetic patients had moderate to severe gingivitis with at least one tooth in the maxillary anterior region showing bleeding upon probing. The Gingival Index and Oral Hygiene Index-Simplified were recorded. Blood oozing from the gingival sulcus/pocket following periodontal pocket probing was collected using a capillary tube and transferred to the test stick of a glucose self-monitoring device (Accu-Chek, Roche Diagnostic, Germany in patients with comparable gingival and oral hygiene status. This value was compared with the peripheral fingerstick blood glucose (PFBG value, which was obtained by pricking the finger tip at the same visit. Statistical analysis was performed using Pearson′s correlation coefficient. Result: There was no statistically significant difference between the gingival crevicular blood glucose (GCBG values and the PFBG values in both the diabetic (P = 0.129, NS and the non-diabetic (P = 0.503, NS groups. Karl Pearson′s product-moment correlation coefficient was calculated, which showed a positive correlation between the two measurements in the diabetic (r = 0.943 as well as the non-diabetic (r = 0.926 groups. Conclusion: The results suggest that GCB can be used as a non-invasive diagnostic aid in screening for diabetes

Comparison of serum lipid profile in non alcoholic fatty liver disease

International Nuclear Information System (INIS)

Latif, A.; Ain, Q.U.A.; Ahmed, N.; Shafiq, A.M.; Sapna, K.

2017-01-01

Objective: To compare serum lipid profile in different ultrasonographic grades of non alcoholic fatty liver disease (NAFLD). Study Design: Cross sectional study. Place and Duration of Study: PNS SHIFA hospital, Karachi, from Oct 2015 to Jul 2016. Material and Methods: Seventy three adults of either gender were consecutively inducted after diagnosis of non alcoholic fatty liver disease (NAFLD) on ultrasonography (USG). These individuals were further classified into grade I, II and III of NAFLD depending on US findings. Fasting blood sample of all the subjects was analyzed for serum fasting lipid profile comprising of total cholesterol (TC), triglycerides (TG), high density lipoprotein cholesterol (HDL-C) and low density lipoprotein cholesterol (LDL-C). Serum non HDL cholesterol (nonHDL-C) was calculated by subtracting HDL-C from TC. Results: Among 73 subjects with NAFLD, 42.5%, 37% and 20.5% had grade I, II and III NAFLD respectively. All parameters showed significant increase in frequency of abnormal results with increasing grade of NAFLD except TG. Significant difference was found in mean TC (p=0.000), LDL-C (p=0.000), HDL-C (p=0.005) and nonHDL-C (p=0.000) between grades of NAFLD. Post hoc analysis revealed that only mean nonHDL-C was significantly different amongst all the grades of NAFLD. Conclusion: The increasing severity of NAFLD was found associated with increased frequency of dyslipidemia. Though most frequent dyslipidemia in NAFLD was low serum HDL-C followed by hypertriglyceridemia, only serum nonHDL-C was statistically different amongst all the grades of NAFLD. (author)

Drug and alcohol use and treatment for Australian Indigenous and non-Indigenous prisoners: demand reduction strategies.

Science.gov (United States)

Dolan, Kate; Rodas, Ana; Bode, Adam

2015-01-01

The purpose of this paper is to compare the use of drugs and alcohol by Indigenous and non-Indigenous prisoners and examine relevant treatment in Australian prisons. Prison authorities were surveyed about alcohol and drug use by prisoners prior to and during imprisonment and drug and alcohol treatment programs in prison. The literature was review for information on alcohol and drug use and treatment in Australian prisons. In 2009, over 80 percent of Indigenous and non-Indigenous inmates smoked. Prior to imprisonment, many Indigenous and non-Indigenous inmates drank alcohol at risky levels (65 vs 47 percent) and used illicit drugs (over 70 percent for both groups). Reports of using heroin (15 vs 21 percent), ATS (21 vs 33 percent), cannabis (59 vs 50 percent) and injecting (61 vs 53 percent) were similarly high for both groups. Prison-based programs included detoxification, Opioid Substitution Treatment, counselling and drug free units, but access was limited especially among Indigenous prisoners. Drug and alcohol use was a significant issue in Australian prisons. Prisoners were over five times more likely than the general population to have a substance use disorder. Imprisonment provides an important opportunity for rehabilitation for offenders. This opportunity is especially relevant to Indigenous prisoners who were more likely to use health services when in prison than in the community and given their vast over representations in prison populations. Given the effectiveness of treatment in reducing re-offending rates, it is important to expand drug treatment and especially culturally appropriate treatment programs for Indigenous inmates. Very little is known about Indigenous specific drug and alcohol programs in Australian prisons.

New insights in the pathogenesis of non-alcoholic fatty liver disease

NARCIS (Netherlands)

Gaemers, Ingrid C.; Groen, Albert K.

2006-01-01

PURPOSE OF REVIEW: The hallmark of non-alcoholic fatty liver disease is hepatic steatosis. This is mostly a benign condition, but for largely unknown reasons it progresses to liver fibrosis, cirrhosis, and ultimately hepatocellular carcinoma in about 10% of patients. In this review we discuss recent

Study of Cytochrome P450 2E1 and its allele Variants in Liver Injury of Nondiabetic, Nonalcoholic Steatohepatitis Obese Women

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NELSON M VARELA

2008-01-01

Full Text Available CYP2E1 enzyme is related to nonalcoholic steatohepatitis (NASH due to its ability for reactive oxygen species production, which can be influenced by polymorphisms in the gene. The aim of this study was to investigate hepatic levels, activity, and polymorphisms of the CYP2E1 gene to correlate it with clinical and histological features in 48 female obese NASH patients. Subjects were divided into three groups: (i normal; (ii steatosis; and (iii steatohepatitis. CYP2E1 protein level was assayed in microsomes from liver biopsies, and in vivo chlorzoxazone hydroxylation was determined by HPLC. Genomic DNA was isolated for genotype analysis through PCR. The results showed that liver CYP2E1 content was significantly higher in the steatohepatitis (45%; p=0.024 and steatosis (22%; p=0.032 group compared with normal group. Chlorzoxazone hydroxylase activity showed significant enhancement in the steatohepatitis group (15%, p=0.027 compared with the normal group. c2 rare allele of RsallPstl polymorphisms but no C allele of Dral polymorphism was positively associated with CHZ hydroxylation, which in turn is correlated with liver CYP2E1 content (r=0.59; p=0.026. In conclusion, c2 allele is positively associated with liver injury in NASH. This allele may determine a higher transcriptional activity of the gene, with consequent enhancement in pro-oxidant activity of CYP2E1 thus affording liver toxicity

Parental alcohol dependence and the transmission of adolescent behavioral disinhibition: a study of adoptive and non-adoptive families.

Science.gov (United States)

King, Serena M; Keyes, Margaret; Malone, Stephen M; Elkins, Irene; Legrand, Lisa N; Iacono, William G; McGue, Matt

2009-04-01

To examine the genetic and environmental influences of parental alcoholism on offspring disinhibited behavior. We compared the effect of parental alcoholism history on offspring in adoptive and non-adoptive families. In families with a history of parental alcohol dependence, we examined the effect of exposure to parental alcoholism symptoms during the life-time of the adolescent. Setting Assessments occurred at the University of Minnesota from 1998 to 2004. Adolescents adopted in infancy were ascertained systematically from records of three private Minnesota adoption agencies; non-adopted adolescents were ascertained from Minnesota birth records. Adolescents and their rearing parents participated in in-person assessments. For adolescents, measures included self- reports of delinquency, deviant peers, substance use, antisocial attitudes and personality. For parents, we conducted DSM-IV clinical assessments of alcohol abuse and dependence. A history of parental alcohol dependence was associated with higher levels of disinhibition only when adolescents were related biologically to their rearing parents. Within families with a history of parental alcoholism, exposure to parental alcohol misuse during the life-time of the adolescent was associated with increased odds of using alcohol in adopted adolescents only. These findings suggest that the association between a history of parental alcohol dependence and adolescent offspring behavioral disinhibition is attributable largely to genetic rather than environmental transmission. We also obtained some evidence for parental alcohol misuse as a shared environmental risk factor in adoptive families.

Bioelectrochemistry of non-covalent immobilized alcohol dehydrogenase on oxidized diamond nanoparticles.

Science.gov (United States)

Nicolau, Eduardo; Méndez, Jessica; Fonseca, José J; Griebenow, Kai; Cabrera, Carlos R

2012-06-01

Diamond nanoparticles are considered a biocompatible material mainly due to their non-cytotoxicity and remarkable cellular uptake. Model proteins such as cytochrome c and lysozyme have been physically adsorbed onto diamond nanoparticles, proving it to be a suitable surface for high protein loading. Herein, we explore the non-covalent immobilization of the redox enzyme alcohol dehydrogenase (ADH) from Saccharomyces cerevisiae (E.C.1.1.1.1) onto oxidized diamond nanoparticles for bioelectrochemical applications. Diamond nanoparticles were first oxidized and physically characterized by X-ray diffraction (XRD), FT-IR and TEM. Langmuir isotherms were constructed to investigate the ADH adsorption onto the diamond nanoparticles as a function of pH. It was found that a higher packing density is achieved at the isoelectric point of the enzyme. Moreover, the relative activity of the immobilized enzyme on diamond nanoparticles was addressed under optimum pH conditions able to retain up to 70% of its initial activity. Thereafter, an ethanol bioelectrochemical cell was constructed by employing the immobilized alcohol dehydrogenase onto diamond nanoparticles, this being able to provide a current increment of 72% when compared to the blank solution. The results of this investigation suggest that this technology may be useful for the construction of alcohol biosensors or biofuel cells in the near future. Copyright © 2011 Elsevier B.V. All rights reserved.

Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

OpenAIRE

Smith, G D; Amos, T A; Mahler, R; Peters, T J

1987-01-01

Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes melli...

A Duty of Care: Non-Drinkers and Alcohol Related Harm among an Australian University Sample

Science.gov (United States)

Mikhailovich, Katja; George, Amanda; Rickwood, Debra; Parker, Rhian

2011-01-01

Studies documenting the harm associated with excessive drinking amongst university students are numerous. Fewer studies have explored the experience of non-drinkers in the university setting. In 2008, 826 students aged 18-29 years responded to an online survey aiming to investigate alcohol use and alcohol related harm at an Australian university.…

Estimated intake of intense sweeteners from non-alcoholic beverages in Denmark

DEFF Research Database (Denmark)

Leth, Torben; Fabricius, N.; Fagt, Sisse

2007-01-01

In 1999, 116 samples of non-alcoholic beverages were analysed for the intense sweeteners cyclamate, acesulfame-K, aspartame and saccharin. High contents of cyclamate close to the maximum permitted level in 1999 of 400 mgl(-1) were found in many soft drinks. The estimated intake of the sweeteners...

Mice heterozygous for the Mdr2 gene demonstrate decreased PEMT activity and diminished steatohepatitis on the MCD diet.

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Igolnikov, Alexander C; Green, Richard M

2006-03-01

The administration of a methionine and choline deficient (MCD) diet to mice serves as an animal model of NASH. The multidrug resistant 2 (Mdr2) P-glycoprotein encodes for the canalicular phospholipid transporter, and Mdr2 (+/-) mice secrete 40% less phosphatidylcholine than wild-type mice. We have hypothesized that phosphatidylethanolamine-N-methyl transferase (PEMT) up-regulation is a consequence of MCD diet administration, and is important for the pathogenesis of steatohepatitis in this model. However, the effect of decreased phosphatidylcholine secretion and modulation of PEMT on the development of diet-induced steatohepatitis in Mdr2 (+/-) mice has not been explored. Thus, the purpose of the study is to examine the effects of the MCD diet on Mdr2 (+/-) mice. Mdr2 (+/-) and Mdr2 (+/+) mice were treated with an MCD or control diet for up to 30 days, and the severity of steatohepatitis, PEMT activity and hepatic S-adenosylmethionine (SAM), and S-adenosylhomocysteine (SAH) levels were measured. Serum ALT levels, hepatic inflammation, and PEMT activity were significantly lower, and hepatic SAM:SAH ratios were significantly higher in Mdr2 (+/-) mice at 7 and 30 days on the MCD diet. Mdr2 (+/-) mice have diminished susceptibility to MCD diet-induced NASH, which is associated with a relative decrease in PEMT activity and increased SAM:SAH ratios.

Alcoholic Beverage Consumption and Chronic Diseases

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Yue Zhou

2016-05-01

Full Text Available Epidemiological and experimental studies have consistently linked alcoholic beverage consumption with the development of several chronic disorders, such as cancer, cardiovascular diseases, diabetes mellitus and obesity. The impact of drinking is usually dose-dependent, and light to moderate drinking tends to lower risks of certain diseases, while heavy drinking tends to increase the risks. Besides, other factors such as drinking frequency, genetic susceptibility, smoking, diet, and hormone status can modify the association. The amount of ethanol in alcoholic beverages is the determining factor in most cases, and beverage types could also make an influence. This review summarizes recent studies on alcoholic beverage consumption and several chronic diseases, trying to assess the effects of different drinking patterns, beverage types, interaction with other risk factors, and provide mechanistic explanations.

Gestational diabetes mellitus screening and outcomes.

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Aktün, Hale Lebriz; Uyan, Derya; Yorgunlar, Betül; Acet, Mustafa

2015-01-01

To verify the usefulness of the World Health Organization criteria for the diagnosis of gestational diabetes mellitus in pregnant women and its effectiveness in the prevention of maternal and neonatal adverse results in women younger than 35 years without apparent risk factors for gestational diabetes mellitus. This is a retrospective study based on population involving 1360 pregnant women who delivered and who were followed-up in a university hospital in Istanbul. All women underwent the 75-g oral glucose tolerance test screening, usually in between the 24(th)-28(th) weeks of pregnancy. In all cases, the identification of gestational diabetes mellitus was determined in accordance with the World Health Organization criteria. Approximately 28% of the pregnant women aged younger than 35 years with no risk factors for gestational diabetes mellitus were diagnosed with the oral glucose tolerance test in this study. In the gestational diabetes mellitus group, the primary cesarean section rate was importantly higher than that in the non-gestational diabetes mellitus group. Preterm delivery was also associated with gestational diabetes mellitus. The diagnosis of gestational diabetes mellitus was strongly associated with admittance to the neonatal intensive care unit. Neonatal respiratory problems didn't showed any significant deviation between the groups. There was a moderate association between gestational diabetes mellitus and metabolic complications. Pregnant women with no obvious risk factors were diagnosed with gestational diabetes mellitus using the World Health Organization criteria. The treatment of these women potentially reduced their risk of adverse maternal and neonatal hyperglycemia-related events, such as cesarean section, polyhydramnios, preterm delivery, admission to neonatal intensive care unit, large for gestational age, and higher neonatal weight.

In vivo cytochrome P450 activity alterations in diabetic nonalcoholic steatohepatitis mice

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Li, Hui; Clarke, John D.; Dzierlenga, Anika L.; Bear, John; Goedken, Michael J.; Cherrington, Nathan J.

2016-01-01

Nonalcoholic steatohepatitis (NASH) has been identified as a source of significant interindividual variation in drug metabolism. A previous ex vivo study demonstrated significant changes in hepatic Cytochrome P450 (CYP) activity in human NASH. This study evaluated the in vivo activities of multiple CYP isoforms simultaneously in prominent diabetic NASH mouse models. The pharmacokinetics of CYP selective substrates: caffeine, losartan, and omeprazole changed significantly in a diabetic NASH mo...

Influence of type 2 diabetes mellitus on liver histology among morbidly obese individuals. A cross-sectional study.

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Cazzo, Everton; Jimenez, Laísa Simakawa; Gallo, Fábio de Felice; Pareja, José Carlos; Chaim, Elinton Adami

2016-01-01

Nonalcoholic fatty liver disease (NAFLD) has become a public health concern. It encompasses a wide spectrum of histological abnormalities and has close relationships with insulin resistance and type 2 diabetes mellitus (T2DM). This study sought to compare the histological alterations observed in morbidly obese individuals with and without T2DM who underwent Roux-en-Y gastric bypass. Cross-sectional study in a tertiary-level public hospital. This was a cross-sectional study on 197 individuals who underwent gastric bypass surgery between 2011 and 2013. NAFLD was assessed through liver biopsies. T2DM was diagnosed through the International Diabetes Federation criteria. Non-diabetics presented significantly more biopsies without any histological abnormalities, regarding steatosis (42.6% versus 25.5%; P = 0.0400), fibrosis (60.6% versus 36.2%; P = 0.0042) and steatohepatitis (27.3% versus 12.8%; P = 0.0495), while diabetics presented significantly higher frequency of moderate forms of steatosis (36.2% versus 20%; P = 0.0307) and fibrosis (23.4% versus 4%; P = 0.0002). T2DM was associated with more advanced forms of NAFLD within the population studied. NAFLD has previously been correlated with severe forms of heart disease. Screening for and early detecting of NAFLD in high-risk populations are important for avoiding further development of severe forms and the need for liver transplantation.

Deletion of Gab2 in mice protects against hepatic steatosis and steatohepatitis: a novel therapeutic target for fatty liver disease.

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Chen, Shuai; Kang, Yujia; Sun, Yan; Zhong, Yanhong; Li, Yanli; Deng, Lijuan; Tao, Jin; Li, Yang; Tian, Yingpu; Zhao, Yinan; Cheng, Jianghong; Liu, Wenjie; Feng, Gen-Sheng; Lu, Zhongxian

2016-12-01

Fatty liver disease is a serious health problem worldwide and is the most common cause for chronic liver disease and metabolic disorders. The major challenge in the prevention and intervention of this disease is the incomplete understanding of the underlying mechanism and thus lack of potent therapeutic targets due to multifaceted and interdependent disease factors. In this study, we investigated the role of a signaling adaptor protein, GRB2-associated-binding protein 2 (Gab2), in fatty liver using an animal disease model. Gab2 expression in hepatocytes responded to various disease factor stimulations, and Gab2 knockout mice exhibited resistance to fat-induced obesity, fat- or alcohol-stimulated hepatic steatosis, as well as methionine and choline deficiency-induced steatohepatitis. Concordantly, the forced expression or knockdown of Gab2 enhanced or diminished oleic acid (OA)- or ethanol-induced lipid production in hepatocytes in vitro, respectively. During lipid accumulation in hepatocytes, both fat and alcohol induced the recruitment of PI3K or Socs3 by Gab2 and the activation of their downstream signaling proteins AKT, ERK, and Stat3. Therefore, Gab2 may be a disease-associated protein that is induced by pathogenic factors to amplify and coordinate multifactor-induced signals to govern disease development in the liver. Our research provides a novel potential target for the prevention and intervention of fatty liver disease. © The Author (2016). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.

The effects of narrative versus non-narrative information in school health education about alcohol drinking for low educated adolescents.

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Zebregs, Simon; van den Putte, Bas; de Graaf, Anneke; Lammers, Jeroen; Neijens, Peter

2015-10-23

Traditionally most health education materials are written in an expository non-narrative format. Scholars have argued that the effectiveness of materials may increase when these texts are replaced by narrative texts, and that the non-narrative texts should be replaced by narrative texts. However, no previous studies have tested these claims in the context of school health education for low educated adolescents. This study aims to do so for an existing preventive health education intervention about alcohol for low educated adolescents. Based on the empirical findings of previous studies, it is expected that the claims about narratives being more effective than non-narrative texts are not true for effects on knowledge. Instead non-narrative texts are expected to have a stronger impact on this outcome variable. For attitude towards alcohol and intention to drink alcohol the claims are expected to be true, because participants are expected to be less aware of the persuasive intent of the narrative texts, which would make them less resistant. As a result, narrative texts are expected to have a stronger effect on attitude and intention. This study compares the effects on knowledge, attitude towards alcohol, and intention to drink alcohol of both information formats in a two-condition (non-narrative vs. narrative information) experiment with repeated measures (pre-measurement, immediate post-measurement, and delayed post-measurement). The experiment was conducted amongst 296 students of the two lowest levels of the Dutch secondary education system. The results showed immediate effects on knowledge and attitude towards alcohol, which did not differ between conditions and school levels. These effects did not persist over time. There were no effects on intention to drink alcohol. It is concluded non-narrative and narrative information are equally effective in the context of school health education, suggesting the claims that scholars have made about the superior effects of

THE EFFECTS OF POOR GLYCEMIC CONTROL AND OF NON-SURGICAL PERIODONTAL THERAPY IN PATIENTS WITH DIABETES MELLITUS

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Cornelia OANȚĂ

2015-09-01

Full Text Available Aim: The aim of the study was to evaluate the relationship between the diabetic status and severity of the periodontal involvement, and also of the non-surgical periodontal therapy on the periodontal status of patients with diabetes mellitus. Materials and method: The study was conducted on 21 patients with type 1 diabetes mellitus (study group and 10 systemically healthy subjects (control group. We examined: the degree of glycemic control (by measuring the glycated hemoglobin, the periodontal and oral hygiene parameters at the baseline and 4 weeks, 6 months and 12 months after the periodontal treatment (scaling and root planning. Results and discussion: Subjects with a poor glycemic control presented a higher percentage of sites with attachment loss, significantly higher amounts of bacterial plaque, sub-gingival calculus and gingival bleeding - when compared with the control group or with subjects with good or moderated glycemic control. In the same group, a rapid recurrence of the deep periodontal pockets was observed after 12 months. Conclusions: A prolonged poor control of glycemia and the time elapsed from the debut of diabetes were closely related with its complications. The comparison between the diabetes and the control groups demonstrated that diabetes mellitus is a risk factor for the periodontal disease.

Resistin expression correlates with steatohepatitis in morbidly obese patients.

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Edwards, Claire R; Hindle, A Katharine; Latham, Patricia S; Fu, Sidney W; Brody, Fred J

2013-04-01

Morbidly obese patients are at risk for nonalcoholic steatohepatitis (NASH) even in the absence of risk factors for liver disease. Unfortunately, NASH is usually not clinically evident, and a definitive, noninvasive test for NASH does not exist. Resistin, a cytokine originating from adipose tissue, is involved in insulin resistance and also initiates proinflammatory signaling from hepatic stellate cells. This study explores the relationship between resistin expression and liver pathology in bariatric surgery patients. Blood samples from 30 patients undergoing bariatric surgery were collected. Total RNA was extracted and cDNA was synthesized. Quantitative RT-PCR was used to quantify relative gene expression using 18s rRNA gene as an internal control. Wedge liver biopsies from these patients were sectioned and stained. Based on a previously published scoring method, biopsies were assigned an overall NASH severity score and subscores for steatosis, inflammation, and fibrosis. Results were analyzed by using Student's t test. Resistin mRNA levels ranged from 0.5 to 9.7. A group of five patients with very high resistin expression (>4) was identified. These patients had a significantly higher average NASH score compared with the rest of the group (7.9 vs. 4.48, p = 0.019). Steatosis and inflammation scores were significantly higher in the high-resistin group (p < 0.05 for both comparisons). There also was a trend toward higher fibrosis score in this group, which approached statistical significance (p = 0.051). In morbidly obese patients, high resistin expression in serum is associated with hepatic steatosis, inflammation, and fibrosis. The development of elevated resistin expression may represent a link between obesity and the onset of steatohepatitis.

Influence of alcohol on condom use pattern during non-spousal sexual encounter in male migrant workers in north India.

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Rizwan, S A; Kant, S; Goswami, K; Rai, S K; Misra, P

2014-01-01

Migrant workers constitute an important risk group for Human Immunodeficiency Virus/Acquired Immuno-Deficiency Syndrome transmission in India. Alcohol consumption before sexual intercourse has been postulated to influence condom use practices. This study aimed to assess this association with regard to non-spousal sexual encounters among male migrant workers in northern India. A cross-sectional facility-based survey was conducted in 2011. Male migrant workers aged ≥18 years, who were born outside Haryana, who had moved to the current location after 15 years of age,had worked in the current factory for at least 1 year, who were willing to participate and were able to give written, informed consent were included in the study. A consecutive sampling was performed. Descriptive, bivariate and multiple logistic regression analyses were carried out. A total of 162 participants reported having experienced non-spousal sexual encounters in the last 1 year. The proportion of men who reported not having used a condom at their last non-spousal sexual encounter was 59.3%, and 78.4% of the men reported having consumed alcohol in the last 1 year. About 48.1% of men reported having consumed alcohol before their last non-spousal sexual encounter. Men who consumed alcohol were three times more likely to not use a condom at their last non-spousal sexual encounter (OR = 3.1, 95% CI: 1.5-6.4). This association persisted even after adjusting for relevant confounders. Alcohol consumption had a negative influence on condom use during non-spousal sexual encounter among male migrant workers. An integrated approach to promote condom use and reduce alcohol consumption among migrant men needs to be undertaken through targeted intervention strategies.

Demographic and Substance Use Factors Associated with Non-Violent Alcohol-Related Injuries among Patrons of Australian Night-Time Entertainment Districts

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Kerri Coomber

2017-01-01

Full Text Available This study examined the relationship between patron demographics, substance use, and experience of recent alcohol-related accidents and injuries that were not due to interpersonal violence in night-time entertainment districts. Cross-sectional interviews (n = 4016 were conducted around licensed venues in entertainment districts of five Australian cities. Demographic factors associated with non-violent alcohol-related injuries were examined, including gender, age, and occupation. The association between substance use on the night of interview; blood alcohol concentration (BAC, pre-drinking, energy drink consumption, and illicit drug use; and experience of injury was also explored. Thirteen percent of participants reported an alcohol-related injury within the past three months. Respondents aged younger than 25 years were significantly more likely to report an alcohol-related injury. Further, a significant occupation effect was found indicating the rate of alcohol-related injury was lower in managers/professionals compared to non-office workers. The likelihood of prior alcohol-related injury significantly increased with BAC, and self-reported pre-drinking, energy drink, or illicit drug consumption on the night of interview. These findings provide an indication of the demographic and substance use-related associations with alcohol-related injuries and, therefore, potential avenues of population-level policy intervention. Policy responses to alcohol-related harm must also account for an assessment and costing of non-violent injuries.