WorldWideScience

Sample records for cholestasis

  1. Progressive familial intrahepatic cholestasis

    OpenAIRE

    Baussan Christiane; Gonzales Emmanuel; Davit-Spraul Anne; Jacquemin Emmanuel

    2009-01-01

    Abstract Progressive familial intrahepatic cholestasis (PFIC) refers to heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 usually appea...

  2. Progressive familial intrahepatic cholestasis

    Directory of Open Access Journals (Sweden)

    Baussan Christiane

    2009-01-01

    Full Text Available Abstract Progressive familial intrahepatic cholestasis (PFIC refers to heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. The exact prevalence remains unknown, but the estimated incidence varies between 1/50,000 and 1/100,000 births. Three types of PFIC have been identified and related to mutations in hepatocellular transport system genes involved in bile formation. PFIC1 and PFIC2 usually appear in the first months of life, whereas onset of PFIC3 may also occur later in infancy, in childhood or even during young adulthood. Main clinical manifestations include cholestasis, pruritus and jaundice. PFIC patients usually develop fibrosis and end-stage liver disease before adulthood. Serum gamma-glutamyltransferase (GGT activity is normal in PFIC1 and PFIC2 patients, but is elevated in PFIC3 patients. Both PFIC1 and PFIC2 are caused by impaired bile salt secretion due respectively to defects in ATP8B1 encoding the FIC1 protein, and in ABCB11 encoding the bile salt export pump protein (BSEP. Defects in ABCB4, encoding the multi-drug resistant 3 protein (MDR3, impair biliary phospholipid secretion resulting in PFIC3. Diagnosis is based on clinical manifestations, liver ultrasonography, cholangiography and liver histology, as well as on specific tests for excluding other causes of childhood cholestasis. MDR3 and BSEP liver immunostaining, and analysis of biliary lipid composition should help to select PFIC candidates in whom genotyping could be proposed to confirm the diagnosis. Antenatal diagnosis can be proposed for affected families in which a mutation has been identified. Ursodeoxycholic acid (UDCA therapy should be initiated in all patients to prevent liver damage. In some PFIC1 or PFIC2 patients, biliary diversion can also relieve pruritus and slow disease progression. However, most PFIC patients are ultimately candidates for liver transplantation

  3. Intrahepatic cholestasis of pregnancy

    Institute of Scientific and Technical Information of China (English)

    Victoria Geenes; Catherine Williamson

    2009-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder characterized by maternal pruritus in the third trimester, raised serum bile acids and increased rates of adverse fetal outcomes. The etiology of ICP is complex and not fully understood, but it is likely to result from the cholestatic effects of reproductive hormones and their metabolites in genetically susceptible women. Equally unclear are the mechanisms by which the fetal complications occur. This article reviews the epidemiology, clinical features, diagnosis, etiology and management of ICP.

  4. Genetics Home Reference: progressive familial intrahepatic cholestasis

    Science.gov (United States)

    ... a protein called the bile salt export pump (BSEP). This protein is found in the liver, and ... ABCB11-related intrahepatic cholestasis ATP8B1-related intrahepatic cholestasis BSEP deficiency Byler disease Byler syndrome FIC1 deficiency low ...

  5. Genetic determinants of drug-induced cholestasis and intrahepatic cholestasis of pregnancy

    OpenAIRE

    Pauli-Magnus, Christiane; Meier, Peter J; Stieger, Bruno

    2010-01-01

    Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding cassette (ABC) transporters as likely targets for these forms of cholestasis. Cholestasis of pregnancy is linked to estrogen and progesterone metabolites. These metabolites have been shown to impa...

  6. Intrahepatic cholestasis without jaundice

    Institute of Scientific and Technical Information of China (English)

    Thomas Namdar; Andreas Raffel; Stefan Andreas Topp; Jan Schulte am Esch; Günther Fürst; Wolfram Trudo Knoefel; Claus Ferdinand Eisenberger

    2009-01-01

    BACKGROUND: Cholangiocarcinoma (CC), the most common biliary tract malignancy, is frequently seen in advanced unresectable stages and is typically localized extrahepatically. Early diagnosis is unusual because of nonspeciifc symptoms. Painless jaundice is usually the ifrst sign of tumor. METHOD: We present a patient with a CC (Klatskin tumor) with a complete biliary drainage by an aberrant bile duct without jaundice. RESULTS: A 67-year-old woman presented with persisting elevation of liver parameters. Diagnostic tests showed a Klatskin tumor typeⅡ. A curative right hepatic trisegmentectomy was performed after liver volume augmentation by preoperative vein embolization. CONCLUSIONS: A direct drainage of the right posterior bile duct into the common bile duct as an aberrant hepatic duct is a rare variation and is present in less than 5% of the population. In case of persistently perturbed liver function tests, an aberrant bile duct can cover up severe intrahepatic cholestasis and even obscure the diagnosis of a Klatskin tumor. Up to now it has not been described in the literature.

  7. Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy

    NARCIS (Netherlands)

    C. Pauli-Magnus; P.J. Meier; B. Stieger

    2010-01-01

    Intrahepatic cholestasis of pregnancy and drug-induced cholestasis are two clinically important forms of acquired cholestatic liver disease. The understanding of the underlying mechanisms of acquired cholestasis has recently made considerable progress by the identification of canalicular ATP-binding

  8. Liver transplant rejection and cholestasis

    International Nuclear Information System (INIS)

    This paper reports on liver transplant biopsies with Tc-99m hepatobiliary scintigraphy in patients with and without rejection (RE) and or cholestasis (CS). The authors reviewed 76 Tc-99m disofenin hepatobiliary studies and corresponding liver biopsies. Uptake was assigned a value of 0 to 3 (0 = normal). Excretion was assigned a value of 0 to 2 (0 = normal). Biopsies were graded on scales of (1) 0 to 12 for findings of CS (0 = normal) and (2) 0 to 2 for RE (0 = normal)

  9. Genetic evidence of heterogeneity in intrahepatic cholestasis of pregnancy

    OpenAIRE

    Savander, M; Ropponen, A; Avela, K.; Weerasekera, N; Cormand, B; Hirvioja, M-L; Riikonen, S.; Ylikorkala, O; Lehesjoki, A-E; C. Williamson; Aittomäki, K.

    2003-01-01

    Background and aims: The aim of this study was to investigate the genetic aetiology of intrahepatic cholestasis of pregnancy (ICP) and the impact of known cholestasis genes (BSEP, FIC1, and MDR3) on the development of this disease.

  10. Intrahepatic cholestasis and cutaneous bullae associated with glibenclamide therapy.

    OpenAIRE

    Wongpaitoon, V.; Mills, P R; Russell, R I; Patrick, R. S.

    1981-01-01

    Intrahepatic cholestasis and cutaneous bullae associated with glibenclamide therapy are described in a 61-year-old diabetic patient who presented wit hypoglycaemic coma. These features have not previously been reported as side effects of glibenclamide therapy, but intrahepatic cholestasis may occur with chlorpropamide, a similar sulphonylurea agent. The mechanism of this cholestasis is not clear at present.

  11. Renal elimination of organic anions in cholestasis

    Institute of Scientific and Technical Information of China (English)

    Adriana Mónica Tortes

    2008-01-01

    The disposition of most drugs is highly dependent on specialized transporters.OAT1 and OAT3 are two organic anion transporters expressed in the basolateral membrane of renal proximal tubule cells,identified as contributors to xenobiotic and endogenous organic anion secretion.It is well known that cholestasis may cause renal damage.Impairment of kidney function produces modifications in the renal elimination of drugs.Recent studies have demonstrated that the renal abundance of OAT1 and OAT3 plays an important role in the renal elimination of organic anions in the presence of extrahepatic cholestasis.Time elapsed after obstructive cholestasis has an important impact on the regulation of both types of organic anion transporters.The renal expression of OAT1 and OAT3 should be taken into account in order to improve pharmacotherapeutic efficacy and to prevent drug toxicity during the onset of this hepatic disease.

  12. Cholestasis and pneumonitis induced by gold therapy.

    Science.gov (United States)

    Farre, J M; Perez, T; Hautefeuille, P; Tonnel, F; Colombel, J F; Duquesnoy, B; Delcambre, B

    1989-12-01

    The authors describe the association of gold salt-induced cholestasis and lymphocytic alveolitis proved by liver biopsy and broncho-alveolar lavage. To our knowledge this is the third case report on the combination of liver disease and pulmonary infiltration induced by gold compounds. PMID:2612124

  13. A Gentleman with Anemia and Cholestasis

    Directory of Open Access Journals (Sweden)

    Siu-Tong Law

    2010-01-01

    Full Text Available Primary sclerosing cholangitis is a rare cause of cholestasis caused by progressive inflammation and fibrosis of both intrahepatic and extrahepatic bile ducts leading to multifocal ductal strictures. Herein, we report a case of primary sclerosing cholangitis and inflammatory bowel disease. The concomitant diagnosis of these two diseases is not typical. The management includes the treatment of inflammatory bowel disease and potential complications of primary sclerosing cholangitis, including dominant strictures of bile duct, portal hypertension, gallbladder diseases, cholangiocarcinoma, and colonoscopic surveillance.

  14. New Insights on Intrahepatic Cholestasis of Pregnancy.

    Science.gov (United States)

    Floreani, Annarosa; Gervasi, Maria Teresa

    2016-02-01

    Intrahepatic cholestasis of pregnancy (ICP) is characterized by maternal pruritus, and elevated serum transaminases and bile acids. Genetic defects in at least 6 canalicular transporters have been found. Association studies stress the variability of genotypes, different penetrance, and influence of environmental factors. Serum autotaxin is a sensitive, specific, and robust diagnostic marker. Elevated maternal bile acids correlate with fetal complications. Long-term sequelae for mothers include the gallstone risk and chronic liver disease. There is an association between ICP and hepatitis C. Current treatment is ursodeoxycholic acid, owing to benefits on pruritus, liver function, safety, and decreased rates of adverse effects. PMID:26593298

  15. Impaired nonspecific cellular immunity in experimental cholestasis.

    Science.gov (United States)

    Roughneen, P T; Drath, D B; Kulkarni, A D; Rowlands, B J

    1987-11-01

    The abilities of polymorphonuclear leukocytes (PMN) and pulmonary alveolar macrophages (PAM), to demonstrate chemotaxis, phagocytosis, and superoxide release after bile duct ligation in the rat were investigated to determine the effect of cholestasis on nonspecific cellular immune mechanisms. Chemotactic response to C5a and FMLP, phagocytosis of 14C labeled Staphylococcus aureus, and zymosan-induced superoxide release were evaluated 21 days after bile duct ligation (BDL), sham operation, or in normal controls. Serum total bilirubin level was elevated after BDL (p less than 0.01). Chemotactic ability was similar to each group. PMN phagocytic uptake of 14C labeled Staphylococcus aureus was depressed in BDL (p less than 0.05). BDL rats exhibited impaired PAM phagocytic indices and improved PMN superoxide release (p less than 0.03). PAM superoxide release was similar in each study group. Alterations in phagocytic function with cholestasis are important deficits in nonspecific cellular immunity that may contribute to the high incidence of infective complications associated with obstructive jaundice. PMID:2823730

  16. Late-Onset Drug-Induced Cholestasis in a Living-Related Liver Transplant Donor With Progressive Familial Intrahepatic Cholestasis.

    Science.gov (United States)

    Harmancı, Özgür; Ensaroğlu, Fatih; Özçay, Figen; Öcal, Serkan; Korkmaz, Murat; Özdemir, B Handan; Selçuk, Haldun; Moray, Gökhan; Haberal, Mehmet

    2015-11-01

    We present a rare case of progressive familial intrahepatic cholestasis within a family. A 34-yearold female became a living-related liver transplant donor for her son, who had the disease. Nine years after the transplant, the mother developed severe intrahepatic cholestasis, for which she was evaluated after using an oral contraceptive drug. She presented with jaundice, pruritus, and increased bilirubin levels, together with elevated gamma glutamyl transferase and alkaline phosphatase levels. A liver biopsy revealed findings consistent with intrahepatic cholestasis. However, despite follow-up management and cessation of the insulting drug, her total bilirubin count continuously increased to 20 mg/dL and was accompanied by intractable pruritus. A total of 9 plasmapheresis sessions were performed, and she was started on a regimen of ursodeoxycholic acid (13 mg/kg/d) and cholestyramine (4 g, 3 times daily). The clinical and laboratory picture dramatically improved following cessation of the oral contraceptive, plasmapheresis sessions, and drug treatment. The patient's cholestasis normalized within 3 months, and she recovered uneventfully. A genetic analysis of the whole family revealed that both parents were heterozygous for the mutation c.124G>A in ABCB11, and the son was homozygous for this mutation. These findings supported varying degrees of bile salt export pump deficiency in the family members. Defective bile salt excretory system function can result in a wide spectrum of clinical presentations, ranging from progressive familial intrahepatic cholestasis requiring liver transplant to late-onset drug-induced cholestasis. Our findings suggest that, in a heterozygous carrier of a progressive familial intrahepatic cholestasis mutation, drug-induced cholestasis is responsive to treatment, after which the clinical picture can normalize within 3 months. PMID:26640927

  17. Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis

    NARCIS (Netherlands)

    Jansen, PLM; Strautnieks, SS; Jacquemin, E; Hadchouel, M; Sokal, EM; Hooiveld, GJEJ; Koning, JH; De Jager-Krikken, A; Kuipers, F; Stellaard, F; Bijleveld, CMA; Gouw, A; Van Goor, H; Thompson, RJ; Muller, M

    1999-01-01

    Background & Aims: Progressive familiar intrahepatic cholestasis (PFIC), an inherited liver disease of childhood, is characterized by cholestasis and either normal or increased serum gamma-glutamyltransferase activity. Patients with normal gamma-glutamyltransferase activity have mutations of the FIC

  18. Impaired localisation and transport function of canalicular Bsep in taurolithocholate induced cholestasis in the rat

    OpenAIRE

    Crocenzi, F A; Mottino, A D; Sánchez Pozzi, E J; Pellegrino, J M; Rodríguez Garay, E A; Milkiewicz, P.; Vore, M; Coleman, R.; Roma, M G

    2003-01-01

    Background: Taurolithocholate induced cholestasis is a well established model of drug induced cholestasis with potential clinical relevance. This compound impairs bile salt secretion by an as yet unclear mechanism.

  19. Intrahepatic cholestasis in subclinical and overt hyperthyroidism: two case reports

    Directory of Open Access Journals (Sweden)

    Soylu Aliye

    2008-04-01

    Full Text Available Abstract Introduction Non-specific abnormalities in liver function tests might accompany the clinical course of hyperthyroidism. Hyperthyroidism can cause the elevation of hepatic enzymes and bilirubin. Jaundice is rare in overt hyperthyroidism, especially in subclinical hyperthyroidism. On the other hand, the use of anti-thyroid drugs has rarely been associated with toxic hepatitis and cholestatic jaundice. Case presentation Here we present two cases of cholestasis that accompanied two distinct forms of clinical hyperthyroidism. The first patient had a clinical presentation of severe cholestasis in the absence of congestive failure related to hyperthyroidism. The second case had developed intrahepatic cholestasis in the presence of subclinical hyperthyroidism, and improved with rifampicin treatment. Conclusion Hyperthyroidism should be a consideration in non-specific liver dysfunction.

  20. Genetic variations of bile salt transporters as predisposing factors for drug-induced cholestasis, intrahepatic cholestasis of pregnancy and therapeutic response of viral hepatitis

    OpenAIRE

    Stieger, B; Geier, A.

    2011-01-01

    INTRODUCTION: Drug-induced cholestasis, intrahepatic cholestasis of pregnancy and viral hepatitis are acquired forms of liver disease. Cholestasis is a pathophysiologic state with impaired bile formation and subsequent accumulation of bile salts in hepatocytes. The bile salt export pump (BSEP) (ABCB11) is the key export system for bile salts from hepatocytes. AREAS COVERED: This article provides an introduction into the physiology of bile formation followed by a summary of the current knowled...

  1. Optimal diagnostic strategy for infantile cholestasis in pediatric surgery

    International Nuclear Information System (INIS)

    The initial goal in treatment for infantile cholestasis is to exclude surgical cholestasis, especially biliary atresia (BA). In this study, we retrospectively reviewed the diagnostic course of infantile cholestasis. Between 2000 and 2009, a total of 44 infants with cholestasis were referred to our department. The median age at admission was 54 days (range: 0-143 days). The medical charts of these infants were reviewed. The initial diagnostic approach was ultrasonography followed by the qualitative detection of bilirubin in stool. The 35 infants with acholic stool and/or a small or absent gallbladder on ultrasonography were subsequently examined by hepatobiliary scintigraphy (HBS). Twenty-nine infants with negative scintigraphy findings underwent intraoperative cholangiography (lOC), and BA was finally confirmed in 24 of 44. A choledochal cyst was noted in 2, Alagille syndrome in 2, cytomegalovirus infection in 2, panhypopituitarism in 2, multiple hemangiomas of the liver in 1, and cholecystolithiasis in 1. The remaining 10 infants were diagnosed as having neonatal hepatitis. The sensitivity and specificity of HBS for BA were 100% and 54.5%, respectively. HBS is a useful modality for detection of BA with a sensitivity of 100%. The indication for IOC should depend on these scan results. (author)

  2. Lithocholic acid disrupts phospholipid and sphingolipid homeostasis leading to cholestasis

    OpenAIRE

    Matsubara, Tsutomu; Tanaka, Naoki; Patterson, Andrew D.; Cho, Joo-Youn; Krausz, Kristopher W.; Frank J. Gonzalez

    2011-01-01

    Lithocholic acid (LCA) is an endogenous compound associated with hepatic toxicity during cholestasis. LCA exposure in mice resulted in decreased serum lysophosphatidylcholine (LPC) and sphingomyelin levels due to elevated lysophosphatidylcholine acyltransferase (LPCAT) and sphingomyelin phosphodiesterase (SMPD) expression. Global metabolome analysis indicated significant decreases in serum palmitoyl-, stearoyl-, oleoyl- and linoleoyl-LPC levels after LCA exposure. LCA treatment also resulted ...

  3. Primary amyloidosis presenting intrahepatic cholestasis and fulminant hepatic failure

    OpenAIRE

    Ozturk Ates; Kemal Kosemehmetoglu; Gunes Guner; Yusuf Bayraktar

    2015-01-01

    A 69-year-old man noticed abdominal pain located on right upper quadrant. Physical examination showed hepatosplenomegaly and icteric discoloration of sclera. On evaluation, patient was diagnosed to have hepatic amyloidosis related monoclonal gammopathy of undetermined significance (MGUS) and sinusoidal obstruction syndrome with intrahepatic cholestasis. In this case report we emphasize fulminant hepatic failure due to primer amyloidosis in diagnosed with MGUS patient.

  4. Urinary reducing substances in neonatal intrahepatic cholestasis caused by citrin deficiency

    OpenAIRE

    Ajmal Kader; Christina Ong; Veena Logarajah; Kong Boo Phua; Ee Shien Tan

    2014-01-01

    Neonatal cholestasis due to citrin deficiency is an autosomal recessive metabolic disorder caused by mutations in SLC25A13 gene. Mutations in this gene have a relatively high prevalence in East-Asian races compared to European or Afro-Caribbean races. Mutations in both sets of chromosomes often lead to self-limiting early onset cholestasis and growth retardation referred as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). It is associated with a wide range of metabolic d...

  5. Intractable itch relieved by 4-phenylbutyrate therapy in patients with progressive familial intrahepatic cholestasis type 1

    OpenAIRE

    Hasegawa, Yasuhiro; Hayashi, Hisamitsu; Naoi, Sotaro; Kondou, Hiroki; Bessho, Kazuhiko; Igarashi, Koji; Hanada, Kentaro; Nakao, Kie; Kimura, Takeshi; Konishi, Akiko; Nagasaka, Hironori; Miyoshi, Yoko; Ozono, Keiichi; Kusuhara, Hiroyuki

    2014-01-01

    Background Progressive familial intrahepatic cholestasis type 1 (PFIC1), an inherited liver disease caused by mutations in ATP8B1, progresses to severe cholestasis with a sustained intractable itch. Currently, no effective therapy has been established for PFIC1. Decreased function of the bile salt export pump (BSEP) in hepatocytes is suggested to be responsible for the severe cholestasis observed in PFIC1. We found a previously unidentified pharmacological effect of 4-phenylbutyrate (4PB) tha...

  6. Intrahepatic cholestasis of pregnancy: When should you look further?

    Institute of Scientific and Technical Information of China (English)

    Winita Hardikar; Shivani Kansal; Ronald P J Oude Elferink; Peter Angus

    2009-01-01

    Pruritis with abnormal liver function tests is the classical presentation of intrahepatic cholestasis of pregnancy (ICP), a condition associated with significant fetal complications. Although the etiology of ICP is unclear in many cases, certain features of the clinical presentation should alert the practitioner to the possibility of an underlying metabolic defect,which may not only affect subsequent pregnancies,but may be an indicator of more serious subsequent liver disease. We report a kindred of Anglo-Celtic descent, among whom many members present with ICP, gallstones or cholestasis related to use of oral contraception. Genetic studies revealed a novel mutation in the ABCB4 gene, which codes for a phospholipid transport protein. The clinical significance of this mutation and the importance of identifying such patients are discussed.

  7. Primary amyloidosis presenting intrahepatic cholestasis and fulminant hepatic failure

    Directory of Open Access Journals (Sweden)

    Ozturk Ates

    2015-06-01

    Full Text Available A 69-year-old man noticed abdominal pain located on right upper quadrant. Physical examination showed hepatosplenomegaly and icteric discoloration of sclera. On evaluation, patient was diagnosed to have hepatic amyloidosis related monoclonal gammopathy of undetermined significance (MGUS and sinusoidal obstruction syndrome with intrahepatic cholestasis. In this case report we emphasize fulminant hepatic failure due to primer amyloidosis in diagnosed with MGUS patient.

  8. Benefit of farnesoid X receptor inhibition in obstructive cholestasis

    OpenAIRE

    Stedman, Catherine; Liddle, Christopher; Coulter, Sally; Sonoda, Junichiro; Alvarez, Jacqueline G.; Evans, Ronald M; Downes, Michael

    2006-01-01

    The nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor have been implicated in regulating bile acid, lipid, carbohydrate, and xenobiotic metabolism. Bile duct ligation was used to increase endogenous bile acids and evaluate the roles of these receptors in modulating cholestatic liver injury. FXR knockout (KO) mice were found to be protected from obstructive cholestasis. Concurrent deletion of FXR also could ameliorate an increase in liver injury that is seen usually ...

  9. Intrahepatic cholestasis in subclinical and overt hyperthyroidism: two case reports

    OpenAIRE

    Soylu Aliye; Taskale Mustafa; Ciltas Aydin; Kalayci Mustafa; Kumbasar A Baki

    2008-01-01

    Abstract Introduction Non-specific abnormalities in liver function tests might accompany the clinical course of hyperthyroidism. Hyperthyroidism can cause the elevation of hepatic enzymes and bilirubin. Jaundice is rare in overt hyperthyroidism, especially in subclinical hyperthyroidism. On the other hand, the use of anti-thyroid drugs has rarely been associated with toxic hepatitis and cholestatic jaundice. Case presentation Here we present two cases of cholestasis that accompanied two disti...

  10. Alpha 1 Antitrypsin Deficiency in Infants with Neonatal Cholestasis

    Directory of Open Access Journals (Sweden)

    Maryam Monajemzadeh

    2013-10-01

    Full Text Available Objective: Alpha1-antitrypsin deficiency (A1ATD is the most important indication for liver transplantation in children. The gene frequencies vary in different ethnic groups. In the present study, we attempt to determine the frequencies of the most common defective alleles, Z and S, in Iranian children suffering from idiopathic neonatal cholestasis. Eighty-seven infants were typed for Z and S alleles.Methods: In a single center study, 87 consecutive liver biopsies from infants with cholestasis were reviewed and patients with neonatal cholestasis enrolled in the study and cases with confirmed biliary tract atresia excluded. Formalin fixed paraffin embedded blocks were used for DNA extraction. AAT genotype was determined by polymerase chain reaction (PCR assay and amplification of the two most common deficiency variants, S and Z alleles, and then sequencing of PCR products.Findings: There were 48 (55.2% males and 39 (44.8% females, with a median age of 60 days. Out of 87 of the study subject, 2 (2.2% were heterozygous for the S allele, and no ZZ, SS or MZ individual was found in the patients. No other polymorphism was found in the sequencing results.Conclusion: In comparison to other populations, AAT deficiency seems not to be an important etiologic factor for neonatal cholestatic liver disease in Iran; however, further studies are recommended to estimate the true mutant gene frequencies.

  11. Ursodeoxycholic acid in neonatal sepsis-associated cholestasis

    Directory of Open Access Journals (Sweden)

    Rita Mey Rina

    2014-07-01

    Full Text Available Background Sepsis-associated cholestasis (SAC is an intrahe-intrahepatic cholestasis caused by inflammatory cytokines. Patients with this condition have poor prognoses. Antibiotics are the mainstay of therapy, however, other adjuvant therapies, such as ursodeoxycholic acid (UDCA, have not been well established. Objective To assess the effect of UDCA for treatment of neonatal sepsis-associated cholestasis. Methods We performed a randomized, double-blind, controlled trial in 37 neonates who were diagnosed with sepsis-associated cholestasis in the Neonatal Care Unit of Cipto Mangunkusumo Hospital. Subjects were divided into two groups, with 19 neonates randomly allocated to the intervention group (received UDCA at 30 mg/kg/day divided into 3 doses for 7 days and 18 neonates to the control group (received placebo. After 7 days of treatment, we evaluated the subjects’ liver function parameters and performed a survival analysis. Results Liver function parameter improvements at day 7 were not significantly different between the UDCA group and the control group, including for mean decrease of total bilirubin (TB levels [2.2 (SD 2.9 mg/dL vs 1.7 (SD 4.6 mg/dL; P=0.080, mean decrease of direct bilirubin (DB levels [1.1 (SD 2.3 mg/dL vs 0.6 (SD 3.6 mg/dL; P=0.080, median indirect bilirubin (IB levels [0.4 (range 0.1- 5.6 mg/dL vs 0.9 (range 0.1-4.1 mg/dL; P=0.358, mean decrease of alanine aminotransferase (ALT levels [0.5 (-80.0 - 21.0 U/L vs -2.0 (ranged -167.0 - 85.0 U/L; P= 0.730, median aspartate aminotransferase (AST levels [43.0 (range 14.0-297.0 U/L vs 150.0 (range 24.0-840.0 U/L; P=0.081, and median gamma-glutamyl transpeptidase (GGT levels [125.0 (48.0-481.0 U/L vs 235.0 (56.0-456.0 U/L; P=0.108]. Five neonates in control group died compared to two in the UDCA group (P=0.232. In addition, UDCA did not significantly lengthen the survival time (hazard ratio/HR 3.62; 95%CI 0.69 to 18.77. Conclusion Ursodeoxycholic acid tends to improve total

  12. A meaningful appraisal of cholestasis in serum total bilirubin, cholyglyine, alpha-fetoprotein and carbohydrate antigen19-9

    International Nuclear Information System (INIS)

    Objective: Appraise the clinical significant how the serum total bilirubin (TB), cholylglycine (CG), α-fetoprotein (AFP), carbohydrate antigen 19-9 (CA 19-9) have their concentration changes in the pathological changes of intrahepatic cholestasis through a combined detection to them. Methods: The serum samples from 96 cases of chronic virus hepatitis, 26 cases of liver cirrhosis and 50 cases of normal people were detected by biochemistry for TB, by radioimmunoassay for CG, by electro chemiluminescence for AFP and CA19-9. Results: There is no obvious deference of serum TB in the group without intrahepatic cholestasis, the group of cholestasis without clinical symptoms and the control groups. There is also a marked deference (P<0.01) in the group of cholestasis with clinical symptoms, the group of liver cirrhosis, the group without intrahepatic cholestasis, the control group and the group of cholestasis without clinical symptoms. the serum CG from the groups of intrahepatic cholestasis, the group without intrahepatic cholestasis, and the control group all show a very obvious deference (P<0.01). The serum CA19-9 from the groups of intrahepatic cholestasis and the group without intrahepatic cholestasis show an obvious deference. The serum AFP, CA19-9 from the group of liver cancer show a very obvious deference (P<0.01). Conclusions: In clinc bilirubin is a rough index to reflect cholestasis. It has its own limit in deciding patterns of deferent bile obstruction. In the early stage of intrahepatic cholestasis, that the index of CG is high obviously points out existence of intrahepatic cholestasis. CG and the liver impairment are well interrelated and they are comparatively sensitive indexes of liver function. AFP reflects the regeneration of the liver cell necrosis and it means alarm to the seriousness of intrahepatic cholestasis. CA19-9 is a marker of tumor of biliary tract. The index increase through an initial observation is interrelated to the seriousness of

  13. Hepatocyte-based in vitro model for assessment of drug-induced cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Chatterjee, Sagnik, E-mail: Sagnik.Chatterjee@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Richert, Lysiane, E-mail: l.richert@kaly-cell.com [KaLy-Cell, 20A rue du Général Leclerc, 67115 Plobsheim (France); Augustijns, Patrick, E-mail: Patrick.Augustijns@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium); Annaert, Pieter, E-mail: Pieter.Annaert@pharm.kuleuven.be [Drug Delivery and Disposition, KU Leuven Department of Pharmaceutical and Pharmacological Sciences, O and N2, Herestraat 49 — bus 921, 3000 Leuven (Belgium)

    2014-01-01

    Early detection of drug-induced cholestasis remains a challenge during drug development. We have developed and validated a biorelevant sandwich-cultured hepatocytes- (SCH) based model that can identify compounds causing cholestasis by altering bile acid disposition. Human and rat SCH were exposed (24–48 h) to known cholestatic and/or hepatotoxic compounds, in the presence or in the absence of a concentrated mixture of bile acids (BAs). Urea assay was used to assess (compromised) hepatocyte functionality at the end of the incubations. The cholestatic potential of the compounds was expressed by calculating a drug-induced cholestasis index (DICI), reflecting the relative residual urea formation by hepatocytes co-incubated with BAs and test compound as compared to hepatocytes treated with test compound alone. Compounds with clinical reports of cholestasis, including cyclosporin A, troglitazone, chlorpromazine, bosentan, ticlopidine, ritonavir, and midecamycin showed enhanced toxicity in the presence of BAs (DICI ≤ 0.8) for at least one of the tested concentrations. In contrast, the in vitro toxicity of compounds causing hepatotoxicity by other mechanisms (including diclofenac, valproic acid, amiodarone and acetaminophen), remained unchanged in the presence of BAs. A safety margin (SM) for drug-induced cholestasis was calculated as the ratio of lowest in vitro concentration for which was DICI ≤ 0.8, to the reported mean peak therapeutic plasma concentration. SM values obtained in human SCH correlated well with reported % incidence of clinical drug-induced cholestasis, while no correlation was observed in rat SCH. This in vitro model enables early identification of drug candidates causing cholestasis by disturbed BA handling. - Highlights: • Novel in vitro assay to detect drug-induced cholestasis • Rat and human sandwich-cultured hepatocytes (SCH) as in vitro models • Cholestatic compounds sensitize SCH to toxic effects of accumulating bile acids • Drug

  14. Relative Frequency of Peptic Ulcer and Erosion in Patients with Different Types of Cholestasis

    Directory of Open Access Journals (Sweden)

    F Joukar

    2008-04-01

    Full Text Available Introduction: Cholestasis is impairment of normal bile excretion into the duodenum and classified as mechanical and non mechanical cholestasis. Mechanical Cholestasis presents with increase in bile duct diameter or obstruction in bile duct in an ERCP. Cholestasis leads to different complications. One of these complications is mucosal peptic erosion leading to gastrointestinal bleeding, perforation and even obstruction due to stricture. We therefore carried out this study to assess the relative frequency of peptic ulcer and erosion in patients with different type of cholestasis. Methods: In a case control study, 170 patients with mechanical cholestasis on the basis of physical examination, liver function tests, radiologic and serologic assay were candidates for ERCP as final therapeutic and diagnostic test. Collected data was registered in questionnaire and evaluated by the Fisher Test. Later, sonography (common bile duct diameter in the two groups: mechanical (85 patients and non mechanical (85 patients and endoscopy was done for exact survey and location of mucosal erosions. Results: Frequency of mucosal peptic erosions in mechanical cholestatic groups was42.6% ( 36 patients and significantly more than frequency of mucosal peptic erosion in non mechanical cholestatic groups (15 patients, 17.6% (P=0.02. 51 patients (30% of the total patients with cholestasis had mucosal erosion. From these patients, 25 patients had peptic ulcer [frequency of duodenal ulcer was 17 patients (68% and gastric ulcer was 8 patients (32% ](P=0.01. There was significant difference in prevalence of duodenal ulcer in patients with mechanical (12 cases, 70.6% and non mechanical (5 cases, 29.4% cholestasis(P=0.01. There was a significant difference between prevalence of duodenal ulcer (12 cases, 70.6% and gastric ulcer(5 cases, 29.4% in patients with mechanical cholestasis (P=0.01 but this was not so in patients with non mechanical cholestasis. Conclusion: According to

  15. A novel ABCB11 mutation in an Iranian girl with progressive familial intrahepatic cholestasis

    Directory of Open Access Journals (Sweden)

    Sassan Saber

    2013-01-01

    Full Text Available Progressive familial intrahepatic cholestasis is an autosomal recessive liver disorder caused by (biallelic mutations in the ATP8B1 of ABCB11 gene. A nine-year-old girl with cholestasis was referred for genetic counseling. She had a family history of cholestasis in two previous expired siblings. Genetic analysis of the ABCB11 gene led to the identification of a novel homozygous mutation in exon 25. The mutation 3593- A > G lead to a missense mutation at the amino acid level (His1198Arg. This mutation caused PFIC2 due to abnormal function in the bile salt export pump protein (BSEP.

  16. Novel A TPSB1 mutation in an adult male with progressive familial intrahepatic cholestasis

    Institute of Scientific and Technical Information of China (English)

    Bao-Cheng Deng; Sa Lv; Wei Cui; Rui Zhao; Xu Lu; Jian Wu; Pei Liu

    2012-01-01

    Progressive familial intrahepatic cholestasis type 1 is a rare disease that is characterized by low serum γ-glutamyltransferase levels due to mutation in ATP8B1.We present a 23-year-old male who experienced persistent marked pruritus for eighteen years and recurrent jaundice for thirteen years,in addition to cholestasis that eventually became fatal.Genetic sequencing studies of the entire coding (exon) sequences of ATP8B1 and ABCB11 uncovered a novel heterozygous missense 3035G>T mutation (S1012I) and a synonymous 696T>C mutation in ATP8B1.The patient's progression was associated with not only impaired familial intrahepatic cholestasis 1 (FIC1) function but also impaired bile salt export pump expression due to the impaired FIC1 function.Our findings show that patients with intermittent cholestasis can develop progressive liver disease even after several decades and require regular follow up.

  17. Clinical Significance of Detection of Serum TBA and ALP in Diagnosis of Intrahepatic Cholestasis of Pregnancy

    International Nuclear Information System (INIS)

    To investigate the clinical value of serum total bile acid (TBA) and alkaline phosphatase (ALP) in diagnosis of intahrpatic cholestasis of pregnancy (ICP), the serum levels of TBA, ALP and cholyglycine (CG) in 47 cases with intahrpatic cholestasis of pregnancy and 60 normal pregnant women were tested by biochemistry analysis and radioimmunoassay. The results showed that the serum levels of TBA and ALP in patients with intahrpatic cholestasis of pregnancy were significantly higher than that of normal pregnancy women. There was a positively correlation between TBA and ALP with CG. The combined determination of serum TBA and ALP could be useful in the diagnosis of intahrpatic cholestasis of pregnancy. Automatic biochemistry analysis of TBA and ALP is more simple and rapid than CG detected by radioimmunoassay,and it is suitable for clinical laboratory application. (authors)

  18. Operative delivery rates following induction of labour for obstetric cholestasis

    Science.gov (United States)

    Webster, Jessica R; Chappell, Lucy; Cheng, Floria; Breeze, Andrew C G; Lucas, Nuala; Plaat, Felicity; Williamson, Catherine

    2011-01-01

    The aim of this study was to determine whether women induced for obstetric cholestasis (OC) have increased rates of operative delivery compared with women without OC who are induced. This retrospective case-control study included 64 women with OC (singleton pregnancies), who had labour induced compared with two control groups (matched for parity and gestational week at delivery). The majority of women were induced at 37 weeks. We found no significant increase in the rate of operative or assisted delivery in OC cases compared with either control group. Women with OC who are induced between 36 and 40 weeks gestation do not have increased rates of assisted or operative delivery compared with induced controls.

  19. Diagnostic value of glycocholic acid for intrahepatic cholestasis in pregnancy

    International Nuclear Information System (INIS)

    The content of glycocholic acid (CG) in pregnant women's sera is detected with CG radioimmunoassay (RIA). The content of CG in sera of normal pregnant women after 32 weeks is ascended slightly with the increasing of pregnant month. It is less than 7.0 μmol/l before 31 weeks in pregnancy and less than 9.4 μmol/l after 32 weeks. The serum CG content of patients with intrahepatic cholestasis in pregnancy (ICP) is increased by 100%. The CG value of about half patients appears earlier than pruritus and ALT rise, the earliest CG increasing appears in the 20th pregnant week. It is the most sensitive method for ICP early diagnosis. 136 cases of ICP patients are observed and the results show that the higher the CG content, the higher the rate of intrauterine fetal anoxia; therefore, the dynamic observation of CG content in ICP patients is a dependable objective for surveillance fetal prognosis

  20. Intrahepatic cholestasis of pregnancy-current achievements and unsolved problems

    Institute of Scientific and Technical Information of China (English)

    Jurate Kondrackiene; Limes Kupcinskas

    2008-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is the most common pregnancy-related liver disorder. Maternal effects of ICP are mild; however, there is a clear association between ICP and higher frequency of fetal distress, preterm delivery, and sudden intrauterine fetal death. The cause of ICP remains elusive, but there is evidence that mutations in genes encoding hepatobiliary transport proteins can predispose for the development of ICP. Recent data suggest that ursodeoxycholic acid is currently the most effective pharmacologic treatment, whereas obstetric management is still debated. Clinical trials are required to identify the most suitable monitoring modalities that can specifically predict poor perinatal outcome. This article aims to review current achievements and unsolved problems of ICP.

  1. Morphologic Findings in Progressive Familial Intrahepatic Cholestasis 2 (PFIC2): Correlation With Genetic and Immunohistochemical Studies

    OpenAIRE

    Evason, Kimberley; Bove, Kevin E.; Finegold, Milton J; Knisely, A. S.; Rhee, Sue; Rosenthal, Philip; Miethke, Alexander G.; Karpen, Saul J; Ferrell, Linda D; Kim, Grace E.

    2011-01-01

    Progressive familial intrahepatic cholestasis, type 2 (PFIC2), characterized by cholestasis in infancy that may progress to cirrhosis, is caused by mutation in ABCB11, which encodes bile salt export pump (BSEP). We correlated histopathologic, immunohistochemical, and ultrastructural features in PFIC2 with specific mutations and clinical course. Twelve patients with clinical PFIC2 and ABCB11 mutations were identified, and 22 liver biopsy and explant specimens were assessed. All had hepatocellu...

  2. Role of ABCC2 common variants in intrahepatic cholestasis of pregnancy

    Institute of Scientific and Technical Information of China (English)

    Silvia Sookoian; Gustavo Castano; Carlos J Pirola

    2008-01-01

    The pathogenesis of intrahepatic cholestasis of pregnancy (ICP), a disorder that adversely affects maternal wellbeing and fetal outcome, is unclear. However, multiple factors probably interact along with a genetic predisposition. We would like to add some comments on a paper recently published concerning the role of ABCB11 and ABCC2 polymorphisms in both ICP and contraceptive-induced cholestasis, especially in the light of our recently published findings about a positive association between ICP and ABCC2 common variants.

  3. Urinary reducing substances in neonatal intrahepatic cholestasis caused by citrin deficiency

    Directory of Open Access Journals (Sweden)

    Ajmal Kader

    2014-06-01

    Full Text Available Neonatal cholestasis due to citrin deficiency is an autosomal recessive metabolic disorder caused by mutations in SLC25A13 gene. Mutations in this gene have a relatively high prevalence in East-Asian races compared to European or Afro-Caribbean races. Mutations in both sets of chromosomes often lead to self-limiting early onset cholestasis and growth retardation referred as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD. It is associated with a wide range of metabolic derangements including galactosemia and aminoacidemia, which can be detected on the newborn blood spot screening. Galactose, being a reducing sugar, can also be detected using Clinitest® (Clinitest® Reagent Tablets, Bayer Corporation, Diagnostics Division, Elkhart, IN, USA, a common screening test used in the work up of metabolic and hepatic diseases. In the western population classical galactosemia is often suspected when non glucose reducing substances are detected in the urine of infants with cholestasis. However in East-Asian races the prevalence of classical galactosemia is very low whilst galactosemia due to altered uridine diphosphate-galactose epimerase activity in NICCD is more common. We present a case of NICCD in an East-Asian infant with cholestasis and persistently positive urine reducing substance. Conclusion: NICCD deficiency should be considered as a differential diagnosis in any infant with cholestasis and persistently positive urinary reducing substances.

  4. Lipoprotein Abnormalities in Cholestasis I. Electro-phoretic and Ultracentrifugal Analyses

    Directory of Open Access Journals (Sweden)

    Watanabe,Makoto

    1979-08-01

    Full Text Available The alterations of lipid composition in sera of patients with liver diseases, particularly intrahepatic cholestasis and biliary obstruction, were studied by ultracentrifugation and polyacrylamide-gel disc-electrophoresis of lipoproteins and apoproteins. The elevation of serum cholesterol in intrahepatic cholestasis was greater than in biliary obstruction. The appearance of lipoprotein X in obstructive disease accounted for most of the increased cholesterol. The level of non-lipoprotein X cholesterol in intrahepatic cholestasis was significantly elevated, this being in part ascribed to the appearance of a new class of cholestatic lipoprotein, Slow-migrating HDL. The electrophoretic pattern of lipoprotein in cholestasis was generally characterized by a decrease in alpha band intensity and, in some types of cholestasis, by the appearance of Slow-migrating HDL. In addition, other abnormal lipoproteins exhibiting the characteristics of triglyceride-rich LDL (LP-Y, LP-X-like HDL and LDL-like HDL were found in some cases of intrahepatic cholestasis and biliary obstruction.

  5. Ultrasonography and computed tomography in diffuse liver disease with cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Partanen, K.; Pikkarainen, P.; Pasanen, P.; Alhava, E.; Soimakallio, S. (Kuopio Univ. Central Hospital (Finland). Dept. of Clinical Radiology Kuopio Univ. Central Hospital (Finland). Dept. of Gastroenterology Kuopio Univ. Central Hospital (Finland). Dept. of Surgery)

    1990-09-01

    Ultrasonography (US) and computed tomography (CT) were performed on respectively 67 and 42 (altogether 72) patients, for the assessment of intrahepatic cholestasis. The diagnostic ability to differentiate between malignant (17 patients) and benign (55 patients) liver disease was analyzed. Coarse echogenicity of the liver led to inconclusive results in differentiating between cirrhosis (2 out of 29 patients) and malignant infiltration (4 out of 15 patients) by US. Other benign liver diseases in 23 patients, including acute hepatitis, chronic active hepatitis, fatty liver, and liver congestion, were correctly interpreted as benign. CT correctly disclosed malignant liver disease in all cases. A false positive diagnosis of malignancy was encountered in 4 (out of 17) patients with decompensated hepatic cirrhosis because of non-homogeneous expansive areas on CT in 3 cases. The true cause was in 2 patients non-uniform fatty infiltration, and in one patient with acute hepatitis A, small hypodense lesions. Among cholestatic patients, decompensated cirrhosis and malignant liver infiltration could not always be differentiated on US or CT. (orig.).

  6. Prolonged cholestasis following successful removal of common bile duct stones: Beware patients on estrogen therapy

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    There are various well described forms of chronic cholestatic jaundice in adults, such as autoimmune cholangitis, drug-induced cholangitis and intrahepatic cholestasis of pregnancy. We present two cases of prolonged cholestasis following removal of gallstones at endoscopic retrograde cholangiopancreatography (ERCP) and subsequent clear cholangiography. Both patients were taking oral estrogens at the time of presentation, which were subsequently withdrawn. The first case responded rapidly to corticosteroid treatment,and the second case had a much slower resolution with ursodeoxycholic acid. Both cases highlighted the significance of estrogen-induced cholestasis in female patients with protracted jaundice following ERCP and removal of intra-ductal stones. After oral estrogens are discontinued, a short course of steroids needs to be considered.

  7. Clinical and ABCB11 profiles in Korean infants with progressive familial intrahepatic cholestasis

    Science.gov (United States)

    Park, Ji Sook; Ko, Jae Sung; Seo, Jeong Kee; Moon, Jin Soo; Park, Sung Sup

    2016-01-01

    AIM: To investigate clinical profiles and mutations of ABCB11 in Koreans with progressive familial intrahepatic cholestasis 2 and review the differences between Koreans and others. METHODS: Of 47 patients with neonatal cholestasis, five infants had chronic intrahepatic cholestasis with normal γ-glutamyl transpeptidase. Direct sequencing analyses of ABCB11, including exons and introns, were performed from peripheral blood. RESULTS: Living donor-liver transplantation was performed in four patients because of rapidly progressive hepatic failure and hepatocellular carcinoma. Three missense mutations were found in two patients: compound heterozygous 677C>T (S226L)/3007G>A (G1003R) and heterozygous 2296G>A (G766R). The mutations were located near and in the transmembranous space. CONCLUSION: Alterations in the transmembrane of the bile salt export pump in the Korean infants were different from those previously reported in Chinese, Japanease, Taiwanese, and European patients. PMID:27239116

  8. Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling.

    Directory of Open Access Journals (Sweden)

    Sabrina Cipriani

    Full Text Available In cholestatic syndromes, body accumulation of bile acids is thought to cause itching. However, the mechanisms supporting this effect remain elusive. Recently, GPBAR1 (TGR5 a G-protein coupled receptor has been shown to mediate itching caused by intradermal administration of DCA and LCA. 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (BAR502 is a non-bile acid dual ligand for FXR and GPBAR1.Cholestasis was induced in wild type and GPBAR1-/- mice by administration of α-naphthyl-isothiocyanate (ANIT or 17α-ethynylestradiol.In naïve mice skin application of DCA, TLCA, 6-ECDCA, oleanolic and betulinic acid induces a GPBAR1 dependent pruritogenic response that could be desensitized by re-challenging the mice with the same GPBAR1 agonist. In wild type and GPBAR1-/- mice cholestasis induced by ANIT fails to induce spontaneous itching and abrogates scratching behavior caused by intradermal administration of DCA. In this model, co-treatment with BAR502 increases survival, attenuates serum alkaline phosphatase levels and robustly modulates the liver expression of canonical FXR target genes including OSTα, BSEP, SHP and MDR1, without inducing pruritus. Betulinic acid, a selective GPBAR1 ligand, failed to rescue wild type and GPBAR1-/- mice from ANIT cholestasis but did not induced itching. In the 17α-ethynylestradiol model BAR502 attenuates cholestasis and reshapes bile acid pool without inducing itching.The itching response to intradermal injection of GPBAR1 agonists desensitizes rapidly and is deactivated in models of cholestasis, explain the lack of correlation between bile acids levels and itching severity in cholestatic syndromes. In models of non-obstructive cholestasis, BAR502 attenuates liver injury without causing itching.

  9. Unusual case of drug-induced cholestasis due to glucosamine and chondroitin sulfate

    Institute of Scientific and Technical Information of China (English)

    Stephen; Ip; Rachel; Jeong; David; F; Schaeffer; Eric; M; Yoshida

    2015-01-01

    Glucosamine(GS) and chondroitin sulfate(CS) are common over-the-counter(OTC) supplements used in the treatment of osteoarthritis. These medications are seemingly safe, but there are increasing reports of hepatotoxicity with these supplements. We reported a unique case of drug-induced cholestasis caused by GS and CS in a combination tablet. The etiology of the jaundice was overlooked despite extensive investigations over a three-month period. Unlike drug-induced hepatocellular injury, drug-induced cholestatic jaundice with GS and CS has only been reported twice before. This case emphasizes the importance of a complete medication history, especially OTC supplements, in the assessment of cholestasis.

  10. [Value of injection hepato-lymphography during percutaneous transhepatic cholangiography in patients with cholestasis].

    Science.gov (United States)

    Sharipov, V Sh

    2000-01-01

    Injection hepatography (IH) was made in 278 patients with cholestasis to study the drainage function of the liver. In 208 cases. IH was performed as a test during percutaneous transhepatic cholangiography (PTHC). The hepatic lymph pathways were imaged in 167 (60%) patients. Images of the biliary tract were obtained in 245 (88.1%) patients with cholestasis, it being not dilated in 34 (12.2%) patients. The fact that hepatolymphography may be performed during PTHC as an independent test permits verification of hepatic lymph circulatory disorders that are an index of the rate of inflammation in the organ. PMID:12717913

  11. Value of injection hepato lymphography during percutaneous transhepatic cholangiography in patients with cholestasis

    International Nuclear Information System (INIS)

    Injection hepatography (IH) was made in 278 patients with cholestasis to study the drainage function of the liver. In 208 cases, IH was performed as a test during percutaneous transhepatic cholangiography (PTHC). Hepatic lymph pathways were imaged in 167 (60%) patients. Images of the biliary tract were obtained in 245 (88.1%) patients with cholestasis, it being not dilated in 34 (12.2%) patients. The fact that hepatolymphography may be performed during PTHC as an independent test permits verification of hepatic lymph circulatory disorders that are an index of the rate of inflammation in the organ

  12. Anabolic Androgen-induced Intrahepatic Cholestasis Presented With Normal AND#947;-Glutamyl-Transpeptidase

    Directory of Open Access Journals (Sweden)

    Savvoula Savvidou

    2014-04-01

    A case report of a young male with remarkable jaundice due to acute anabolic androgen-induced cholestasis is presented. Interestingly, and #947;-glutamyl transpeptidase remained normal throughout the patient's diagnostic workup. Histopathology was indicative of pure, and ldquo;bland and rdquo; intrahepatic cholestasis with minimal inflammation but significant fibrosis. The patient was successfully treated with ursodeoxycholic acid and glucocorticosteroids. The significance of normal and #947;-glutamyl transpeptidase along with the histopathological findings and the possible pathophysiological mechanisms are finally discussed. [J Interdiscipl Histopathol 2014; 2(2.000: 98-103

  13. Mrp2 is essential for estradiol-17 beta(beta-D-glucuronide)-induced cholestasis in rats

    NARCIS (Netherlands)

    Huang, LY; Smit, JW; Meijer, DKF; Vore, M

    2000-01-01

    The present study evaluates the roles of the multidrug resistance-1 P-glycoprotein, Mdr1a/1b, the bile salt export pump (Bsep), and the multidrug resistance-associated protein-2 (Mrp2) in mediating cholestasis induced by estradiol-17 beta(beta-D-glucuronide) (E(2)17G). Administration of [H-3]E(2)17G

  14. Genetics and Molecular Modeling of New Mutations of Familial Intrahepatic Cholestasis in a Single Italian Center

    Science.gov (United States)

    Giovannoni, Isabella; Callea, Francesco; Bellacchio, Emanuele; Torre, Giuliano; De Ville De Goyet, Jean; Francalanci, Paola

    2015-01-01

    Familial intrahepatic cholestases (FICs) are a heterogeneous group of autosomal recessive disorders of childhood that disrupt bile formation and present with cholestasis of hepatocellular origin. Three distinct forms are described: FIC1 and FIC2, associated with low/normal GGT level in serum, which are caused by impaired bile salt secretion due to defects in ATP8B1 encoding the FIC1 protein and defects in ABCB11 encoding bile salt export pump protein, respectively; FIC3, linked to high GGT level, involves impaired biliary phospholipid secretion due to defects in ABCB4, encoding multidrug resistance 3 protein. Different mutations in these genes may cause either a progressive familial intrahepatic cholestasis (PFIC) or a benign recurrent intrahepatic cholestasis (BRIC). For the purposes of the present study we genotyped 27 children with intrahepatic cholestasis, diagnosed on either a clinical or histological basis. Two BRIC, 23 PFIC and 2 BRIC/PFIC were identified. Thirty-four different mutations were found of which 11 were novel. One was a 2Mb deletion (5’UTR- exon 18) in ATP8B1. In another case microsatellite analysis of chromosome 2, including ABCB11, showed uniparental disomy. Two cases were compound heterozygous for BRIC/PFIC2 mutations. Our results highlight the importance of the pathogenic role of novel mutations in the three genes and unusual modes of their transmission. PMID:26678486

  15. Hydrolysed Formula Is a Risk Factor for Vitamin K Deficiency in Infants With Unrecognised Cholestasis

    NARCIS (Netherlands)

    van Hasselt, P. M.; de Vries, W.; de Vries, E.; Kok, K.; Cranenburg, E. C. M.; de Koning, T. J.; Schurgers, L. J.; Verkade, H. J.; Houwen, R. H. J.; Havinga, Rick

    2010-01-01

    Objectives: Vitamin K deficiency (VKD) may cause life-threatening haemorrhages, especially in breast-fed infants with unrecognised cholestasis. Interestingly, hypoallergenic formulas appear overrepresented in reported cases of VKD bleeding (VKDB) in formula-fed infants. We therefore assessed whether

  16. [Relative increase and metacritic aggravation in the diagnosis of anicteric cholestasis].

    Science.gov (United States)

    Albot, G; Geraudias, P; Kind, M

    1975-02-14

    The authors report 3 cases and report the diagnostic usefulness of two signs of minor cholestasis described by one of them in 1966. A relative increase, in the absence of obvious virus hepatitis or cirrhosis, of the serum bilirubin, cholesterol, lipids and alkaline phosphatase, together with B.S.P. excretion. suggest minor cholestasis. The sign of "metacritical aggravation" when there is some suspicion of minor cholestasis, the supervision of the course of the disease, or a retrospective inquiry, permit, in the presence of minor symptoms, such as, pain, fever, jaundice, or pruritus, one to make the diagnosis of minor cholestasis. The latter is due either to the presence of small gall stones in the common bile duct, or to inflammation of the ampulla of Vater, or sphincter of Oddi, a Vaterian ampulloma, pancreatitis, or following damage to the common bile duct. In practice, liver biopsy confirms the diagnosis, and intravenous cholangiography, by the perfusion method, is usually able to demonstrate obstruction of the common bile duct. PMID:169583

  17. Male sex predisposes the newborn surgical patient to parenteral nutrition-associated cholestasis and to sepsis

    NARCIS (Netherlands)

    Albers, MJIJ; de Gast-Bakker, DAH; van Dam, NAM; Madern, GC; Tibboel, D

    2002-01-01

    Hypothesis: Sepsis is an epiphenomenon of parenteral nutrition-associated cholestasis (PNAC) and not a causative factor, and the incidence of sepsis is not affected by the presence or absence of PNAC. Design: Observational cohort study. Setting: Pediatric surgery department in a tertiary referral ch

  18. Gadopentetate dimeglumine-enhanced MR cholangiopancreatography in infants with cholestasis

    International Nuclear Information System (INIS)

    Biliary atresia (BA) is a progressive, obliterative cholangiopathy that occurs in neonates with hepatic portoenterostomy the treatment of choice, but early surgery is important for optimum outcomes. MRI, including MR cholangiopancreatography (MRCP) may be a diagnostically useful alternative to US, but the heavily T2-weighted sequences used include not only bile duct signals, but also other heterogeneously high signal intensities from surrounding structures. To evaluate the effects of gadolinium when used to decrease background signal intensity on T2-weighted MR cholangiopancreatography (MRCP) in infants and to evaluate the qualitative improvement of the depiction of the common bile duct (CBD) for evaluating neonatal cholestasis. Our Institutional Review Board approved this prospective study. MRCP was performed with gadopentetate dimeglumine injection using a 1.5-T scanner. Pre- and postcontrast MRCP images were compared. Forty-nine infants (male:female = 21:28; age 0-12 months, mean 2.3) were included. The final diagnoses were biliary atresia (BA) in 28 cases and non-BA in 21. Quantitative analysis was conducted using region-of-interest measurements of mean signal intensities of the liver, pancreatic head and gallbladder (if defined). Qualitative analysis was performed by four radiologists who subjectively scored image confidence in the presence of CBD on a 4-point scale (0 for definitely absent, 1 for probably absent, 2 for probably present, and 3 for definitely present). The signal-to-noise ratios were significantly decreased in the liver and pancreatic head after contrast medium enhancement (mean 5.7→4.0 in liver and mean 44.9→12.7 in the pancreatic head; P < 0.0001), and this finding was constant in both the BA and the non-BA group. The mean confidence score in the presence of CBD decreased in the BA group (0.9→0.5; P < 0.0001), but did not change significantly in the non-BA group (2.0→2.1; P = 0.459) after contrast medium enhancement. Both intra- and

  19. Toxicity of taurolithocholate as a model for cholestasis in the rat liver

    Energy Technology Data Exchange (ETDEWEB)

    Spitzer, V.M.; Loo, C.Y.

    1985-05-01

    A model was investigated to facilitate the detection of mild diffuse liver disease. The introduction of sodium taurolithocholate(TLC) into the bloodstream of rats has been shown to produce cholestasis. This study was undertaken to assess the available control over the cholestatic effect with regulated TLC. The rat model then utilized to evaluate the ability of Tc-99m Hepatolite (IDA) to predict the extent of cholestasis in mildly diseased liver. 27 Charles River rats (300-350 grams) were studied. Pentabarbital was used for anesthesia and body temperature was maintained between 37.5 and 38.5/sup 0/C. A standard tracheostomy and jugular vein and carotid artery cannulation was performed for the administration of the TLC and IDA and for blood sampling. The common bile duct was cannulated for bile collection. Bile was collected for 10 minutes post surgery and then the TLC, or just vehicle for controls, was administered. 5 minute bile collections continued for 60 minutes and blood samples were collected 9 times during the same hour period. The cumulative percent dose of IDA in the bile was found to be controllable while the blood clearance was not appreciably different for the doses investigated. Doses of 5.0, 3.75, 2.75 and 0 micromoles of TLC per 100 grams of rat weight were found to yield a 85%, 68% 45% and 15% cholestatic effect. The 45% cholestasis is reproducible and most clinically interesting the authors' studies. The 15% cholestasis for the control rats demonstrates a baseline cholestasis from the surgical intervention.

  20. Intrahepatic Cholestasis of Pregnancy Levels of Sulfated Progesterone Metabolites Inhibit Farnesoid X Receptor Resulting in a Cholestatic Phenotype

    OpenAIRE

    Abu-Hayyeh, Shadi; Papacleovoulou, Georgia; Lövgren-Sandblom, Anita; Tahir, Mehreen; Oduwole, Olayiwola; Jamaludin, Nurul Akmal; Ravat, Sabiha; Nikolova, Vanya; Chambers, Jenny; Selden, Clare; Rees, Myrddin; Marschall, Hanns-Ulrich; Parker, Malcolm G.; Williamson, Catherine

    2013-01-01

    Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy-specific liver disease and is associated with an increased risk of adverse fetal outcomes, including preterm labor and intrauterine death. The endocrine signals that cause cholestasis are not known but 3α-sulfated progesterone metabolites have been shown to be elevated in ICP, leading us to study the impact of sulfated progesterone metabolites on farnesoid X receptor (FXR)-mediated bile acid homeostasis pathways. Here...

  1. Sustained Repression and Translocation of NTCP and Expression of MRP4 for Cholestasis after Rat 90% Partial Hepatectomy

    OpenAIRE

    Miura, Takuya; Kimura, Norihisa; Yamada, Toshiyuki; Shimizu, Takeshi; Nanashima, Naoki; YAMANA, DAISUKE; HAKAMADA, KENICHI; Tsuchida, Shigeki

    2013-01-01

    Background/Aims: To clarify the mechanism of persistent cholestasis after massive hepatectomy, the relationship between such cholestasis and the expression and localization of organic anion transporters for bile acids was examined in a rat model.Methods: Male Sprague-Dawley rats were subjected to 90% hepatectomy, and tissues were harvested on 0, 1, 3, and 7 days for microarray analysis, the quantitative real-time polymerase chain reaction (RT-PCR), Western blotting and immunohistochemistry to...

  2. Effects of ursodeoxycholic acid treatment on nutrition and liver function in patients with cystic fibrosis and longstanding cholestasis.

    OpenAIRE

    Cotting, J; Lentze, M J; Reichen, J

    1990-01-01

    The prevalence of biliary and hepatic diseases is increasing in patients with cystic fibrosis as more of them reach adult life. There is no effective treatment or method of preventing cholestasis in cystic fibrosis, although beneficial effects have been ascribed to the tertiary bile acid, ursodeoxycholate, in other forms of chronic cholestasis. We evaluated prospectively the effects of a six month course of ursodeoxycholate (15-20 mg/kg per day) in eight, mostly adult, patients with cystic fi...

  3. Liver transplant rejection and cholestasis: Comparison of technetium 99m-diisopropyl iminodiacetic acid hepatobiliary imaging with liver biopsy

    Energy Technology Data Exchange (ETDEWEB)

    Engeler, C.M.; Kuni, C.C.; Engeler, C.E.; DuCret, R.P.; Boudreau, R.J. (Minnesota Univ., Minneapolis, MN (United States). Dept. of Radiology); Nakhieh, R. (Henry Ford Hospital, Detroit, MI (United States). Dept. of Lab. Medicine and Pathology)

    1992-10-01

    To determine whether the scintigraphic evaluation of technetium-99m diisopropyl iminodiacetic acid (DISIDA) uptake and excretion can distinguish among liver transplant patients with biopsy evidence for rejection, cholestasis or neither condition, we reviewed scintigrams and biopsies in 36 patients. There were 76 scintigrams with corresponding biopsies. Uptake and excretion were graded from image data on scales reflecting normal through severely abnormal values. Biopsies were evaluated for findings of cholestasis and rejection. The majority of scintigrams demonstrated normal uptake (60/75, 80%) and delayed excretion (65/76, 85%), which was most marked immediately after transplantation. One-way analysis of variance showed that the mean excretion values significantly differed between patients with normal biopsies and those with cholestasis and/or rejection (P=0.0003). However, mean uptake scores demonstrated no statistically significant difference between these two groups of patients (P=0.1). These findings suggest that {sup 99m}-Tc-DISIDA scintigraphy can differentiate between transplants with and without rejection/cholestasis but not between rejection and cholestasis. If {sup 99m}-Tc-DISIDA excretion is normal, rejection and cholestasis and unlikely. (orig.).

  4. Liver transplant rejection and cholestasis: Comparison of technetium 99m-diisopropyl iminodiacetic acid hepatobiliary imaging with liver biopsy

    International Nuclear Information System (INIS)

    To determine whether the scintigraphic evaluation of technetium-99m diisopropyl iminodiacetic acid (DISIDA) uptake and excretion can distinguish among liver transplant patients with biopsy evidence for rejection, cholestasis or neither condition, we reviewed scintigrams and biopsies in 36 patients. There were 76 scintigrams with corresponding biopsies. Uptake and excretion were graded from image data on scales reflecting normal through severely abnormal values. Biopsies were evaluated for findings of cholestasis and rejection. The majority of scintigrams demonstrated normal uptake (60/75, 80%) and delayed excretion (65/76, 85%), which was most marked immediately after transplantation. One-way analysis of variance showed that the mean excretion values significantly differed between patients with normal biopsies and those with cholestasis and/or rejection (P=0.0003). However, mean uptake scores demonstrated no statistically significant difference between these two groups of patients (P=0.1). These findings suggest that 99m-Tc-DISIDA scintigraphy can differentiate between transplants with and without rejection/cholestasis but not between rejection and cholestasis. If 99m-Tc-DISIDA excretion is normal, rejection and cholestasis and unlikely. (orig.)

  5. Successful Outcome of Chronic Intrahepatic Cholestasis in an Adult Patient with Sickle Cell/β+ Thalassemia

    Directory of Open Access Journals (Sweden)

    Efthymia Vlachaki

    2014-01-01

    Full Text Available Sickle cell/β+ thalassemia (Hb S/β+thal is considered as a variant form of sickle cell disease. Acute episodes of vasoocclusive pain crisis are characteristic for sickle cell disorders and may be complicated by an acute or chronic life-threatening organ dysfunction. Chronic intrahepatic cholestasis is a rare and severe complication in sickle cell disease, characterized by marked hyperbilirubinemia and acute hepatic failure with an often fatal course. Despite the fact that patients with Hb S/β+thal usually have a mild type of disease, herein we describe an interesting case of chronic intrahepatic cholestasis with successful outcome in an adult patient with Hb S/β+thal.

  6. Experimental cholestasis promotes the deposition of glomerular IgA immune complexes.

    OpenAIRE

    Emancipator, S. N.; Gallo, G. R.; Razaboni, R.; Lamm, M. E.

    1983-01-01

    Previous experimental and clinical studies support a role for the hepatobiliary system in the clearance of oligomeric IgA from serum, and alterations of this system have been associated with the deposition of IgA in the renal mesangium. The present studies in mice address the question of whether the mesangial deposition of IgA following cholestasis includes immune complexes. While bile duct ligation resulted in mesangial IgA deposition within several days in approximately 75% of animals, whet...

  7. Intrahepatic Cholestasis of Pregnancy and Serum Bile Acids in HIV-Infected Pregnant Women

    OpenAIRE

    Weinberg, Adriana; Allshouse, Amanda; Kinzie, Kay; Cho, Alice; Davies, Jill K.; Mc Farland, Elizabeth J

    2015-01-01

    Objectives Intra-hepatic cholestasis of pregnancy (ICP) is uncommon, but has severe effects on pregnancy outcomes. ICP is characterized by elevated serum bile acids and liver enzymes and preferentially affects women with liver disorders. We compared bile acids and pregnancy outcomes of HIV-infected pregnant women, who commonly have elevated live enzymes, with uninfected controls. Methods Twenty-four HIV-infected, including 2 co-infected with hepatitis C virus (HCV), and 25 uninfected women we...

  8. Fasciola hepatica infestation as a very rare cause of extrahepatic cholestasis

    Institute of Scientific and Technical Information of China (English)

    Ahmet Dobrucali; Rafet Yigitbasi; Yusuf Erzin; Oguzhan Sunamak; Erdal Polat; Hakan Yakar

    2004-01-01

    Fasciola hepatica, an endemic parasite in Turkey, is still a very rare cause of cholestasis worldwide. Through ingestion of contaminated water plants like watercress, humans can become the definitive host of this parasite. Cholestatic symptoms may be sudden but in some cases they may be preceeded by a long period of fever, eosinophilia and vague gastrointestinal symptoms. We report a woman with cholangitis symptoms of sudden onset which was proved to be due to Fasciola hepatica infestation by an endoscopic retrograde cholangiography.

  9. Effects of Three Different Fibrates on Intrahepatic Cholestasis Experimentally Induced in Rats

    OpenAIRE

    Alaa El-Sisi; Sahar Hegazy; Eman El-Khateeb

    2013-01-01

    Background. Activation of PPAR α modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of PPAR α agonists, fenofibrate, bezafibrate, and gemfibrozil, on acute cholestasis induced by ethinylestradiol (EE) plus chlorpromazine (CPZ) in rats. Method. 100 male albino rats (150–200 gm) were divided randomly into 10 equal groups. Control group received 1% methylcellulose vehicle; disease group received CPZ plus EE for 5 consecutive days; four gro...

  10. ER stress contributes to alpha-naphthyl isothiocyanate-induced liver injury with cholestasis in mice.

    Science.gov (United States)

    Yao, Xiaomin; Li, Yue; Cheng, Xiaoyan; Li, Hongwei

    2016-06-01

    Endoplasmic reticulum (ER) stress is involved in the development of several liver diseases and tumors. This study investigated the underlying mechanisms of α-naphthyl isothiocyanate (ANIT)-induced liver injury with cholestasis in mice and found ER stress contributes to the injury. All animals were randomly divided into three groups. In the ANIT-intoxicated group, mice were intragastrically given 100mg/kg ANIT (dissolved in corn oil), while the other groups received an equal volume of vehicle as control. After 24 and 48h of ANIT administration, blood samples and liver tissues of all animals were collected for serum biochemistry and hepatic histopathological examinations to evaluate liver injuries with cholestasis. Hepatocellular apoptosis was assessed by the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay. The expression of hepatic ER stress-related markers was determined by real-time PCR, immunohistochemical assay and Western blot. ANIT was found to significantly induce liver injury with cholestasis compared with control mice as evidenced by the increase of serum transaminases and total bilirubin (TBil), and histopathological changes in mice. ANIT remarkably induced hepatocellular apoptosis, upregulated the expression of caspase-9 and cytochrome c, and inhibited the gene and protein expression of proliferating cell nuclear antigen (PCNA). The gene expression of ER stress-related markers, including glucose-regulated protein 78 (GRP78), protein kinase R-like ER kinase (PERK), eukaryotic initiation factor 2α (eIF2α), inositol requiring enzyme-1α (IRE-1α) and activating transcription factor 6 (ATF6) was upregulated by ANIT in mice. ANIT also upregulated the protein expression of GRP78 and activated the phosphorylation of IRE1. These results suggested that ANIT induced liver injury with cholestasis partly due to its ability to activate the ER stress pathway. PMID:27173049

  11. Novel ABCB11 mutations in a Thai infant with progressive familial intrahepatic cholestasis

    OpenAIRE

    Treepongkaruna, Suporn; Gaensan, Amornphun; Pienvichit, Paneeya; Luksan, Ondrej; Knisely, AS; Sornmayura, Pattana; Jirsa, Milan

    2009-01-01

    Progressive familial intrahepatic cholestasis (PFIC) type 2 is caused by mutations in ABCB11, which encodes bile salt export pump (BSEP). We report a Thai female infant who presented with progressive cholestatic jaundice since 1 mo of age, with normal serum γ-glutamyltransferase. Immunohistochemical staining of the liver did not demonstrate BSEP along the canaliculi, while multidrug resistance protein 3 was expressed adequately. Novel mutations in ABCB11, a four-nucleotide deletion in exon 3,...

  12. Autoimmune BSEP disease: disease recurrence after liver transplantation for progressive familial intrahepatic cholestasis.

    Science.gov (United States)

    Kubitz, Ralf; Dröge, Carola; Kluge, Stefanie; Stross, Claudia; Walter, Nathalie; Keitel, Verena; Häussinger, Dieter; Stindt, Jan

    2015-06-01

    Severe cholestasis may result in end-stage liver disease with the need of liver transplantation (LTX). In children, about 10 % of LTX are necessary because of cholestatic liver diseases. Apart from bile duct atresia, three types of progressive familial intrahepatic cholestasis (PFIC) are common causes of severe cholestasis in children. The three subtypes of PFIC are defined by the involved genes: PFIC-1, PFIC-2, and PFIC-3 are due to mutations of P-type ATPase ATP8B1 (familial intrahepatic cholestasis 1, FIC1), the ATP binding cassette transporter ABCB11 (bile salt export pump, BSEP), or ABCB4 (multidrug resistance protein 3, MDR3), respectively. All transporters are localized in the canalicular membrane of hepatocytes and together mediate bile salt and phospholipid transport. In some patients with PFIC-2 disease, recurrence has been observed after LTX, which mimics a PFIC phenotype. It could be shown by several groups that inhibitory anti-BSEP antibodies emerge, which most likely cause disease recurrence. The prevalence of severe BSEP mutations (e.g., splice site and premature stop codon mutations) is very high in this group of patients. These mutations often result in the complete absence of BSEP, which likely accounts for an insufficient auto-tolerance against BSEP. Although many aspects of this "new" disease are not fully elucidated, the possibility of anti-BSEP antibody formation has implications for the pre- and posttransplant management of PFIC-2 patients. This review will summarize the current knowledge including diagnosis, pathomechanisms, and management of "autoimmune BSEP disease." PMID:25342496

  13. Partial Internal Biliary Diversion: A Solution for Intractable Pruritus in Progressive Familial Intrahepatic Cholestasis Type 1

    Science.gov (United States)

    Ganesh, Ramaswamy; Suresh, Natarajan; Sathiyasekeran, Malathi; Ramachandran, Priya

    2011-01-01

    Biliary diversion offers a potential option for intractable pruritus in children with chronic cholestatic disorders. Progressive familial intrahepatic cholestasis (PFIC) is an inherited disorder of impaired bile acid transport and excretion, which presents with jaundice and pruritus in the first few months of life and progresses to cirrhosis by infancy or adolescence. We report a child with PFIC type 1 who underwent internal biliary diversion for intractable pruritus and was relieved of his symptoms. PMID:21546727

  14. Fasciola hepatica infestation as a very rare cause of extrahepatic cholestasis

    OpenAIRE

    Dobrucali, Ahmet; Yigitbasi, Rafet; Erzin, Yusuf; Sunamak, Oguzhan; Polat, Erdal; Yakar, Hakan

    2004-01-01

    Fasciola hepatica, an endemic parasite in Turkey, is still a very rare cause of cholestasis worldwide. Through ingestion of contaminated water plants like watercress, humans can become the definitive host of this parasite. Cholestatic symptoms may be sudden but in some cases they may be preceeded by a long period of fever, eosinophilia and vague gastrointestinal symptoms. We report a woman with cholangitis symptoms of sudden onset which was proved to be due to Fasciola hepatica infestation by...

  15. Severe Cholestasis and Bile Acid Nephropathy From Anabolic Steroids Successfully Treated With Plasmapheresis.

    Science.gov (United States)

    Flores, Avegail; Nustas, Rosemary; Nguyen, Hoang-Lan; Rahimi, Robert S

    2016-01-01

    Severe cholestasis with anabolic androgenic steroids is well-known to cause acute liver injury. Treatment is usually supportive after withdrawal of the offending agent. Acute kidney injury (AKI) frequently occurs in acute liver injury and may complicate management and prognosis. We highlight the use of plasmapheresis resulting in rapid improvement in cholestatic jaundice with resolution of AKI. Plasmapheresis should be considered in special cases in which there is progressive clinical decline despite supportive care. PMID:26958570

  16. Altered integrity and decreased expression of hepatocyte tight junctions in rifampicin-induced cholestasis in mice

    International Nuclear Information System (INIS)

    Rifampicin is a well-known hepatotoxicant, but little is known about the mechanism of rifampicin-induced hepatotoxicity. The aim of this study was to characterize the expression and localization of hepatocyte tight junctions in rifampicin-induced cholestasis in mice. Cholestasis was induced by administration of rifampicin (200 mg/kg) for 7 consecutive days or treatment with a single dose of rifampicin (200 mg/kg) by gastric intubation. The expression of mRNA for hepatic zonula occludens (ZO)-1, ZO-2, ZO-3, occludin and claudin-1 was determined using RT-PCR. Localization of ZO-1 and occludin was detected using immunofluorescence. Results showed that there was an 82-fold increase in the conjugated bilirubin in serum in rifampicin-treated mice. In addition, an 8-fold increase in total bile acid in serum was observed after a seven-day administration of rifampicin. The integrity of hepatocyte ZO-1 and occludin was altered by a seven-day administration of rifampicin. Importantly, the integrity and intensity of hepatocyte tight junctions were altered as early as 30 min after a single dose of rifampicin. The expression of hepatic ZO-1 and ZO-2 mRNA was significantly decreased, beginning as early as 30 min and remaining a lower level 12 h after a single dose of rifampicin. Taken together, these results suggest that the altered integrity and internalization of hepatocyte tight junctions are associated with rifampicin-induced cholestasis.

  17. Effect of Obstructive Cholestasis on Sperm Parameters in the Adult Male Rats

    Directory of Open Access Journals (Sweden)

    E. Nasiri

    2005-10-01

    Full Text Available Introduction & Objective: Obstructive cholestasis is associated with overproduction of endogenous opioids , nitric oxide and cytokins in the blood streams. These consequences may affect sex hormones since proper fertility will be resulted from physiological balance of sex hormones, we investigated the relationship between obstructive cholestasis and gonadotropins and sperm parameters in adult male rats.Materials & Methods: To study this, we used three groups of animals: control (No-surgery, Sham (surgical control, and cholestatic (surgical ligation of the bile duct. After 3 weeks all animals were killed by ether, and serum concentrations of FSH and LH were determined by radioimmunoassay, sperm parameters were evaluated by light microscop.Results: The findings of this study showed that LH and FSH levels decreased significantly in cholestatic compared to control and sham groups (p0.05.Conclusion: These findings indicated that obstructive cholestasis lead to decrease in the levels of serum gonadotropins, but it has no significant effect on sperm parameters. We speculated that spermatogenesis, and sperm parameters were not dependent on gonadotropin hormones but other factors may involved.

  18. Influence of distal ileum exclusion on hepatic and renal functions in presence of extrahepatic cholestasis

    Directory of Open Access Journals (Sweden)

    Evandro Luis de Oliveira Costa

    2014-04-01

    Full Text Available OBJECTIVE: To verify whether the ileal exclusion interferes with liver and kidney functional changes secondary to extrahepatic cholestasis. METHODS: We studied 24 rats, divided into three groups with eight individuals each: Group 1 (control, Group 2 (ligation of the hepatic duct combined with internal biliary drainage, and Group 3 (bile duct ligation combined with internal biliary drainage and exclusion of the terminal ileum. Animals in Group 1 (control underwent sham laparotomy. The animals of groups 2 and 3 underwent ligation and section of the hepatic duct and were kept in cholestasis for four weeks. Next, they underwent an internal biliary bypass. In Group 3, besides the biliary-enteric bypass, we associated the exclusion of the last ten centimeters of the terminal ileum and carried out an ileocolic anastomosis. After four weeks of monitoring, blood was collected from all animals of the three groups for liver and kidney biochemical evaluation (albumin, ALT, AST, direct and indirect bilirubin, alkaline phosphatase, cGT, creatinine and urea. RESULTS: there were increased values of ALT, AST, direct bilirubin, cGT, creatinine and urea in rats from Group 3 (p < 0.05. CONCLUSION: ileal exclusion worsened liver and kidney functions in the murine model of extrahepatic cholestasis, being disadvantageous as therapeutic procedure for cholestatic disorders.

  19. Expression and function of renal and hepatic organic anion transporters in extrahepatic cholestasis

    Institute of Scientific and Technical Information of China (English)

    Anabel Brandoni; María Herminia Hazelhoff; Romina Paula Bulacio; Adriana Mónica Torres

    2012-01-01

    Obstructive jaundice occurs in patients suffering from cholelithiasis and from neoplasms affecting the pancreas and the common bile duct.The absorption,distribution and elimination of drugs are impaired during this pathology.Prolonged cholestasis may alter both liver and kidney function.Lactam antibiotics,diuretics,non-steroidal anti-inflammatory drugs,several antiviral drugs as well as endogenous compounds are classified as organic anions.The hepatic and renal organic anion transport pathways play a key role in the pharmacokinetics of these compounds.It has been demonstrated that acute extrahepatic cholestasis is associated with increased renal elimination of organic anions.The present work describes the molecular mechanisms involved in the regulation of the expression and function of the renal and hepatic organic anion transporters in extrahepatic cholestasis,such as multidrug resistanceassociated protein 2,organic anion transporting polypeptide 1,organic anion transporter 3,bilitranslocase,bromosulfophthalein/bilirubin binding protein,organic anion transporter 1 and sodium dependent bile salt transporter.The modulation in the expression of renal organic anion transporters constitutes a compensatory mechanism to overcome the hepatic dysfunction in the elimination of organic anions.

  20. Ursodeoxycholic acid for treatment of cholestasis in patients with hepatic amyloidosis

    Directory of Open Access Journals (Sweden)

    Faust Dominik

    2009-01-01

    Full Text Available Background. Amyloidosis represents a group of different diseases characterized by extracellular accumulation of pathologic fibrillar proteins in various tissues and organs. Severe amyloid deposition in the liver parenchyma has extrahepatic involvement predominantly in the kidney or heart. We evaluated the effect of ursodeoxycholic acid, in four patients with severe hepatic amyloidosis of different etiologies, who presented with increased alkaline phosphatase and γ-glutamyl transferase. Case report. The study included four patients who presented with amyloidosis-associated intrahepatic cholestasis. Three of them had renal amyloidosis which developed 1-3 years before cholestasis occurred, the remaining one having intrahepatic cholestasis as the primary sign of the disease. Amyloidosis was identified from liver biopsies in all patients by its specific binding to Congo red and green birefringence in polarized light. The biochemical nature and the class of amyloid deposits were identified immunohistochemically. In addition to their regular treatment, the patients received 750 mg ursodeoxycholic acid per day. After 2-4 weeks all patients had a significant decrease of serum alkaline phosphatase and γ-glutamyl transferase, and their general status significantly improved. Conclusion. Treatment with ursodeoxycholic acid may be beneficial in patients with hepatic amyloidosis, and do extend indications for the use of ursodeoxycholic acid in amyloidotic cholestatic liver disease.

  1. Dioscin protects against ANIT-induced cholestasis via regulating Oatps, Mrp2 and Bsep expression in rats.

    Science.gov (United States)

    Zhang, Aijie; Jia, Yongming; Xu, Qinghan; Wang, Changyuan; Liu, Qi; Meng, Qiang; Peng, Jinyong; Sun, Huijun; Sun, Pengyuan; Huo, Xiaokui; Liu, Kexin

    2016-08-15

    Alpha-naphthylisothiocyanate (ANIT) is a toxicant that is widely used in rodents to model human intrahepatic cholestasis. The aim of the study is to investigate whether effects of dioscin on ANIT-induced cholestasis are related to changes in expression of hepatic transporters in rats. Effects of dioscin on cholestasis were examined by histology and biochemical marker levels. The functional changes of hepatic transporters were determined by in vitro, in situ and in vivo. qRT-PCR and western blot were used to assess the expression of hepatic transporters in cholestatic rats. Dioscin administration could ameliorate cholestasis, as evidenced by reduced biochemical markers as well as improved liver pathology. The uptakes of organic anion transporting polypeptide (Oatp) substrates were altered in liver uptake index in vivo, perfused rat liver in situ and isolated rat hepatocytes in vitro in cholestasis rats. qRT-PCR and western blot analysis indicated co-treatment of ANIT with dioscin prevented the adaptive down-regulation of Oatp1a1, 1b2, and prompted the up-regulation of Oatp1a4, multidrug resistance-associated protein (Mrp) 2 and bile salt export pump (Bsep). In addition, concerted effects on Mrp2 and Bsep occurred through up-regulation of small heterodimer partner by activating farnesoid X receptor. Dioscin might prevent impairment of hepatic function by restoring hepatic transporter expression. PMID:27317372

  2. Plasma microRNA profiles in rat models of hepatocellular injury, cholestasis, and steatosis.

    Directory of Open Access Journals (Sweden)

    Yu Yamaura

    Full Text Available MicroRNAs (miRNAs are small RNA molecules that function to modulate the expression of target genes, playing important roles in a wide range of physiological and pathological processes. The miRNAs in body fluids have received considerable attention as potential biomarkers of various diseases. In this study, we compared the changes of the plasma miRNA expressions by acute liver injury (hepatocellular injury or cholestasis and chronic liver injury (steatosis, steatohepatitis and fibrosis using rat models made by the administration of chemicals or special diets. Using miRNA array analysis, we found that the levels of a large number of miRNAs (121-317 miRNAs were increased over 2-fold and the levels of a small number of miRNAs (6-35 miRNAs were decreased below 0.5-fold in all models except in a model of cholestasis caused by bile duct ligation. Interestingly, the expression profiles were different between the models, and the hierarchical clustering analysis discriminated between the acute and chronic liver injuries. In addition, miRNAs whose expressions were typically changed in each type of liver injury could be specified. It is notable that, in acute liver injury models, the plasma level of miR-122, the most abundant miRNA in the liver, was more quickly and dramatically increased than the plasma aminotransferase level, reflecting the extent of hepatocellular injury. This study demonstrated that the plasma miRNA profiles could reflect the types of liver injury (e.g. acute/chronic liver injury or hepatocellular injury/cholestasis/steatosis/steatohepatitis/fibrosis and identified the miRNAs that could be specific and sensitive biomarkers of liver injury.

  3. Maternal and neonatal outcome in obstetric cholestasis: a comparison of early versus late term delivery

    International Nuclear Information System (INIS)

    To evaluate maternal and neonatal outcome in Obstetric Cholestasis (OC) in early versus late term delivery. Study Design: Retrospective cohort study. Place and Duration of Study: Aga khan hospital for women (AKHW) Karimabad, Karachi, from 1st Jan, 2011 to 31st Oct, 2012. Patient and Methods: This was a retrospective cohort study. All patients of OC with singleton pregnancy, admitted for labor induction between Jan 2011 to Oct 2012 were included in the study. At or after 37 week of gestation, patient is offered labor induction. Patients were divided in two groups as in early term delivery (Group A) and late term delivery (Group B). Early term delivery is taken from 37+o to 37+6 and late term delivery at or after 38 weeks of gestation. The demographic, laboratory and clinical data of these patients were collected from their medical record. Maternal and neonatal outcome were analyzed using SPSS version 19. Results: The study found that in obstetric cholestasis patients admitted for labor induction, the risk of caesarean delivery was higher in group A (before 38 weeks) as compared to group B (after 38 weeks). There was no difference in postpartum hemorrhage and drop in hemoglobin between two groups. Obstetric cholestasis was not associated with adverse perinatal outcome such as intrauterine death (IUD), low Apgar Scores, respiratory distress and neonatal intensive care admission in both the groups. However more cases of neonatal jaundice were observed in babies born after 38 weeks. Conclusion: OC patients who deliver after 38 weeks of gestation have a higher chance of vaginal delivery without increasing the risk of IUD. (author)

  4. Impaired Itching Perception in Murine Models of Cholestasis Is Supported by Dysregulation of GPBAR1 Signaling

    OpenAIRE

    Sabrina Cipriani; Barbara Renga; Claudio D'Amore; Michele Simonetti; Antonio Angelo De Tursi; Adriana Carino; Maria Chiara Monti; Valentina Sepe; Angela Zampella; Stefano Fiorucci

    2015-01-01

    Background & Aims In cholestatic syndromes, body accumulation of bile acids is thought to cause itching. However, the mechanisms supporting this effect remain elusive. Recently, GPBAR1 (TGR5) a G-protein coupled receptor has been shown to mediate itching caused by intradermal administration of DCA and LCA. 6α-ethyl-3α, 7α-dihydroxy-24-nor-5β-cholan-23-ol (BAR502) is a non-bile acid dual ligand for FXR and GPBAR1. Methods Cholestasis was induced in wild type and GPBAR1-/- mice by administratio...

  5. Value of fasting serum glycocholic acid radioimmunoassay in the diagnosis of intrahepatic cholestasis of pregnancy

    International Nuclear Information System (INIS)

    1606 pregnant women were detected for their fasting serum glycocholic acid with radioimmunoassay (CG RIA) during January 1990 to April 1992. 63 cases of intrahepatic cholestasis of pregnancy (ICP) were diagnosed and verified. The upper limit of normal CG was 2640 mg/L, the positive detected rate was 98% and the incidence of ICP was 3.9%. A preliminary analysis was made on its value in the diagnosis of ICP, its relationship to contamination of amniotic fluid and choice of child delivery way. It is found that CG RIA is of value in early diagnosis of ICP, in predication of fetal distress and hence, is helpful in lowering perinatal mortality

  6. Successful pregnancy after ileal exclusion in progressive familial intrahepatic cholestasis type 2.

    Science.gov (United States)

    Czubkowski, Piotr; Jankowska, Irena; Pawlowska, Joanna

    2015-01-01

    Progressive familial intrahepatic cholestasis type 2 (PFIC 2) results from mutations in ABCB11 gene coding bile salt export pump (BSEP). Medical treatment is usually unsuccessful and surgery intervention is necessary. Partial external biliary diversion (PEBD) is regarded as the first choice of surgical treatment. Ileal exclusion (IE) is an alternative operation if external stoma is not tolerated; however, a favorable outcome is uncertain. In chronic liver diseases pregnancy brings additional risk of deterioration of liver function and generally is not recommended. We present the first case report of successful pregnancy in a genetically confirmed PFIC 2 patient after surgical conversion from PEBD to IE. PMID:26019043

  7. The role of bile salt export pump mutations in progressive familial intrahepatic cholestasis type II

    OpenAIRE

    Wang, Lin; Soroka, Carol J.; Boyer, James L.

    2002-01-01

    PFIC II is a subtype of progressive familial intrahepatic cholestasis (PFIC) that is associated with mutations in the ABCB11 gene encoding the bile salt export pump (BSEP). However it is not known how these mutations cause this disease. To evaluate these mechanisms, we introduced seven PFIC II–associated missense mutations into rat Bsep and assessed their effects on Bsep membrane localization and transport function in MDCK and Sf9 cells, respectively. Five mutations, G238V, E297G, G982R, R115...

  8. Pilot study for a trial of ursodeoxycholic acid and/or early delivery for obstetric cholestasis

    Directory of Open Access Journals (Sweden)

    Briley Annette

    2009-05-01

    Full Text Available Abstract Background Obstetric cholestasis (OC is a serious problem in pregnancy. It affects about 4500 women per year in the UK. Affected women develop itching and occasionally jaundice. More importantly, the condition is associated with premature delivery, fetal distress and is believed to be an important cause of stillbirth. However, even now, there is no clear evidence as to whether the most popular treatment, a drug called ursodeoxycholic acid is beneficial to the baby, or even if it is safe in pregnancy. Nor do we know whether planned early delivery of the baby at 37–38 weeks, another popular treatment, does more good than harm. A randomised trial to evaluate both ursodeoxycholic acid and timed delivery is needed but will be complicated and expensive. We plan a preliminary study, Pilot study for a trial of ursodeoxycholic acid and/or early delivery for obstetric cholestasis (Acronym PITCH- Pregnancy Intervention Trial in Cholestasis trial, to evaluate the feasibility of a larger trial. The trial is funded by the NHS Research for Patient Benefit (RfPB Programme. Methods PITCH is a multi-centre, double blinded, randomised, controlled, factorial design trial. The trial is being run in six UK centres and women with obstetric cholestasis will be recruited for eighteen months. In this pilot trial we aim to collect data to finalise the design for the main trial. This will include measuring trial recruitment rate, including recruitment to each factorial comparison separately. We will also measure the spectrum of disease among recruits and non-recruits and compliance with the four possible treatment allocations. We will use these data to design the main trial. Discussion The ultimate aim of the main trial is to enable clinicians to manage this condition more effectively. If it transpires that ursodeoxycholic acid and early delivery are both safe and effective then steps will be taken to ensure that all women with OC who could benefit from them

  9. Nervous and Neuroendocrine regulation of the pathophysiology of cholestasis and of biliary carcinogenesis

    Institute of Scientific and Technical Information of China (English)

    Marco Marzioni; Giammarco Fava; Antonio Benedetti

    2006-01-01

    Cholangiocytes, the epithelial cells lining the biliary ducts, are the target cells in several liver diseases.Cholangiopathies and cholangiocarcinoma generate interest in many scientists since the genesis. The developing mechanisms, and the therapeutic tools of these diseases are still undefined. Several studies demonstrate that many hormones, neuropeptides and neurotransmitters regulate malignant and non-malignant cholangiocyte pathophysiology in the course of chronic biliary diseases. The aim of this review is to present the findings of several studies published in the recent years that contributed to clarifying the role of nervous and neuroendocrine regulation of the pathophysiologic events associated with cholestasis and cholangiocarcinoma development. This manuscript is organized into two parts. The first part offers an overview of the innervation of the liver and the origin of neuroendocrine hormones,neurotransmitters and neuropeptides affecting cholangiocyte function and metabolism. The first section also reviews the effects played by several neuroendocrine hormones and nervous system on cholangiocyte growth,survival and functional activity in the course of cholestasis. In the second section, we summarize the results of some studies describing the role of nervous system and neuroendocrine hormones in the regulation of malignant cholangiocyte growth.

  10. Cholestasis induced antinociception and decreased gene expression of MOR1 in rat brain.

    Science.gov (United States)

    Ahmadi, S; Karami, Z; Mohammadian, A; Khosrobakhsh, F; Rostamzadeh, J

    2015-01-22

    We examined antinociception and gene expression of mu-opioid receptor 1 (MOR1) in some brain areas of cholestatic rats, 21 days after common bile duct ligation (BDL). Cholestasis was induced in male Wistar rats during laparotomy and common BDL. Pain behavior was assessed on days 7, 14 or 21 of BDL using a hotplate test in control, sham and cholestatic groups. On day 21 of BDL, other groups of rats were sacrificed, whole brains were extracted, and the hypothalamus, prefrontal cortex (PFC), hippocampus and striatum in control, sham and cholestatic rats were dissected. We used a semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method for evaluating MOR1 gene expression. The results revealed that cholestatic rats showed significant antinociception on days 14 and 21 of ligation with the most significant effect on day 21, which was prevented by naloxone (1 mg/kg). On the other hand, the expression of MOR1 gene compared to the sham group was decreased by 42% in the hypothalamus, 41% in the PFC, and 67% in the hippocampus after 21 days of BDL, while no significant change in its expression in the striatum was observed. It can be concluded that a change in endogenous opioid levels and its subsequent influence on the gene expression of MOR in some areas of the rat brain may underlie the altered nociception and other possible pathological changes such as pruritus after induction of cholestasis. PMID:25290008

  11. CCBE1 mutation in two siblings, one manifesting lymphedema-cholestasis syndrome, and the other, fetal hydrops.

    Directory of Open Access Journals (Sweden)

    Sohela Shah

    Full Text Available BACKGROUND: Lymphedema-cholestasis syndrome (LCS; Aagenaes syndrome is a rare autosomal recessive disorder, characterized by 1 neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and 2 severe chronic lymphedema, mainly lower limb. LCS was originally described in a Norwegian kindred in which a locus, LCS1, was mapped to a 6.6cM region on chromosome 15. Mutations in CCBE1 on chromosome 18 have been reported in some cases of lymphatic dysplasia, but not in LCS. METHODS: Consanguineous parents of Mexican ancestry had a child with LCS who did not exhibit extended homozygosity in the LCS1 region. A subsequent pregnancy was electively terminated due to fetal hydrops. We performed whole-genome single nucleotide polymorphism genotyping to identify regions of homozygosity in these siblings, and sequenced promising candidate genes. RESULTS: Both siblings harbored a homozygous mutation in CCBE1, c.398 T>C, predicted to result in the missense change p.L133P. Regions containing known 'cholestasis genes' did not demonstrate homozygosity in the LCS patient. CONCLUSIONS: Mutations in CCBE1 may yield a phenotype not only of lymphatic dysplasia, but also of LCS or fetal hydrops; however, the possibility that the sibling with LCS also carries a homozygous mutation in an unidentified gene influencing cholestasis cannot be excluded.

  12. A progressive familial intrahepatic cholestasis type 2 mutation causes an unstable, temperature-sensitive bile salt export pump

    NARCIS (Netherlands)

    Plass, JRM; Mol, O; Heegsma, J; Geuken, M; Elling, G; Muller, M; Faber, KN; Jansen, PLM

    2004-01-01

    Background Aims: Progressive familial intrahepatic cholestasis type 2 (PFIC-2) patients have a defect in the hepatocanalicular bile salt secretion. The disease is caused by mutations in the bile salt export pump (BSEP). Ten different missense mutations have been described. In this study, we analysed

  13. The adverse influence of pregnancy upon sulphation: a clue to the pathogenesis of intrahepatic cholestasis of pregnancy?

    Science.gov (United States)

    Davies, M H; Ngong, J M; Yucesoy, M; Acharya, S K; Mills, C O; Weaver, J B; Waring, R H; Elias, E

    1994-12-01

    Sulphation of oestrogens and monohydroxy bile acids is important in attenuating their cholestatic potential. Thus, impairment of sulphation could lead to retention of cholestatic compounds and precipitate intrahepatic cholestasis in susceptible individuals. We tested the hypothesis that such a mechanism may be involved in the pathogenesis of intrahepatic cholestasis of pregnancy. In vivo and in vitro assessment of sulphation capacity was performed in patients with cholestasis of pregnancy, compared with control females on and off the oestrogen-containing oral contraceptive pill and control individuals during normal pregnancy and post partum, to assess the influence of high oestrogen states upon this metabolic pathway. During in vivo studies utilising paracetamol as a metabolic probe, the proportion of paracetamol sulphate and sulphate: glucuronide ratio were decreased in those with elevated oestrogens, whether the rise in oestrogens was endogenous, in pregnancy (paracetamol sulphate p < 0.05; paracetamol sulphate:glucuronide ratio p < 0.01), or exogenous, with the contraceptive pill (paracetamol sulphate p = 0.2; paracetamol sulphate:glucuronide ratio p < 0.001). In vitro, platelet sulphotransferase activity was measured, utilising phenol as substrate. Sulphotransferase activity decreased during pregnancy compared with repeat measurements post partum (p < 0.005) and compared with non-pregnant individuals (p < 0.05). In conclusion, we have shown that elevated oestrogens are associated with significant impairment in sulphation capacity. An imbalance of sulphation with glucuronidation provoked by high circulating oestrogen levels may be contributory in the pathogenesis of cholestasis of pregnancy. PMID:7699239

  14. Dermatological Diseases Associated with Pregnancy: Pemphigoid Gestationis, Polymorphic Eruption of Pregnancy, Intrahepatic Cholestasis of Pregnancy, and Atopic Eruption of Pregnancy

    OpenAIRE

    Christine Sävervall; Freja Lærke Sand; Simon Francis Thomsen

    2015-01-01

    Dermatoses unique to pregnancy are important to recognize for the clinician as they carry considerable morbidity for pregnant mothers and in some instances constitute a risk to the fetus. These diseases include pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of pregnancy, and atopic eruption of pregnancy. This review discusses the pathogenesis, clinical importance, and management of the dermatoses of pregnancy.

  15. Hypervitaminosis A inducing intra-hepatic cholestasis--a rare case report.

    Science.gov (United States)

    Ramanathan, Vivek S; Hensley, Gary; French, Samuel; Eysselein, Victor; Chung, David; Reicher, Sonya; Pham, Binh

    2010-04-01

    The use of over-the-counter supplements is commonplace in today's health conscious society. We present an unusual case of intrahepatic cholestasis caused by vitamin A intoxication. The patient consumed one Herbalife shake with two multivitamin tablets of the same brand for 12 years. When calculated this equated to more than the recommended daily allowance for vitamin A consumption. Deranged liver function tests were consistent with a cholestatic process. Liver biopsy was obtained and revealed features pathognomonic of vitamin A toxicity, without the usual fibrosis. When the supplements were ceased, his jaundice and alkaline phosphatase completely normalized. This case highlights the importance of health care providers documenting non-prescribed dietary supplements and considering them in the etiology of cholestatic liver disease. PMID:19944093

  16. The observation of serum cholyglycine levels in patients with intrahepatic cholestasis of pregnancy

    International Nuclear Information System (INIS)

    To explore the clinical significance of empty abdominal serum Cholyglycine(CG) levels on the diagnosis of patient with Intrahepatic Cholestasis of Pregnancy(ICP), the serum levels of CG, TBA, TBIL and ALT in 400 normal pregnant women and in 87 pregnant patients with ICP were analyzed retrospectively. The results showed that the serum CG levels of patients with ICP were significant higher than that of normal control (P<0.001). The positive rate of serum CG was 100%. The serum levels of TBA, TBIL and ALT in patients with ICP were slightly higher than that of normal controls. The positive rates of TBA, TBIL and ALT were 36.5%, 12.2% and 35.6% respectively. The serum CG levels may be regarded as an economical and sensitive indicator in diagnosis of patients with ICP in the earlier stage. (authors)

  17. Novel ABCB11 mutations in a Thai infant with progressive familial intrahepatic cholestasis

    Institute of Scientific and Technical Information of China (English)

    Suporn Treepongkaruna; Amornphun Gaensan; Paneeya Pienvichit; Ondrej Luksan; AS Knisely; Pattana Sornmayura; Milan Jirsa

    2009-01-01

    Progressive familial intrahepatic cholestasis (PFIC) type 2 is caused by mutations in ABCB11 , which encodes bile salt export pump (BSEP). We report a Thai female infant who presented with progressive cholestatic jaundice since 1 mo of age, with normal serum γ-glutamyltransferase. Immunohistochemical staining of the liver did not demonstrate BSEP along the canaliculi, while multidrug resistance protein 3 was expressed adequately. Novel mutations in ABCB11 , a four-nucleotide deletion in exon 3, c.90_93delGAAA, and a single-nucleotide insertion in exon 5, c.249_250insT, were identified, with confirmation in her parents. These mutations were predicted to lead to synthesis of truncated forms of BSEP. Immunostaining and mutation analysis thus established the diagnosis of PFIC type 2.

  18. Clinical significance of serum glycochlicacid detection in diagnosis of intrahepatic cholestasis of pregnancy

    International Nuclear Information System (INIS)

    Intrahepatic cholestasis of pregnancy (ICP) occurred in the middle and later phase of pregnancy. ICP had considerable effect on the perinatal babies. To further study the effect of serum glycochlicacid in diagnosis of ICP, serum glycochlicacid was measured by radio-immunoassay in normal pregnancy women and ICP pregnant women. The determination of alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were taken as contrast. Serum glycochlicacid is significantly higher (P < 0.01) in ICP pregnant women than in normal pregnant women. The positive rate of serum glycochlicacid was 100%, the positive rate of ALT was 80%, the positive rate of ALP was 40%. Serum glycochlicacid is the most sensitive serologic index in diagnosis of ICP

  19. Infection by cytomegalovirus in patients with neonatal cholestasis Infecção por cytomegalovirus em pacientes com colestase neonatal

    Directory of Open Access Journals (Sweden)

    Nara Léia Gelle de OLIVEIRA

    2002-04-01

    Full Text Available Background - Neonatal cholestasis syndrome with an intra or extrahepatic origin has been associated to viral infections. The participation of the cytomegalovirus in the etiopathogenesis of neonatal hepatitis has been already known for some time, but only recently there have been indications that this virus may be one of the possible etiological factors for extrahepatic biliary atresia. Aims - To assess the prevalence of infection by cytomegalovirus in patients with intrahepatic cholestasis and extrahepatic cholestasis. To compare the clinical characteristics of the intrahepatic cholestasis and extrahepatic cholestasis groups with the cytomegalovirus serological results. Patients and Methods - This study consisted of 76 patients with neonatal cholestasis who were admitted between January 1980 and January 1999 when they underwent a cytomegalovirus serologic study using the ELISA method. A case note was kept on each patient with the following data: age of patient at admission, serologic result for cytomegalovirus, history of maternal infection, prematurity, fetal distress, birth weight, ponderal gain, choluria and fecal acholia. The final anatomic diagnosis of cholestasis was based on the results of an abdominal ultrasonography, a liver biopsy and its evolution. The patients were then divided into two groups: group I - intrahepatic cholestasis and group II - extrahepatic cholestasis. Each of these groups were then divided into two subgroups: subgroup A - positive serology (IgM for cytomegalovirus and subgroup B - negative serology (IgM for cytomegalovirus. Results - The frequency of positive serology (IgM for cytomegalovirus was 29.4% in children with intrahepatic cholestasis and 28.5% in children with extrahepatic cholestasis. In comparison with group IIB, group IIA presented a higher rate of maternal infection history. The patients in group IIA demonstrated a delayed access to the service in comparison with group IA. The groups did not

  20. Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Woolbright, Benjamin L.; Dorko, Kenneth [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Antoine, Daniel J.; Clarke, Joanna I. [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Gholami, Parviz [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Li, Feng [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Kumer, Sean C.; Schmitt, Timothy M.; Forster, Jameson [Department of Surgery, University of Kansas Medical Center, Kansas City, KS (United States); Fan, Fang [Department of Pathology, University of Kansas Medical Center, Kansas City, KS (United States); Jenkins, Rosalind E.; Park, B. Kevin [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Hagenbuch, Bruno [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Olyaee, Mojtaba [Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS (United States); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology & Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2015-03-15

    Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury

  1. IGF-1R contributes to stress-induced hepatocellular damage in experimental cholestasis.

    Science.gov (United States)

    Cadoret, Axelle; Rey, Colette; Wendum, Dominique; Elriz, Khaldoun; Tronche, François; Holzenberger, Martin; Housset, Chantal

    2009-08-01

    The insulin-like growth factor type 1 receptor (IGF-1R) controls aging and cellular stress, both of which play major roles in liver disease. Stimulation of insulin-like growth factor signaling can generate cell death in vitro. Here, we tested whether IGF-1R contributes to stress insult in the liver. Cholestatic liver injury was induced by bile duct ligation in control and liver-specific IGF-1R knockout (LIGFREKO) mice. LIGFREKO mice displayed less bile duct ligation-induced hepatocyte damage than controls, while no differences in bile acid serum levels or better adaptation to cholestasis by efflux transporters were found. We therefore tested whether stress pathways contributed to this phenomenon; oxidative stress, ascertained by both malondialdehyde content and heme oxygenase-1 expression, was similar in knockout and control animals. However, together with a lower level of eukaryotic initiation factor-2 alpha phosphorylation, the endoplasmic reticulum stress protein CHOP and its downstream pro-apoptotic target Bax were induced to lesser extents in LIGFREKO mice than in controls. Expression levels of cytokeratin 19, transforming growth factor-beta1, alpha-smooth muscle actin, and collagen alpha1(I) in LIGFREKO mice were all lower than in controls, indicating reduced ductular and fibrogenic responses and increased cholestasis tolerance in these mutants. This stress resistance phenotype was also evidenced by longer post-bile duct ligation survival in mutants than controls. These results indicate that IGF-1R contributes to cholestatic liver injury, and suggests the involvement of both CHOP and Bax in this process. PMID:19628767

  2. Role of Multidrug Resistance Protein 3 in Antifungal-Induced Cholestasis.

    Science.gov (United States)

    Mahdi, Zainab M; Synal-Hermanns, Uta; Yoker, Aylin; Locher, Kaspar P; Stieger, Bruno

    2016-07-01

    Drug-induced liver injury is an important clinical entity resulting in a considerable number of hospitalizations. While drug-induced cholestasis due to the inhibition of the bile salt export pump (BSEP) is well investigated, only limited information on the interaction of drugs with multidrug resistance protein 3 (MDR3) exists and its role in the pathogenesis of drug-induced cholestasis is poorly understood. Therefore, we aimed to study the interaction of drugs with MDR3 and the effect of drugs on canalicular lipid secretion in a newly established polarized cell line system that serves as a model of canalicular lipid secretion. LLC-PK1 cells were stably transfected with human Na(+)-taurocholate cotransporting polypeptide, BSEP, MDR3, and ABCG5/G8 and grown in the Transwell system. Apical phospholipid secretion and taurocholate transport were assayed to investigate the effect of selected drugs on MDR3-mediated phospholipid secretion as well as inhibition of BSEP. The established cell line displayed vectorial bile salt transport and specific phosphatidylcholine secretion into the apical compartment. The antifungal azoles, posaconazole, itraconazole, and ketoconazole, significantly inhibited MDR3-mediated phosphatidylcholine secretion. In contrast, amoxicillin clavulanate and troglitazone did not interfere with MDR3 activity. Drugs interfering with MDR3 activity did not display a parallel inhibition of BSEP. Our in vitro model for MDR3-mediated phospholipid secretion facilitates parallel screening for MDR3 and BSEP inhibitors. Our data demonstrate that the cholestatic potential of certain drugs may be aggravated by simultaneous inhibition of BSEP and MDR3. PMID:27112167

  3. Bile acid-induced necrosis in primary human hepatocytes and in patients with obstructive cholestasis

    International Nuclear Information System (INIS)

    Accumulation of bile acids is a major mediator of cholestatic liver injury. Recent studies indicate bile acid composition between humans and rodents is dramatically different, as humans have a higher percent of glycine conjugated bile acids and increased chenodeoxycholate content, which increases the hydrophobicity index of bile acids. This increase may lead to direct toxicity that kills hepatocytes, and promotes inflammation. To address this issue, this study assessed how pathophysiological concentrations of bile acids measured in cholestatic patients affected primary human hepatocytes. Individual bile acid levels were determined in serum and bile by UPLC/QTOFMS in patients with extrahepatic cholestasis with, or without, concurrent increases in serum transaminases. Bile acid levels increased in serum of patients with liver injury, while biliary levels decreased, implicating infarction of the biliary tracts. To assess bile acid-induced toxicity in man, primary human hepatocytes were treated with relevant concentrations, derived from patient data, of the model bile acid glycochenodeoxycholic acid (GCDC). Treatment with GCDC resulted in necrosis with no increase in apoptotic parameters. This was recapitulated by treatment with biliary bile acid concentrations, but not serum concentrations. Marked elevations in serum full-length cytokeratin-18, high mobility group box 1 protein (HMGB1), and acetylated HMGB1 confirmed inflammatory necrosis in injured patients; only modest elevations in caspase-cleaved cytokeratin-18 were observed. These data suggest human hepatocytes are more resistant to human-relevant bile acids than rodent hepatocytes, and die through necrosis when exposed to bile acids. These mechanisms of cholestasis in humans are fundamentally different to mechanisms observed in rodent models. - Highlights: • Cholestatic liver injury is due to cytoplasmic bile acid accumulation in hepatocytes. • Primary human hepatocytes are resistant to BA-induced injury

  4. The Effect of Fish Oil-Based Lipid Emulsion and Soybean Oil-Based Lipid Emulsion on Cholestasis Associated with Long-Term Parenteral Nutrition in Premature Infants

    Science.gov (United States)

    Wang, Leilei; Zhang, Jing; Gao, Jiejin; Qian, Yan; Ling, Ya

    2016-01-01

    Purpose. To retrospectively study the effect of fish oil-based lipid emulsion and soybean oil-based lipid emulsion on cholestasis associated with long-term parenteral nutrition in premature infants. Methods. Soybean oil-based lipid emulsion and fish oil-based lipid emulsion had been applied in our neonatology department clinically between 2010 and 2014. There were 61 qualified premature infants included in this study and divided into two groups. Soybean oil group was made up of 32 premature infants, while fish oil group was made up of 29 premature infants. Analysis was made on the gender, feeding intolerance, infection history, birth weight, gestational age, duration of parenteral nutrition, total dosage of amino acid, age at which feeding began, usage of lipid emulsions, and incidence of cholestasis between the two groups. Results. There were no statistical differences in terms of gender, feeding intolerance, infection history, birth weight, gestational age, duration of parenteral nutrition, total dosage of amino acid, and age at which feeding began. Besides, total incidence of cholestasis was 21.3%, and the days of life of occurrence of cholestasis were 53 ± 5.0 days. Incidence of cholestasis had no statistical difference in the two groups. Conclusion. This study did not find the different role of fish oil-based lipid emulsions and soybean oil-based lipid emulsions in cholestasis associated with long-term parenteral nutrition in premature infants.

  5. The angiotensin-converting enzyme gene insertion–deletion polymorphism in a white British patient cohort with obstetric cholestasis

    Science.gov (United States)

    Müllenbach, Roman; Tetlow, Natasha; Bennett, Amanda; Pipkin, Fiona Broughton; Morgan, Linda; Williamson, Catherine

    2009-01-01

    The DD genotype of the angiotensin-converting enzyme (ACE) gene is over-represented in Finnish patients with obstetric cholestasis (OC). The purpose of this study was to establish whether this genotype is associated with cholestasis in UK cases. In a retrospective case-control study, we determined the ACE insertion/deletion frequencies in 166 British cases and 100 control women by polymerase chain reaction analysis. No significant difference in allele frequencies was found between these groups, but allele frequencies differed significantly between Finnish and UK OC cases (P = 0.0005). The prevalence of the DD genotype is lower in UK cases than in controls (χ2 [1 d.f.] = 4.32, P = 0.05) and the odds ratio for OC associated with the DD genotypeis 0.54, 95% confidence interval 0.30–0.97. In contrast to Finnish OC cases, the DD genotype of the ACE is not increased in UK cases.

  6. The Effects of Cholestasis and Cirrhosis on Gastric Acid and Pepsin Secretions in Rat: Involvement of Nitric Oxide

    OpenAIRE

    Fatemeh Nabavizadeh; Rohallah Moloudi; Ahmad Reza Dehpour; Hossein Nahrevanian; Kaveh Shahvaisi; Ehsan Salimi

    2010-01-01

    Objective(s)The liver has major role in the organism homeostasis, interactions with other systems, synthesis and metabolism of bile production, drug detoxification and hormone inactivation. Cholestasis can be defined as an impairment of the bile flow which can lead to hepatocytes necrosis and finally cirrhosis. Some studies reported a gastric acid secretion reduction in cirrhotic subjects, while others reported normal production gastric acid secretion. Our aim was to evaluate the effects of c...

  7. Discovery that theonellasterol a marine sponge sterol is a highly selective FXR antagonist that protects against liver injury in cholestasis.

    Directory of Open Access Journals (Sweden)

    Barbara Renga

    Full Text Available BACKGROUND: The farnesoid-x-receptor (FXR is a bile acid sensor expressed in the liver and gastrointestinal tract. Despite FXR ligands are under investigation for treatment of cholestasis, a biochemical condition occurring in a number of liver diseases for which available therapies are poorly effective, mice harboring a disrupted FXR are protected against liver injury caused by bile acid overload in rodent models of cholestasis. Theonellasterol is a 4-methylene-24-ethylsteroid isolated from the marine sponge Theonella swinhoei. Here, we have characterized the activity of this theonellasterol on FXR-regulated genes and biological functions. PRINCIPAL FINDINGS: Interrogation of HepG2 cells, a human hepatocyte cell line, by microarray analysis and transactivation assay shows that theonellasterol is a selective FXR antagonist, devoid of any agonistic or antagonistic activity on a number of human nuclear receptors including the vitamin D receptor, PPARs, PXR, LXRs, progesterone, estrogen, glucorticoid and thyroid receptors, among others. Exposure of HepG2 cells to theonellasterol antagonizes the effect of natural and synthetic FXR agonists on FXR-regulated genes, including SHP, OSTα, BSEP and MRP4. A proof-of-concept study carried out to investigate whether FXR antagonism rescues mice from liver injury caused by the ligation of the common bile duct, a model of obstructive cholestasis, demonstrated that theonellasterol attenuates injury caused by bile duct ligation as measured by assessing serum alanine aminostrasferase levels and extent of liver necrosis at histopathology. Analysis of genes involved in bile acid uptake and excretion by hepatocytes revealed that theonellasterol increases the liver expression of MRP4, a basolateral transporter that is negatively regulated by FXR. Administering bile duct ligated mice with an FXR agonist failed to rescue from liver injury and downregulated the expression of MRP4. CONCLUSIONS: FXR antagonism in vivo

  8. Transcriptional Dynamics of Bile Salt Export Pump during Pregnancy: Mechanisms and Implications in Intrahepatic Cholestasis of Pregnancy

    OpenAIRE

    Song, Xiulong; Vasilenko, Alexander; Chen, Yuan; Valanejad, Leila; Verma, Ruchi; Yan, Bingfang; Deng, Ruitang

    2014-01-01

    Bile salt export pump (BSEP) is responsible for biliary secretion of bile acids, a rate limiting step in the enterohepatic circulation of bile acids and transactivated by nuclear receptor farnesoid x receptor (FXR). Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent disorder among diseases unique to pregnancy and primarily occurs in the third trimester of pregnancy with a hallmark of elevated serum bile acids. Currently, the transcriptional regulation of BSEP during pregnancy a...

  9. INCREASE OF GLYCOSAMINOGLYCANS AND METALLOPROTEINASES 2 AND 9 IN LIVER EXTRACELLULAR MATRIX ON EARLY STAGES OF EXTRAHEPATIC CHOLESTASIS

    Directory of Open Access Journals (Sweden)

    Pedro Luiz Rodrigues GUEDES

    2014-12-01

    Full Text Available Context Cholestasis produces hepatocellular injury, leukocyte infiltration, ductular cells proliferation and fibrosis of liver parenchyma by extracellular matrix replacement. Objective Analyze bile duct ligation effect upon glycosaminoglycans content and matrix metalloproteinase (MMPs activities. Methods Animals (6-8 weeks; n = 40 were euthanized 2, 7 or 14 days after bile duct ligation or Sham-surgery. Disease evolution was analyzed by body and liver weight, seric direct bilirubin, globulins, gamma glutamyl transpeptidase (GGT, alkaline phosphatase (Alk-P, alanine and aspartate aminotransferases (ALT and AST, tissue myeloperoxidase and MMP-9, pro MMP-2 and MMP-2 activities, histopathology and glycosaminoglycans content. Results Cholestasis caused cellular damage with elevation of globulins, GGT, Alk-P, ALT, AST. There was neutrophil infiltration observed by the increasing of myeloperoxidase activity on 7 (P = 0.0064 and 14 (P = 0.0002 groups which leads to the magnification of tissue injuries. Bile duct ligation increased pro-MMP-2 (P = 0.0667, MMP-2 (P = 0.0003 and MMP-9 (P<0.0001 activities on 14 days indicating matrix remodeling and establishment of inflammatory process. Bile duct ligation animals showed an increasing on dermatan sulfate and/or heparan sulfate content reflecting extracellular matrix production and growing mitosis due to parenchyma depletion. Conclusions Cholestasis led to many changes on rats’ liver parenchyma, as so as on its extracellular matrix, with major alterations on MMPs activities and glycosaminoglycans content.

  10. Cholestasis and protein-losing enteropathy secondary to hyperthyroidism in a 6-year-old girl.

    Science.gov (United States)

    Gargouri, Lamia; Charfi, Manel; Maalej, Bayen; Majdoub, Imen; Safi, Faiza; Fourati, Hela; Hentati, Yosr; Daoud, Emna; Mnif, Zeineb; Abid, Mohamed; Mahfoudh, Abdelmajid

    2014-09-01

    Hepatic dysfunctions are not infrequent in patients with hyperthyroidism. These disorders may be related to the effects of the excess thyroid hormone secretion, to the uses of antithyroid drugs, or to the presence of concomitant hepatic diseases. Our aim is to describe the clinical and biochemical features of liver dysfunction related to thyrotoxicosis. We report here a case of a 6-year-old girl who was admitted for jaundice and pruritus as a result of the development of hyperthyroidism due to Graves' disease. On physical examination at admission, she was found to have jaundice and hepatomegaly. Laboratory data show cholestasis and protein-losing enteropathy. Investigations exclude other causes of hepatic disorder. One month after the initiation of antithyroid drug, the patient became euthyroid with improvement in jaundice and pruritus and normalization of hepatic tests and alpha antitrypsine clearance. In conclusion, the diagnosis of hyperthyroidism may be delayed in patients in whom the primary manifestations were pruritus and jaundice. The physician should suspect thyrotoxicosis prior to hepatitis or skin manifestations. PMID:24825088

  11. Effect of Bile Acid on Fetal Lung in Rat Model of Intrahepatic Cholestasis of Pregnancy

    Directory of Open Access Journals (Sweden)

    Ling Yu

    2014-01-01

    Full Text Available Objective. To determine the correlation between maternal bile acid (BA level and fetal pulmonary surfactant in rats and study the effects of BA on fetal lung in rat model of intrahepatic cholestasis of pregnancy. Methods. Forty pregnant rats were treated with (A 5.5 mg/kg BA, (B 1.4 mg/kg BA, and (C 1 ml physiological saline. Levels of total bile acid (TBA, ALT, AST, TBIL, DBIL, and SP-A were determined and the lungs of fetal rats were analyzed for pathological changes. Results. Groups A and B intervened with BA showed significant higher level of TBA in both maternal and fetal serum, more mortality rate of fetal rats, more concentration of SP-A in fetal serum, and wider alveolus mesenchyme of fetal rats than the control Group C. Higher level of BA associated with increased fetal risk and lower numerical density of mitochondria in type II alveolar epithelial cells. The levels of TBA in maternal serum were found to have significant positive correlation with those in fetal serum and SP-A level but negatively with the area of alveolus and the numerical density of lamellar body. Conclusions. The TBA level in maternal serum showed significant association with lung pathological changes in fetal rats.

  12. In Search of an Accurate Evaluation of Intrahepatic Cholestasis of Pregnancy

    Directory of Open Access Journals (Sweden)

    Manuela Martinefski

    2012-01-01

    Full Text Available Until now, biochemical parameter for diagnosis of intrahepatic cholestasis of pregnancy (ICP mostly used is the rise of total serum bile acids (TSBA above the upper normal limit of 11 μM. However, differential diagnosis is very difficult since overlapped values calculated on bile acids determinations, are observed in different conditions of pregnancy including the benign condition of pruritus gravidarum. The aim of this work was to determine the better markers in ICP for a precise diagnosis together with parameters associated with severity of symptoms and treatment evaluation. Serum bile acid profiles were evaluated using capillary electrophoresis in 38 healthy pregnant women and 32 ICP patients and it was calculated the sensitivity, specificity, accuracy, predictive values and the relationships of certain individual bile acids in pregnant women in order to replace TSBA determinations. The evaluation of the results shows that LCA and UDCA/LCA ratio provided information for a more complete and accurate diagnosis and evaluation of ICP than calculation of solely TSBA levels in pregnant women.

  13. Cytomegalovirus frequency in neonatal intrahepatic cholestasis determined by serology, histology, immunohistochemistry and PCR

    Institute of Scientific and Technical Information of China (English)

    Maria Angela Bellomo-Brandao; Paula D Andrade; Sandra CB Costa; Cecilia AF Escanhoela; Jose Vassallo; Gilda Porta; Adriana MA De Tommaso; Gabriel Hessel

    2009-01-01

    AIM: To determine cytomegalovirus (CMV) frequency in neonatal intrahepatic cholestasis by serology,histological revision (searching for cytomegalic cells), immunohistochemistry, and polymerase chain reaction (PCR), and to verify the relationships among these methods. METHODS: The study comprised 101 non-consecutive infants submitted for hepatic biopsy between March 1982 and December 2005. Serological results were obtained from the patient's files and the other methods were performed on paraffin-embedded liver samples from hepatic biopsies. The following statistical measures were calculated: frequency, sensibility, specific positive predictive value, negative predictive value, and accuracy.RESULTS: The frequencies of positive results were as follows: serology, 7/64 (11%); histological revision, 0/84; immunohistochemistry, 1/44 (2%),and PCR, 6/77 (8%). Only one patient had positive immunohistochemical findings and a positive PCR. The following statistical measures were calculated between PCR and serology: sensitivity, 33.3%; specificity,88.89%; positive predictive value, 28.57%; negative predictive value, 90.91%; and accuracy, 82.35%.CONCLUSION: The frequency of positive CMV varied among the tests. Serology presented the highest positive frequency. When compared to PCR, the sensitivity and positive predictive value of serology were low.

  14. Two Case Reports of Successful Treatment of Cholestasis With Steroids in Patients With PFIC-2.

    Science.gov (United States)

    Engelmann, Guido; Wenning, Daniel; Herebian, Diran; Sander, Oliver; Dröge, Carola; Kluge, Stefanie; Kubitz, Ralf

    2015-05-01

    Mutations in the gene encoding the canalicular bile salt export pump (BSEP) can result in progressive familial intrahepatic cholestasis type 2 (PFIC-2). Treatment options are limited, and PFIC-2 often necessitates liver transplantation. We report on a young woman and a boy who clinically presented with PFIC-2 phenotypes and dramatically improved with steroid treatment. Gene sequencing of ABCB11 encoding for BSEP revealed 2 relevant mutations in both patients. The young woman was compound heterozygous for p.T919del and p.R1235X. At the age of 5 years, partial biliary diversion was performed and rescued liver function but left serum bile salt levels elevated. At age 23 she developed systemic lupus erythematosus. Unexpectedly, steroid therapy normalized serum bile salt levels, with a strong correlation with the steroid dose. She is currently in clinical remission. The boy was compound heterozygous for the ABCB11 mutations c.150+3A>C and p.R832C and presented with intractable pruritus. When he developed colitis, he was treated with steroids. The pruritus completely disappeared and relapsed when steroids were withdrawn. To date, with low-dose budesonide, the boy has been symptom-free for >3 years. In conclusion, the clinical courses suggest that patients with BSEP deficiency and residual BSEP activity may benefit from steroid-based therapy, which represents a new treatment option. PMID:25847799

  15. Effects of Three Different Fibrates on Intrahepatic Cholestasis Experimentally Induced in Rats

    Directory of Open Access Journals (Sweden)

    Alaa El-Sisi

    2013-01-01

    Full Text Available Background. Activation of PPARα modulates cholesterol metabolism and suppresses bile acid synthesis. This study aims to evaluate the effect of PPARα agonists, fenofibrate, bezafibrate, and gemfibrozil, on acute cholestasis induced by ethinylestradiol (EE plus chlorpromazine (CPZ in rats. Method. 100 male albino rats (150–200 gm were divided randomly into 10 equal groups. Control group received 1% methylcellulose vehicle; disease group received CPZ plus EE for 5 consecutive days; four groups received either ursodeoxycholic acid, fenofibrate, bezafibrate, or gemfibrozil for 7 days; 2 days before EE + CPZ, three other groups received one of the three fibrates after GW6471, a selective PPARα antagonist in addition to EE + CPZ. The final group received GW6471 alone. Results. The three fibrates showed marked reduction ( in serum levels of ALP, GGT, ALT, AST, total bile acids, bilirubin, TNFα, and IL-1β and in hepatic malondialdehyde level as well as a significant increase in bile flow rate ( in addition to improvements in histopathological parameters compared to diseased group. In groups which received GW6471, these effects were completely abolished with fenofibrate and partially blocked with bezafibrate and gemfibrozil. Conclusion. Short-term administration of fibrates to EE/CPZ-induced intrahepatic cholestatic rats exerted beneficial effects on hepatocellular damage and apoptosis. Fenofibrate anticholestatic effect was solely PPARα dependent while other mechanisms played part in bezafibrate and gemfibrozil actions.

  16. Incidence and Risk Factors of Parenteral Nutrition-Associated Cholestasis in Omani Neonates; Single centre experience

    Directory of Open Access Journals (Sweden)

    Sharef W. Sharef

    2015-05-01

    Full Text Available Objectives: Parenteral nutrition-associated cholestasis (PNAC is one of the most challenging complications of prolonged parenteral nutrition (PN in neonates. There is a lack of research investigating its incidence in newborn infants in Oman and the Arab region. Therefore, this study aimed to assess the incidence of PNAC and its risk factors in Omani neonates. Methods: This retrospective study took place between January and April 2014. All neonates who received PN for ≥14 days during a four-year period (June 2009 to May 2013 at the neonatal intensive care unit (NICU in Sultan Qaboos University Hospital, Muscat, Oman, were enrolled. Results: A total of 1,857 neonates were admitted to the NICU over the study period and 135 neonates (7.3% received PN for ≥14 days. Determining the incidence of PNAC was only possible in 97 neonates; of these, 38 (39% had PNAC. The main risk factors associated with PNAC were duration of PN, duration of enteral starvation, gastrointestinal surgeries, blood transfusions and sepsis. Neonates with PNAC had a slightly higher incidence of necrotising enterocolitis in comparison to those without PNAC. Conclusion: This study found a PNAC incidence of 39% in Omani neonates. There were several significant risk factors for PNAC in Omani neonates; however, after logistic regression analysis, only total PN duration remained statistically significant. Preventive strategies should be implemented in NICUs so as to avoid future chronic liver disease in this population.

  17. Role of ciprofloxacin in patients with cholestasis after endoscopic retrograde cholangiopancreatography

    Institute of Scientific and Technical Information of China (English)

    Thawee Ratanachu-ek; Pitchaya Prajanphanit; Kawin Leelawat; Suchart Chantawibul; Sukij Panpimanmas; Somboon Subwongcharoen; Jerasak Wannaprasert

    2007-01-01

    AIM: To determine the role of ciprofloxacin in reducing cholangitis in cholestatic patients with adequate biliary drainage after endoscopic retrograde cholangiopancreatography (ERCP).METHODS: A randomized, controlled trial was performed in 48 cholestatic patients at Rajavithi Hospital (Tertiary Referral Center for ERCP: 600 cases per year). All the 48 patients received 200 mg ciprofloxacin intravenous injection for 30 min before starting any procedures, and then were randomly divided in two groups. Twenty-two patients in study group continually received ciprofloxacin until 48 h after ERCP. Causes of biliary obstruction, bacteriology of bile and blood (in cholangitis) and clinical cholangitis were recorded.RESULTS: Forty-eight patients were enrolled and divided into continuous ciprofloxacin treatment group (n = 22) and discontinuous ciprofloxacin treatment group (n = 26). During ERCP, stones were found in 22 patients,malignant diseases in 24 patients and other pathologic lesions in 5 patients. One (4.5%) of the 22 patients who received ciprofloxacin and 2 (6.3%) of the 26 patients who discontinued ciprofloxacin after ERCP developed cholangitis (relative risk = 0.71; 95% CI = 0.14-3.65;P = 0.88). Bacterobilia was found in 27 (56.3%) out of 48 patients. E. coli and Streptococcus viridans were the most common organisms.CONCLUSION: Continual use of ciprofloxacin in patients with cholestasis after adequate biliary drainage procedures plays no role in reducing cholangitis.

  18. Growth evaluation in infants with neonatal cholestasis Antropometria em crianças com colestase neonatal

    Directory of Open Access Journals (Sweden)

    Camila Carbone Prado

    2006-12-01

    Full Text Available BACKGROUD: Chronic liver diseases in childhood often cause undernutrition and growth failure. To our knowledge, growth parameters in infants with neonatal cholestasis are not available AIM: To evaluate the nutritional status and growth pattern in infants with intrahepatic cholestasis and extrahepatic cholestasis. PATIENTS AND METHODS: One hundred forty-four patients with neonatal cholestasis were followed up at the Pediatric Gastroenterology Service of the Teaching Hospital, State University of Campinas, Campinas, SP, Brazil, in a 23-year period, from 1980 to 2003. The records of these patients were reviewed and patients were classified into two groups, according to their anatomical diagnosis: patients with intrahepatic cholestasis - group 1, and patients with extrahepatic cholestasis - group 2. Records of weight and height measurements were collected at 4 age stages of growth, in the first year of life: 1 from the time of the first medical visit to the age of 4 months (T1; 2 from the 5th to the 7th month (T2; 3 from the 8th to the 10th month (T3; and 4 from the 11th to the 13th month (T4. The weight-by-age and height-by-age Z-scores were calculated for each patient at each stage. In order for the patient to be included in the study it was necessary to have the weight and/or height measurements at the 4 stages. Analyses of variance and Tukey's tests were used for statistical analysis. Repeated measurement analyses of variance of the weight-by-age Z-score were performed in a 60-patient sample, including 29 patients from group 1 and 31 patients from group 2. The height-by-age data of 33 patients were recorded, 15 from group 1 and 18 from group 2 RESULTS: The mean weight-by-age Z-scores of group 1 patients at the 4 age stages were: T1=-1.54; T2=-1.40; T3=-0.94; T4=-0.78. There was a significant difference between T2 X T3 and T1 X T4. The weight-by-age Z-scores for group 2 patients were :T1=-1.04; T2=-1.67; T3=-1.93 and T4=-1.77, with a significant

  19. Inflammatory cell function in young rodents with experimental cholestasis: investigations of functional deficits, their etiology, and their reversibility.

    Science.gov (United States)

    Roughneen, P T; Drath, D B; Kulkarni, A D; Kumar, S C; Andrassy, R J; Rowlands, B J

    1989-07-01

    Children with cholestasis are susceptible to infective complications. This may be attributable to impaired host defense. We postulated that cholestasis affects systemic polymorphonuclear leukocyte (PMN) function by impeding chemotaxis, phagocytosis, and superoxide release, which are all critical in eliciting an adequate immune response. Sprague Dawley rats (225 g) were assigned to three groups: bile duct ligated (BDL), sham (SH), and normal control (NC). On day 21 after operation, PMN and sera were isolated. Chemotactic response to C5a and FMLP (formyl-methionyl-leucyl-phenylalanine), superoxide release, and phagocytic uptake of 14C-labeled Staphylococcus aureus were performed on pooled PMN samples. Results were expressed as mean +/- SD. Serum bilirubin at day 21 was 6.3 +/- 2.9 v 0.1 +/- 0.1 and 0.1 +/- 0 mg/dL (P less than .01) in BDL, SH, and NC groups, respectively. Kinetic studies of PMN phagocytosis demonstrated impaired 14C S aureus uptake by BDL neutrophils at 60 (P less than .05), 90 (P less than .05), and 120 minutes (P less than .05) compared with SH and NC groups. No differences in PMN chemotactic response to C5a and FMLP was observed in BDL, SH and NC groups (43 +/- 14 v 40 +/- 12 and 33 +/- 1, and 43 +/- 20 v 43 +/- 14 and 28 +/- 1 cell per field, respectively). Zymosan stimulated superoxide release did not differ between groups (14.3 +/- 3.6 (BDL) v 15.1 +/- 8.7 (SH) and 12 +/- 2.0 (NC) nmol/30 min/mg cell protein, respectively. Thus, cholestasis impairs neutrophil phagocytosis in vitro.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2547052

  20. Colestasis intrahepática del embarazo en una adolescente Intrahepatic cholestasis of a pregnant teenager

    Directory of Open Access Journals (Sweden)

    Alberto Martínez Sarmiento

    2013-06-01

    Full Text Available Introducción: la colestasis gravídica es una afección que se presenta con mayor frecuencia en el segundo o tercer trimestres, siendo el prurito y la elevación de los ácidos biliares en sangre sus características fundamentales. Se considera una enfermedad multifactorial y aunque el pronóstico materno es bueno, puede ocurrir prematuridad, sufrimiento y muerte fetales. Objetivo: presentar el caso y la revisión bibliográfica en la literatura nacional e internacional. Caso clínico: se presenta el caso de una gestante de 18 años de edad con un tiempo de gestación de 17,5 sem, que fue vista en consulta de hepatología por presentar prurito, íctero y coluria. Durante su estudio lo más significativo fue un aumento ligero de las transaminasas (ALAT/ASAT, asociado a un aumento de la bilirrubina y de la fosfatasa alcalina (FA. Resultados: a las 29,3 sem, la gestante comenzó con manifestaciones de parto pretérmino por lo que se decidió la interrupción del embarazo (cesárea. El recién nacido presentó al nacer 1 260 g y fue trasladado a sala de terapia intensiva neonatológica. La evolución clínica posparto de la madre fue satisfactoria, con desaparición de la sintomatología en las primeras 48 h y la normalización de las alteraciones analíticas en el transcurso de 4-8 sem. Conclusiones: la presentación clínica y bioquímica de la gestante así como su evolución, fueron suficientes para establecer el diagnóstico de una colestasis gravídica. La paciente es seguida por consulta de hepatología y está pendiente de valoración por el genetista debido al riesgo de esta afección en embarazos sucesivos.Introduction: cholestasis of pregnancy is a condition that occurs most often in the second or third quarters. Pruritus and elevated bile acids in blood are its fundamental characteristics. It is considered a multifactorial disease and although maternal prognosis is good, prematurity, fetal distress and death can occurred. Objective: to

  1. Suppression of the HPA Axis During Cholestasis Can Be Attributed to Hypothalamic Bile Acid Signaling.

    Science.gov (United States)

    McMillin, Matthew; Frampton, Gabriel; Quinn, Matthew; Divan, Ali; Grant, Stephanie; Patel, Nisha; Newell-Rogers, Karen; DeMorrow, Sharon

    2015-12-01

    Suppression of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to occur during cholestatic liver injury. Furthermore, we have demonstrated that in a model of cholestasis, serum bile acids gain entry into the brain via a leaky blood brain barrier and that hypothalamic bile acid content is increased. Therefore, the aim of the current study was to determine the effects of bile acid signaling on the HPA axis. The data presented show that HPA axis suppression during cholestatic liver injury, specifically circulating corticosterone levels and hypothalamic corticotropin releasing hormone (CRH) expression, can be attenuated by administration of the bile acid sequestrant cholestyramine. Secondly, treatment of hypothalamic neurons with various bile acids suppressed CRH expression and secretion in vitro. However, in vivo HPA axis suppression was only evident after the central injection of the bile acids taurocholic acid or glycochenodeoxycholic acid but not the other bile acids studied. Furthermore, we demonstrate that taurocholic acid and glycochenodeoxycholic acid are exerting their effects on hypothalamic CRH expression after their uptake through the apical sodium-dependent bile acid transporter and subsequent activation of the glucocorticoid receptor. Taken together with previous studies, our data support the hypothesis that during cholestatic liver injury, bile acids gain entry into the brain, are transported into neurons through the apical sodium-dependent bile acid transporter and can activate the glucocorticoid receptor to suppress the HPA axis. These data also lend themselves to the broader hypothesis that bile acids may act as central modulators of hypothalamic peptides that may be altered during liver disease. PMID:26431088

  2. Primum non nocere: how active management became modus operandi for intrahepatic cholestasis of pregnancy.

    Science.gov (United States)

    Henderson, Cassandra E; Shah, Reena R; Gottimukkala, Sri; Ferreira, Khaldun K; Hamaoui, Abraham; Mercado, Ray

    2014-09-01

    The Royal College of Obstetrics and Gynecology does not endorse routine active management of intrahepatic cholestasis of pregnancy (ICP)-affected pregnancies. In contrast, the American College of Obstetricians and Gynecologists supports active management protocols for ICP. To investigate this controversy, we evaluated the evidence supporting ICP as a medical indication for early term delivery and the evolution of active management protocols for ICP. Sixteen articles published between 1986 and 2011 were identified. We created 2 groups based on whether obstetric care included active management. Group 1 comprised 6 uncontrolled reports without active management that were published between 1967 and 1983 that described high perinatal mortality rates that primarily were related to prematurity sequel. This group became the fundamental 'core' evidence for ICP-associated stillbirths and by extrapolation justification for active management. Group 2 was comprised of 10 reports in which the authors credited empirically adopted active management with the observed low stillbirth rates in ICP-affected pregnancies. Although the group 1 articles routinely are cited as evidence of ICP-associated stillbirth risk, the 1.2% stillbirth rate (4/331) in this group is similar to the background stillbirth rates of 1.1% (11/1000) and 0.6% (6/1000) in 1967 and 2011, respectively (P = .062 and P = .0614, respectively). Likewise, the stillbirth rates for articles in group 2 were similar to their respective national stillbirth rate. Nevertheless, group 2 articles have become the evidence-based support for active management. We found no evidence to support the practice of active management for ICP. PMID:24704063

  3. RIP3 Inhibits Inflammatory Hepatocarcinogenesis but Promotes Cholestasis by Controlling Caspase-8- and JNK-Dependent Compensatory Cell Proliferation

    Directory of Open Access Journals (Sweden)

    Mihael Vucur

    2013-08-01

    Full Text Available For years, the term “apoptosis” was used synonymously with programmed cell death. However, it was recently discovered that receptor interacting protein 3 (RIP3-dependent “necroptosis” represents an alternative programmed cell death pathway activated in many inflamed tissues. Here, we show in a genetic model of chronic hepatic inflammation that activation of RIP3 limits immune responses and compensatory proliferation of liver parenchymal cells (LPC by inhibiting Caspase-8-dependent activation of Jun-(N-terminal kinase in LPC and nonparenchymal liver cells. In this way, RIP3 inhibits intrahepatic tumor growth and impedes the Caspase-8-dependent establishment of specific chromosomal aberrations that mediate resistance to tumor-necrosis-factor-induced apoptosis and underlie hepatocarcinogenesis. Moreover, RIP3 promotes the development of jaundice and cholestasis, because its activation suppresses compensatory proliferation of cholangiocytes and hepatic stem cells. These findings demonstrate a function of RIP3 in regulating carcinogenesis and cholestasis. Controlling RIP3 or Caspase-8 might represent a chemopreventive or therapeutic strategy against hepatocellular carcinoma and biliary disease.

  4. High rates of resolution of cholestasis in parenteral nutrition-associated liver disease with fish oil-based lipid emulsion monotherapy

    Science.gov (United States)

    Our research was conducted to determine factors leading to resolution of cholestasis in patients with parenteral nutrition-associated liver disease treated with fish-oil-based lipid emulsion (FOLE). We used a prospective observational study of 57 infants <6 months of age with parenteral nutrition-as...

  5. Effect of Intrahepatic Cholestasis of Pregnancy on Cytokines, Hemorheology and Coagulation Function of Pregnant Women

    Directory of Open Access Journals (Sweden)

    Cui-ge YU

    2015-12-01

    Full Text Available Abstract Objective: To explore the effect of intrahepatic cholestasis of pregnancy (ICP on the cytokines, hemorheology and coagulation function of pregnant women. Methods: A total of 43 singleton pregnant women with ICP delivered in Shaanxi Provincial People’s Hospital from June 2014 to June 2015 were selected as observation group, and 45 singleton healthy pregnant women accompanied by indications of cesarean section were selected as control group. Automatic Viscometer was used to detect the hematological indexes, Automatic Coagulometer to detect the indexes related to coagulation function and radioimmunoassay to determine the levels of cell inflammatory factors, and the pregnancy outcomes were closely observed. Results: The levels of interleukin-12 (IL-12, interleukin-18 (IL-18, tumor necrosis factor-α (TNF-α, high and low shear rates of whole blood viscosity, hematokrit, plasma viscosity and erythrocyte sedimentation rate (ESR in observation group were all dramatically higher than those in control group, and all the differences were statistically significant (P<0.01. There was no statistical significance between two groups with regard to prothrombin When compared with control group, the levels of D-dimer (D-D and fibrinogen (FIB in observation group increased dramatically (P<0.01, but platelet (PLT decreased markedly (P<0.01. The incidence of amniotic fluid pollution and premature delivery in observation group was higher than in control group (P<0.05 or P<0.01, and that of fetal distress, neonatal asphyxia and low birth weight tended to be higher than in control group, but there was no statistical significance (P>0.05. Conclusion: Both the hemorheology and coagulation function of pregnant women with ICP manifest significantly high viscosity and hypercoagulability, and the release of cell inflammatory factors increases, which all exert adverse influence on pregnancy outcome. time (PT and activated

  6. Oleanolic acid attenuates obstructive cholestasis in bile duct-ligated mice, possibly via activation of NRF2-MRPs and FXR antagonism.

    Science.gov (United States)

    Chen, Pan; Li, Jingjie; Fan, Xiaomei; Zeng, Hang; Deng, Rongrong; Li, Dongshun; Huang, Min; Bi, Huichang

    2015-10-15

    Obstructive cholestasis is characterized by impairment of hepatic canalicular bile efflux and there are no clinically effective drugs to cure except surgeries. Previously we revealed that oleanolic acid (OA) protected against lithocholic acid (LCA)-induced intrahepatic cholestasis in mice. Cholestasis caused by LCA is characterized by segmental bile duct obstruction, whether OA possesses the beneficial effect on completed obstructive cholestasis induced by bile duct ligation (BDL) remains unknown. In this study, we demonstrated that BDL-induced mice liver pathological change, and increase in serum levels of ALT, AST and ALP were all significantly reduced by OA (20 mg/kg, i.p.). Meanwhile, OA also lowered total bilirubin and total bile acids levels in serum, as well as total bile acids level in liver, in contrast, urinary total bile acids output was remarkably up-regulated by OA. Gene expression analysis showed that OA caused significant increased mRNA expression of MRP3 and MRP4 located at hepatic basolateral membrane, and restoration of MRP2 and BSEP located at hepatic cannalicular membrane. Furthermore, significant NRF2 protein accumulation in nucleus was also observed in OA treated mice. In mice primary cultured hepatocytes, the effects of OA on MRP2, MRP3 and MRP4 expression were directly proved to be mediated via NRF2 activation, and BSEP downregulation induced by OA was in part due to FXR antagonism. Luciferase assay performed in Hep G2 cells also illustrated that OA was a partial FXR antagonist. Taken together, we conclude that OA attenuates obstructive cholestasis in BDL mice, possibly via activation of NRF2-MRPs and FXR antagonism. PMID:26297978

  7. Study of a new hepatobiliary radiotracer: sup(99m)Tc diethyl IDA. Its value in the diagnosis of cholestasis

    International Nuclear Information System (INIS)

    This work examines a new means of investigation: Technetium 99 (2,6 diethyl acetanilido) imino-diacetic acid, or HEPATOBIDA, hepatobiliary scintigraphy. A survey of different scintigraphic techniques is necessary. At first the kinetic study of hepatobiliary radiotracers was carried out with multiprobe systems giving quantitative information on the various organs or pools concerned. With the appearance of the scintillation camera it became possible to obtain not only quantitative data but also topographical and morphological information. Since 1976 the derivatives of iminodiacetic acid have been widely adopted, possessing features most closely resembling those of the ideal hepatobiliatropic molecules. Examinations have been performed at the Angers Radioisotopes Service with the diethyl derivative or HEPATOBIDA (Nuclear Solca Lab.) The results recorded in a group of cholestasis patients are studied, with normal data supplied by a set of 8 reference subjects free from hepatobiliary diseases

  8. Dynamic biliary cholecystography with mebrofenin-Tc-99m in a patient with benign recurrent intrahepatic cholestasis

    International Nuclear Information System (INIS)

    A Caucasian boy with a 16-year history of benign recurrent intrahepatic cholestasis (BRIC) presented dissociation between normal hepatic extraction fraction of mebrofenin-Tc-99m (HEF over 90%) and that of intensive delayed liver 'washout' T 1/2 210 m (normal 20-25 m). This is the second case in Macedonia (population 2.3 million) showing the same pattern of bile dynamic with mebrofenin-Tc-99m: normal HEF, prolonged 'washout'. In Rotor's disease and Dubin-Johnson's syndrome HEF is depressed and 'washout' delayed, whereas in Gilbert's syndrome we found both parameters normal. In our patient the episodes of pruritus were intensive and prolonged, hyperbilirubinaemia 50-100 micromol/L. Gallbladder was hypovolemic, ejection fraction reduced (59%, normal with the employed method over 70%). Growth, body weight and bone age were subnormal. Technetium-sulfur-colloid scans showed enlarged liver, splenomegaly and reduced portal contribution to hepatic blood flow (65%, normal over 70%). (Author)

  9. Relapsing features of bile salt export pump deficiency after liver transplantation in two patients with progressive familial intrahepatic cholestasis type 2

    OpenAIRE

    Maggiore, G; E Gonzales; Sciveres, M; Redon, M-J; Grosse, B; Stieger, B; Davit-Spraul, A; Fabre, M.; Jacquemin, E.

    2010-01-01

    BACKGROUND & AIMS: PFIC2 is caused by mutations in ABCB11 encoding BSEP. In most cases affected children need liver transplantation that is thought to be curative. We report on two patients who developed recurrent normal GGT cholestasis mimicking primary BSEP disease, after liver transplantation. METHODS: PFIC2 diagnosis was made in infancy in both patients on absence of canalicular BSEP immunodetection and on ABCB11 mutation identification. Liver transplantation was performed at age 9 (patie...

  10. Oxidative stress markers, secondary bile acids and sulfated bile acids classify the clinical liver injury type: Promising diagnostic biomarkers for cholestasis.

    Science.gov (United States)

    Masubuchi, Noriko; Sugihara, Masahiro; Sugita, Tomonori; Amano, Katsushi; Nakano, Masanori; Matsuura, Tomokazu

    2016-08-01

    Clinicians sometimes encounter difficulty in choosing a therapeutic strategy due to the uncertainty regarding the type of liver injury. In particular, cholestasis is difficult to diagnose by conventional markers at an early stage of disease. The aim of this study was to identify promising biomarkers for distinguishing the symptom-based types of liver injury (e.g. hepatocellular injury, cholestasis), which was derived from a rigorously statistical perspective. The associations between diagnostic biomarkers (e.g. bile acid components, oxidative stress markers and liver fibrosis markers) and the liver injury types were assessed by a multiple logistic regression analysis using 304 blood samples from patients with liver disease. As a result, reductions in the lithocholic acid (LCA) and deoxycholic acid (DCA) levels, and elevation of the serum sulfated bile acid (SSBA), liver fibrosis marker IV collagen (type IV collagen), hyaluronic acid (HA) and reactive oxygen species (ROS) levels were all significantly associated with cholestasis. On the other hand, elevations in the LCA and type IV collagen levels, and a reduction in the ursodeoxy cholic acid (UDCA) level, were significantly associated with hepatocellular injury. The receiver operating characteristic (ROC) analyses showed that the largest area under the ROC curve (AUC) was found for ROS, followed by DCA, HA, LCA, SSBA and type IV collagen in the cholestatic-type cases. These results indicated that ROS, the secondary bile acid levels such as DCA and LCA, and SSBA are promising biomarkers for cholestasis and for classifying the type of liver injuries. This comprehensive approach will allow for an accurate diagnosis, which will facilitate the selection of an appropriate therapy at the onset of disease. PMID:26325587

  11. Cholecysto-appendicostomy as partial internal biliary drainage in Progressive Familial Intrahepatic Cholestasis Type 1: A case report and review of literature

    Directory of Open Access Journals (Sweden)

    Yee Ian Yik

    2016-01-01

    Full Text Available Intractable pruritus secondary to bile salts retention in Progressive Familial Intrahepatic Cholestasis (PFIC can be relieved surgically by diverting bile drainage from ileum to reduce bile salts reabsorption into entero-hepatic circulation. We are reporting on the successful biliary diversion in a child with PFIC, with the use of the appendix as a conduit to drain bile from gallbladder to the colon (cholecysto-appendicostomy.

  12. Bsep蛋白表达及调控与胆汁淤积的关系%Correlation between Bsep Protein Expression and Regulation and Cholestasis

    Institute of Scientific and Technical Information of China (English)

    王火平

    2012-01-01

    Bsep protein, also known bile salt export pump, belongs to superfamily of ATP binding cas-sette( ABC )transporters. The research on hepatocellular minute structure confirmed that it's mainly expressed in hepatocytic canalicular membrane, is an important transporter of the process of bile excretion. At present many studies indicate that there is close association between Bsep protein expression changes and functional deficiency and cholestasis. Studies of Bsep protein and other bile salt transporters comprehensively and deeply is helpful to reveal molecular mechanism of cholestasis,providing theoretical basis and new ideas for the prevention , diagnosis and treatment of cholestasis.%Bsep蛋白即胆盐输出泵,属于ATP结合盒转运体超家族.对肝细胞细微结构的研究证实其主要表达于肝细胞胆管膜侧,为胆汁生成过程中重要的转运载体.目前大量研究表明,其表达量变化及功能缺失与胆汁淤积发生之间存在密切关系.对Bsep蛋白及其他胆酸转运体的研究有助于全面深入地揭示胆汁淤积发生的部分分子机制,为胆汁淤积的预防、诊治提供理论依据和新的思路.

  13. Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice

    International Nuclear Information System (INIS)

    Cholestasis is a pathological common component of numerous liver diseases that results in hepatotoxicity, inflammation, and cirrhosis when untreated. While the predominant hypothesis in cholestatic liver injury remains hepatocyte apoptosis due to direct toxicity of hydrophobic bile acid exposure, recent work suggests that the injury occurs through inflammatory necrosis. In order to resolve this controversy, we used novel plasma biomarkers to assess the mechanisms of cell death during early cholestatic liver injury. C57Bl/6 mice underwent bile duct ligation (BDL) for 6–72 h, or sham operation. Another group of mice were given D-galactosamine and endotoxin as a positive control for apoptosis and inflammatory necrosis. Plasma levels of full length cytokeratin-18 (FL-K18), microRNA-122 (miR-122) and high mobility group box-1 protein (HMGB1) increased progressively after BDL with peak levels observed after 48 h. These results indicate extensive cell necrosis after BDL, which is supported by the time course of plasma alanine aminotransferase activities and histology. In contrast, plasma caspase-3 activity, cleaved caspase-3 protein and caspase-cleaved cytokeratin-18 fragments (cK18) were not elevated at any time during BDL suggesting the absence of apoptosis. In contrast, all plasma biomarkers of necrosis and apoptosis were elevated 6 h after Gal/End treatment. In addition, acetylated HMGB1, a marker for macrophage and monocyte activation, was increased as early as 12 h but mainly at 48–72 h. However, progressive neutrophil accumulation in the area of necrosis started at 6 h after BDL. In conclusion, these data indicate that early cholestatic liver injury in mice is an inflammatory event, and occurs through necrosis with little evidence for apoptosis. - Highlights: • The mechanism of cell death during cholestasis remains a controversial topic. • Plasma biomarkers offer new insight into cell death after bile duct ligation. • Cytokeratin-18, microRNA-122 and HMGB

  14. Neonatal intrahepatic cholestasis caused by citrin deficiency: prevalence and SLC25A13 mutations among thai infants

    Directory of Open Access Journals (Sweden)

    Treepongkaruna Suporn

    2012-10-01

    Full Text Available Abstract Background The most common causes of cholestatic jaundice are biliary atresia and idiopathic neonatal hepatitis (INH. Specific disorders underlying INH, such as various infectious and metabolic causes, including neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD especially, in East Asian populations are increasingly being identified. Since most NICCD infants recovered from liver disease by 1 year of age, they often are misdiagnosed with INH, leading to difficulty in determining the true prevalence of NICCD. Mutation(s of human SLC25A13 gene encoding a mitochondrial aspartate/glutamate carrier isoform 2 (AGC2, can lead to AGC2 deficiency, resulting in NICCD and an adult-onset fatal disease namely citrullinemia type II (CTLN2. To study the prevalence of NICCD and SLC25A13 mutations in Thai infants, and to compare manifestations of NICCD and non-NICCD, infants with idiopathic cholestatic jaundice or INH were enrolled. Clinical and biochemical data were reviewed. Urine organic acid and plasma amino acids profiles were analyzed. PCR-sequencing of all 18 exons of SLC25A13 and gap PCR for the mutations IVS16ins3kb and Ex16+74_IVS17-32del516 were performed. mRNA were analyzed in selected cases with possible splicing error. Results Five out of 39 (12.8% unrelated infants enrolled in the study were found to have NICCD, of which three had homozygous 851del4 (GTATdel and two compound heterozygous 851del4/IVS16ins3kb and 851del4/1638ins23, respectively. Two missense mutations (p.M1? and p.R605Q of unknown functional significance were identified. At the initial presentation, NICCD patients had higher levels of alkaline phosphatase (ALP and alpha-fetoprotein (AFP and lower level of alanine aminotransferase (ALT than those in non-NICCD patients (pp Conclusion NICCD should be considered in infants with idiopathic cholestasis. The preliminary estimated prevalence of NICCD was calculated to be 1/48,228 with carrier rate of 1/110 among

  15. Plasma biomarkers of liver injury and inflammation demonstrate a lack of apoptosis during obstructive cholestasis in mice

    Energy Technology Data Exchange (ETDEWEB)

    Woolbright, Benjamin L. [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Antoine, Daniel J.; Jenkins, Rosalind E. [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Bajt, Mary Lynn [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States); Park, B. Kevin [MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool (United Kingdom); Jaeschke, Hartmut, E-mail: hjaeschke@kumc.edu [Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS (United States)

    2013-12-15

    Cholestasis is a pathological common component of numerous liver diseases that results in hepatotoxicity, inflammation, and cirrhosis when untreated. While the predominant hypothesis in cholestatic liver injury remains hepatocyte apoptosis due to direct toxicity of hydrophobic bile acid exposure, recent work suggests that the injury occurs through inflammatory necrosis. In order to resolve this controversy, we used novel plasma biomarkers to assess the mechanisms of cell death during early cholestatic liver injury. C57Bl/6 mice underwent bile duct ligation (BDL) for 6–72 h, or sham operation. Another group of mice were given D-galactosamine and endotoxin as a positive control for apoptosis and inflammatory necrosis. Plasma levels of full length cytokeratin-18 (FL-K18), microRNA-122 (miR-122) and high mobility group box-1 protein (HMGB1) increased progressively after BDL with peak levels observed after 48 h. These results indicate extensive cell necrosis after BDL, which is supported by the time course of plasma alanine aminotransferase activities and histology. In contrast, plasma caspase-3 activity, cleaved caspase-3 protein and caspase-cleaved cytokeratin-18 fragments (cK18) were not elevated at any time during BDL suggesting the absence of apoptosis. In contrast, all plasma biomarkers of necrosis and apoptosis were elevated 6 h after Gal/End treatment. In addition, acetylated HMGB1, a marker for macrophage and monocyte activation, was increased as early as 12 h but mainly at 48–72 h. However, progressive neutrophil accumulation in the area of necrosis started at 6 h after BDL. In conclusion, these data indicate that early cholestatic liver injury in mice is an inflammatory event, and occurs through necrosis with little evidence for apoptosis. - Highlights: • The mechanism of cell death during cholestasis remains a controversial topic. • Plasma biomarkers offer new insight into cell death after bile duct ligation. • Cytokeratin-18, microRNA-122 and HMGB

  16. Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice

    Directory of Open Access Journals (Sweden)

    Kyung-Hyun Kim

    2015-08-01

    Full Text Available Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy.

  17. Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice.

    Science.gov (United States)

    Kim, Kyung-Hyun; Sung, Hyun-Jung; Lee, Woo-Ram; An, Hyun-Jin; Kim, Jung-Yeon; Pak, Sok Cheon; Han, Sang-Mi; Park, Kwan-Kyu

    2015-09-01

    Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) to mice is a well-established animal model to study cholangitis and biliary fibrosis. To investigate the effects of melittin on cholangiopathy, mice were fed with a 0.1% DDC-containing diet with or without melittin treatment for four weeks. Liver morphology, serum markers of liver injury, cholestasis markers for inflammation of liver, the degree of ductular reaction and the degree of liver fibrosis were compared between with or without melittin treatment DDC-fed mice. DDC feeding led to increased serum markers of hepatic injury, ductular reaction, induction of pro-inflammatory cytokines and biliary fibrosis. Interestingly, melittin treatment attenuated hepatic function markers, ductular reaction, the reactive phenotype of cholangiocytes and cholangitis and biliary fibrosis. Our data suggest that melittin treatment can be protective against chronic cholestatic disease in DDC-fed mice. Further studies on the anti-inflammatory capacity of melittin are warranted for targeted therapy in cholangiopathy. PMID:26308055

  18. Pediatric parenteral nutrition-associated liver disease and cholestasis: Novel advances in pathomechanisms-based prevention and treatment.

    Science.gov (United States)

    Orso, Giuseppe; Mandato, Claudia; Veropalumbo, Claudio; Cecchi, Nicola; Garzi, Alfredo; Vajro, Pietro

    2016-03-01

    Parenteral nutrition constitutes a life-saving therapeutic tool in patients unable to ingest/absorb oral or enteral delivered nutrients. Liver function tests abnormalities are a common therapy-related complication, thus configuring the so-called Parenteral Nutrition Associated Liver Disease (PNALD) or cholestasis (PNAC). Although the damage is frequently mild, and resolves after discontinuation of parenteral nutrition, in some cases it progresses into cirrhotic changes, especially in neonates and infants. We present a literature review focusing on the pathogenetic mechanisms-driven prevention and therapies for the cases where parenteral nutrition cannot be discontinued. Ursodeoxycholic acid has been proposed in patients with cholestatic hepatopathy, but its efficacy needs to be better established. Little evidence is available on efficacy of anti-oxidants, antibiotics, probiotics and anti TNFα. Lipid emulsions based on fish oil with a high content of long-chain polyunsaturated fatty acids ω-3 appear effective both in decreasing intrahepatic inflammation and in improving biliary flow. Most recent promising variations such as soybean/MCT/olive/fish oil emulsion [third generation lipid emulsion (SMOFlipid)] are under investigation. In conclusion, we remark the emergence of a number of novel pathomechanisms underlying the severe liver impairment damage (PNALD and PNAC) in patients treated with parenteral nutrition. Only few traditional and innovative therapeutic strategies have hitherto been shown promising. PMID:26698410

  19. Differential diagnosis of infantile cholestasis%婴儿胆汁淤积症的鉴别诊断思路

    Institute of Scientific and Technical Information of China (English)

    朱启镕; 王建设

    2011-01-01

    胆汁淤积是婴儿肝脏疾病最常见的临床表现.病因在很大程度上决定其预后,有些病因需要医生做出快速的诊断及采取恰当的治疗.胆道闭锁、败血症、尿路感染、甲状腺功能低下、Citrin缺陷病、酪氨酸血症及先天性胆汁酸合成缺陷都要及早诊断,因为对这些疾病及时适当的治疗可显著的改善预后.%Cholestasis is the most common manifestation of liver diseases in infancy. The clinical outcome is mostly dependent on the etiology, some of them require prompt identification and then proper management. Biliary atresia, sepsis, urinary tract infection,hypothyroidism, citrin deficiency, tyrosemia and congenital bile acid synthetic defects need highest priority, because proper management could improve the outcome significantly.

  20. The state of membrane of the hepatocytes and the blood erytrocytes in pations with chronic hepatitis with signs of cholestasis.

    Directory of Open Access Journals (Sweden)

    Zakharash A.D.

    2007-01-01

    Full Text Available The purpose of work was to give morphological and morphometric characteristic of the hepatocytes and the blood erytrocytes against a background to determine the state of lipid peroxidation and antioxidant system of protection in case chronic cryptogenic hepatitis. Morphological and morphometric liver parameters were measured at the icteris in 5 patients (control – 5 patients. It was found that in patients with chronic hepatitis square of hepatocytes, square of their nuclei have been decreased, their relationship change for the better of cytoplasm. The hepatocytes and their nuclei have been deformed. The modifications of morphological and morphometric characteristic of the hepatocytes and the blood erytrocytes have been determined, drastic increase of the level CD95+ lymphocytes is evidence of the system reaction of apoptosis of the cells were studied in case chronic hepatitis with signs of cholestasis. In same patients with chronic hepatitis of non-virus etiology there were determined changes of area, perimeter and deformity of erythrocytes both on the basis of free radical reactions disorder and antioxidate protection system disorders; it induces us to quest their pathogenetically substantiated treatment.

  1. Emergency use of intravenous phytonadione (vitamin K1) for treatment of severe bleeding in a child with chronic cholestasis.

    Science.gov (United States)

    Glatstein, Miguel; Idan-Prusak, Dafna; Yahav, Aiala; Ovental, Amit; Rimon, Ayelet; Scolnik, Dennis

    2013-01-01

    We present a 5-year-old boy with multiple hematomas associated with chronic cholestasis. A week before admission he suffered minor trauma at day care. The next day he complained of trunk and limb pain and orthopedic consultation, including leg x-rays, revealed no abnormalities. Over the next 5 days multiple hematomas developed over his body and increased in size. In the Emergency Department he was in pain and looked sick but alert. He had fever and tachycardia, with normal blood pressure and respiratory status and physical examination showed several hematomas on the legs, which increased in size during observation in the Emergency Department over 2 hours. Blood work revealed multiple coagulation abnormalities, and International Normalized Ratio was 12. Intravenous phytonadione (vitamin K1) was immediately administered with normalization of coagulation abnormalities within 1 hour and the hematomas stopped growing in size. In addition to missing follow-up with the Pediatric Gastroenterology Department, social service agency inquiry found he had not taken his medications for several months. With severe abnormal bleeding and hepatic disease, intravenous vitamin K1 may be lifesaving, even before obtaining confirmatory blood work, fresh-frozen plasma, or blood transfusion. PMID:21642829

  2. Proteomic analysis of polypeptides captured from blood during extracorporeal albumin dialysis in patients with cholestasis and resistant pruritus.

    Directory of Open Access Journals (Sweden)

    Marina Gay

    Full Text Available Albumin dialysis using the molecular adsorbent recirculating system (MARS is a new therapeutic approach for liver diseases. To gain insight into the mechanisms involved in albumin dialysis, we analyzed the peptides and proteins absorbed into the MARS strong anion exchange (SAX cartridges as a result of the treatment of patients with cholestasis and resistant pruritus. Proteins extracted from the SAX MARS cartridges after patient treatment were digested with two enzymes. The resulting peptides were analyzed by multidimensional liquid chromatography coupled to tandem mass spectrometry. We identified over 1,500 peptide sequences corresponding to 144 proteins. In addition to the proteins that are present in control albumin-derived samples, this collection includes 60 proteins that were specific to samples obtained after patient treatment. Five of these proteins (neutrophil defensin 1 [HNP-1], secreted Ly-6/uPAR-related protein 1 [SLURP1], serum amyloid A, fibrinogen alpha chain and pancreatic prohormone were confirmed to be removed by the dialysis procedure using targeted selected-reaction monitoring MS/MS. Furthermore, capture of HNP-1 and SLURP1 was also validated by Western blot. Interestingly, further analyses of SLURP1 in serum indicated that this protein was 3-fold higher in cholestatic patients than in controls. Proteins captured by MARS share certain structural and biological characteristics, and some of them have important biological functions. Therefore, their removal could be related either to therapeutic or possible adverse effects associated with albumin dialysis.

  3. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis.

    Science.gov (United States)

    Meng, Qiang; Chen, Xin-Li; Wang, Chang-Yuan; Liu, Qi; Sun, Hui-Jun; Sun, Peng-Yuan; Huo, Xiao-Kui; Liu, Zhi-Hao; Yao, Ji-Hong; Liu, Ke-Xin

    2015-03-15

    Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes. PMID:25655198

  4. Ca2+-DEPENDENT PROTEIN KINASE C ISOFORMS ARE CRITICAL TO ESTRADIOL 17β-D-GLUCURONIDE-INDUCED CHOLESTASIS IN THE RAT

    OpenAIRE

    Crocenzi, Fernando A.; Enrique J Sánchez Pozzi; Ruiz, María Laura; Zucchetti, Andrés E.; Roma, Marcelo G.; Mottino, Aldo D.; Vore, Mary

    2008-01-01

    The endogenous estradiol metabolite estradiol 17β-D-glucuronide (E217G) induces an acute cholestasis in rat liver coincident with retrieval of the canalicular transporters Bsep (Abcc11) and Mrp2 (Abcc2) and their associated loss of function. We assessed the participation of Ca2+-dependent PKC isoforms (cPKC) in the cholestatic manifestations of E217G in the perfused rat liver (PRL) and in isolated rat hepatocyte couplets (IRHC). In the PRL, E217G (2 μmol/liver; intraportal, single injection) ...

  5. Swertianlarin, an Herbal Agent Derived from Swertia mussotii Franch, Attenuates Liver Injury, Inflammation, and Cholestasis in Common Bile Duct-Ligated Rats

    Directory of Open Access Journals (Sweden)

    Liangjun Zhang

    2015-01-01

    Full Text Available Swertianlarin is an herbal agent abundantly distributed in Swertia mussotii Franch, a Chinese traditional herb used for treatment of jaundice. To study the therapeutic effect of swertianlarin on cholestasis, liver injury, serum proinflammatory cytokines, and bile salt concentrations were measured by comparing rats treated with swertianlarin 100 mg/kg/d or saline for 3, 7, or 14 days after bile duct ligation (BDL. Serum alanine aminotransferase (ATL and aspartate aminotransferase (AST levels were significantly decreased in BDL rats treated with swertianlarin for 14 days (P<0.05. The reduced liver injury in BDL rats by swertianlarin treatment for 14 days was further confirmed by liver histopathology. Levels of serum tumor necrosis factor alpha (TNFα were decreased by swertianlarin in BDL rats for 3 and 7 days (P<0.05. Moreover, reductions in serum interleukins IL-1β and IL-6 levels were also observed in BDL rats treated with swertianlarin (P<0.05. In addition, most of serum toxic bile salt concentrations (e.g., chenodeoxycholic acid (CDCA and deoxycholic acid (DCA in cholestatic rats were decreased by swertianlarin (P<0.05. In conclusion, the data suggest that swertianlarin derived from Swertia mussotii Franch attenuates liver injury, inflammation, and cholestasis in bile duct-ligated rats.

  6. Paeonia lactiflora Pall. protects against ANIT-induced cholestasis by activating Nrf2 via PI3K/Akt signaling pathway

    Directory of Open Access Journals (Sweden)

    Ma X

    2015-09-01

    Full Text Available Xiao Ma,1,2 Yan-ling Zhao,2 Yun Zhu,3 Zhe Chen,1,2 Jia-bo Wang,4 Rui-yu Li,1,4 Chang Chen,1,2 Shi-zhang Wei,1,2 Jian-yu Li,3 Bing Liu,5 Rui-lin Wang,3 Yong-gang Li,3 Li-fu Wang,3 Xiao-he Xiao4 1Pharmacy College, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China; 2Department of Pharmacy, 302 Military Hospital of People’s Liberation Army, Beijing, People’s Republic of China; 3Department of Integrative Medical Center, 302 Military Hospital of People’s Liberation Army, Beijing, People’s Republic of China; 4China Military Institute of Chinese Medicine, 302 Military Hospital of People’s Liberation Army, Beijing, People’s Republic of China; 5School of Chinese Medicine, The University of Hong Kong, Hong Kong Background: Paeonia lactiflora Pall. (PLP, a traditional Chinese herbal medicine, has been used for hepatic disease treatment over thousands of years. In our previous study, PLP was shown to demonstrate therapeutic effect on hepatitis with severe cholestasis. The aim of this study was to evaluate the antioxidative effect of PLP on alpha-naphthylisothiocyanate (ANIT-induced cholestasis by activating NF-E2-related factor 2 (Nrf2 via phosphatidylinositol 3-kinase (PI3K/Akt signaling pathway. Materials and methods: Liquid chromatography-mass spectrometry (LC-MS was performed to identify the main compounds present in PLP. The mechanism of action of PLP and its therapeutic effect on cholestasis, induced by ANIT, were further investigated. Serum indices such as total bilirubin (TBIL, direct bilirubin (DBIL, aspartate aminotransferase (AST, alanine aminotransferase (ALT, alkaline phosphatase (ALP, γ-glutamyl transpeptidase (γ-GT, and total bile acid (TBA were measured, and histopathology of liver was also performed to determine the efficacy of treatment with PLP. Moreover, in order to illustrate the underlying signaling pathway, liver glutathione (GSH content and mRNA or protein levels of glutamate

  7. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

    International Nuclear Information System (INIS)

    Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes. - Highlights: • AB23A has at least three roles in protection against ANIT-induced liver injury. • AB23A decreases Ntcp, and increases Bsep, Mrp2 and Mdr2 expression. • AB23A represses Cyp7a1 and Cyp8b1 through inducing Shp and Fgf15 expression. • AB23A increases bile acid metabolism through inducing Sult2a1 expression. • FXR activation is involved

  8. Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

    Energy Technology Data Exchange (ETDEWEB)

    Meng, Qiang; Chen, Xin-li; Wang, Chang-yuan; Liu, Qi; Sun, Hui-jun; Sun, Peng-yuan; Huo, Xiao-kui; Liu, Zhi-hao; Yao, Ji-hong; Liu, Ke-xin, E-mail: kexinliu@dlmedu.edu.cn

    2015-03-15

    Intrahepatic cholestasis is a clinical syndrome with systemic and intrahepatic accumulation of excessive toxic bile acids that ultimately cause hepatobiliary injury. Appropriate regulation of bile acids in hepatocytes is critically important for protection against liver injury. In the present study, we characterized the protective effect of alisol B 23-acetate (AB23A), a natural triterpenoid, on alpha-naphthylisothiocyanate (ANIT)-induced liver injury and intrahepatic cholestasis in mice and further elucidated the mechanisms in vivo and in vitro. AB23A treatment dose-dependently protected against liver injury induced by ANIT through reducing hepatic uptake and increasing efflux of bile acid via down-regulation of hepatic uptake transporters (Ntcp) and up-regulation of efflux transporter (Bsep, Mrp2 and Mdr2) expression. Furthermore, AB23A reduced bile acid synthesis through repressing Cyp7a1 and Cyp8b1, increased bile acid conjugation through inducing Bal, Baat and bile acid metabolism through an induction in gene expression of Sult2a1. We further demonstrate the involvement of farnesoid X receptor (FXR) in the hepatoprotective effect of AB23A. The changes in transporters and enzymes, as well as ameliorative liver histology in AB23A-treated mice were abrogated by FXR antagonist guggulsterone in vivo. In vitro evidences also directly demonstrated the effect of AB23A on FXR activation in a dose-dependent manner using luciferase reporter assay in HepG2 cells. In conclusion, AB23A produces protective effect against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes. - Highlights: • AB23A has at least three roles in protection against ANIT-induced liver injury. • AB23A decreases Ntcp, and increases Bsep, Mrp2 and Mdr2 expression. • AB23A represses Cyp7a1 and Cyp8b1 through inducing Shp and Fgf15 expression. • AB23A increases bile acid metabolism through inducing Sult2a1 expression. • FXR activation is involved

  9. Diagnóstico diferencial de colestase neonatal: parâmetros clínicos e laboratoriais Differential diagnosis of neonatal cholestasis: clinical and laboratory parameters

    Directory of Open Access Journals (Sweden)

    Maria Angela Bellomo-Brandao

    2010-02-01

    Full Text Available OBJETIVO: Avaliar se os parâmetros clínicos e laboratoriais poderiam auxiliar no diagnóstico diferencial da colestase neonatal (CN intra- e extra-hepática. MÉTODOS: Estudo retrospectivo de pacientes com CN hospitalizados na Clínica de Hepatologia Pediátrica do Hospital de Clínicas da Universidade Estadual de Campinas (UNICAMP, Campinas (SP, entre dezembro de 1980 e março de 2005. A abordagem para o diagnóstico da CN foi padronizada. De acordo com o diagnóstico, os pacientes foram classificados em dois grupos: I (colestase neo natal intra-hepática e II (colestase neonatal extrahepática. Para verificar se havia associação com a variável categórica, os testes de qui-quadrado e Mann-Whitney foram utilizados com correções para idade para a análise de covariância (ANCOVA. A determinação da precisão das variáveis clínicas e laboratoriais para a diferenciação dos grupos foi realizada através da análise da curva ROC. RESULTADOS: Cento e sessenta e oito pacientes foram avaliados (grupo I = 54,8% e grupo II = 45,2%. Nos pacientes com menos de 60 dias de vida, houve predominância de causas intra-hepáticas, enquanto que naqueles com mais de 60 dias, houve predominância de etiologia extrahepática (p OBJECTIVE: To evaluate if clinical and laboratory parameters could assist in the differential diagnosis of intra and extra-hepatic neonatal cholestasis (NC. METHODS: Retrospective study of NC patients admitted at the Pediatric Hepatology Outpatient Clinic of the teaching hospital of Universidade Estadual de Campinas (UNICAMP, Campinas, Brazil, between December 1980 and March 2005. The approach to the diagnosis of NC was standardized. According to diagnosis, patients were classified into two groups: I (intra-hepatic neonatal cholestasis and II (extra-hepatic neonatal cholestasis. In order to verify if there was association with the categorical variable, the chi-square and Mann-Whitney tests were used, with corrections for age for

  10. Ultrasonography of Neonatal Cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Cheon, Jung Eun [Seoul National University Hospital, Seoul (Korea, Republic of)

    2012-06-15

    Ultrasonography (US) is as an important tool for differentiation of obstructive and non-obstructive causes of jaundice in infants and children. Beyond two weeks of age, extrahepatic biliary atresia and neonatal hepatitis are the two most common causes of persistent neonatal jaundice: differentiation of extrahepatic biliary atresia, which requires early surgical intervention, is very important. Meticulous analysis should focus on size and configuration of the gallbladder and anatomical changes of the portahepatis. In order to narrow the differential diagnosis, combined approaches using hepatic scintigraphy, MR cholangiography, and, at times, percutaneous liver biopsy are necessary. US is useful for demonstrating choledochal cyst, bile plug syndrome, and spontaneous perforation of the extrahepatic bile duct

  11. The effect of acetaminophen on the expression of BCRP in trophoblast cells impairs the placental barrier to bile acids during maternal cholestasis

    International Nuclear Information System (INIS)

    Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48 h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis. - Highlights: • Acetaminophen induces changes in placental BCRP expression in vitro. • This drug reduces the ability of placental cells to export BCRP substrates. • Acetaminophen induces changes in Bcrp expression in rat placenta. • Placental barrier to bile acids is impaired in rats treated with this drug

  12. Tumor necrosis factor-α promotes cholestasis-induced liver fibrosis in the mouse through tissue inhibitor of metalloproteinase-1 production in hepatic stellate cells.

    Directory of Open Access Journals (Sweden)

    Yosuke Osawa

    Full Text Available Tumor necrosis factor (TNF-α, which is a mediator of hepatotoxicity, has been implicated in liver fibrosis. However, the roles of TNF-α on hepatic stellate cell (HSC activation and liver fibrosis are complicated and remain controversial. To explore this issue, the role of TNF-α in cholestasis-induced liver fibrosis was examined by comparing between TNF-α(-/- mice and TNF-α(+/+ mice after bile duct ligation (BDL. Serum TNF-α levels in mice were increased by common BDL combined with cystic duct ligation (CBDL+CDL. TNF-α deficiency reduced liver fibrosis without affecting liver injury, inflammatory cell infiltration, and liver regeneration after CBDL+CDL. Increased expression levels of collagen α1(I mRNA, transforming growth factor (TGF-β mRNA, and α-smooth muscle actin (αSMA protein by CBDL+CDL in the livers of TNF-α(-/- mice were comparable to those in TNF-α(+/+ mice. Exogenous administration of TNF-α decreased collagen α1(I mRNA expression in isolated rat HSCs. These results suggest that the reduced fibrosis in TNF-α(-/- mice is regulated in post-transcriptional level. Tissue inhibitor of metalloproteinase (TIMP-1 plays a crucial role in the pathogenesis of liver fibrosis. TIMP-1 expression in HSCs in the liver was increased by CBDL+CDL, and the induction was lower in TNF-α(-/- mice than in TNF-α(+/+ mice. Fibrosis in the lobe of TIMP-1(-/- mice with partial BDL was also reduced. These findings indicate that TNF-α produced by cholestasis can promote liver fibrosis via TIMP-1 production from HSCs. Thus, targeting TNF-α and TIMP-1 may become a new therapeutic strategy for treating liver fibrosis in cholestatic liver injury.

  13. The effect of acetaminophen on the expression of BCRP in trophoblast cells impairs the placental barrier to bile acids during maternal cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Blazquez, Alba G., E-mail: albamgb@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Briz, Oscar, E-mail: obriz@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Gonzalez-Sanchez, Ester, E-mail: u60343@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); Perez, Maria J., E-mail: mjperez@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); University Hospital of Salamanca, IECSCYL-IBSAL, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain); Ghanem, Carolina I., E-mail: cghanem@ffyb.uba.ar [Instituto de Investigaciones Farmacologicas, Facultad de Farmacia y Bioquimica, CONICET, Universidad de Buenos Aires, Buenos Aires (Argentina); Marin, Jose J.G., E-mail: jjgmarin@usal.es [Laboratory of Experimental Hepatology and Drug Targeting (HEVEFARM), IBSAL, University of Salamanca, Salamanca (Spain); CIBERehd, Instituto de Salud Carlos III, Madrid (Spain)

    2014-05-15

    Acetaminophen is used as first-choice drug for pain relief during pregnancy. Here we have investigated the effect of acetaminophen at subtoxic doses on the expression of ABC export pumps in trophoblast cells and its functional repercussion on the placental barrier during maternal cholestasis. The incubation of human choriocarcinoma cells (JAr, JEG-3 and BeWo) with acetaminophen for 48 h resulted in no significant changes in the expression and/or activity of MDR1 and MRPs. In contrast, in JEG-3 cells, BCRP mRNA, protein, and transport activity were reduced. In rat placenta, collected at term, acetaminophen administration for the last three days of pregnancy resulted in enhanced mRNA, but not protein, levels of Mrp1 and Bcrp. In fact, a decrease in Bcrp protein was found. Using in situ perfused rat placenta, a reduction in the Bcrp-dependent fetal-to-maternal bile acid transport after treating the dams with acetaminophen was found. Complete biliary obstruction in pregnant rats induced a significant bile acid accumulation in fetal serum and tissues, which was further enhanced when the mothers were treated with acetaminophen. This drug induced increased ROS production in JEG-3 cells and decreased the total glutathione content in rat placenta. Moreover, the NRF2 pathway was activated in JEG-3 cells as shown by an increase in nuclear NRF2 levels and an up-regulation of NRF2 target genes, NQO1 and HMOX-1, which was not observed in rat placenta. In conclusion, acetaminophen induces in placenta oxidative stress and a down-regulation of BCRP/Bcrp, which may impair the placental barrier to bile acids during maternal cholestasis. - Highlights: • Acetaminophen induces changes in placental BCRP expression in vitro. • This drug reduces the ability of placental cells to export BCRP substrates. • Acetaminophen induces changes in Bcrp expression in rat placenta. • Placental barrier to bile acids is impaired in rats treated with this drug.

  14. Histone H3K4 trimethylation by MLL3 as part of ASCOM complex is critical for NR activation of bile acid transporter genes and is downregulated in cholestasis

    OpenAIRE

    Ananthanarayanan, M.; Li, Yanfeng; Surapureddi, S.; Balasubramaniyan, N; Ahn, Jaeyong; Goldstein, J. A.; Suchy, Frederick J.

    2010-01-01

    The nuclear receptor Farnesoid x receptor (FXR) is a critical regulator of multiple genes involved in bile acid homeostasis. The coactivators attracted to promoters of FXR target genes and epigenetic modifications that occur after ligand binding to FXR have not been completely defined, and it is unknown whether these processes are disrupted during cholestasis. Using a microarray, we identified decreased expression of mixed lineage leukemia 3 (MLL3), a histone H3 lysine 4 (H3K4) lysine methyl ...

  15. Feasibility of urinary microRNA profiling detection in intrahepatic cholestasis of pregnancy and its potential as a non-invasive biomarker

    Science.gov (United States)

    Ma, Li; Zhang, Xiao-Qing; Zhou, Da-Xue; Cui, Yue; Deng, Lin-Lin; Yang, Ting; Shao, Yong; Ding, Min

    2016-01-01

    Intrahepatic cholestasis of pregnancy (ICP), a pregnancy-related liver disease, leads to complications for both mother and fetus. Circulating microRNAs (miRNAs) have emerged as candidate biomarkers for many diseases. So far, the circulating miRNAs profiling of ICP has not been investigated. To assess the urinary miRNAs as non-invasive biomarkers for ICP, a differential miRNA profiling was initially analyzed by individual quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) assay in urinary samples from a screening set including 10 ICP and 10 healthy pregnancies. The selected candidate miRNAs were then validated by a validation set with 40 ICP and 50 healthy pregnancies using individual qRT-PCR assay. Compared with the expression in urine of healthy pregnant women, the expression levels of hsa-miR-151-3p and hsa-miR-300 were significantly down-regulated, whereas hsa-miR-671-3p and hsa-miR-369-5p were significantly up-regulated in urine from ICP patients (p microRNA profiling detection in ICP is feasible and maternal urinary miRNAs have the potential to be non-invasive biomarkers for the diagnosis of ICP. PMID:27534581

  16. Low dose of oleanolic acid protects against lithocholic acid-induced cholestasis in mice: potential involvement of nuclear factor-E2-related factor 2-mediated upregulation of multidrug resistance-associated proteins.

    Science.gov (United States)

    Chen, Pan; Zeng, Hang; Wang, Yongtao; Fan, Xiaomei; Xu, Chenshu; Deng, Rongrong; Zhou, Xunian; Bi, Huichang; Huang, Min

    2014-05-01

    Oleanolic acid (OA) is a natural triterpenoid and has been demonstrated to protect against varieties of hepatotoxicants. Recently, however, OA at high doses was reported to produce apparent cholestasis in mice. In this study, we characterized the protective effect of OA at low doses against lithocholic acid (LCA)-induced cholestasis in mice and explored further mechanisms. OA cotreatment (5, 10, and 20 mg/kg, i.p.) significantly improved mouse survival rate, attenuated liver necrosis, and decreased serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase; more importantly, serum total bile acids and bilirubin, as well as hepatic total bile acids were also remarkably reduced. Gene and protein expression analysis showed that hepatic expression of multidrug resistance-associated protein 2 (Mrp2), Mrp3, and Mrp4 was significantly increased by OA cotreatment, whereas other bile acid metabolism- and transport-related genes, including Na+/taurocholate cotransporter, organic anion transporter 1b2, bile salt export pump, multidrug resistance protein 3, Cyp3a11, Cyp2b10, Sulfotransferase 2a1 (Sult2a1), and UDP-glucuronosyltransferase 1a1 (Ugt1a1), were only slightly changed. OA also caused increased nuclear factor-E2-related factor (Nrf2) mRNA expression and nuclear protein accumulation, whereas nuclear receptors farnesoid X receptor (FXR), pregnane X receptor (PXR), and constitutive androstane receptor were not significantly influenced by OA. Luciferase (Luc) assays performed in HepG2 cells illustrated that OA was a strong Nrf2 agonist with moderate PXR and weak FXR agonism. Finally, in mouse primary cultured hepatocytes, OA dose- and time-dependently induced expression of Mrp2, Mrp3, and Mrp4; however, this upregulation was abrogated when Nrf2 was silenced. In conclusion, OA produces a protective effect against LCA-induced hepatotoxicity and cholestasis, possibly due to Nrf2-mediated upregulation of Mrp2, Mrp3, and Mrp4. PMID:24510383

  17. 3α-6α-Dihydroxy-7α-fluoro-5β-cholanoate (UPF-680), physicochemical and physiological properties of a new fluorinated bile acid that prevents 17α-ethynyl-estradiol-induced cholestasis in rats

    International Nuclear Information System (INIS)

    3α-6α-Dihydroxy-7α-fluoro-5β-cholanoate (UPF-680), the 7α-fluorine analog of hyodeoxycholic acid (HDCA), was synthesized to improve bioavailability and stability of ursodeoxycholic acid (UDCA). Acute rat biliary fistula and chronic cholestasis induced by 17α-ethynyl-estradiol (17EE) models were used to study and compare the effects of UPF-680 (dose range 0.6-6.0 μmol/kg min) with UDCA on bile flow, biliary bicarbonate (HCO3-), lipid output, biliary bile acid composition, hepatic enzymes and organic anion pumps. In acute infusion, UPF-680 increased bile flow in a dose-related manner, by up to 40.9%. Biliary HCO3- output was similarly increased. Changes were observed in phospholipid secretion only at the highest doses. Treatment with UDCA and UPF-680 reversed chronic cholestasis induced by 17EE; in this model, UDCA had no effect on bile flow in contrast to UPF-680, which significantly increased bile flow. With acute administration of UPF-680, the biliary bile acid pool became enriched with unconjugated and conjugated UPF-680 (71.7%) at the expense of endogenous cholic acid and muricholic isomers. With chronic administration of UPF-680 or UDCA, the main biliary bile acids were tauro conjugates, but modification of biliary bile acid pool was greater with UPF-680. UPF-680 increased the mRNA for cytochrome P450 7A1 (CYP7A1) and cytochrome P450 8B (CYP8B). Both UDCA and UPF-680 increased the mRNA for Na+ taurocholate co-transporting polypeptide (NCTP). In conclusion, UPF-680 prevented 17EE-induced cholestasis and enriched the biliary bile acid pool with less detergent and cytotoxic bile acids. This novel fluorinated bile acid may have potential in the treatment of cholestatic liver disease

  18. Screening for the inherited metabolic diseases in infants with cholestasis and changing pattern of diagnosis%遗传代谢病的筛查与婴儿胆汁淤积病因诊断的变化

    Institute of Scientific and Technical Information of China (English)

    李晓瑜; 马华梅; 陈红珊; 李燕虹; 沈振宇; 杜敏联

    2010-01-01

    Objective To investigate the changing pattern of diagnosis of infantile cholestasis after screening the inherited metabolic diseases in infants with cholestasis. Methods Infants under 12 months with cholestasis were identified retrospectively from hospital records from Jan. 1996 to Dec. 2007. The data were retrieved from the medical records and analyzed by focusing particularly on the changing etiology of cholestasis and inherited metabolic diseases in these infants after performing routine screening and diagnostic procedures. Results Among 421 infants identified as having cholestasis during 12-years study period, the common causes of infantile cholestasis were cytomegalovirus (CMV) infection (36. 11% ), bile duct hypoplasia or congenital biliary atresia (31.59%), metabolic disease (8.08%), miscellaneous (10.69%), and unknown ( 13.54% ). The proportion of infants with metabolic diseases after screening increased 16 folds compared with before screening( 15.76% vs 0. 92% ,P<0. 01 ), whereas the proportion of infants with unknown cause decreased from 17.43% to 9.36% (P<0.05). There was no significant change in the proportions of CMV infection, congenital biliary atresia, and miscellaneous causes. The major metabolic diseases of 34 infants included citrin deficiency (41. 18% ) and tyrosinemia (23.53%), followed by galactosemia and progressive familial intrahepatic cholestasis (8. 82% )etc. Conclusions Inherited metabolic disease has become an important cause of infantile cholestasis, which is mainly due to citrin deficiency. Therefore, it is necessary to set a routing screening of citrin deficiency in infants with cholestasis.%目的 了解开展遗传代谢病筛查后婴儿胆汁淤积的病因谱变化及与之相关的遗传代谢病种类.方法 回顾性总结1996年1月至2007年12月本院收治的婴儿胆汁淤积病例的临床资料,分析进行遗传代谢病筛查前后婴儿胆汁淤积病因的年代变迁及与胆汁淤积相关的遗

  19. Therapeutic effects of antigen affinity-purified polyclonal anti-receptor of advanced glycation end-product (RAGE) antibodies on cholestasis-induced liver injury in rats.

    Science.gov (United States)

    Xia, Peng; Deng, Qing; Gao, Jin; Yu, Xiaolan; Zhang, Yang; Li, Jingjing; Guan, Wen; Hu, Jianjun; Tan, Quanhui; Zhou, Liang; Han, Wei; Yuan, Yunsheng; Yu, Yan

    2016-05-15

    Cholestasis leads to acute hepatic injury, fibrosis/cirrhosis, inflammation, and duct proliferation. We investigated whether blocking receptor of advanced glycation end-products (RAGE) with polyclonal anti-RAGE antibodies (anti-RAGE) could regulate acute liver injury and fibrosis in a rat bile duct ligation (BDL) model. Male Wister rats received 0.5mg/kg rabbit anti-RAGE or an equal amount of rabbit IgG by subcutaneous injection twice a week after BDL. Samples of liver tissue and peripheral blood were collected at 14 days after BDL. Serum biochemistry and histology were used to analyze the degree of liver injury. Quantitative real-time PCR (qPCR) and immunohistochemical staining were used to further analyze liver injury. Anti-RAGE improved the gross appearance of the liver and the rat survival rate. Liver tissue histology and relevant serum biochemistry indicated that anti-RAGE attenuated liver necrosis, inflammation, liver fibrosis, and duct proliferation in the BDL model. qPCR and western blotting showed significant reductions in interleukin-1β expression levels in the liver by treatment with anti-RAGE. Anti-RAGE also significantly reduced the mRNA levels of α1(1) collagen (Col1α1) and cholesterol 7α-hydroxylase, and the ratio of tissue inhibitor of matrix metalloproteinase-1 to matrix metalloproteinases (MMPs) in the liver. In addition, anti-RAGE regulated the transcriptional level of Col1α1 and MMP-9 in transforming growth factor-β-induced activated LX-2 cells in vitro. Anti-RAGE was found to inhibit hepatic stellate cell proliferation in vivo and in vitro. Therefore, anti-RAGE can protect the liver from injury induced by BDL in rats. PMID:26970185

  20. INSULIN-LIKE GROWTH FACTOR-1, CYTOLYSIS AND CHOLESTASIS IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE AND ITS COMBINATION WITH TYPE 2 DIABETES MELLITUS

    Directory of Open Access Journals (Sweden)

    L. V. Zhuravlyova

    2014-07-01

    Full Text Available Purpose. The study was designed to assess the relationship between the level of plasma concentration of insulin-like growth factor-1 (IGF-1 and indices of the functional state of the liver in patients with non-alcoholic fatty liver disease (NAFLD and its combination with diabetes mellitus (DM 2 types depending on the trophological status.Materials and methods. It were examined 90 patients with non-alcoholic fatty liver disease and its combination with type 2 diabetes mellitus –with normal body weight and obesity, as well as 20 healthy individuals. The study was carried out using the following methods: clinical, laboratory and instrumental (including liver biopsy.Results. It was inverse the relationship between the level of IGF-1, and the level of AST, ALT, AST/ALT, total and conjugated bilirubin, alkaline phosphatase in groups of patients with comorbid disorder. There was established the significant decrease of plasma level of IGF-1, and also impairment of liver function indices in all groups in comparison with the controls, and most pronounced changes in patients with comorbid disorders and obesity.Conclusion. The established relationships suggests that the decrease of IGF-1 may represent the presence of syndromes of cytolysis and cholestasis in patients with NAFLD, type 2 DM and obesity. In order to determination the disorder of the reparative function of the liver isrecommended to determine the level of IGF-1 in patients with combination of NAFLD and type 2 DM. Patients with the level of IGF-1 < 143,9 ± 4,92 ng/ml should refer to the risk of progression of liver function disorders.

  1. Clinical study on 67 cases of intrahepatic cholestasis during pregnancy%妊娠期肝内胆汁淤积症67例临床分析

    Institute of Scientific and Technical Information of China (English)

    赵菁; 陈瑶

    2012-01-01

    目的 探讨妊娠期肝内胆汁淤积症(ICP)的危害、监护与诊治方法.方法 以67例ICP患者为研究对象,并选择同期分娩的70例非ICP患者作为对照组,进行回顾性分析.结果 研究组胎儿窘迫率、羊水污染率、早产率、剖宫产率及产后出血率均显著高于对照组,差异有显著性(P<0.05).结论 ICP对胎儿危害严重,及时诊断、积极治疗、密切胎儿监护并适时终止妊娠能有效改善妊娠结局.%Objective To explore the hazard of intrahepatic cholestasis during pregnancy ( ICP ) and the method for its monitoring, diagnosis and treatment. Methods The clinical data of 67 cases of ICP were retrospectively analyzed, and 70 normal pregnant women were selected as control group. Results In comparison with control group, there were significant differences in rates of contaminated amniotic fluid, fetal distress, preterm labor, cesarean section and postpartum hemorrhage( P <0.05 ). Conclusion ICP will cause serious hazard to embryo, hence prompt diagnosis , proper treatment, carefully monitoring and timely termination of pregnancy are effective ways to improve the outcome of pregnancy.

  2. SLC25A13 gene mutation screening in infants with intrahepatic cholestasis%特发性婴儿肝内胆汁淤积症患儿 SLC25 A13基因突变分析

    Institute of Scientific and Technical Information of China (English)

    陈允; 伍秋频; 王琳琳; 陈秀奇; 唐清; 单庆文; 黄丽; 连淑君; 云翔; 高国鹏

    2014-01-01

    Objective To evaluate the SLC25A13 gene mutation in the pathogenesis of infants with intrahepatic cholestasis.Methods The genomic DNA was obtained from peripheral blood of 95 infants with intrahepatic cholestasis , who hospitalized in the department of pediatrics of the first affiliated hospital of Guangxi medical university from Oct .2011 to Mar.2012, as case group.Case group diagnosis was proven by blood amino acid mass chromatography analysis , and suspected citrin deficiency children were further proved with direct gene sequencing analysis .Fifty normal liver function infants without intrahepatic cholestasis were selected as control group .All exons of SLC25A13 gene were genotyped by pol-ymerase chain reaction single strand conformation polymorphism (PCR-SSCP) and DNA sequenced.The correlation be-tween the SLC25A13 gene and intrahepatic cholestasis in infants was analyzed .Results SLC25A13 gene mutation was found 4 patients;among whom 3 patients were found with abnormal blood amino acid mass chromatography , including 2 patients with homozygous mutation 851del4/851del4 and 1 patient with heterozygous mutation 851del4.Conclusion Ho-mozygous mutation 851del4/851del4 and heterozygous mutation 851del4 in SLC25A13 gene are revealed in infants with in-trahepatic cholestasis from Guangxi .A new mutation type P502L in patients without abnormal blood amino acid mass chro-matography analysis was reported .%目的:探讨特发性婴儿肝内胆汁淤积症患儿SLC25A13基因的突变情况。方法收集特发性婴儿肝内胆汁淤积症患儿95例作为病例组,另取50例无肝内胆汁淤积、肝功能正常的婴儿作为对照组。所有研究对象全为广西籍。病例组患儿送检血氨基酸质谱分析筛查,对筛查怀疑为Citrin缺乏症的7例全部行DNA测序分析。同时提取病例组其他患儿和对照组婴儿外周血DNA,采用聚合酶链反应-单链构象多态性和DNA测序技术检测SLC25A13基因上18

  3. Níveis plasmáticos de vitamina D em crianças e adolescentes com colestase Blood levels of vitamin D in children and adolescents with chronic cholestasis

    Directory of Open Access Journals (Sweden)

    Marília D. Bastos

    2003-06-01

    Full Text Available OBJETIVO: verificar os níveis plasmáticos de vitamina D de pacientes colestáticos crônicos e relacionar com estado nutricional, tempo de colestase e uso de suplemento vitamínico. MÉTODOS: estudo transversal controlado, cujo fator em estudo é colestase crônica e o desfecho, o nível plasmático de vitamina D. Pacientes entre quatro meses a 18 anos, atendidos na unidade de gastroenterologia pediátrica do HCPA; como controles, crianças eutróficas da mesma faixa etária. Foi coletado sangue para as dosagens por radioimunoensaio, e realizadas avaliação antropométrica, pesquisa de tempo de colestase e uso de suplemento vitamínico. RESULTADOS: foram avaliadas 22 crianças e adolescentes com colestase crônica e 17 controles. O valor médio de vitamina D entre os pacientes foi de 13,7 ± 8,39 ng/ml, enquanto que nos controles foi de 25,58 ± 16,73 ng/ml (p = 0,007. A prevalência de hipovitaminose D, entre os pacientes, foi de 36%. A mediana do tempo de colestase foi de um ano. A avaliação antropométrica (NCHS demonstrou 36% de desnutrição pelo peso, e 41% para estatura. Na avaliação antropométrica pelo escore z, obtivemos prevalência de desnutrição para os critérios altura/idade e peso/idade de 33,3% e 23,8%, respectivamente. Avaliado peso em relação altura, não observamos valores abaixo de dois desvios padrão. Não foi observada relação entre o estado nutricional, o uso de suplemento oral e os níveis plasmáticos de vitamina D CONCLUSÕES: os níveis plasmáticos de vitamina D em colestáticos foram menores do que os dos controles, sem relação com estado nutricional, tempo de colestase e/ou uso suplementação vitamínica.OBJECTIVE: to verify blood levels of vitamin D in patients with chronic cholestasis, and relate them to nutritional status, length of time since the onset of cholestasis and use of vitamin supplement. METHODS: controlled cross-sectional study with chronic cholestasis as study factor and blood

  4. 皮肤瘙痒对ICP围产儿结局的影响%Influence of skin pruritus on perinatal outcomes of intrahepatic cholestasis of pregnancy

    Institute of Scientific and Technical Information of China (English)

    刘翠; 王勇; 楼方

    2013-01-01

    Objective To study the influence of skin pruritus on the perinatal outcomes of intrahepatic cholestasis of pregnancy ( ICP ). Methods A retrospective analysis was conducted on 455 cases of ICP, who were divided into group with skin pruritus and group without skin pruritus. The group with skin pruritus was further divided into group with long-term pruritus and group with short-term pruritus. The incidence of adverse perinatal outcomes was compared among different groups. Results The differences between group with skin pruritus and group without skin pruritus were not statistically significant in the incidence of fetus distress, birth asphyxia, premature rupture of membranes, pollution of amniotic fluid, premature, small for gestational age and respiratory system disease (χ2 value was 2.010, 0.791, 2.687, 2.004, 0.770, 1.082 and 0.705, respectively, all P >0.05 ). The differences in incidence of adverse perinatal outcomes were not significantly between group with long-term pruritus and group with short-term pruritus (χ2 value was 0. 651, 2. 622, 1. 518, 0. 218, 0.034, 1. 353 and 1. 105, respectively, all P > 0.05 ). Conclusion The perinatal outcomes of ICP are not impacted by skin pruritus or the duration of pruritus. Skin pruritus neither can be used as the index to determine the severity of ICP, nor can it be used to predict perinatal outcomes.%目的 探讨皮肤瘙痒对妊娠期肝内胆汁淤积症(ICP)围产儿结局的影响.方法 采用回顾性分析的方法,将455例ICP患者分为皮肤瘙痒组、无皮肤瘙痒组,再将皮肤瘙痒组分为长时间瘙痒组、短时间瘙痒组,比较各组围产儿不良结局发生率的差异.结果 皮肤瘙痒组与无皮肤瘙痒组在胎儿窘迫、出生窒息、胎膜早破、羊水污染、早产儿、小于胎龄儿、呼吸系统疾病发生率的差异均无统计学意义(χ2值分别为2.010、0.791、2.687、2.004、0.770、1.082、0.705,均P>0.05);长时间瘙痒组与短时间瘙痒组围产儿

  5. Acute cholestasis related to desloratidine

    Institute of Scientific and Technical Information of China (English)

    Ramón Pérez; Luis Rodrigo; Rosa Pérez; Ruth de Francisco

    2005-01-01

    @@ TO THE EDITOR Desloratidine (Clarinex, Neoclarytin, Aerius, Azomyr, Opulis,Allex), the principal active metabolite of loratadine is itself a new oral antihistamine drug Its main indications are for the treatment of seasonal allergic rhinitis (SAR) and chronic idiopathic urticaria (CIU). The pharmacologic profile of desloratidine offers particular benefits, in terms of histamine H1-receptor binding potency and H1 selectivity. It has a half-life of 21-27 h, permitting a once-daily dose. No specific precautions are required with respect to its administration in renal or hepatic failure. No clinically relevant racial or gender variations in the disposition of desloratidine have been noted. We present here a clinical case of acute reversible idiosyncratic liver toxicity, related to its administration.

  6. Cholestasis induced by total parenteral nutrition: effects of the addition of Taurine (Tauramin®) on hepatic function parameters; possible synergistic action of structured lipids (SMOFlipid®) Colestasis inducida por nutrición parenteral total: efecto de la adición de Taurina (Tauramin®) sobre los parámetros de función hepática; posible acción sinérgica de lípidos estructurados (SMOFlipid®)

    OpenAIRE

    J. González-Contreras; J. L. Villalobos Gámez; A. I. Gómez-Sánchez; J. M. García-Almeida; A. Enguix Armanda; F. Rius Díaz; M. I. Lucena González

    2012-01-01

    Objective: Assess the hepatoprotective effect of Taurine (Tau) in cases of hepatic cholestasis induced by Total Parenteral Nutrition (TPN). Methods: We describe a retrospective series of 54 patients who received TPN, in which cholestasis was detected at an (Intermediate) point that separates the duration of TPN into 2 Phases. From this moment -Phase 2- on, and according to clinical criteria, some patients (Group A, n = 27) received amino acids with Tau (22.41 ± 3.57 mg/kg/day)(Tauramin®), whi...

  7. Hepatoprotective effect of water soluble extract of Coleus barbatus on cholestasis on young rats Efeito hepatoprotetor do extrato aquoso de Coleus barbatus na colestase em ratos jovens

    Directory of Open Access Journals (Sweden)

    Ana Paula Ronquesel Battochio

    2008-06-01

    Full Text Available PURPOSE: To test the effects of water extract of Coleus barbatus (WEB on liver damage in biliary obstruction in young rats. METHODS: Forty 21 day-old male Wistar rats were divided into four groups of ten 21 day old (P21 submitted to sham or actual operation (S or L combined with WEB or Water (B or A. At P48 pentobarbital sleeping time (ST was measured. At P49 they were submitted to euthanasia to determine of serum activities of aspartate aminotransferase (AST and alanine aminotransferase (ALT, liver wet weight (PFF and, on hepatic histological slides, the frequency of mitoses (FM, the number of necrotic areas (NN, intensity of fibrosis (IF and intensity of ductal proliferation (IPD. Two Way ANOVA, the S.N.K. test and the Wilcoxon test for paired multiple comparisons were employed to study the effects of cholestasis and those of EAB and their interactions. The Pearson's coefficient of linear correlation of between paired histological variables separately for the groups LA and LD was determined. The test results were considered statistically significant when the p of alpha error OBJETIVO: Testar os efeitos do extrato aquoso de Coleus barbatus (EAB na cirrose biliar secundária por obstrução das vias biliares extra-hepáticas em ratos jovens. MÉTODOS: Quarenta ratos Wistar machos com 21 dias de vida (P21, foram distribuídos em quatro grupos de 10 animais, submetidos a operação simulada ou dupla ligadura e ressecção do ducto biliar (S ou L combinados EAB e a Água (B ou A. No P48, foi medido o tempo de sono com o pentobarbital (TS. No P49, foram submetidos a eutanásia para a determinação das atividades séricas do aspartato aminotransferase (AST e da alanina aminotransferases (ALT; após a eutanásia foram avaliados o peso fresco do fígado (PFF e, em cortes histológicos do fígado, a freqüência de mitoses (FM, o número de áreas de necrose (NN, a intensidade da fibrose (IF e da proliferação ductal (IPD. Os efeitos da colestase, os

  8. 胆盐输出泵基因V444A与特发性婴儿肝炎肝内胆汁淤积的关系%Association between BSEP V444A polymorphism and risk of idiopathic neonatal hepatitis/cholestasis

    Institute of Scientific and Technical Information of China (English)

    邓亚楠; 王琳琳; 唐清; 陈秀奇; 陈萍; 单庆文; 连淑君; 云翔

    2011-01-01

    目的:探讨胆盐输出泵BSEP基因V444A(BSEP V444A)与特发性婴儿肝炎肝内胆汁淤积的相关性.方法:以81例特发性婴儿肝炎肝内胆汁淤积患儿(病例组)和48例无肝内胆汁淤积婴儿(对照组)为研究对象,应用聚合酶链-限制性片段长度多态性(PCR-RFLP)技术对V444A片段行扩增及酶切分析.结果:BSEPV444A有3种基因型:AA纯合子、GA杂合子、GG纯合子,AA,AG和GG 3种基因型在病例组和对照组频率分别为4.9%,50.6%,44.40%和14.6%,62.5%,22.9%,两组差异显著(P=0.019).等位基因频率的相时风险分析发现,其中GG基因型在两组人群中的分布差异有显著性(P<0.05,OR=2.691,95%CI:1.205-6.008);G等位基因携带者患特发性婴儿肝炎肝内胆汁淤积的风险是A等位基因的1.951倍(OR=1.951,95%CI:1.56-3.291).结论:在广西地区小儿当中发现BSEP V444A单链核苷酸的多态性位点,BSEP V444A G等位基因可能是特发性婴儿肝炎肝内胆汁淤积的一个危险因素,G等位基因携带者可能增加特发性婴儿肝炎肝内胆汁淤积的相对危险度.%AIM: To explore the association between the V444A polymorphism in the bile salt export pump (BSEP) gene and the risk of idiopathic neonatal hepatitis/cholestasis.METHODS: Eighty-one infants with idiopathic hepatitis/cholestasis (case group) and 48 healthy infants without intrahepatic cholestasis (control group) were included in this study.The V444A polymorphism was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).RESULTS: There are three V444A genotypes:AA homozygote, GA heterozygote, and GG homozygote.The frequencies of AA and AG and GG genotypes were 0.6%, 4.9% and 44.4% in the case group and 14.6%, 62.5% and 22.9% in the control group, respectively, with a significant difference between the two groups (P = 0.019).The distribution of GG genotype was significantly different between the two groups (P <0.05, OR = 2.691, 95%CI: 1

  9. Colestasis postinfección por virus de Epstein-Barr sin elevación de gamma glutamil transpeptidasa Post-infection cholestasis due to Epstein-Barr virus infection without elevation of gamma glutamyl transpeptidase

    Directory of Open Access Journals (Sweden)

    E. González Salas

    2010-01-01

    Full Text Available El virus de Epstein-Barr es el agente responsable de la mayoría de los casos de mononucleosis infecciosa, síndrome linfoproliferativo que suele ser benigno y autolimitado, aunque puede acompañarse en ocasiones de complicaciones neurológicas, respiratorias o hematológicas. A la sintomatología clínica habitual, caracterizada por fiebre, malestar general, odinofagia y adenopatías generalizadas, es frecuente que se asocie una hepatopatía subclínica, caracterizada en el niño por un leve y transitorio aumento de las transaminasas. A diferencia del adulto, en el niño, la existencia de un síndrome colestásico es excepcional.
    Presentamos el caso clínico de una niña de 6 años que presenta una colestasis clínico-bioquímica en el curso de una infección aguda por el virus de Epstein-Barr, en la que destaca la normalidad de las cifras de gamma glutamil transpeptidasa durante toda la evolución de su proceso. The Epstein-Barr virus is the responsible agent for most of the cases of infectious mononucleosis, a lymphoproliferative syndrome that is generally benign and self-limited, although it may sometimes be accompanied by neurological, respiratory or hematological complications. Frequently, it is frequent to find that subclinical liver disease, characterized in the child by mild and transitory increase of transaminases is associated to the usual clinical symptoms, characterized by fever, general malaise, odinophagia and generalized abnormal lymph nodes. On the contrary to the adult, the existence of a cholestatic syndrome in the child is rare.
    We present the case of a 6-year old girl who presented a clinical-biochemical cholestasis during an acute infection due to Epstein-Barr virus in which the normality of the gamma glutamyl transpeptidase values during the entire course stands outs.

  10. ERK1/2 and p38 MAPKs are complementarily involved in estradiol 17ß-D-glucuronide-induced cholestasis: crosstalk with cPKC and PI3K.

    Directory of Open Access Journals (Sweden)

    Andrea C Boaglio

    Full Text Available OBJECTIVE: The endogenous, cholestatic metabolite estradiol 17ß-D-glucuronide (E(217G induces endocytic internalization of the canalicular transporters relevant to bile formation, Bsep and Mrp2. We evaluated here whether MAPKs are involved in this effect. DESIGN: ERK1/2, JNK1/2, and p38 MAPK activation was assessed by the increase in their phosphorylation status. Hepatocanalicular function was evaluated in isolated rat hepatocyte couplets (IRHCs by quantifying the apical secretion of fluorescent Bsep and Mrp2 substrates, and in isolated, perfused rat livers (IPRLs, using taurocholate and 2,4-dinitrophenyl-S-glutathione, respectively. Protein kinase participation in E(217G-induced secretory failure was assessed by co-administering selective inhibitors. Internalization of Bsep/Mrp2 was assessed by confocal microscopy and image analysis. RESULTS: E(217G activated all kinds of MAPKs. The PI3K inhibitor wortmannin prevented ERK1/2 activation, whereas the cPKC inhibitor Gö6976 prevented p38 activation, suggesting that ERK1/2 and p38 are downstream of PI3K and cPKC, respectively. The p38 inhibitor SB203580 and the ERK1/2 inhibitor PD98059, but not the JNK1/2 inhibitor SP600125, partially prevented E(217G-induced changes in transporter activity and localization in IRHCs. p38 and ERK1/2 co-inhibition resulted in additive protection, suggesting complementary involvement of these MAPKs. In IPRLs, E(217G induced endocytosis of canalicular transporters and a rapid and sustained decrease in bile flow and biliary excretion of Bsep/Mrp2 substrates. p38 inhibition prevented this initial decay, and the internalization of Bsep/Mrp2. Contrarily, ERK1/2 inhibition accelerated the recovery of biliary secretion and the canalicular reinsertion of Bsep/Mrp2. CONCLUSIONS: cPKC/p38 MAPK and PI3K/ERK1/2 signalling pathways participate complementarily in E(217G-induced cholestasis, through internalization and sustained intracellular retention of canalicular transporters

  11. 妊娠期肝内胆汁淤积症的临床特点和发病危险因素分析%The risk factors analysis and control for intrahepatic cholestasis of pregnancy

    Institute of Scientific and Technical Information of China (English)

    兰易; 黄健容

    2014-01-01

    Objective To investigate the clinical characteristics and risk factors for intrahepatic cholestasis of pregnancy(ICP), and put forward relevant control measures.Methods May 2009 to February 2013 in our hospital maternity clinic built card ICP 60 cases of pregnant women as the observation group,choosed the same period in our hospital 60 cases of childbirth without ICP as the control group,two groups have carried out surveys of maternal and neonatal outcomes,and laboratory tests.While observing the pa-tients were given drug therapy.Results All mothers were smooth delivery of the newborn,no maternal and neonatal mortality.Pro-duction of the observation group was significantly shorter than the control group gestational age,neonatal apgar 1 minute(s)and birth weight was significantly lower,cesarean section rate was significantly higher(P 0.05).Observation group BUN,LDH,PT,APTT,FIB levels higher,the differ-ence was statistically significant(P 0.05).blood pressure control and kidney damage and prenatal affecting intrahepatic cholestasis of pregnancy independent risk factor for the inci-dence(P<0.05).After treatment,the observation group 42 cases were cured,14 cases markedly effective,4 cases ecfectiveness and no case failure.markedly effective rate was 93.3%,the effective rate was 100.0%.Conclusion ICP for maternal and newborn have a certain influence,many accompanied by renal dysfunction,blood pressure control and kidney damage and check-ups during preg-nancy that affect the incidence of ICP independent risk factors,drug therapy can achieve better results.%目的:探讨妊娠期肝内胆汁淤积症(ICP)的临床特点和发病危险因素,提出相关控制措施。方法选择2009年5月至2013年2月在该院产科门诊建卡的 ICP产妇60例作为观察组,同期选择在该院住院分娩的非 ICP产妇60例作为对照组,两组都同时进行实验室检查和产妇及新生儿的预后调查。观察组给予药物综合治疗。结果所有产妇

  12. Citrin缺陷所致婴儿肝内胆汁淤积症43例分析%Intrahepatic cholestasis caused by citrin deficiency:a clinical analysis of 43 infants

    Institute of Scientific and Technical Information of China (English)

    姜涛; 姚蔚; 欧阳文献; 谭艳芳; 李双杰

    2014-01-01

    Objective To analyze the clinical characteristics and prognosis of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD)in infants.Methods The clinical data of 43 infants with NICCD in our hospital from July 201 1 to April 2014 were collected.The diagnosis was confirmed by tandem mass spectrometry (MS-MS)analysis of blood,gas chromatography-mass spectrometry (GC-MS)a-nalysis of urine,and genetic testing,and an analysis was performed with reference to clinical manifestations and laboratory results.Results Most patients with NICCD developed jaundice early,with a round,fat face,hepatomegaly,and growth retardation.Laboratory examina-tions showed increased bilirubin,total bile acids,blood lactic acid,alpha-fetoprotein,and procalcitonin in all patients,increased alanine aminotransferase,gamma-glutamyl transpeptidase,and blood ammonia,decreased albumin and blood glucose,and dyslipidemia and coag-ulation disorders in most patients,and abnormal liver fibrosis markers (20/24)and low ceruloplasmin (17/20)in some patients.Abdomi-nal ultrasound showed hepatomegaly in 32 patients.MS-MS analysis of blood samples revealed distinctive elevation of methionine,citrul-line,tyrosine,threonine,and a variety of acyl carnitine in most patients.GC-MS analysis of urine samples revealed elevated galactose and galactitol in 20 patients,elevated 4-hydroxyphenyllactic acid and 4-hydroxyphenylpyruvic acid in 10 patients,and no abnormalities in 6 patients.Genetic testing revealed 851del4,1638ins23,and IVS6+5G>A mutations,especially 851del4 mutation.After being treated by giving lactose-free diet,strengthening medium-chain fatty acid diet,protecting the liver,and relieving cholestasis,most patients had nor-malized indices 2 months later,2 cases had liver cirrhosis,and 7 cases died.Conclusion The clinical manifestations of NICCD vary in children.MS-MS analysis of blood,GC-MS analysis of urine,and genetic testing should be performed early in children with clinically suspected NICCD

  13. The value of serum bile acid in diagnosis of intrahepatic cholestasis of pregnancy%血清胆汁酸在妊娠期肝内胆汁淤积症中的诊断价值

    Institute of Scientific and Technical Information of China (English)

    王晓丽; 李博; 赵彦梅; 王昕

    2012-01-01

    目的 探讨血清胆汁酸在妊娠期肝内胆汁淤积症(ICP)诊断中的应用价值.方法 对待产的92例ICP患者的临床资料进行回顾性分析,按血清胆汁酸水平将患者分为两组,血清胆汁酸>40μmol/L为观察组(46例),血清胆汁酸≤40μmol/L为对照组(46例),观察比较两组患者皮肤瘙痒出现时间,黄疸程度,血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST),羊水污染程度.结果 观察组皮肤瘙痒出现时间早于对照组[(29.1±3.4)周比(33.9±3.2)周,P<0.05];重度黄疸、ALT>100 U/L、AST>100 U/L及羊水Ⅲ度污染例数均多于对照组[27例比15例、28例比20例、28例比18例、23例比15例,P<0.01或<0.05].结论 血清胆汁酸可作为评估ICP的敏感指标,对孕妇病情的判断、预后分析具有重要的意义,具有反映其发生妊娠不良结局的可能性.%Objective To evaluate the application value of serum bile acid in diagnosing intrahepatic cholestasis of pregnancy (ICP).Methods The clinical data of 92 prepartal patients with ICP was analyzed retrospectively.The patients were divided into observation group ( > 40 μ mol/L ) and control group ( ≤40 μ mol/L) with 46 cases each according to serum bile acid level.The nccurrence time of skin pruritus,jaundice degree,serum alanine aminotransferase (ALT),aspartate aminotransferase (AST) and degree of polluted amniotic fluid of two groups were observed and compared.Results The occurrence of skin pruritus in observation group was earlier than that in control group [(29.1 ± 3.4) weeks vs.(33.9 ± 3.2) weeks,P<0.05 ] ;the cases with severe jaundice,ALT > 100 U/L,AST > 100 U/L and amniotic fluid contamination Ⅲ degree in observation group were more than control group [27 cases vs.15 cases,28 cases vs.20 cases,28 cases vs.18 cases,23 cases vs.15 cases,P< 0.01 or < 0.05].Conclusions Serum bile acid,as a sensitive indicator to assess TCP,has important value in determining the

  14. Cholestasis in newborn and infancy period

    OpenAIRE

    Çokuğraş, Fügen Çullu; Beşer, Ömer Faruk

    2012-01-01

    Dear Editor Isotretinoin is a synthetic vitamin A derivative which is used for treatment of nodulocystic and severe acne It is a teratogenic factor which can lead to intrauterine death and congenital anomalies in humans and the clinical picture it causes is named isotretinoin embryopathy 1 A three months old infant who was born from a mother who used isotretinoin during her first month of pregnancy without realising that she was pregnant is presented in this article to emphasize that this dru...

  15. Biliary scintigraphy in neonatal cytomegalovirus cholestasis

    International Nuclear Information System (INIS)

    Diagnostic value of hepatobiliary scintigraphy using mebrofenin-Te-99m was assessed in three newborns with cytomegalovirus (CMV) hepatitis and one baby with hepatitis B jaundice. All cases were affected by persistent jaundice with predominately conjugated bilirubin, alcoholic stools, anemia. One of this newborns (case number 1) was suspected of having biliary atresia due to the absence of intestinal excretion of the tracer. After three weeks intestinal passage was seen in scintiscan late after 24 h. Hepatobiliary scintigraphy represents a non-invasive diagnostic procedure which enables the detection of permeability of the biliary tract. (Author)

  16. Genetics Home Reference: intrahepatic cholestasis of pregnancy

    Science.gov (United States)

    ... a protein called the bile salt export pump (BSEP). This protein is found in the liver, and ... pregnancy reduce the amount or function of the BSEP protein, although enough function remains for sufficient bile ...

  17. Obstructive Jaundice: A Case of Idiopathic Cholestasis

    OpenAIRE

    Worobetz, Lawrence; Haight, Ken; Brown, Murray

    1984-01-01

    A 44-year-old man presented to his family physician with intrahepatic cholestatic jaundice, which he had had for seven days. He was admitted to the Family Medicine Service of University Hospital, Saskatoon, and the jaundice was extensively investigated. Initially, it was thought to be induced by antibiotics, but this was not confirmed on controlled drug rechallenge. The precise cause was not found. This article outlines a rational and systematic method for investigating obstructive jaundice. ...

  18. 胆盐输出泵基因多态性与特发性婴儿肝炎肝内胆汁瘀积的关系%Relationship between Bile Salt Export Pump Gene Polymorphisms and lntrahepatic Cholestasis in Idiopathic In-fantile Hepatitis

    Institute of Scientific and Technical Information of China (English)

    邓亚楠; 王琳琳; 陈秀奇; 唐清; 高国鹏; 单庆文; 云翔

    2011-01-01

    目的 探讨特发性婴儿肝炎肝内胆汁瘀积患儿胆盐输出泵(BSEP)基因的突变情况.方法 收集2008年10月- 2010年2月就诊于广西医科大学第一附属医院儿科的婴儿胆汁瘀积性肝炎患儿81例(病例组),48例无肝内胆汁瘀积、肝功能正常的婴儿为对照组.提取病例组和对照组儿童外周血DNA,采用聚合酶链反应-单链构象多态性(PCR-SSCP)和DNA测序技术检测BSEP基因上2、3、4、5、6、9、10、16、17、23、24外显子基因多态性,分析BSEP基因多态性与特发性婴儿肝炎肝内胆汁瘀积之间的关系.结果在外显子24上检测到BSEP A1028A同义突变,编码的氨基酸未改变,均为丙氨酸;其他10个外显子均未发现异常突变.A1028A基因型在病例组,CC型53例(占65.4%),TC型28例(占34.6%),C等位基因频率为82.7%;对照组中CC型32例(占66.7%),TC型16例(占33.3%),C等位基因频率为83.3%.二组基因型差异经Fisher's精确概率法检验,差异无统计学意义(P>0.05);等位基因频率经Fisher's精确概率法检验,差异亦无统计学意义(P>0.05).结论 尚不能认为BSEP A1028A是特发性婴儿肝炎肝内胆汁瘀积的一个危险因素.BSEP A1028A与特发性婴儿肝炎肝内胆汁瘀积发生的易感性无关.%Objective To evaluate the bile salt export pump(BSEP) gene polymorphisms in the pathogenesis of intrahepatic cholestasis in idiopathic infantile hepatitis. Methods The genomic DNA was obtained from peripheral blood of 81 patients with idiopathic infantile cholestasis as case group, who hospitalized in the Department of Pediatrics of the First Affiliated Hospital of Guangxi Medical University from Oct. 2008 to Feb.2010,and 48 normal liver function infants without intrahepatic cholestasis as control group. The BSEP gene 2,3,4,5,6,9,10, 16,17,23,24 exons polymorphism were genotyped by polymerase chain reaction - single strand conformation polymorphism(PCR - SSCP) and sequenced. The statistical

  19. Estado nutricional e absorção intestinal de ferro em crianças com doença hepática crônica com e sem colestase Nutritional status and intestinal iron absorption in children with chronic hepatic disease with and without cholestasis

    Directory of Open Access Journals (Sweden)

    Regina Helena Guedes da Motta Mattar

    2005-08-01

    Full Text Available OBJETIVO: Avaliar a ingestão alimentar, a ocorrência de desnutrição energético-protéica e de anemia e a absorção intestinal de ferro em crianças com doença hepática crônica. CASUÍSTICA E MÉTODOS: Foram estudados 25 pacientes com doença hepática crônica, sendo 15 com colestase e 11 sem colestase. A idade variou entre 6,5 meses e 12,1 anos. A absorção intestinal de ferro foi avaliada pela elevação do ferro sérico uma hora após a ingestão de 1 mg/kg de ferro elementar e pela resposta à ferroterapia oral. A absorção intestinal de ferro foi comparada com um grupo de crianças com anemia ferropriva. RESULTADOS: A ingestão média de energia e proteínas nos pacientes com doença hepática com colestase foi maior do que nos pacientes sem colestase. O déficit nutricional foi mais grave nos pacientes com colestase, predominando os déficits de estatura-idade e peso-idade. A anemia foi freqüente tanto nas crianças com doença hepática com colestase (11/14; 78,6% como nas sem colestase (7/11; 63,6%. Na doença hepática com colestase, observou-se menor (p OBJECTIVES: to evaluate food intake, occurrence of energy-protein malnutrition and anemia, and intestinal iron absorption in children with chronic liver disease. METHODS: The study included 25 children with chronic liver disease, 15 with cholestasis and 11 without cholestasis. The age varied between 6.5 months and 12.1 years. Intestinal iron absorption was evaluated by the increment of serum iron one hour after the ingestion of 1 mg/kg of elemental iron and by the response to oral iron therapy. Iron intestinal absorption was compared to a group with iron deficiency anemia (without liver disease. RESULTS: The mean intake of energy and protein in the cholestatic group was higher than in patients without cholestasis. The nutritional deficit was more severe in cholestatic patients, especially with regard to height-for-age and weight-for-age indices. Anemia was found in both

  20. Therapeutical Effect of Kidney-Tonifying and Dampness-Expelling Chinese Herbal Medicine on Intrahepatic Cholestasis of Pregnancy Mediated Through Up-Regulating Expressions of MRP2 and BSEP in Rat Hepatocytes%补肾祛湿方增加大鼠肝细胞MRP2、BSEP表达对抗雌激素致胆汁淤积作用

    Institute of Scientific and Technical Information of China (English)

    侯莉莉; 刘佳; 赵翠英

    2013-01-01

    目的:观察补肾祛湿方含药血清对雌激素致大鼠胆汁淤积肝细胞胆汁酸转运蛋白MRP2与BSEP表达的作用,探讨补肾祛湿方治疗妊娠肝内胆汁淤积症可能的分子机制.方法:用1 μmol/L的17β雌二醇干预大鼠原代肝细胞24 h诱导形成胆汁淤积模型后,加入补肾祛湿方含药血清处理24 h,放射免疫法测定培养液中总胆汁酸含量,提取细胞总RNA及蛋白,实时荧光定量PCR法和蛋白免疫印迹法检测MRP2、BSEP mRNA与蛋白表达水平.电子显微镜观察培养肝细胞超微结构变化.结果:补肾祛湿方含药血清可减轻肝细胞损伤,显著增加细胞培养上清总胆汁酸含量,P<0.01,并且可明显增加肝细胞MRP2、BSEP mRNA与蛋白表达水平,P<0.01.结论:补肾祛湿方治疗妊娠肝内胆汁淤积症的分子机制可能是通过改善肝细胞超微结构的损伤,增加肝细胞胆汁酸转运蛋白MRP2、BSEP mRNA与蛋白表达水平实现的.%Objective:To investigate the effect of kidney-tonifying and dampness-expelling Chinese herbal medicine on the expressions of MRP2 and BSEP in cholestasis induced by estrogen in rat hepatocytes.Methods:The model of cholestasis was induced by 17β-estradiol in cultured rat heaptocytes for 24 hours,and then the serum containing kidney-tonifying and dampness-expelling Chinese herbal medicine serum was treated for 24 hours.The level of total bile acid was detected,and the expressions of MRP2 and BSEP were analyzed by real-time RT PCR and western blotting analysis.The changes in ultrastructure of hepatocytes were observed by electron microscope.Results:The observation under electron microscope showed that compared with the blank serum group,the most hepatocytes in kidney-tonifying and dampness-expelling Chinese herbal medicine group were with normal structure.Further more,compared with the serum blank group,the serum levels of TBA was remarkably increased in group containing kidney-tonifying and dampness

  1. 胎盘胆盐输出泵蛋白的表达及其与妊娠期肝内胆汁淤积症的关系%Study on the Placental Expression of BSEP in Intrahepatic Cholestasis of Pregnancy

    Institute of Scientific and Technical Information of China (English)

    顾丽萍; 刘晓慧; 宋晔; 侯顺玉; 戴建荣

    2016-01-01

    Objective:To explore the expression of bile salt export pump(BSEP) in placenta tissue and its relationship with intrahepatic cholestasis of pregnancy (ICP). Methods:The expression of BSEP in the placenta was detected by immunohisto-chemistry and western blotting respectively in 30 women with ICP (ICP group) and 30 normal gravidas (control group) from February 2012 to August 2013 in Department of Obstetrics of Suzhou Municipal Hospital. Results:BSEP was located at the cytoplasm in the placental trophoblastic cells. The expression of BSEP in ICP group was significantly lower than control group [(0.197 7±0.111 8) vs. (0.616 0±0.384 9),P<0.001]. Conclusions:Decreased expression of BSEP in placenta may be asso-ciated with ICP.%目的:探讨胎盘组织中胆盐输出泵(bile salt export pump,BSEP)的表达水平及其与妊娠期肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)的关系.方法:选取2012年2月—2013年8月在苏州市立医院本部产科住院分娩的ICP孕妇30例作为研究组(ICP组),同期分娩的健康妊娠晚期孕妇30例作为对照组,采用免疫组化(SP)法和蛋白质印迹(western blotting)法测定2组孕妇胎盘组织中BSEP蛋白的表达.结果:BSEP蛋白表达于胎盘滋养细胞的细胞质中.ICP患者胎盘组织BSEP的表达低于正常胎盘组织,差异有统计学意义[(0.197 7±0.111 8)vs.(0.616 0±0.384 9), P<0.001].结论:BSEP蛋白在胎盘组织中表达的降低可能与ICP有关.

  2. Imaging characteristics of hepatobiliary scintigraphy in neonatal intrahepatic cholestasis caused by citrin deficiency%Citrin缺陷所致婴儿肝内胆汁淤积症的肝胆显像特征

    Institute of Scientific and Technical Information of China (English)

    张梅虹; 赵瑞芳; 陈瑞; 王建设

    2014-01-01

    目的 探讨citrin缺陷导致的婴儿肝内胆汁淤积症(NICCD)患儿99Tcm-二乙基乙酰苯胺亚氨二醋酸(EHIDA)肝胆显像的特征.方法 回顾性分析28例(男16例,女12例,1~8月龄)经基因确诊、同时行99Tcm-EHIDA肝胆动态显像检查的NICCD患儿资料.肝胆动态显像时心、肝、肾按正常时序和强度显影定义为摄取功能正常,肝影模糊和(或)心肾影持续时间延长者为摄取功能差;60 min内肠道显影为排泄通畅,60 min后为排泄延迟,24 h肠道仍不显影为排泄受阻.分析肝胆显像特征与血清总胆红素(TB)、直接胆红素(DB)、ALT、总胆汁酸(TBA)等指标间的关系.数据分析采用Kruskal-Wallis秩和检验.结果 28例中,20例表现为摄取功能正常,其中10例排泄通畅,10例排泄延迟;8例表现为摄取功能差,其中4例排泄延迟,4例排泄受阻.与摄取功能正常组相比,摄取功能差组TB和DB明显增高[183.6(128.7~ 280.9) mmol/L和105.5(80.0~ 141.7) mmol/L,135.6(95.7~212.6) mmol/L和73.1(53.9~ 97.9) mmol/L;Z=-2.25和-2.73,均P<0.05].与排泄通畅者相比,排泄延迟者TB、DB和TBA明显升高[分别为137.5(122.0~170.9) mmol/L和81.7(65.7~93.5) mmol/L,96.5(81.1~ 108.0) mmol/L和54.1(45.3~72.6) mmol/L,245.6(183.9~299.2) mmol/L和136.0(73.5 ~163.2) mmol/L;Z=-3.92、-3.74和-2.57,均P<0.05];排泄受阻者TB[262.0(152.1 ~ 542.8) mmol/L]和DB[192.7(118.1~407.2) mmol/L]更高(均Z=-2.82,均P<0.05).与排泄延迟组相比,排泄受阻者ALT明显增高[71.5(48.5~144.8) U/L和20.0(16.5~27.7) U/L;Z=-2.66,P<0.05).结论 99Tcm-EHIDA肝胆显像可反映NICCD患儿肝脏摄取和排泄功能受损的状况,摄取功能受损严重时,可出现排泄受阻的征象.%Objective To investigate the scintigraphic features of neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and to explore the clinical significance of 99Tcm-EHIDA hepatobiliary scintigraphy.Methods Hepatobiliary scintigraphy with

  3. Protective effect of Zhizi Bopi decoction on α-naphthylisothiocyanate induced intrahepatic cholestasis in rats%栀子柏皮汤对α-萘异硫氰酸酯诱导的肝内胆汁淤积大鼠的保护作用

    Institute of Scientific and Technical Information of China (English)

    曹璐; 李俊; 黄成; 韩静文

    2013-01-01

    Objective To investigate the protective effects of Zhizi Bopi decoction on rats against a-naphthyliso-thiocyanaten ( ANIT )induced liver injury with cholestasis and analyzed the possible mechanism. Methods ANIT was used to mimick the drug-induced liver injuery. 48 h after the ANIT treatment, serum of total bilirubin ( TBIL ), alkaline phosphatase ( ALP ), alanine aminotransferase ( ALT ), aspartate aminotransferase ( AST ), 7-glutamyltranspeptidase ( GGT ), liver specimens of superoxide dismutase ( SOD ), malondialdehyde ( MDA ), gluta-thione ( GSH ), and glutathione peroxidase ( GSH-Px ) were measured. To further explore the molecular mechanisms , we measured the expression of the bile metabolism-related transporters: bile salt export pump ( BSEP ), sodi-um-taurocholate cotrans-porting polypeptide ( NTCP ) and the enzyme related to oxidative stress: cytochrome P4502E1 ( CYP2E1 ) in both mRNA and protein level. Results Zhizi Bopi decoction improved live history with reduced the serum levels of TBIL, ALP, ALT, AST, GGT. Furthermore, hepatic MDA activities and contents in liver tissue were significantly reduced, while SOD, GSH, GSH-Px activities, which had been suppressed by ANIT were significantly elevated in the groups pretreated with Zhizi Bopi decoction in a dose-dependent manmer. Additionally, Zhizi Bopi decoction was found to increase the expression of liver NTCP, and decrease the BSEP in ANIT-induced liver injury with cholestasis. CYP2E1 was decreased in accordance with the protein expression. Conclusion Zhizi Bopi decoction exerts protective effects against ANIT-induced liver injury. The mechanisms could be related to transshipment of bile metabolism-related transporters and anti-oxidative damage.%目的 探讨栀子柏皮汤对α-萘异硫氰酸酯(ANIT)诱导的肝内胆汁淤积大鼠的保护作用及可能机制.方法 实验组大鼠灌胃给予栀子柏皮汤7 d,第7天给药后4 h给ANIT造模.48 h后,测血清总胆红素(TBIL)含量、碱性磷酸

  4. Effect of ursodeoxycholic acid on the expression of the hepatocellular BSEP and FXR in pregnant rats with ethinylestradiol induced intrahepatic cholestasis%熊脱氧胆酸对抗乙炔雌二醇诱发孕大鼠肝内胆汁淤积的作用机制

    Institute of Scientific and Technical Information of China (English)

    刘红; 刘建; 李金艳

    2005-01-01

    目的:研究熊脱氧胆酸(ursodeoxycholic acid,UDCA)对雌激素诱发孕鼠肝内胆汁淤积肝脏胆盐输出泵(bile salt export pump,BSEP)及肝脏法尼醇受体(farnesoid X receptor,FXR)表达的影响,探讨UDCA治疗妊娠期肝内胆汁淤积症(intrahepatis cholestasis of pregnancy,ICP)的作用机制.方法: 随机将孕15d的大鼠40只分成4组,1,2-丙二醇(propylene Glycol,PG)组,17-α-乙炔雌二醇(ethinylestradiol,EE)组,UDCA组和UDCA+EE组.用药前,用药后5d测血浆中谷丙转氨酶(ALT),谷草转氨酶(AST),碱性磷酸酶(ALP),总胆酸(TBA).同时观察肝脏形态学变化及胎鼠生长发育情况;应用免疫组化法分析肝脏BSEP及FXR的表达.结果:用药后EE组的孕鼠ALT、AST、ALP、TBA比用药前显著升高(P<0.05),PG组无明显变化(P>0.05),UDCA组,UDCA+EE组ALT,AST,ALP无明显变化(P>0.05),但TBA明显升高(P<0.05).EE组孕鼠肝脏出现肝内胆汁淤积表现,其余3组肝脏形态结构正常.EE组胎仔身长,尾长,体重,死胎数,活胎数,孕天数与其余3组比较有显著差异(P<0.05).EE组BSEP表达降低,FXR表达升高,与PG组,UDCA组,UDCA+EE组差异均有显著性(P<0.05).结论:UDCA对雌激素诱发孕鼠肝内胆汁淤积肝脏具有保护作用,能改善胎仔预后,可能是通过恢复肝脏BSEP的表达促进胆汁分泌,而不是通过影响FXR表达调节胆汁酸的合成.

  5. Effect of Yinhuang Mixture on Expression of MRP2 and BSEP in Rats with Intrahepatic Cholestasis of Pregnancy Induced by Estrogen and Progesterone%茵黄合剂对雌孕激素共诱导妊娠肝内胆汁淤积症大鼠胆汁酸转运蛋白MRP2与BSEP表达的影响

    Institute of Scientific and Technical Information of China (English)

    刘佳; 侯莉莉; 赵翠英

    2013-01-01

    目的:观察茵黄合剂对雌孕激素共诱导妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)大鼠胆汁酸转运蛋白多药耐药相关蛋白2(multidrug resistance-associated protein 2,MRP2)与胆盐输出泵(bile salt export pump,BSEP)表达的影响,探讨茵黄合剂治疗妊娠肝内胆汁淤积症可能的分子机制.方法:运用雌孕激素联合的方法建立孕鼠妊娠肝内胆汁淤积症模型,随机分为正常组、模型组、茵黄合剂低剂量组(9 g·kg-1·d-1,ig)和茵黄合剂高剂量组(18 g·kg-1 ·d-1,ig),分别给予生理盐水、低剂量与高剂量的茵黄合剂5d,取血,检测血清总胆汁酸(total bile acid,TBA)、总胆红素(total bilirubin,TBil)、丙氨酸转氨酶(alanine transarninase,ALT)、天冬氨酸转氨酶(aspartate aminotransferase,AST)活性,留取肝脏组织,置于液氮中保存,分别运用实时定量PCR法及蛋白免疫印迹法检测胆汁酸转运蛋白MRP2 BSEP mRNA与蛋白表达情况.结果:与正常组比较,模型组大鼠血清TBA,TBil水平增加,MRP2,BSEP mRNA与蛋白表达水平降低(P<0.01),模型组ALT,AST含量与正常组比较虽有增加,但差异无统计学意义.与模型组比较,茵黄合剂低、高剂量均能降低妊娠肝内胆汁淤积症模型大鼠血清TBA,TBil水平(P<0.01),并且可明显增加肝脏组织MRP2,BSEPmRNA与蛋白表达水平,P<0.01.结论:茵黄合剂治疗妊娠肝内胆汁淤积症的分子机制可能是通过增加肝脏组织胆汁酸转运蛋白MRP2,BSEP,mRNA与蛋白表达水平实现的.

  6. 妊娠期肝内胆汁淤积症IL-10、TNF-α表达变化及其与肝功能变化的关系%The expression levels of IL-10 and TNF-α in patients with intrahepatic cholestasis of pregnancy and the relationship with liver function

    Institute of Scientific and Technical Information of China (English)

    曹丽琼; 曲广第; 王冬梅

    2012-01-01

    This study aims to investigate the expression and significance of IL-10 and TNF-α in the placenta with intrahepatic cholestasis of pregnancy (ICP). Total of 37 ICP gravidas delivered by cesarean section were selected as the ICP group, and another 35 healthy pregnant women were chosen as control. Placentas of the all gravidas were collected for TNF-α and IL-10 proteins detection by Envision immunohistochemical method. The results showed that TNF-α and IL-10 were mainly expressed in intra cytoplasma of trophoeyte of placentas of both groups. In the ICP group, the expression of IL-10 was obviously lower than that of control, meanwhile the expression of TNF-a was obviously higher than that control (P< 0.05). Furthermore, TNF-a and serum transaminase were positively correlated (r = 0.270, 0.246, P < 0.05), but serum transaminase and II,-10 levels demonstrated negative correlation (r= -0.250, -0.128, P< 0.05). We can conclude that the increase of type 1 cytokine (TNF-α) is associated with a decrease of type 2 cylokine (IL-10) in TCP, and the imbalance of cytokine network may participate in the pathogenesis of ICP through affecting the liver function.%目的 探讨白细胞介素10(interleukin- 10,IL-10)、肿瘤坏死因子(tumor necrosis factor-alpha,TNF-α)在妊娠期肝内胆汁淤积症(ICP)孕妇胎盘组织中的表达及其与门冬氨酸转移酶(aspartate aminotransferase AST)、丙氨酸转移酶(alanine aminotransferase,ALT)的关系.方法 选择2010年10月至2011年5月在新疆医科大学第一附属医院产科剖宫产分娩的ICP孕妇37例为ICP组,选择同期健康孕妇35例为对照组.采用Envision免疫组化法测定IL-10、TNF-α在孕妇胎盘组织中的定位与表达水平,术前静脉血测定肝功指标:AST,ALT,采用SPSS17.0统计软件进行统计分析,计量资料比较采用t检验;等级经秩转换后采用秩和检验并进行相关性分析.结果 IL-10、TNF-α在两组孕妇胎盘组

  7. Effects of PTPRO on Th1/Th2 bias in pregnant women with intraheptic cholestasis%PTPRO 对妊娠期肝内胆汁淤积症患者Th1/Th2 细胞偏倚的影响

    Institute of Scientific and Technical Information of China (English)

    王增芳; 王萍萍; 王增艳; 孙芳; 赵金华; 修霞

    2015-01-01

    目的 探讨受体O型蛋白酪氨酸磷酸酶(PTPRO)对妊娠期肝内胆汁淤积症(ICP)患者Th1/T h2细胞偏倚的影响.方法 分离获取正常妊娠(A组 ,30例)、轻型ICP (B组 ,28例)和重型ICP(C组 ,30例)孕妇胎盘来源的单核-巨噬细胞 ,采用RT-PCR和Western blot法分别检测 PTPRO mRNA和蛋白的表达 ,Western blot法检测NF-κB/p65的磷酸化水平.分离获取孕妇外周血T淋巴细胞 ,与胎盘来源的单核-巨噬细胞共培养 ,ELISA法检测细胞培养上清液中IFN-γ、IL-12、IL-4和IL-10水平.结果 与A组相比 ,B、C组单核-巨噬细胞 PTPRO表达和 NF-κB/p65磷酸化水平升高 ,与其共培养的外周血T淋巴细胞高分泌IFN-γ和IL-12(P<0 .05);与B组相比 ,C组PTPRO表达和NF-κB/p65磷酸化水平升高 ,IFN-γ和IL-12分泌增多(P<0 .05).结论 ICP患者胎盘单核-巨噬细胞高表达PTPRO ,促使T淋巴细胞向Th1细胞偏倚.%Objective To explore the effects of protein tyrosine phosphatase receptor-type O (PTPRO) on Th1/Th2 bias in pregnant women with intraheptic cholestasis(ICP) .Methods Monocyte-macrophages were separated from placental tissues of pregnant women with normal term (group A , 30 cases) ,mild ICP (group B ,28 cases) and severe ICP (group C ,30 cases) .The expressions of PTPRO protein and mRNA and the level of phosphorylated NF-κB/p65 were detected by RT-PCR and Western blot ,respectively .The T lymphocytes of eripheral blood and monocyte-macrophages separated from placental tissues were co-cultured and the expressions of IFN-γ,IL-12 ,IL-4 and IL-10 in supernatant were determined by ELISA .Results The expression of PTPRO and the phosphorylation level of NF-κB/p65 in monocyte-macrophages were higher and the secretions of IFN-γand IL-12 from T lymphocytes were more in groups of B and C than those in group A (P<0 .05) ,which were more in group C than those in group B(P<0 .05) .Conclusion PTPRO is highly expressed in placental monocyte-macrophages of pregnant women with

  8. Scintigraphic appearance and particular arteriographic aspects intrahepatic cholestasis

    International Nuclear Information System (INIS)

    Based on one case history, it is reviewed that prolonged cases of obstructive jaundice can take on deceiving appearances, and all the more so when they fall within the framework of a 'biological gap'. Extensive distension of the extra and intrahepatic bile ducts are at the basis of images with multiple, radiating hilar gaps on scintigraphy, and of 'chicken nests' and 'Swiss cheese' at hepatographic times in selective hepatic arteriography. These rather uncommon images should lead to a diagnosis of a surgical cholestatic liver

  9. Langerhans Cell Histiocytosis in 2 Cases of Cholestasis

    OpenAIRE

    Erkan, Tülay; Kutlu, Tufan; Çokuğraş, Fügen; Ceyhan, İpek; Yıldız, İnci; Özbay, Gülşen; T.Tümay, Güngör

    1995-01-01

    Two cases of Langerhans cell histiocytosis who had multiorgan involvement with obstructive jaundice anemia and hepatosplenomegaly painful ulceration purulent exudation squamous and maculopapular rash in the skin were presented The diagnosis of Langerhans cell histiocytosis was made by skin biopsies that showed the presence of S 100 staining cells We suggest that the diagnosis of Langerhans cell histiocytosis should be considered in patients presenting with clinical and biochemical evidence of...

  10. Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis

    Directory of Open Access Journals (Sweden)

    Green Richard M

    2010-03-01

    Full Text Available Abstract Background BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP. BSEP disease is associated with an increased risk of hepatobiliary cancer. Case Presentation A 36 year old woman with BSEP disease developed pancreatic adenocarcinoma at age 36. She had been treated with a biliary diversion at age 18. A 1.7 × 1.3 cm mass was detected in the pancreas on abdominal CT scan. A 2 cm mass lesion was found at the neck and proximal body of the pancreas. Pathology demonstrated a grade 2-3 adenocarcinoma with invasion into the peripancreatic fat. Conclusions Clinicians should be aware of the possibility of pancreatic adenocarcinoma in patients with BSEP disease.

  11. Cathepsin B inactivation attenuates hepatic injury and fibrosis during cholestasis

    OpenAIRE

    Canbay, Ali; Guicciardi, Maria Eugenia; Higuchi, Hajime; Feldstein, Ariel; Bronk, Steven F.; Rydzewski, Robert; Tanai, Makiko; Gores, Gregory J.

    2004-01-01

    Although a lysosomal, cathepsin B–dependent (Ctsb-dependent) pathway of apoptosis has been described, the contribution of this pathway to tissue damage remains unclear. Our aim was to ascertain if Ctsb inactivation attenuates liver injury, inflammation, and fibrogenesis after bile duct ligation (BDL). In 3-day BDL mice, hepatocyte apoptosis, mitochondrial cytochrome c release, and serum alanine aminotransferase (ALT) values were reduced in Ctsb–/– versus Ctsb+/+ animals. Likewise, R-3032 (a C...

  12. Pancreatic adenocarcinoma in type 2 progressive familial intrahepatic cholestasis

    OpenAIRE

    Green Richard M; Rao M Sambasiva; Patil Deepa; Bass Lee M; Whitington Peter F

    2010-01-01

    Abstract Background BSEP disease results from mutations in ABCB11, which encodes the bile salt export pump (BSEP). BSEP disease is associated with an increased risk of hepatobiliary cancer. Case Presentation A 36 year old woman with BSEP disease developed pancreatic adenocarcinoma at age 36. She had been treated with a biliary diversion at age 18. A 1.7 × 1.3 cm mass was detected in the pancreas on abdominal CT scan. A 2 cm mass lesion was found at the neck and proximal body of the pancreas. ...

  13. Comparison of different diagnostic methods in infants with Cholestasis

    Institute of Scientific and Technical Information of China (English)

    Seyed Mohsen Dehghani; Mahmood Haghighat; Mohammad Hadi Imanieh; Bita Geramizadeh

    2006-01-01

    AIM: To evaluate different methods in differentiating idiopathic neonatal hepatitis from biliary atresia.METHODS: Sixty-five infants with cholestatic jaundice and final diagnosis of idiopathic neonatal hepatitis and biliary atresia were studied prospectively from September 2003 to March 2006. A thorough history and physical examination were undertaken and the liver enzymes were examined. All cases underwent abdominal ultrasonography, hepatobiliary scintigraphy,and percutaneous liver biopsy. The accuracy, sensitivity,specificity and predictive values of these various methods were compared.RESULTS: There were 34 girls and 31 boys, among them 46 subjects had idiopathic neonatal hepatitis (age,61 ± 17 d) and 19 had biliary atresia (age, 64 ± 18 d).The mean age at onset of jaundice was significantly lower in cases of biliary atresia when compared to idiopathic neonatal hepatitis cases (9 ± 13 d vs 20 ± 21 d;P = 0.032). The diagnostic accuracy of different methods was as follows: liver biopsy, 96.9%; clinical evaluation,70.8%; ultrasonography, 69.2%; hepatobiliary scintigraphy, 58.5%; and liver enzymes, 50.8%.CONCLUSION: Our results indicate that clinical evaluation by an experienced pediatric hepatologist and a biopsy of the liver are considered as the most reliable methods to differentiate idiopathic neonatal hepatitis and biliary atresia.

  14. Percutaneous transhepatic biliary drainage in malignant extrahepatic cholestasis

    Energy Technology Data Exchange (ETDEWEB)

    Hoevels, J.

    1985-03-01

    The technique of non-surgical percutaneous transhepatic biliary drainage has been improved recently. Combined internal and external drainage of bile was enabled by manipulation of a guide wire and a drainage catheter through the stenosed or obstructed section of the extrahepatic biliary ducts. Experience have been gained concerning internal drainage of bile by percutaneous transhepatic insertion of an endoprosthesis for some years now.

  15. Percutaneous transhepatic biliary drainage in malignant extrahepatic cholestasis

    International Nuclear Information System (INIS)

    The technique of non-surgical percutaneous transhepatic biliary drainage has been improved recently. Combined internal and external drainage of bile was enabled by manipulation of a guide wire and a drainage catheter through the stenosed or obstructed section of the extrahepatic biliary ducts. Experience have been gained concerning internal drainage of bile by percutaneous transhepatic insertion of an endoprosthesis for some years now. (orig./WU)

  16. Effect of a selective JNK inhibitor on pregnant rats with ethinylestradiol induced intrahepatic cholestasis%c-Jun氨基末端激酶选择性抑制剂对雌激素诱导致妊娠期大鼠肝内胆汁淤积症的影响

    Institute of Scientific and Technical Information of China (English)

    陈秋玲; 吴新华; 李苏萍

    2012-01-01

    Objective To evaluate the influence of SP600125,a selective c-Jun N-terminal kinase (JNK) inhibitor,on the levels of serum total bile salt (TBA) and Bsep,Ntcp expression in the hepatic tissue of rats with ethinylestradiol induced intrahepatic cholestasis.Methods Rats pregnant for 15days were administered the subcutaneous injection of 17- b -estradiol propylene ( EE ) to modulate the ICP animal models,and be SP600125 to intervene.Testing the level of serum TBA and the expression of c-Jun,Bsep,Ntcp in the hepalatic tissue.Results The average gray values of c-Jun in the group of ICP models were significantly lower than the normal control group ( 101.05 ± 5.20 vs 118.99 ± 5.95,P < 0.05 ).After the intervention of SP600125,comparing with the group of ICP models,the expression of Bsep,Ntcp in the group of SP600125 intervention were significantly higher,and this change in the high dose of SP600125 intervention group was more obvious ( low dose intervention group Bsep:0.452 ±0.031 vs 0.291 ±0.043,Ntcp:0.462 ± 0.015 vs 0.285 ± 0.021,P < 0.05 ; high dose intervention group Bsep:0.568 ± 0.038 vs 0.291 ±0.043,Ntcp:0.605±0.020 vs 0.285 ±0.021,P <0.05),while the level of TBA in the serum was significantly lower.Conclusions Treatment with SP600125 can down-regulate the level of c-Jun/AP-1,and it may participate in the lower expression of Bsep、Ntcp in the ICP rats which were induced by 17-bestradiol.%目的 探讨c-Jun氨基末端激酶(JNK)选择性抑制剂SP600125对雌激素诱导的妊娠期肝内胆汁淤积症大鼠肝组织内Bsep、Ntcp蛋白的表达情况及血清总胆汁酸浓度的影响.方法 将孕15d SD大鼠皮下注射17-β-乙炔雌二醇建立ICP动物模型,并予以SP600125进行干预,检测各组孕鼠血清胆汁酸(TBA)、各组孕鼠肝脏组织c-Jun、胆盐输出泵(Bsep)及胆酸共转运蛋白(Ntcp)的表达水平.结果 在ICP模型组中c-Jun的灰度值较正常对照组显著降低(101.05 ±5.20 vs 118.99±5.95,P<0.05),

  17. Effects of farnesoid X receptor ligand on the metabolism of bile acids in rats with estrogen-induced intrahepatic cholestasis of pregnancy%法尼醇X受体激动剂对雌激素诱导的肝内胆汁淤积症孕鼠胆汁酸代谢的影响及其分子机制

    Institute of Scientific and Technical Information of China (English)

    邹姝丽; 刘建; 兰易; 程浩; 甘晓玲

    2008-01-01

    目的 研究法尼醇X受体(FXR)激动剂鹅去氧胆酸(CDCA)对雌激素诱导的肝内胆汁淤积孕鼠胆汁酸代谢的影响及其分子机制.方法 用苯甲酸雌二醇诱导孕鼠发生肝内胆汁淤积,建立妊娠期肝内胆汁淤积症(ICP)模型,将FXR激动剂CDCA作用于ICP模型组,比色法检测孕鼠血总胆汁酸,RT-PCR和免疫组织化学法检测孕鼠肝组织FXR及其靶基因胆盐转运泵(BSEP)的mRNA及蛋白质表达.结果 与模型组相比,CDCA治疗组孕鼠血清胆汁酸水平明显降低[(17.2±4.1)μmol/L比(29.3±6.4)μmol/L,P<0.017],肝组织FXR mRNA(0.76±0.09比0.53±0.06,P<0.05)及蛋白质表达(2.35±0.06比1.83±0.05,P<0.017)明显升高,BSEP mRNA(0.99±0.21比0.76±0.07,P<0.017)及蛋白质表达(1.88±0.03比1.46±0.06,P<0.017)也明显升高.结论 FXR在调节胆汁酸代谢过程中起重要作用,其激动剂CDCA通过上调BSEP的表达促进胆汁酸转运降低血胆汁酸水平,可能为ICP的治疗提供新的思路和药物靶点.%Objective To investigate the effects and mechanism of farnesoid X receptor(FXR)and its ligands on the metabolism of bile acids in rats with estrogen-induced intrahepatic cholestasis of pregnancy (ICP).Methods An ICP rat model was established with estradiol benzoate(EB)injections.Then FXR ligand chenodeoxycholic acid(CDCA)was administrated(100 mg/kg daily)to ICP rats for 5 days.The serum TBA and expression of FXR and bile salt export pump(BSEP)in the rat livers were examined by immunohistochemistry and reverse transcription PCR.Results The levels of TBA in the CDCA group rats were significantly lower than the untreated rats[(17.2±4.1)μmol/L vs(29.3±6.4)/μmol/L,P<0.017],and the expressions of mRNA and protein of FXR were significantly higher[(0.76±0.09 vs 0.53±0.06,P<0.05 and 2.35±0.06 vs 1.83±0.05,P<0.017,respectively)],and the expressions of BSEP were also higher[(0.99±0.21 vs 0.76±0.07,P<0.017 and 1.88±0.03 vs 1.46±0.06,P<0.017,respectively

  18. Cholestasis induced by total parenteral nutrition: effects of the addition of Taurine (Tauramin® on hepatic function parameters; possible synergistic action of structured lipids (SMOFlipid® Colestasis inducida por nutrición parenteral total: efecto de la adición de Taurina (Tauramin® sobre los parámetros de función hepática; posible acción sinérgica de lípidos estructurados (SMOFlipid®

    Directory of Open Access Journals (Sweden)

    J. González-Contreras

    2012-12-01

    Full Text Available Objective: Assess the hepatoprotective effect of Taurine (Tau in cases of hepatic cholestasis induced by Total Parenteral Nutrition (TPN. Methods: We describe a retrospective series of 54 patients who received TPN, in which cholestasis was detected at an (Intermediate point that separates the duration of TPN into 2 Phases. From this moment -Phase 2- on, and according to clinical criteria, some patients (Group A, n = 27 received amino acids with Tau (22.41 ± 3.57 mg/kg/day(Tauramin®, while the rest (Group B, n = 27 received the standard solution without Tau. The mean TPN durations were 39.2 ± 17.1 and 36.4 ± 18.1 days respectively, with the Intermediate points on days 19.56 ± 10.51 and 17.89 ± 11.14. They all received diets that were homogeneous in terms of kcal and macronutrients. In Phase 2, 21 patients from Group A received structured lipids (SMOFlipid®; while 20 from Group B received soy MCT/LCT [ Medium Chain Triglycerides/Long Chain Triglycerides ] (physical or structured mixture. In a retrospective study, differences could not be avoided. The analytical parameters from three periods (Initial, Intermediate, and Final were obtained from Nutridata® and Servolab®. We compared interperiod values using the Wilcoxon test SPSS® (p Objetivo: Evaluar el papel hepatoprotector de Taurina (Tau en situación de colestasis hepática inducida por Nutrición Parenteral Total (NPT. Métodos: Se describe una serie retrospectiva de 54 pacientes, que recibieron NPT, detectándose colestasis en un momento (Intermedio que separa en 2 Fases la duración de la NPT. A partir de este momento - Fase 2- y según criterios clínicos, unos -grupo A, n = 27- recibieron aminoácidos con Tau -22,41 ± 3,57 mg/kg/día (Tauramin®, mientras otros -grupo B, n = 27- recibieron solución estándar sin Tau. La duración media de NPT fue de 39,2 ± 17,1 y 36,4 ± 18,1 días respectivamente; con el punto Intermedio en día 19,56 ± 10,51 y 17,89 ± 11,14. Todos

  19. Oxidized low-density-lipoprotein accumulation is associated with liver fibrosis in experimental cholestasis

    Directory of Open Access Journals (Sweden)

    Güldeniz Karadeniz

    2008-01-01

    Full Text Available OBJECTIVE: The aim of the present study was to examine the probable relationship between the accumulation of oxLDL and hepatic fibrogenesis in cholestatic rats. INTRODUCTION: There is growing evidence to support the current theories on how oxidative stress that results in lipid peroxidation is involved in the pathogenesis of cholestatic liver injury and fibrogenesis. One of the major and early lipid peroxidation products, OxLDL, is thought to play complex roles in various immuno-inflammatory mechanisms. METHODS: A prolonged (21-day experimental bile duct ligation was performed on Wistar-albino rats. Biochemical analysis of blood, histopathologic evaluation of liver, measurement of the concentration of malondialdehyde (MDA and superoxide-dismutase (SOD in liver tissue homogenates, and immunofluorescent staining for oxLDL in liver tissue was conducted in bile-duct ligated (n = 8 and sham-operated rats (n = 8. RESULTS: Significantly higher levels of MDA and lower concentrations of SOD were detected in jaundiced rats than in the sham-operated rats. Positive oxLDL staining was also observed in liver tissue sections of jaundiced rats. Histopathological examination demonstrated that neither fibrosis nor other indications of hepatocellular injury were found in the sham-operated group, while features of severe hepatocellular injury, particularly fibrosis, were found in jaundiced rats. CONCLUSION: Our results support the finding that either oxLDLs are produced as an intermediate agent during exacerbated oxidative stress or they otherwise contribute to the various pathomechanisms underlying the process of liver fibrosis. Whatever the mechanism, it is clear that an association exists between elevated oxLDL levels and hepatocellular injury, particularly with fibrosis. Further studies are needed to evaluate the potential effects of oxLDLs on the progression of secondary biliary cirrhosis.

  20. Effect of exercise on placental blood flow in pregnancies complicated by hypertension, diabetes or intrahepatic cholestasis.

    Science.gov (United States)

    Rauramo, I; Forss, M

    1988-01-01

    The effects of a standardized exercise test on intervillous placental blood flow were studied in 13 hypertensive, 10 diabetic and 8 cholestatic pregnant women in late pregnancy, and the results were compared with those of a normal control group. Analysis of variance for repeated measures revealed that in all the pathologic groups, placental blood flow was lower than in the controls. In all groups placental blood flow rose slightly 1 min after the cessation of exercise. The diabetics showed a decreased placental blood flow 30 min after the cessation of the exercise test (p less than 0.02). In diabetics, a fall was found in stroke volume, from 63 +/- 12 ml (mean +/- SD) before the exercise to 53 +/- 11 ml 30 min after the cessation of exercise (p less than 0.05), and a rise in peripheral vascular resistance, from 1540 +/- 200 (mean +/- SD) dynes/cm5 before exercise to 1750 +/- 390 dynes/cm5 30 min after the cessation of exercise (p less than 0.05). Pre-eclamptic patients had a higher peripheral vascular resistance than had normal controls. Pre-eclamptic, diabetic and cholestatic patients had lower cardiac index values than the normal subjects. The difference was significant in the pre-eclamptic and diabetic patients at 30 min after the cessation of exercise. Maternal heart rate, and systolic, diastolic and mean arterial blood pressures rose significantly from values at rest to values at the end of exercise in all groups. One of the pre-eclamptic patients showed a 74% decline in placental blood flow 1 min after the cessation of exercise coincident with fetal bradycardia.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3176908

  1. Bile acids affect liver mitochondrial bioenergetics: possible relevance for cholestasis therapy

    OpenAIRE

    Rolo, Anabela P.; Oliveira, Paulo J.; Moreno, António J. M.; Palmeira, Carlos M.

    2000-01-01

    It has been pointed out that intracellular accumulation of bile acids cause hepatocyte injury in cholestatic disease process. This study was aimed to test if cytotoxicity of these compounds is mediated through mitochondria dysfunction. Bile acids effects on isolated rat liver mitochondrial were analyzed by monitoring changes in membrane potential and mitochondrial respiration, as well as alterations in H+ membrane permeability and mitochondrial permeability transition pore induction. Increasi...

  2. Role of the bile salt export pump, BSEP, in acquired forms of cholestasis

    OpenAIRE

    Stieger, B

    2010-01-01

    Generation of bile is a key function of the liver. Its impairment leads to accumulation of cytotoxic bile salts in hepatocytes and, consequently, to liver disease. The bile salt export pump, BSEP, is critically involved in the secretion of bile salts into bile. Its function can be disturbed or abolished by inherited mutations. This will lead to progressive intrahepatic cholestais and severe liver disease. In addition to mutations, BSEP can be inhibited by acquired factors, such as xenobiotics...

  3. Role of the bile salt export pump, BSEP, in acquired forms of cholestasis

    NARCIS (Netherlands)

    B. Stieger

    2010-01-01

    Generation of bile is a key function of the liver. Its impairment leads to accumulation of cytotoxic bile salts in hepatocytes and, consequently, to liver disease. The bile salt export pump, BSEP, is critically involved in the secretion of bile salts into bile. Its function can be disturbed or aboli

  4. Role of membrane transport in hepatotoxicity and pathogenesis of drug-induced cholestasis

    OpenAIRE

    Stieger, Bruno; Kullak-Ublick, Gerd A.

    2013-01-01

    Drug-induced liver injury is an important clinical entity, which can be grouped into cholestatic liver injury, hepatocellular liver injury, and mixed liver injury. Cholestatic liver injury is characterized by a reduction in bile flow and the retention within hepatocytes of cholephilic compounds such as bile salts that cause hepatotoxicity. Bile salts are taken up by hepatocytes in a largely sodium-dependent manner and to a lesser extent in a sodium-independent manner. The former process is...

  5. Exfoliation, cholestasis, and apparent biliary sepsis in a woman with adult-onset diabetes.

    OpenAIRE

    Heiman, D. F.; Levine, R A; Bia, F. J.

    1985-01-01

    In consultation the authors were requested to evaluate a middle-aged diabetic woman for an apparent episode of biliary sepsis. The patient had been admitted to the dermatology service with a four-day history of rash and pruritus. This was initially thought to represent an allergic reaction to dicloxacillin in someone with a previous history of penicillin hypersensitivity. Persistent right upper quadrant pain, fevers, elevations of serum alkaline phosphatase, and a radionuclide scan which did ...

  6. TYPE IC CHOLEDOCHAL CYST PRESENTING AN EXTRAHEPATAL CHOLESTASIS IN A 3 YEAR OLD BOY

    Directory of Open Access Journals (Sweden)

    Muhammad Reza

    2015-10-01

    Full Text Available Choledochal cyst is a rare congenital dilatation of the bile ducts, mostly diagnosed in childhood. Whenappropriate resection is not performed, cholangiocarcinoma may occur in a high incidence within thesecond decade of life. This report aims to present a rare case in experience of diagnosis and managementtype IC choledochal cyst in children. We present case of a 3-year-old boy who came with jaundice anditchy skin, abdominal pain, brownish urine, pales colored of stool. Abdominal ultrasonography andcomputed tomography scan revealed type IC choledochal cyst. Patient underwent complete cyst removalsurgery and bilioenteric anastomosis through Roux-en-y hepaticojejunostomy. Excision biopsy confirmedthe diagnosis of type IC choledochal cyst. Post surgical follow up shown good physical and laboratorycondition  and  there was no  recurrence  of  symptoms. Early  surgical  procedure  through Roux-en-yhepatojejunostomy, has been performed. Long  term  follow up also  facilities good prognostic  to  thepatient. [MEDICINA 2015;46:56-60].Kista  koledokus  adalah merupakan  penyakit  saluran  empedu  bawaan  yang  jarang  dijumpai  danbanyak terdiagnosis pada saat usia anak-anak. Tindakan berupa reseksi kista adalah yang terpentingdilakukan,  jika  tidak  segera  dilakukan  maka  dapat  meningkatkan  resiko  terjadinyacholangiocarcinoma dalam usia dekade kedua penderita dalam kehidupan. Tujuan kasus ini dilaporkanuntuk menggambarkan pengalaman dalam mendiagnosis dan tata  laksana kista koledokal tipe ICyang jarang pada anak-anak. Laporan kasus ini pada anak laki-laki berumur 3 tahun dengan keluhankulit tampak kuning dan gatal, nyeri perut, urin berwarna kecoklatan, tinja yang pucat. Ultrasonografidan CT  scan abdomen memperlihatkan adanya kista koledokus. Tindakan bedah  eksisi kista dananastomosis bilioenterik dengan menggunakan tehnik hepatojejunostomi Roux-en-y. Diagnosa kistakoledokus  tipe  IC  terkonfirmasi  saat  tindakan  eksisi biopsi. Evaluasi  setelah dilakukan  tindakanbedah memperlihatkan hasil yang bagus, baik dari pemeriksaan fisik maupun pemeriksaan penunjangdan hilangnya keluhan yang ada sebelumnya. Walaupun prosedur tindakan hepatojejunustomi Roux-en-y secara dini telah dilakukan, penderita masih membutuhkan evaluasi dalam jangka waktu yanglama. [MEDICINA 2015;46:56-60].

  7. Results of the evaluation of numerical parameters of the hepatobiliary functional scintigraphy in the differential diagnosis of neonatal cholestasis

    International Nuclear Information System (INIS)

    The present study serves to differentiate the various causes of pathological icterus in the neonatal and infant period by means of data from hepatobiliary functional scintigraphy. There is only good differentiation between extrahepatic biliary atresia and the group of intrahepatic liver-diseases. The neonatal hepatitis and intrahepatic biliary atresia, both located primarily in the liver, can be differentiated only with difficulty by the hepatobiliary functional scintigraphy, because in both diseases the hepatocytes are impaired. The other causes, such as choledochal cysts, are represented by too few patients in the study to perform a useful statistical analysis. The most appropriate parameters can be found by a statistical method, the so-called Maximum-Likelihood-Method. These are the ascent of the liver curve at the time of 420 seconds p.i. (cut-off-point 0.14), the activity in the liver at the end of the examination (cut-off-point 29), the maximum of the intestinal activity (cut-off-point 11), the quotient between liver activity and the activity of the whole range of measurement at the time of the maximum of the activity of the whole range of measurement (cut-off-point 0.65), the elimination-index (cut-off-point 970) and the clinical parameter GGT (cut-off-point 200). Besides these parameters we determine in this study some others, which describe the phases of the tracer-uptake in the liver (accumulation, retention and elimination) quantitatively. From these the best are described above. We find a sensitivity of the test of 100% for diagnosing an extrahepatic biliary atresia. The specificity of the test is 85.7%

  8. Effects of Melittin Treatment in Cholangitis and Biliary Fibrosis in a Model of Xenobiotic-Induced Cholestasis in Mice

    OpenAIRE

    Kyung-Hyun Kim; Hyun-Jung Sung; Woo-Ram Lee; Hyun-Jin An; Jung-Yeon Kim; Sok Cheon Pak; Sang-Mi Han; Kwan-Kyu Park

    2015-01-01

    Cholangiopathy is a chronic immune-mediated disease of the liver, which is characterized by cholangitis, ductular reaction and biliary-type hepatic fibrosis. There is no proven medical therapy that changes the course of the disease. In previous studies, melittin was known for attenuation of hepatic injury, inflammation and hepatic fibrosis. This study investigated whether melittin provides inhibition on cholangitis and biliary fibrosis in vivo. Feeding 3,5-diethoxycarbonyl-1,4-dihydrocollidin...

  9. Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis

    OpenAIRE

    Liu, Yaping; Binz, Jane; Numerick, Mary Jo; Dennis, Steve; Luo, Guizhen; Desai, Bhasha; MacKenzie, Kathleen I.; Mansfield, Traci A.; Kliewer, Steven A.; Goodwin, Bryan; Jones, Stacey A.

    2003-01-01

    Farnesoid X receptor (FXR) is a bile acid–activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestat...

  10. Clinical, molecular and functional investigation on an infant with neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD.

    Directory of Open Access Journals (Sweden)

    Zhan-Hui Zhang

    Full Text Available BACKGROUND AND OBJECTIVE: SLC25A13 analysis has provided reliable evidences for the definitive diagnosis of citrin deficiency (CD in the past decade. Meanwhile, these studies generated some issues yet to be resolved, including the pathogenicity of SLC25A13 missense mutations and the mRNA product from the mutation c.615+5G>A. This study aims to investigate the effect of a novel missense mutation on the aspartate/glutamate carrier (AGC function of citrin protein, and to explore the aberrant transcript from c.615+5G>A in the same CD infant. METHODS AND RESULTS: By means of screening for prevalent SLC25A13 mutations and exons sequencing, the patient proved a compound heterozygote of c.615+5G>A and a novel c.1064G>A (p.Arg355Gln mutation. An aberrant transcript with retention of the entire intron 6, r.[615+1_615+1789ins; 615+5 g>a] (GenBank accession number KJ128074, which was resulted from c.615+5G>A, was detected by RT-PCR and cDNA sequencing. After bioinformatic analyses of the novel missense mutation c.1064G>A, the growth abilities of three agc1Δ yeast strains were tested, which had been transformed with recombinant or empty vectors, respectively. Besides the bioinformatically pathogenic evidences, the growth ability of the agc1Δ strains transformed with mutant recombinant was the same as with empty vector, but significantly lower than that with normal control in functional analysis. CONCLUSIONS: A CD infant was definitely diagnosed in this paper by a genetic, transcriptional and functional analysis of SLC25A13 gene. This study provided direct laboratory evidences supporting the splice-site nature of the c.615+5G>A mutation, and the novel c.1064G>A variation, which proved a pathogenic mutation bioinformatically and functionally, enriched the SLC25A13 mutation spectrum.

  11. Degradation of the Bile Salt Export Pump at Endoplasmic Reticulum in Progressive Familial Intrahepatic Cholestasis Type II (PFIC II)

    OpenAIRE

    Wang, Lin; Dong, Huiping; Soroka, Carol J.; WEI, NING; Boyer, James L.; Hochstrasser, Mark

    2008-01-01

    The bile salt export pump (Bsep) represents the major bile salt transport system at the canalicular membrane of hepatocytes. When examined in model cell lines, genetic mutations in the BSEP gene impair its targeting and transport function, contributing to the pathogenesis of PFIC II. PFIC II mutations are known to lead to a deficiency of BSEP in human hepatocytes, suggesting that PFIC II mutants are unstable and degraded in the cell. To investigate this further, we have characterized the impa...

  12. Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high-carbohydrate diet

    NARCIS (Netherlands)

    M.T. Flowers; A.K. Groen; A.T. Oler; M.P. Keller; Y. Choi; K.L. Schueler; O.C. Richards; H. Lan; M. Miyazaki; F. Kuipers; C.M. Kendziorski; J.M. Ntambi; A.D. Attie

    2006-01-01

    Stearoyl-coenzyme A desaturase 1-deficient (SCD1(-/-)) mice have impaired MUFA synthesis. When maintained on a very low-fat (VLF) diet, SCD1(-/-) mice developed severe hypercholesterolemia, characterized by an increase in apolipoprotein B (apoB)-containing lipoproteins and the appearance of lipoprot

  13. High Incidence of Rickets in Extremely Low Birth Weight Infants with Severe Parenteral Nutrition-Associated Cholestasis and Bronchopulmonary Dysplasia

    OpenAIRE

    Lee, Soon Min; Namgung, Ran; Park, Min Soo; Eun, Ho Sun; Park, Kook In; Lee, Chul

    2012-01-01

    Risk factors for rickets of prematurity have not been re-examined since introduction of high mineral formula, particularly in ELBW infants. We analyzed the incidence and the risk factors of rickets in extremely low birth weight (ELBW) infants. As a retrospective case-control study from 2004 to 2008, risk factors were analyzed in 24 patients with rickets versus 31 patients without. The frequency of rickets in ELBW infants was 24/55 (44%). Infants with rickets were diagnosed at 48.2 ± 16.1 days...

  14. Clinical significance of determination of changes of serum FE3 and immuno-function parameters levels in patients with intrahepatic cholestasis of pregnancy (ICP)

    International Nuclear Information System (INIS)

    Objective: To study the changes of serum levels of free E3, β-HCG, IgG, IgM, IgA, C3, C4 and peripheral blood CD4+, CD8+ contents in patients with ICP. Methods Serum free E3, β-HCG (with RIA), IgG, IgM, IgA, C3 and C4 (with immuno-turbidity assay) levels and peripheral blood CD4+, CD8+ contents (with flow-cytometry) were determined in 40 patients with ICP and 40 normal pregnant controls. Results Serum free E3 levels in patients with ICP were significantly higher than those in controls (P0.05). The serum IgG contents in patients with ICP were significantly lower than those in controls (P3 and C4 contents in patients with ICP were not significantly different from those in controls (P>0.05). CD4+ percentages in the patients were not significantly different from those in controls while the CD8+ percentages were significantly higher (P+/CD8+ ratio. Conclusion Significant changes of contents of serum free E3 and IgG and a lower CD4+/CD8+ ratio were present in patients with ICP, the exact mechanisms were not determined yet. (authors)

  15. A homozygous nonsense mutation (c.214C->A) in the biliverdin reductase alpha gene (BLVRA) results in accumulation of biliverdin during episodes of cholestasis

    DEFF Research Database (Denmark)

    Nytofte, Nikolaj S; Serrano, Maria A; Monte, Maria J;

    2011-01-01

    Green jaundice is a rare finding usually associated with end-stage liver disease. OBJECTIVE The authors investigated two unrelated Inuit women from different geographical areas in Greenland who had episodes of green jaundice associated with biliary obstruction.......Green jaundice is a rare finding usually associated with end-stage liver disease. OBJECTIVE The authors investigated two unrelated Inuit women from different geographical areas in Greenland who had episodes of green jaundice associated with biliary obstruction....

  16. 双歧三联活菌片对淤胆幼鼠移行性肌电复合波影响及其干预胆汁淤积的机制%Effect of Probiotics on Migrating Myoelectric Complexes of α-Naphthylisothiocyanate Induced Cholestasis on Weaned Rats and Mechanism of Probiotics on Cholestasis

    Institute of Scientific and Technical Information of China (English)

    胡玉莲; 黄志华; 王晓东; 刘萍

    2007-01-01

    目的 观察益生菌制剂对急性肝内胆汁淤积幼鼠胃肠消化间期移行性肌电复合波(MMC)影响,探讨其干预胆汁淤积的可能机制.方法 SD幼鼠96只随机分为健康对照组16只,中毒组、干预组各40只.各组随机选出8只在胃窦、十二指肠、空肠埋置3对银丝电极,余大鼠行假手术.术后7~10 d中毒及干预组1次灌服异硫氰酸萘酯(ANIT)(200 mg/kg)诱导急性肝内胆汁淤积;干预组于ANIT灌胃前2 d,灌服双歧三联活菌片4.2×108活菌/(kg·d).观察各组灌服ANIT后48、96、144、192 h胆汁流量、血总胆红素(TB)、ALT及MMC变化.结果 1.灌服ANIT后,干预组胆汁流量减少程度及血清中TB和ALT上升较中毒组轻,且恢复快.2.灌服ANIT后中毒及干预组MMC节律完全消失,代之以Ⅱ期样节律紊乱波;随后2组MMC逐渐恢复,但干预组MMC恢复时间(132.0±42.55)h明显短于中毒组(174.0±24.84)h(P<0.05);MMC节律恢复后,192 h时中毒组MMC持续时间较干预及健康对照组明显延长,其中主要是Ⅱ期持续时间延长.结论 幼鼠急性肝内胆汁淤积时MMC周期延长,甚至节律性运动消失.双歧三联活菌片能促进肠道MMC节律性运动恢复,减轻肝脏损害,有助于改善胆汁淤积.

  17. ATP8B1 deficiency; Pathophysiology and treatment of a cholestatic syndrome with extrahepatic symptoms

    OpenAIRE

    Stapelbroek, J.M.

    2009-01-01

    ATP8B1 deficiency is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It generally presents as a permanent disorder, progressive familial intrahepatic cholestasis type 1 (PFIC1), or with intermittent cholestasis (benign recurrent intrahepatic cholestasis type 1 (BRIC1)). Currently there is no effective medical therapy, and most patients need invasive surgery such as partial biliary drainage (PBD) or liver transplantation....

  18. The Bile Salt Export Pump: Clinical and Experimental Aspects of Genetic and Acquired Cholestatic Liver Disease

    OpenAIRE

    Lam, Ping; Soroka, Carol J.; Boyer, James L.

    2010-01-01

    The primary transporter responsible for bile salt secretion is the bile salt export pump (BSEP, ABCB11), a member of the ATP-binding cassette (ABC) superfamily, which is located at the bile canalicular apical domain of hepatocytes. In humans, BSEP deficiency results in several different genetic forms of cholestasis, which include progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2), as well as other acquired forms of cholestasi...

  19. ATP8B1 deficiency; Pathophysiology and treatment of a cholestatic syndrome with extrahepatic symptoms

    NARCIS (Netherlands)

    Stapelbroek, J.M.

    2009-01-01

    ATP8B1 deficiency is a severe and clinically highly variable hereditary disorder that is primarily characterized by intrahepatic cholestasis. It generally presents as a permanent disorder, progressive familial intrahepatic cholestasis type 1 (PFIC1), or with intermittent cholestasis (benign recurren

  20. Study on the relationship between the expression of placental FXR,BSEP and intrahepatic cholestasis of pregnacy%胎盘中FXR、BSEP的表达及其与ICP关系的研究

    Institute of Scientific and Technical Information of China (English)

    孟莉; 徐建英

    2011-01-01

    目的 探讨ICP胎盘中FXR、BSEP的表达,以及母、脐血清中CG(甘胆酸)水平的变化,进而从胎盘角度探讨ICP发病机制.方法 以35例ICP患者为ICP组,对照组为40例正常妊娠者.测定两组母、脐血清CG水平、母血清肝功能指标、两组胎盘组织中FXR、BSEP的表达.结果 ICP组胎盘组织中FXR的表达与母血清、脐血清CG水平呈正相关性.BSEP的表达量与母血清、脐血清CG水平呈负相关性.结论 ICP组母、脐血清CG水平明显高于对照组.ICP时,患者胎盘上FXR表达虽明显增强,但BSEP的表达并未因此而上调,反而表达减低,引起胎盘排泌胎儿胆汁酸下降,胎儿体内胆汁酸瘀积,可能是ICP发病机制之一.

  1. 基于FXR探讨茵栀黄注射液利胆退黄的机制研究%Mechanism of Yinzhihuang Injection for Intrahepatic Cholestasis Based on FXR

    Institute of Scientific and Technical Information of China (English)

    吴海滨; 佘世锋; 兰绍阳

    2016-01-01

    目的:通过研究茵栀黄注射液对肝内胆汁淤积湿热证大鼠FXR、BSEP、NTCP蛋白和基因表达的影响,探讨茵栀黄注射液的作用靶点及机制.方法:51只雄性SD大鼠随机分为正常对照组(7只)、模型组(7只)、茵栀黄注射液组(7只)、GW4064组(7只)、Guggulsterone组(7只)、茵栀黄+GW4064组(8只)、茵栀黄+Guggulsterone组(8只)共7组.造模干预后观察各组大鼠肝组织FXR、BSEP、NTCP蛋白和基因的表达.结果:茵栀黄注射液可以上调FXR蛋白和基因的表达,P<0.05.FXR和BSEP在蛋白和基因表达量上存在显著相关,P<0.05.结论:茵栀黄注射液通过干预FXR上调BSEP利胆退黄治疗肝内胆汁淤积.

  2. Regulatory Effect of UDCA on Mrp2 and Bsep of Cholestasis in Infantile Rats%熊去氧胆酸对胆汁淤积幼年大鼠Mrp2和Bsep的调控作用

    Institute of Scientific and Technical Information of China (English)

    欧巧群; 张伟; 周永梅; 于生友; 罗梅娟

    2015-01-01

    目的:研究熊去氧胆酸(UDCA)对胆汁淤积幼年大鼠的治疗作用以及胆汁酸转运体多药耐药相关蛋白2(MRP2,大鼠基因表达为Mrp2)和胆盐输出泵(BSEP,大鼠基因表达为Bsep)表达的影响,探讨该药物作用的分子机制.方法:将SD幼年大鼠随机分为正常对照组(Normal组)、胆汁淤积模型组(ANIT组)和熊去氧胆酸治疗组(UDCA组).α-萘异硫氰酸酯(ANIT)灌胃法(80 mg/kg,每周1次,共2次)诱导肝内胆汁淤积大鼠模型,分别给予安慰剂对照以及熊去氧胆酸口服(100 mg/kg,qd)治疗10 d.实验第10天处死大鼠,留取血标本进行丙氨酸氨基转移酶(ALT)、直接胆红素(DBIL)、总胆汁酸(TBA)检查,肝脏标本分别行组织病理学检查、免疫组化以及荧光定量RT-PCR检查胆汁酸转运体Mrp2和Bsep的分布以及RNA表达情况.结果:UDCA组与ANIT组比较,ALT、DBIL和TBA水平明显下降(分别为153 U/L vs 203 U/L、7 mmol/L vs 16 mmol/L、28 mmol/L vs 51 mmol/L,P<0.05),病理损害减轻,Mrp2和Bsep表达增强.结论:熊去氧胆酸能改善胆汁淤积幼年大鼠肝脏功能,减少肝细胞损害以及炎症渗出,上调胆汁酸转运体Mrp2和Bsep的表达.

  3. To investigate the mechanism of cholestasis after rat hepatic ischemia-reperfusion%鼠肝缺血再灌注后胆汁淤积发生的分子机制

    Institute of Scientific and Technical Information of China (English)

    舒明; 彭承宏; 陈皓; 沈柏用; 邱伟华; 李宏为

    2006-01-01

    目的 探讨鼠肝缺血再灌注后胆汁淤积发生的分子机制.方法 应用70%的鼠肝缺血35 min再灌注模型,检测胆汁、血浆中胆红素、胆酸的含量;荧光定量聚合酶链反应(PCR)、免疫组织化学方法分析毛细胆管膜上胆盐输出泵(Bsep)、多耐药相关蛋白2(Mrp2)的表达;激光共聚焦方法分析Mrp2定位的改变.结果 再灌注后6 h、1、3 d,Bsep的表达明显下调(mRNA表达水平分别为0.189±0.044、0.240±0.078、0.224±0.068),与胆汁、血浆中胆酸的异常改变一致.Mrp2表达的明显下调仅发生于再灌注后的6 h(mRNA表达水平为0.038±0.032),与再灌注后1 h~5 d胆红素的异常变化不相符.再灌注后6 h~5 d,Mrp2在毛细胆管膜上定位减少、向胞浆内分布.结论 Bsep表达的减少以及Mrp2定位的异常是鼠肝缺血再灌注后胆汁淤积发生的主要分子机制.

  4. Recent advances about the role of ABCB11 in intrahepatic cholestasis of pregnancy%ABCB11基因在妊娠期肝内胆汁淤积症中研究进展

    Institute of Scientific and Technical Information of China (English)

    杜永江; 吕时铭; 姚琦玮

    2008-01-01

    ABCB11基因,也称BSEP基因,其编码的蛋白称为ABCB11蛋白,是ABC转运蛋白超家族B族成员之一.ABCB11基因的表达主要受法尼醇X受体(F3(R)调控.近年研究发现,一些药物或体内的代谢产物等对ABCB11基因的调控及由基因变异等因素引起的相关蛋白功能障碍,可能在妊娠期肝内胆汁淤积症(ICP)发病中发挥重要作用,并且ABCB11基因有可能成为靶基因而作为ICP基因治疗的一种手段.

  5. ERK1/2 and p38 MAPKs Are Complementarily Involved in Estradiol 17ß-d-Glucuronide-Induced Cholestasis: Crosstalk with cPKC and PI3K

    OpenAIRE

    Andrea C Boaglio; Zucchetti, Andrés E.; Toledo, Flavia D.; Barosso, Ismael R.; Enrique J Sánchez Pozzi; Crocenzi, Fernando A.; Roma, Marcelo G.

    2012-01-01

    OBJECTIVE: The endogenous, cholestatic metabolite estradiol 17ß-D-glucuronide (E(2)17G) induces endocytic internalization of the canalicular transporters relevant to bile formation, Bsep and Mrp2. We evaluated here whether MAPKs are involved in this effect. DESIGN: ERK1/2, JNK1/2, and p38 MAPK activation was assessed by the increase in their phosphorylation status. Hepatocanalicular function was evaluated in isolated rat hepatocyte couplets (IRHCs) by quantifying the apical secretion of fluor...

  6. Colestasia Intrahepática Familiar Progresiva Tipo 3: Presentación de Casos Clínicos y Actualización de Tema Type 3 Familial Intrahepatic Cholestasis: Clinical Cases and Update

    OpenAIRE

    JOSÉ ZACARÍAS S

    2009-01-01

    La Colestasia Intrahepática Familiar Progresiva (CIFP) comprende un grupo heterogéneo de alteraciones autosómicas recesiva caracterizadas por una colestasia hepatocelular secundaria a una interrupción del proceso normal de síntesis de la bilis. Objetivo: Describir la presentación de CIFP en 3 de 5 hijos de una familia estudiada. Caso clínico: Paciente de 5 años de edad (caso 1), que presenta una hepatoesplenomegalia, aumento de enzimas hepáticas y de ácidos biliares en suero. La ecotomografía...

  7. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity

    OpenAIRE

    Verhaag, Esther M.; Manon Buist-Homan; Martijn Koehorst; Groen, Albert K; Han Moshage; Klaas Nico Faber

    2016-01-01

    Introduction Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis. Aim To investigate the mechanisms that underlie the hormetic response that protect hepatocytes agai...

  8. Steps forward, backward, and sideways: Intravenous lipid emulsions for critically ill neonates

    Science.gov (United States)

    A neonatologist doesn't need long-term memory to recall caring for babies who developed severe cholestasis leading to death or the need for a liver and/or intestinal transplant. Fortunately, there is no doubt that the situation has improved dramatically in the past 5 years. Cholestasis is resolving ...

  9. REVERSIBILITY OF CHOLESTATIC CHANGES FOLLOWING EXPERIMENTAL COMMON BILE-DUCT OBSTRUCTION - FACT OR FANTASY

    NARCIS (Netherlands)

    ARONSON, DC; CHAMULEAU, RAFM; FREDERIKS, WM; GOOSZEN, HG; HEIJMANS, HSA; JAMES, J

    1993-01-01

    In 36 male Wistar rats extrahepatic cholestasis was induced by ligation and transsection of the common bile duct. After 1, 2 and 3 weeks of cholestasis the bile flow was restored by means of a Roux-en-Y choledochojejunostomy. Plasma levels of bilirubin, alkaline phosphatase, GOT and clotting factor

  10. Vitamin A-induced cholestatic hepatitis: a case report

    DEFF Research Database (Denmark)

    Becker, P.; Maurer, B.; Schirrmacher, P.;

    2007-01-01

    We report a case of intrahepatic cholestasis due to chronic vitamin A supplementation. A 70-year-old woman was admitted to the hospital for jaundice and reduced nutritional and general status with a 2-month history of increasing cholestasis. Some years previously she had suffered from breast and ...

  11. Aquaporins: Their role in cholestatic liver disease

    Institute of Scientific and Technical Information of China (English)

    2008-01-01

    This review focuses on currant knowledge on hepato-cyte aquaporins (AQPs) and their significance in bile formation and cholestasis. Canalicular bile secretion results from a combined interaction of several solute transporters and AQP water channels that facilitate wa-ter flow in response to the osmotic gradients created. During choleresis, hepatocytes rapidly increase their canalicular membrane water permeability by modulat-ing the abundance of AQP8. The question was raised as to whether the opposite process, i.e. a decreased canalicular AQP8 expression would contribute to the development of cholestasis. Studies in several experi-mental models of cholestasis, such as extrahepatic obstructive cholestasis, estrogen-induced cholestasis, and sepsis-induced cholestasis demonstrated that the protein expression of hepatocyte AQP8 was impaired. In addition, biophysical studies in canalicular plasma membranes revealed decreased water permeability as-sociated with AQP8 protein downregulation. The com-bined alteration in hepatocyte solute transporters and AQP8 would hamper the efficient coupling of osmotic gradients and canalicular water flow. Thus cholestasis may result from a mutual occurrence of impaired sol-ute transport and decreased water permeability.

  12. Disease: H00624 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available is (PFIC); Benign recurrent intrahepatic cholestasis (BRIC); Intrahepatic cholestasis of pregnancy (ICP); North American Indian child...sis defect type 1. North American Indian childhood cirrhosis (NAIC) is a distinct, rapidly evolving form of ...familial cholestasis found in aboriginal children from northwestern Quebec. It has reported that a missense ...ssense mutation (R565W) in cirhin (FLJ14728) in North American Indian childhood cirrhosis. Am J Hum Genet 71...:1443-9 (2002) PMID:11045837 Drouin E, Russo P, Tuchweber B, Mitchell G, Rasquin-Weber A North American Indian cirrhosis in child

  13. Albumin liver dialysis as pregnancy-saving procedure in cholestatic liver disease and intractable pruritus

    Institute of Scientific and Technical Information of China (English)

    Maud Lemoine; Aurélie Revaux; Claire Francoz; Guillaume Ducarme; Sabine Brechignac; Emmanuel Jacquemin; Michèle Uzan; Nathalie Ganne-Carrié

    2008-01-01

    Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare cholestatic liver disease. Such liver disease can get worse by female hormone disorder. Albumin dialysis or Molecular Adsorbent Recirculating System (MARS) has been reported to reverse severe cholestasis-linked pruritus. Here, we report the first use of HARS during a spontaneous pregnancy and its successful outcome in a patient with PFIC3 and intractable pruritus. Albumin dialysis could be considered as a pregnancy-saving procedure in pregnant women with severe cholestasis and refractory pruritus.C 2008 The WJG Press. All rights reserved.

  14. Activated Charcoal

    Science.gov (United States)

    ... reduce intestinal gas (flatulence), lower cholesterol levels, prevent hangover, and treat bile flow problems (cholestasis) during pregnancy. ... pregnancy, according to some early research reports. Preventing hangover. Activated charcoal is included in some hangover remedies, ...

  15. Disease: H00950 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available F, Borrone C Arthrogryposis, renal dysfunction and cholestasis syndrome: report of five patients... E, Lee JJ, Park YS, Yoo HW Clinical characteristics and VPS33B mutations in patients

  16. Effect of melatonin on myocardial oxidative stress induced by experimental obstructive jaundice Efecto de la melatonina en el estrés oxidativo del miocardio en un modelo experimental de obstrucción biliar

    Directory of Open Access Journals (Sweden)

    A. Cruz

    2009-07-01

    Full Text Available Objective: melatonin has been demonstrated to have active antioxidant properties in different tissues during experimental cholestasis. The aim of this research was to study myocardial oxidative stress on obstructive jaundice, and to analyze the effect of melatonin on myocardial oxidative lesions. Material and methods: we achieved cholestasis by ligature and sectioning of the main bile duct. Melatonin was administered intraperitoneally (500 µg/kg/day. We measured malondialdehyde (MDA, reduced glutathione (GSH, catalase (CAT, superoxide dismutase (SOD and glutathione peroxydase (GPx antioxidant enzyme levels in the heart tissue. Results: obstructive cholestasis increased MDA and decreased GSH as well as all antioxidant enzymes. Melatonin administration significantly decreased MDA values, and increased GSH and antioxidant enzymes on the icteric animal myocardium. Conclusions: melatonin treatment prevents oxidative stress in the cardiac tissue as induced by experimental cholestasis.

  17. Jaundice

    Science.gov (United States)

    ... Autoimmune hepatitis Bile Biliary atresia Biliary stricture Bilirubin blood test Cholestasis Delta agent (Hepatitis D) Dubin-Johnson syndrome Gallstones Gilbert disease Hemolytic anemia Hepatitis A Hepatitis B Hepatitis C Malaria Newborn jaundice Pancreatic cancer Primary ...

  18. Quantitative liver gallbladder scintigraphy interest in the liver transplant complication and following

    International Nuclear Information System (INIS)

    Initially asked to eliminate the gallbladder complication during a cholestasis the isotope ratio may inscribe the QLBS in a grafted patient evolutive following, according to the forecast complications. 1 ref., 5 figs

  19. 妊娠肝内胆汁淤积症胎盘雌激素受体及血管舒缩因子的变化%The changes and sign ificance of the estrogen receptors on placenta and the levels of serum free estr iol,blood vessel endothelium factor in intrahepatic cholestasis of pregnancy.

    Institute of Scientific and Technical Information of China (English)

    王冬梅; 朱启英; 腊晓琳

    2002-01-01

    目的:探讨妊娠肝内胆汁淤积症(ICP )患者血清中一氧化氮(NO)、内皮素(ET)、游离雌三醇(E3)水平的变化和胎盘雌激素受体( ER)表达强度在ICP病理生理改变中的作用.方法:以ICP组30例为研究组 ,手术前30min取外周静脉血测定NO、ET及游离E3的含量,以年龄相近同期手术的30例正常孕妇作为对照组,产后从研究组和对照组中随机抽取20例的胎盘中央组织块用免疫组化法检测ER的表达强度.结果:ICP组的血清ET水平明显高于对照组(P<0.05),NO水平与对照组差异无显著性(P>0.05). ICP组血清游离E3水平显著高于对照组(P<0.01),胎盘ER阳性表达百分比显著高于对照组(P<0.05),血清中E3水平与胎盘组织中E R水平间呈正相关(r′s=0.598,P<0.01).结论:雌激素水平升高及胎盘中ER表达增强和ET水平的升高可能与ICP的发生、发展有关.

  20. Expression of bile salt export pump in placenta tissue of patients with intrahepatic cholestasis of pregnancy%胆盐输出泵在妊娠期肝内胆汁淤积症患者胎盘组织中的表达

    Institute of Scientific and Technical Information of China (English)

    宋晔; 戴建荣; 侯顺玉

    2015-01-01

    目的 探讨胆盐输出泵(BSEP)在妊娠期肝内胆汁淤积症(ICP)患者胎盘组织中的表达及意义.方法 采用免疫组织化学方法测定30例ICP患者及30例正常妊娠者胎盘组织中BSEP的表达,采用Western blot检测胎盘组织中BSEP蛋白的表达.结果 正常妊娠者和ICP患者胎盘组织中BSEP阳性表达率分别为76.7% (23/30)和36.7% (11/30),ICP患者胎盘组织中BSEP阳性表达率显著低于正常妊娠者胎盘组织(P<0.05).BSEP蛋白在正常妊娠者和ICP患者胎盘组织中的表达分别为0.754±0.274和0.193±0.122,BSEP蛋白在ICP患者胎盘组织中的表达显著少于正常妊娠者胎盘组织(P <0.001).结论 BSEP在ICP患者胎盘组织中表达显著减少,可能是导致ICP的发病机制之一.

  1. The potential risky factors incurring the bad outcomes of intrahepatic cholestasis of pregnancy%影响ICP围生儿不良结局潜在风险因素及其与BSEP基因多态性的关系研究

    Institute of Scientific and Technical Information of China (English)

    林萍

    2014-01-01

    目的 探讨影响妊娠期肝内胆汁淤积症围生儿不良结局的潜在风险因素.方法 对该院2010年5月-2013年5月接受治疗的40例不良结局和46例良好结局的ICP患者进行病史记录搜集,对肝功能、血清总胆汁酸、胎儿监测结果以及BSEP基因等指标进行回顾性分析,并采用SPSS 18.0软件对搜集的数据进行独立样本t检验和X 2检验.结果 两种结局患者的TBA,S/D值,NST值差异具有统计学意义,其他指标差异无统计学意义;不良结局组BSEP基因rs2287622位点C、T等位基因频率分别为83.75%和16.25%,良好结局组该位点C、T等位基因频率分别为66.30%和33.70%,两组间比较差异有统计学意义(P<0.05).结论 血清总胆汁酸水平以及脐血流(S/D)和胎心无负荷试验(NST)的检测结果是ICP围生儿出现不良结局的高危风险因素,也是很敏感的指标,对预测ICP围生儿是否产生不良结局具有很大的指导意义,BSEP基因rs2287622位点多态性(C/T)可能和妊娠期肝内胆汁淤积有关.

  2. Expression of Bsep and Mrp2 in liver of cirrhotic rats with intrahepatic cholestasis after ischemia-reperfusion injury%肝硬化大鼠肝缺血-再灌注损伤后Bsep、Mrp2表达在胆汁淤积中的作用研究

    Institute of Scientific and Technical Information of China (English)

    舒明; 王火平; 胡笑蓉; 黄左安; 黄丹丹; 王咖; 张顺

    2015-01-01

    目的 研究肝硬化大鼠肝缺血-再灌注损伤(HIRI)后胆汁淤积的部分分子机制.方法 将健康SD大鼠随机分成A、B、C3组,每组15只,建立肝硬化、HIRI模型.A组为正常大鼠HIRI组,B组为肝硬化大鼠假手术组,C组为肝硬化大鼠HIRI组.每组大鼠肝门阻断时间为30min.分别检测各组大鼠术后第1、3、5天的胆汁DBil、TBil含量,血清AST、ALT、TBil、DBil含量;Western blot分析各组大鼠术后第1、3、5天胆盐输出泵(Bsep)、多耐药相关蛋白2(Mrp2)表达变化;免疫组织化学法分析Bsep蛋白的细胞亚定位.结果 术后第1天,C组大鼠胆汁TBil、DBil含量均低于A组(均P<0.05);术后第3天,C组大鼠胆汁TBil、DBil含量均低于A组和B组(均P<0.05);术后第5天,3组大鼠胆汁TBil、DBil含量比较差异均无统计学意义(均P>0.05).C组大鼠术后第1、3天血清AST、ALT水平均高于A组,术后第1、3、5天血清TBil、DBil含量均高于A、B组(均P<0.05).术后第1、3、5天,C组大鼠Bsep蛋白表达量均低于A组,术后第3、5天均低于B组(均P<0.05);C组Mrp2表达均低于A、B组(均P<0.05).肝细胞Bsep蛋白明显向细胞质移位.结论 与正常肝脏相比,硬化肝对缺血耐受能力差,HIRI后硬化肝的胆汁淤积情况更加严重.Bsep、Mrp2表达降低以及Bsep蛋白由细胞膜向细胞质移位的改变在硬化肝HIRI后胆汁淤积中起了重要作用.

  3. 茵陈对肝内胆汁淤积湿热证大鼠利胆退黄作用机制的研究%The Choleretic and Jaundice-relieving Mechanism of Yinchen on Rat with Intrahepatic Cholestasis and Damp-heat

    Institute of Scientific and Technical Information of China (English)

    兰绍阳; 佘世锋

    2012-01-01

    目的 通过研究茵陈对肝内胆汁淤积湿热证大鼠肝组织中胆盐输出泵(BSEP)基因表达的影响,从分子水平探讨茵陈利胆退黄的作用机制.方法 45只雄性SD大鼠随机分为3组:正常组、模型对照组和茵陈组.检测治疗后大鼠血清生化指标、肝脏组织病理的变化和肝脏BSEP的表达.结果 治疗后茵陈组大鼠体质量增加明显高于模型对照组(P<0.05).茵陈组大鼠血清TB、DB、ALT、AST、ALP、TBA浓度低于模型对照组(P<0.05);HE染色显示茵陈组大鼠肝脏的病理损害轻于模型对照组.免疫组织化学染色显示茵陈组大鼠比模型对照组有更多的BSEP阳性细胞.荧光定量RT-PCR法显示模型对照组大鼠肝组织中BSEP mRNA表达明显低于茵陈组(P<0.05).结论 茵陈能有效改善肝内胆汁淤积湿热证大鼠的肝功能、减轻病理损害,并能上调肝脏BSEP的表达.

  4. 白藜芦醇退黄保肝作用及其与胆汁酸排泄的相关性研究%Protective effects of resveratrol against α-naphthylisothiocyanate-induced cholestasis and its relationship with bile acid excretion

    Institute of Scientific and Technical Information of China (English)

    姜超; 刘家云; 翟兢; 李为苏; 王琼; 许哲

    2015-01-01

    目的:研究白藜芦醇的退黄保肝作用及其与胆汁酸代谢转运的相关性.方法:采用α-萘异硫氰酸酯(ANIT)致大鼠胆汁淤积性肝损伤模型,观察白藜芦醇退黄保肝的作用;原代大鼠三明治肝细胞模型上,观察白藜芦醇对ANIT损伤的肝细胞胆汁排泄,肝细胞内总胆固醇、总胆汁酸和总胆红素,以及对胆汁酸排泄相关代谢酶、转运体基因表达的影响.结果:白藜芦醇能显著降低ANIT所致胆汁淤积性肝损伤大鼠模型中血清丙氨酸氨基转移酶(ALT)、天门冬氨酸氨基转移酶(AST)活性及总胆红素(TBIL)、直接胆红素(DBIL)和间接胆红素(IBIL)的含量.在原代大鼠三明治肝细胞模型上白藜芦醇可恢复ANIT所致原代肝细胞胆管外排指数(BEI)的降低;显著降低ANIT所致的肝细胞内总胆汁酸和总胆红素的升高,恢复ANIT所致的总胆固醇水平的降低.白藜芦醇可显著改善ANIT所致的胆汁外排转运体Bsep、Mrp2、胆汁酸摄取转运体Ntcp及胆汁酸代谢相关酶Cyp7a1、Cyp8b1 mRNA表达的降低.结论:白藜芦醇具有退黄保肝、改善胆汁淤积的作用,其机制与调节肝细胞上胆汁酸排泄相关代谢酶和转运体相关.

  5. 利福平对小鼠肝细胞胆汁酸转运体Bsep和Mrp2表达与定位的影响%Change of expression and localization of canalicular Bsep and Mrp2 in rifampicin-induced cholestasis in mice

    Institute of Scientific and Technical Information of China (English)

    曹云海; 陈熙; 张程; 石嫦娥; 徐德祥; 许建明

    2010-01-01

    目的 利福平(Rifampicin, RIF)具有肝毒性,但其机制尚不清楚.本研究在RIF诱导的肝内胆汁淤积小鼠中,探讨RIF对肝细胞胆汁酸转运体胆汁酸输出泵(bile salt export pump, Bsep)和多药抵抗相关蛋白-2(multidrug resistance-associated protein-2, Mrp2)表达和定位影响.方法 48只♀ ICR小鼠随机分为4组,RIF 1 wk组:经灌胃给予RIF(200 mg·kg-1·d -1),连续1周,于末次给药后6 h取材;RIF 6 h组:单次灌胃给予RIF(200 mg·kg-1)后6 h取材;RIF 1周对照组(CON 1 wk)与RIF 6 h对照组 (CON 6 h):经灌胃给予等容积生理盐水.所有小鼠均收集血液和肝组织,常规生化检测血清丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)、碱性磷酸酶(ALP)、总胆红素(TB)和结合胆红素(DB),并检测小鼠血清和肝组织总胆汁酸(TBA)水平.HE染色分析肝组织病理改变.RT-PCR测定肝脏肝细胞胆汁酸转运体Bsep和Mrp2 mRNA表达.免疫荧光法分析Bsep和Mrp2在肝细胞的位置.结果 给予RIF 1周后,小鼠血清TB由(1.25±0.69) μmol·L-1上升至(65.73±12.08) μmol·L-1,上升近70倍,DB由(0.77±0.40) μmol·L-1上升至(53.33±12.43) μmol·L-1,上升约80倍,ALP由(110.2±13.8) U·L-1上升至(279.5±80.4) U·L-1,上升约1.5倍,TBA由(3.15±0.89) μmol·L-1上升至(13.54±6.51) μmol·L-1,上升约5倍并伴有血清ALT和AST轻度升高;肝脏组织TBA由(0.15±0.04) μmol·g-1 liver上升至(0.30±0.19) μmol·g-1 liver,上升约2倍;肝脏组织HE染色显示肝细胞出现脂肪变性、轻度坏死和炎症.单次给予RIF 6 h后血清TB、DB、ALP、ALT、AST和TBA明显上升,但未观察到小鼠肝脏组织病理发生改变.免疫荧光分析显示,给予小鼠RIF 1 wk与单次给予RIF 6 h后肝细胞中Bsep和Mrp2的定位发生了改变.而无论单次给予RIF还是连续给药1周,肝细胞Bsep和Mrp2 mRNA表达水平均未发生变化.结论 肝细胞胆汁酸转运体Bsep和Mrp2定位改变可能是RIF诱发肝内胆汁淤积的重要机制.

  6. Study on hepatotoxicity of aqueous extracts of Polygonum multiflorum in rats after 28-day oral administration: cholestasis-related mechanism%何首乌水提物大鼠连续灌胃给药28 d肝毒性研究——胆汁淤积相关机制探讨

    Institute of Scientific and Technical Information of China (English)

    王涛; 王佳颖; 周植星; 江振洲; 李妍妍; 张良; 张陆勇

    2015-01-01

    目的:考察何首乌水提物(AEPM)对大鼠肝脏中胆汁酸合成、代谢、转运相关分子影响,探讨何首乌肝毒性相关机制.方法:SD大鼠分别灌胃AEPM60,30 g·kg-1,每天1次,连续28 d.28 d后解剖取肝脏,分别采用荧光定量PCR和Westernblot检测肝脏MRP3,MRP2,BSEP,FXR,CYP7A1等分子的mRNA和蛋白表达水平.结果:与正常组相比,AEPM高剂量组雄性大鼠肝脏中MRP3和BSEP的mRNA表达均显著升高(P<0.05),而AEPM高、低剂量组肝脏FXR的mRNA表达均显著降低(P<0.05);AEPM高、低剂量组雌性大鼠肝脏MRP3,MRP2,BSEP,CYP7A1的mRNA表达均显著升高(P<0.05).Westernblot检测结果显示,AEPM高、低剂量给药组雄性和雌性大鼠肝脏中MRP3,MRP2,BSEP,FXR,CYP7A1蛋白表达水平与mRNA变化基本一致,但均未达统计学显著差异.结论:AEPM大鼠灌胃给药28 d对肝脏胆汁酸合成、转运、排泄相关蛋白的表达具有一定的影响,在mRNA表达水平既具有胆汁淤积分子特征,同时也可见促进胆汁酸排泄的分子特征.

  7. Effect of Choleretic and Jaundice-relieving Method on the BSEP expresion in the livers of rats with intrahepatic cholestasis and damp-heat%利胆退黄法对肝内胆汁淤积湿热证大鼠BSEP表达的影响

    Institute of Scientific and Technical Information of China (English)

    兰绍阳; 佘世锋; 张达坤; 陶双友

    2012-01-01

    目的:通过研究利胆退黄法对肝内胆汁淤积湿热证大鼠肝组织中BSEP基因表达的影响,以期进一步从分子水平探讨利胆退黄法的作用靶点及机制.方法:45只雄性SD大鼠随机分为3组:正常组、模型对照组和治疗组.检测治疗后大鼠血清生化指标、肝脏组织病理的变化和肝脏BSEP的表达.结果:治疗后治疗组大鼠体重增加(31.39±3.72 g)明显高于模型对照组大鼠(22.36±3.32 g),P<0.05.治疗组大鼠血清TB、DB、ALT、AST、ALP、TBA分别为13.90±2.88 μmol/L,7.47±2.70μmol/L,75.33±9.42 U/L,216.64±31.20 U/L,226.40±32.86 U/L,19.73±2.10 μmol/L),低于模型对照组(34.72±3.65μmol/L,19.33±3.27 μmol/L,123.73±18.51 U/L,353.78±63.08 U/L,355.49±63.08 U/L,36.15±6.77 μmol/L),P <0.05;HE染色显示治疗组大鼠肝脏的病理损害轻于模型对照组.免疫组织化学染色显示治疗组大鼠比模型对照组表达更多BSEP阳性细胞.荧光定量RT- PCR法显示模型对照组大鼠肝组织中BSEP mRNA表达(2-△△CT值1.49±0.49)明显低于治疗组(2-△△CT值1.96±0.66),P<0.05.结论:利胆退黄法能有效改善肝内胆汁淤积湿热证大鼠的肝功能、减轻病理损害,并能上调肝脏BSEP的表达.

  8. Acute Cholestatic Hepatitis A Virus Infection Presenting with Hemolytic Anemia and Renal Failure: A Case Report

    OpenAIRE

    Lapp, Robert T.; Fedja Rochling

    2013-01-01

    Hepatitis A virus is the most common acute viral hepatitis worldwide with approximately 1.5 million cases annually. Hepatitis A virus infection in general is self-limited. In rare cases, hepatitis A virus infection may cause renal failure, hemolytic anemia, and/or cholestasis. We report the first case of acute cholestatic hepatitis A virus infection complicated by hemolytic anemia, and renal failure in one patient. A 42-year-old Caucasian male presented with cholestasis, hemolytic anemia and ...

  9. Management of common bile duct stricture caused by chronic pancreatitis with metal mesh self expandable stents.

    OpenAIRE

    Deviere, J; M Cremer; Baize, M; Love, J; Sugai, B; Vandermeeren, A

    1994-01-01

    Twenty patients with chronic pancreatitis and signs of biliary obstruction were treated by endoscopic placement of self expandable metal mesh stents, and followed up prospectively. Eleven had been treated previously with plastic endoprostheses. All had persistent cholestasis, seven patients had jaundice, and three overt cholangitis. Endoscopic stent placement was successful in all cases. No early clinical complication was seen and cholestasis, jaundice or cholangitis rapidly resolved in all p...

  10. TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury[S

    OpenAIRE

    Matsubara, Tsutomu; Tanaka, Naoki; Sato, Misako; Kang, Dong Wook; Krausz, Kristopher W.; Flanders, Kathleen C.; Ikeda, Kazuo; Luecke, Hans; Wakefield, Lalage M.; Frank J. Gonzalez

    2012-01-01

    Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohisto...

  11. Conjugated bile acids promote cholangiocarcinoma cell invasive growth through activation of sphingosine 1-phosphate receptor 2

    OpenAIRE

    Liu, Runping; Zhao, Renping; Zhou, Xiqiao; Liang, Xiuyin; Campbell, Deanna JW; Zhang, Xiaoxuan; ZHANG, LUYONG; Shi, Ruihua; Wang, Guangji; Pandak, William M.; Sirica, Alphonse E.; Hylemon, Phillip B.; Zhou, Huiping

    2014-01-01

    Cholangiocarcinoma (CCA) is an often fatal primary malignancy of the intra- and extrahepatic biliary tract that is commonly associated with chronic cholestasis and significantly elevated levels of primary and conjugated bile acids (CBAs), which are correlated with bile duct obstruction (BDO). BDO has also recently been shown to promote CCA progression. However, whereas there is increasing evidence linking chronic cholestasis and abnormal bile acid profiles to CCA development and progression, ...

  12. Hereditäre Defekte hepatobiliärer Transportproteine

    OpenAIRE

    Mwinyi, J.; Kullak-Ublick, G A

    2010-01-01

    Defects in transport proteins that are expressed at the hepatocyte canalicular membrane can cause severe impairment of hepatobiliary transport processes. Progressive familial intrahepatic cholestasis (PFIC) typically manifests in early childhood. Genetic variants in the aminophospholipid transporter FIC1 (ATP8B1 gene) cause PFIC1, characterized by elevated serum bile acids but normal or only mildly elevated gamma-GT levels. Benign recurrent intrahepatic cholestasis type 1 (BRIC1) is also caus...

  13. The Role of Bile Salt Export Pump Gene Repression in Drug-Induced Cholestatic Liver Toxicity

    OpenAIRE

    Garzel, Brandy; Yang, Hui; Zhang, Lei; Huang, Shiew-Mei; Polli, James E.; Wang, Hongbing

    2014-01-01

    The bile salt export pump (BSEP, ABCB11) is predominantly responsible for the efflux of bile salts, and disruption of BSEP function is often associated with altered hepatic homeostasis of bile acids and cholestatic liver injury. Accumulating evidence suggests that many drugs can cause cholestasis through interaction with hepatic transporters. To date, a relatively strong association between drug-induced cholestasis and attenuated BSEP activity has been proposed. However, whether repression of...

  14. Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump

    OpenAIRE

    Chen, Yuan; Vasilenko, Alex; Song, Xiulong; Valanejad, Leila; Verma, Ruchi; You, Sangmin; Yan, Bingfang; Shiffka, Stephanie; Hargreaves, Leeza; Nadolny, Christina; Deng, Ruitang

    2015-01-01

    Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such tr...

  15. Biosynthesis and Trafficking of the Bile Salt Export Pump, BSEP: Therapeutic Implications of BSEP Mutations

    OpenAIRE

    Soroka, Carol J.; Boyer, James L.

    2013-01-01

    The bile salt export pump (BSEP, ABCB11) is the primary transporter of bile acids from the hepatocyte to the biliary system. This rate-limiting step in bile formation is essential to the formation of bile salt dependent bile flow, the enterohepatic circulation of bile acids, and the digestion of dietary fats. Mutations in BSEP are associated with cholestatic diseases such as progressive familial intrahepatic cholestasis type 2 (PFIC2), benign recurrent intrahepatic cholestasis type 2 (BRIC2),...

  16. Function and regulation of the human bile salt export pump

    OpenAIRE

    Plass, Jacqueline Regina Maria

    2005-01-01

    During the past decade, important progress has been made in our understanding of the pathophysiology of cholestasis. Inherited disorders have been explained at the molecular level and were shown to be the result of mutations in enzymes involved in bile salt biosynthesis or transmembrane transporters involved in bile formation. Acquired cholestasis, for instance due to inflammation, is linked to disregulation of these proteins. The challenge of future research is to use this knowledge to devel...

  17. Alagille syndrome.

    OpenAIRE

    Krantz, I D; Piccoli, D A; Spinner, N B

    1997-01-01

    Alagille syndrome (OMIM 118450) is an autosomal dominant disorder associated with abnormalities of the liver, heart, eye, skeleton, and a characteristic facial appearance. Also referred to as the Alagille-Watson syndrome, syndromic bile duct paucity, and arteriohepatic dysplasia, it is a significant cause of neonatal jaundice and cholestasis in older children. In the fully expressed syndrome, affected subjects have intrahepatic bile duct paucity and cholestasis, in conjunction with cardiac ma...

  18. Congenital Cholestatic Syndromes: What Happens When Children Grow Up?

    OpenAIRE

    Ling, Simon C.

    2007-01-01

    Although advances in the management of children with congenital cholestasis have enabled many to survive into adulthood with their native livers, even the most common of these conditions remains rare in adult hepatology practice. Among four congenital cholestatic syndromes (biliary atresia, Alagille syndrome, Caroli disease and congenital hepatic fibrosis, and progressive familial intrahepatic cholestasis), the published data on outcomes of the syndromes into adulthood suggest that a spectrum...

  19. Oxidative stress influence on renal dysfunction in patients with obstructive jaundice: A case and control prospective study

    OpenAIRE

    David Martínez-Cecilia; María Reyes-Díaz; Juan Ruiz-Rabelo; Manuel Gomez-Alvarez; Carmen Muñoz Villanueva; José Álamo; Jordi Muntané; Francisco Javier Padillo

    2016-01-01

    Background: Obstructive Jaundice (OJ) is associated with a significant risk of developing acute renal failure (ARF). The involvement of oxidative stress in the development of cholestasis has been demonstrated in different experimental models. However, its role in the morbidity of human cholestasis is far to be elucidated. The aim of the study was the evaluation of oxidative stress markers in blood from patients with OJ and its relation to complications and benign/malignant evolution of choles...

  20. Urosodeoxycholic Acid Therapy in a Child with Trimethoprim-Sulfamethoxazole-induced Vanishing Bile Duct Syndrome

    OpenAIRE

    Cho, Hyun Jeong; Jwa, Hye Jeong; Kim, Kyu Seon; Gang, Dae Yong; Kim, Jae Young

    2013-01-01

    We present a case of a 7-year-old boy who had cholestasis after trimethoprim-sulfamethoxazole combination therapy. Liver biopsy was performed 36 days after the onset of jaundice because of no evidence of improving cholestasis. Liver histology revealed portal inflammation, bile plug, and biliary stasis around the central vein with the loss of the interlobular bile ducts. Immunohistochemical stains for cytokeratin 7 and 19 were negative. These findings were consistent with those of vanishing bi...

  1. Preventive effect of ursodeoxycholic acid on parenteral nutrition-associated liver disease in infants

    OpenAIRE

    Simić Dušica; Milojević Irina; Bogićević Dragana; Milenović Miodrag; Radlović Vladimir; Drašković Biljana; Uram-Benka Anna; Sinđić Sanja; Maksimović Ružica

    2014-01-01

    Introduction. Parenteral nutrition-associated cholestasis is well recognized phenomenon in the term and preterm infant receiving long-term parenteral nutrition. Objectives. The aim of this study was to evaluate the effect of ursodeoxycholic acid (UDCA) use on cholestasis in newborns on prolonged TPN. Methods. A total of 56 infants were enrolled in this retrospective study: control group consisted of lower (1500 g) birth weight infants (n=30), as well as the...

  2. Severe sustained cholestatic hepatitis following temozolomide in a patient with glioblastoma multiforme: case study and review of data from the FDA adverse event reporting system.

    Science.gov (United States)

    Sarganas, Giselle; Orzechowski, Hans D; Klimpel, Andreas; Thomae, Michael; Kauffmann, Wolfgang; Herbst, Hermann; Bronder, Elisabeth; Garbe, Edeltraut

    2012-05-01

    Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults. Its established first-line adjuvant treatment is radiotherapy in combination with temozolomide (TZM). Hematotoxicity is listed as a frequent adverse drug reaction in the US prescribing information and hepatotoxicity has been reported infrequently in the postmarketing period. We here present the case of a patient diagnosed with GBM who developed severe sustained cholestatic hepatitis following treatment with TZM. The cholestasis was not reversible after withdrawal of TZM during 6 months before the patient's death. Another 2 published case reports of sustained cholestasis following TZM treatment were identified; however, the sustained nature of cholestasis was not emphasized in these reports. Sixteen cases of cholestatic hepatitis/cholestasis associated with TZM were identified in the FDA spontaneous reporting system between 2007 and 2010. Information on the course of the cholestasis in these cases could not be retrieved. In the literature there are other published reports of hepatotoxicity associated with TZM that have reported reversibility upon withdrawal of the drug. Thus, TZM appears to cause different types of hepatotoxicity. Particular attention should be paid to sustained cholestasis as a very serious type of TZM-associated liver toxicity. PMID:22394496

  3. Taking the next step forward - Diagnosing inherited infantile cholestatic disorders with next generation sequencing.

    Science.gov (United States)

    Herbst, S M; Schirmer, S; Posovszky, C; Jochum, F; Rödl, T; Schroeder, J A; Barth, T F; Hehr, U; Melter, M; Vermehren, J

    2015-10-01

    Identifying rare genetic forms of infantile cholestasis is challenging due to their similar clinical presentation and their diverse etiology. After exclusion of common non-genetic causes a huge list of rare differential diagnosis remains to be solved. More than 90 genes are associated with monogenic forms of infantile cholestasis, thus preventing routine genetic workup by Sanger sequencing. Here we demonstrate a next generation sequencing approach to discover the underlying cause in clinically well characterized patients in whom common causes of infantile cholestasis have been excluded. After validation of the analytical sensitivity massive parallel sequencing was performed for 93 genes in six prospectively studied patients. Six novel mutations (PKHD1: p.Thr777Met, p.Tyr2260Cys; ABCB11: p.Val1112Phe, c.611+1G > A, p.Gly628Trpfs*3 and NPC1: p.Glu391Lys) and two known pathogenic mutations were detected proving our multi gene panel for infantile cholestasis to be a sensitive and specific method overcoming the complexity of the phenotype-based, candidate gene approach. Three exemplary clinical cases of infants with cholestasis are presented and discussed in the context of their genetic and histopathological findings (autosomal recessive polycystic kidney disease, atypical PFIC and Niemann-Pick syndrome type C1). These case reports highlight the critical impact of integrating clinical, histopathological and genetic data during the process of multi gene panel testing to ultimately pinpoint rare genetic diagnoses. PMID:25771912

  4. Ondansetron to Treat Pruritus Due to Cholestatic Jaundice

    Science.gov (United States)

    Dillon, Sarah; Tobias, Joseph D.

    2013-01-01

    Intractable itching is a symptom of cholestatic liver disease of various causes that is bothersome and difficult to manage. Although treatment of the primary cause of cholestasis is paramount in resolving the issue, given the debilitating consequences of pruritus, symptomatic treatment is frequently necessary. Although many medications including cholestyramine, rifampin, opioid antagonists (i.e., naloxone, naltrexone), phenobarbital, and antihistamines have been used to treat cholestatic-induced pruritus, none has resulted in uniform success. We report anecdotal success with the use of ondansetron to treat pruritus associated with cholestasis following prolonged intensive care unit course of a 16-year-old. The theories accounting for pruritus with cholestasis are presented, treatment options are reviewed, and the role of ondansetron in the treatment of pruritus is discussed. PMID:24052788

  5. Disseminated langerhans cell histiocytosis presenting as cholestatic jaundice.

    Science.gov (United States)

    Kapoor, Rohit; Loizides, Anthony M; Sachdeva, Soumya; Paul, Premila

    2015-02-01

    Langerhans cell histiocytosis (LCH) is a disorder associated with proliferation of Langerhans cells in various organs. LCH secondary to multisystem involvement can present in a variety of ways. Because of its infiltrative nature, LCH can involve the skin, lymph nodes, the lung or the liver. Jaundice in LCH is a manifestation of liver disease; biliary dilatation secondary to lithiasis or may be due to coexistent Niemann-Pick disease. However, a case of cholestasis has been very rarely described. Cholestasis may result from lymph nodes obstructing the porta hepatis. In this report, we describe a case of type II histiocytosis X with obstructive cholestasis and pulmonary involvement in the form of cysts without significant lymphadenopathy at the porta. PMID:25859497

  6. Ondansetron to treat pruritus due to cholestatic jaundice.

    Science.gov (United States)

    Dillon, Sarah; Tobias, Joseph D

    2013-07-01

    Intractable itching is a symptom of cholestatic liver disease of various causes that is bothersome and difficult to manage. Although treatment of the primary cause of cholestasis is paramount in resolving the issue, given the debilitating consequences of pruritus, symptomatic treatment is frequently necessary. Although many medications including cholestyramine, rifampin, opioid antagonists (i.e., naloxone, naltrexone), phenobarbital, and antihistamines have been used to treat cholestatic-induced pruritus, none has resulted in uniform success. We report anecdotal success with the use of ondansetron to treat pruritus associated with cholestasis following prolonged intensive care unit course of a 16-year-old. The theories accounting for pruritus with cholestasis are presented, treatment options are reviewed, and the role of ondansetron in the treatment of pruritus is discussed. PMID:24052788

  7. Different morphologic aspects and clinical features in massive hepatic amyloidosis.

    Science.gov (United States)

    Melato, M; Manconi, R; Magris, D; Morassi, P; Benussi, D G; Tiribelli, C

    1984-01-01

    4 cases of massive hepatic amyloidosis are reported with special reference to their clinical profiles and histologic features. On the basis of these data, two different clinical and histologic courses of the disease can be distinguished. 2 patients showed marked hepatomegaly without cholestasis, whereas in the other 2 the clinical picture was characterized by much less pronounced hepatomegaly, but by severe and progressive intrahepatic cholestasis. The time course of the disease seems to be different in the two forms, the cholestatic form being more rapidly fatal than the other. PMID:6745505

  8. Phospholipase D2 mediates signaling by ATPase class I type 8B membrane 1[S

    OpenAIRE

    Chen, Frank; Ghosh, Ayantika; Shneider, Benjamin L.

    2013-01-01

    Functional defects in ATPase class I type 8B membrane 1 (ATP8B1 or familial intrahepatic cholestasis 1, FIC1) lead to cholestasis by mechanism(s) that are not fully understood. One proposed pathophysiology involves aberrant signaling to the bile acid sensor, the farnesoid X receptor (FXR), via protein kinase C ζ (PKCζ). The following cell line-based studies investigated whether phospholipase D2 may transduce a signal from FIC1 to FXR. PLD2 gain of function led to activation of the bile salt e...

  9. Altered expression and function of canalicular transporters during early development of cholestatic liver injury in Abcb4-deficient mice

    OpenAIRE

    Cai, Shi-Ying; Mennone, Albert; Soroka, Carol J.; Boyer, James L.

    2014-01-01

    Deficiency of ABCB4 is associated with several forms of cholestasis in humans. Abcb4−/− mice also develop cholestasis, but it remains uncertain what role other canalicular transporters play in the development of this disease. We examined the expression of these transporters in Abcb4−/− mice compared with their wild-type littermate controls at ages of 10 days and 3, 6, and 12 wk. Elevated plasma bile acid levels were already detected at 10 days and at all ages thereafter in Abcb4−/− mice. The ...

  10. Hepatocyte transplantation in bile salt export pump-deficient mice: selective growth advantage of donor hepatocytes under bile acid stress

    OpenAIRE

    Chen, Huey-Ling; Chen, Hui-Ling; Yuan, Ray-Hwang; Wu, Shang-Hsin; Chen, Ya-Hui; Chien, Chin-Sung; Chou, Shi-Ping; Wang, Renxue; Ling, Victor; Chang, Mei-Hwei

    2012-01-01

    The bile salt export pump (Bsep) mediates the hepatic excretion of bile acids, and its deficiency causes progressive familial intrahepatic cholestasis. The current study aimed to induce bile acid stress in Bsep −/− mice and to test the efficacy of hepatocyte transplantation in this disease model. We fed Bsep −/− and wild-type mice cholic acid (CA) or ursodeoxycholic acid (UDCA). Both CA and UDCA caused cholestasis and apoptosis in the Bsep −/− mouse liver. Wild-type mice had minimal liver inj...

  11. Oral contraceptives induced hepatotoxicity

    Directory of Open Access Journals (Sweden)

    B. Akshaya Srikanth

    2013-02-01

    Full Text Available Oral Contraceptives are the pharmacological agents used to prevent pregnancy. These are divided as the combined and progestogen methods and are administered orally, transdermally, systemically and via vaginal route. All these methods contain both oestrogen and progestogen. Vigorous usage of oral contraceptives and anabolic steroids as associated with cholestasis, vascular lesions and hepatic neoplasm. Benign hepatic neoplasms are clearly associated with oral contraceptives. In this article we discuss the various hepatocellular complications like cholestasis, benign neoplasm and hepatocellular carcinoma occurred by oral contraceptives. [Int J Basic Clin Pharmacol 2013; 2(1.000: 91-93

  12. Cystic diseases of the biliary tract and liver

    Directory of Open Access Journals (Sweden)

    Nafiye Urgancı

    2008-06-01

    Full Text Available Cystic diseases of liver are recognized in infancy and childhood initially. Cystic diseases of liver and biliary tract are choledocal cysts, autosomal recessive and autosomal dominant polycystic kidney disease, congenital hepatic fibrosis and Caroli disease (cystic dilatation of intrahepatic bile ducts. Choledochal cysts and Caroli disease do not allow biliary flow, cause chronic or obstructive cholestasis and progressive liver disease. In congenital hepatic fibrosis and polycystic kidney disease there is cystic formations at terminal interlobular bile ducts, but cholestasis is not seen. They don’t cause liver and biliary tract functional disturbances. (Turk Arch Ped 2008; 43: 40-5

  13.  Bile salt export pump deficiency disease: two novel, late onset, ABCB11 mutations identified by next generation sequencing.

    Science.gov (United States)

    Vitale, Giovanni; Pirillo, Martina; Mantovani, Vilma; Marasco, Elena; Aquilano, Adelia; Gamal, Nesrine; Francalanci, Paola; Conti, Fabio; Andreone, Pietro

    2016-01-01

     Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive cholestatic diseases of childhood and represents the main indication for liver transplantation at this age; PFIC2 involves ABCB11 gene, that encodes the ATPdependent canalicular bile salt export pump (BSEP). Benign intrahepatic cholestasis (BRIC) identifies a group of diseases involving the same genes and characterized by intermittent attacks of cholestasis with no progression to liver cirrhosis. Diagnosis with standard sequencing techniques is expensive and available only at a few tertiary centers. We report the application of next generation sequencing (NGS) in the diagnosis of the familial intrahepatic cholestasis with a parallel sequencing of three causative genes. We identified the molecular defects in ABCB11 gene in two different probands who developed a severe cholestatic disease of unknown origin. In the first patient a compound heterozygosity for the novel frameshift mutation p.Ser1100GlnfsX38 and the missense variant p.Glu135Lys was detected. In the second patient, triggered by contraceptive therapy, we identified homozygosity for a novel missense variant p.Ala523Gly. In conclusion, these mutations seem to have a late onset and a less aggressive clinical impact, acting as an intermediate form between BRIC and PFIC. PMID:27493120

  14. Newly Identified Mechanisms of Total Parenteral Nutrition Related Liver Injury

    OpenAIRE

    Ajay Kumar Jain; Teckman, Jeffrey H.

    2014-01-01

    Total parenteral nutrition (TPN), a lifesaving therapy, involves providing nutrition by bypassing the gut. Unfortunately it is associated with significant complications including gut atrophy and parenteral nutrition associated liver disease (PNALD). PNALD includes steatosis, cholestasis, disrupted glucose metabolism, disrupted lipid metabolism, cirrhosis, and liver failure. The etiopathogenesis remains poorly defined; however, an altered enterohepatic circulation, disrupting nuclear receptor ...

  15. Lipid emulsions containing fish oil protect against PN-induced cholestatic liver disease in preterm piglets

    Science.gov (United States)

    During their first weeks of life preterm infants are dependent on parenteral nutrition (PN). However, PN is associated with the development of cholestasis (PN Associated Liver Disease PNALD). Studies in children showed that fish oil-based lipid emulsions can reverse PNALD; whether they prevent PNALD...

  16. Hepatobiliary scintigraphy in the evaluation of feline liver disease.

    Science.gov (United States)

    Newell, S M; Selcer, B A; Roberts, R E; Cornelius, L M; Mahaffey, E A

    1996-01-01

    Hepatobiliary scintigraphy (HBS) was performed in 10 cats with histologically documented hepatobiliary disease. The scintigraphic patterns were classified into one of 5 categories: normal, primary hepatocellular dysfunction, primary intrahepatic cholestasis, mixed hepatocellular and intrahepatic cholestasis, and extrahepatic obstructive patterns. Initial attempts were made to correlate specific disease entities with HBS patterns, but a consistent relationship could not be determined. A correlation between the histological severity of a given hepatic disease and the HBS pattern was made. All cats (n = 5) with a mixed hepatocellular and intrahepatic cholestasis scintigraphic pattern with normal gallbladder function had a histologically severe form of their individual hepatic disease. Three of the 4 cats with an intrahepatic cholestasis pattern and normal hepatocellular and gallbladder function had histologically mild or moderate forms of their individual hepatic diseases. One cat had an extrahepatic obstructive pattern where no radiopharmaceutical was identified in the gallbladder or small intestine by 3 hours postinjection. This study suggests that HBS can be useful in cats with hepatobiliary disease to assess the severity of hepatic dysfunction, and to determine if extrahepatic biliary obstruction is present. Correlation between HBS patterns and specific disease entities such as hepatic lipidosis or cholangitis-cholangiohepatitis syndrome could not be made in this study. PMID:8884717

  17. Dermatological Diseases Associated with Pregnancy

    DEFF Research Database (Denmark)

    Sävervall, Christine; Sand, Freja Lærke; Thomsen, Simon Francis

    2015-01-01

    Dermatoses unique to pregnancy are important to recognize for the clinician as they carry considerable morbidity for pregnant mothers and in some instances constitute a risk to the fetus. These diseases include pemphigoid gestationis, polymorphic eruption of pregnancy, intrahepatic cholestasis of...

  18. Obstetric dermatoses

    DEFF Research Database (Denmark)

    Hjortø, Sofie; Skov, Lone; Lykke, Jacob Alexander

    2014-01-01

    The specific dermatoses of pregnancy are rare and consist of pemphigoid gestationis (PG), intrahepatic cholestasis of pregnancy (ICP), polymorphic eruption of pregnancy and atopic eruption of pregnancy. The dermatoses are characterized by pruritus, and they are important to recognize since PG and...

  19. Mice lacking Mrp3 (Abcc3) have normal bile salt transport, but altered hepatic transport of endogenous glucuronides

    NARCIS (Netherlands)

    N. Zelcer; K. van de Wetering; R. de Waart; G.L. Scheffer; H.U. Marschall; P.R. Wielinga; A. Kuil; C. Kunne; A. Smith; M. Valk; J. Wijnholds; R. Oude Elferink; P. Borst

    2006-01-01

    Background/Aim: Multidrug Resistance Protein 3 (MRP3) transports bile salts and glucuronide conjugates in vitro and is postulated to protect the liver in cholestasis. Whether the absence of Mrp3 affects these processes in vivo is tested. Methods: Mrp3-deficient mice were generated and the contributi

  20. The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump

    NARCIS (Netherlands)

    Gooijert, K. E. R.; Havinga, R.; Wolters, Henk; Wang, R.; Ling, V.; Tazuma, S.; Verkade, H. J.

    2015-01-01

    Human bile salt export pump (BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep(-/-) mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological cond

  1. In silico identification and in vitro validation of potential cholestatic compounds through 3D ligand-based pharmacophore modeling of BSEP inhibitors

    NARCIS (Netherlands)

    Ritschel, T.; Hermans, S.M.; Schreurs, M.J.; Heuvel, J.J.M.W. van den; Koenderink, J.B.; Greupink, R.; Russel, F.G.

    2014-01-01

    Drug-induced cholestasis is a frequently observed side effect of drugs and is often caused by an unexpected interaction with the bile salt export pump (BSEP/ABCB11). BSEP is the key membrane transporter responsible for the transport of bile acids from hepatocytes into bile. Here, we developed a phar

  2. Reversal of intestinal failure-associated liver disease (IFALD)

    DEFF Research Database (Denmark)

    Hvas, Christian; Kodjabashia, Kamelia; Nixon, Emma;

    2016-01-01

    Patients with intestinal failure (IF) and home parenteral nutrition commonly develop abnormal liver function tests. The presentations of IF-associated liver disease (IFALD) range from mild cholestasis or steatosis to cirrhosis and decompensated liver disease. We describe the reversal of IFALD in an...

  3. Vitamin E added to intralipid and enriched in omegaven protects against PNALD in TPN-fed preterm pigs

    Science.gov (United States)

    Prolonged parenteral nutrition (PN) may lead to cholestasis and parenteral nutrition associated liver disease (PNALD). The etiology of PNALD is unknown, but plant phytosterols in soybean oil emulsions (e.g., Intralipid) have been suggested to negatively impact bile acid homeostasis (BAH) by antagoni...

  4. Unusual causes of intrahepatic cholestatic liver disease

    Institute of Scientific and Technical Information of China (English)

    Elias E Mazokopakis; John A Papadakis; Diamantis P Kofteridis

    2007-01-01

    We report five cases with unusual causes of intrahepatic cholestasis,including consumption of Teucrium polium (family Lamiaceae) in the form of tea,Stauffer's syndrome,treatment with tamoxifen citrate for breast cancer,infection with Coxiella Burnetii (acute Q fever),and infection with Brucella melitensis (acute brucellosis).

  5. Bile acids modulate glucocorticoid metabolism and the hypothalamic-pituitary-adrenal axis in obstructive jaundice

    DEFF Research Database (Denmark)

    McNeilly, Alison D; Macfarlane, David P; O'Flaherty, Emmett;

    2010-01-01

    Suppression of the hypothalamic-pituitary-adrenal axis occurs in cirrhosis and cholestasis and is associated with increased concentrations of bile acids. We investigated whether this was mediated through bile acids acting to impair steroid clearance by inhibiting glucocorticoid metabolism by 5bet...

  6. Unusual causes of intrahepatic cholestatic liver disease

    OpenAIRE

    Mazokopakis, Elias E.; Papadakis, John A; Kofteridis, Diamantis P.

    2007-01-01

    We report five cases with unusual causes of intrahepatic cholestasis, including consumption of Teucrium polium (family Lamiaceae) in the form of tea, Stauffer’s syndrome, treatment with tamoxifen citrate for breast cancer, infection with Coxiella Burnetii (acute Q fever), and infection with Brucella melitensis (acute brucellosis).

  7. Pathogenesis and Management of Pruritus in PBC and PSC.

    Science.gov (United States)

    Kremer, Andreas E; Namer, Barbara; Bolier, Ruth; Fischer, Michael J; Oude Elferink, Ronald P; Beuers, Ulrich

    2015-01-01

    Pruritus is a preeminent symptom in patients with chronic cholestatic liver disorders such as primary biliary cirrhosis and primary sclerosing cholangitis. More than two-thirds of these patients experience itching during the course of their disease. This symptom is also frequently observed in patients with other causes of cholestasis such as cholangiocarcinoma, inherited forms of cholestasis and intrahepatic cholestasis of pregnancy, but may accompany almost any other liver disease. The pathogenesis of pruritus of cholestasis remains largely elusive. Increased concentrations of bile salts, histamine, serotonin, progesterone metabolites and endogenous opioids have been controversially discussed as potential pruritogens. However, for these molecules, neither a correlation with itch intensity nor a causative link could be established. The G protein-coupled receptor for bile salts, TGR5, has been shown to be expressed in dorsal root ganglia and give rise to itch in rodents, albeit upon stimuli with suprapathological concentrations of bile salts. The potent neuronal activator lysophosphatidic acid (LPA) and its forming enzyme, autotaxin (ATX), could be identified in the serum of patients with cholestatic pruritus. ATX activity correlated with itch severity and effectiveness of several anti-pruritic therapeutic interventions in cholestatic patients. Thus, the ATX-LPA-axis may represent a key element in the pathogenesis of this agonizing symptom. Treatment options for pruritus of cholestasis remain limited to a few evidence-based and several experimental medical and interventional therapies. The current guideline-based recommendations include the anion exchange resins colestyramine, the pregnane X receptor-agonist and enzyme inducer rifampicin, the μ-opioid antagonist naltrexone, and the selective serotonin reuptake inhibitors sertraline. Still, a considerable part of patients is unresponsive to these drugs and requires experimental approaches including phototherapy

  8. Obeticholic acid for the treatment of primary biliary cirrhosis.

    Science.gov (United States)

    Trivedi, Palak J; Hirschfield, Gideon M; Gershwin, M Eric

    2016-01-01

    Primary biliary cirrhosis (PBC) is characterized by progressive nonsuppurative destruction of small bile ducts, resulting in intrahepatic cholestasis, fibrosis and ultimately end-stage liver disease. Timely intervention with ursodeoxycholic acid is associated with excellent survival, although approximately one-third of all patients fail to achieve biochemical response, signifying a critical need for additional therapeutic strategies. Obeticholic acid (OCA) is a potent ligand of the nuclear hormone receptor farnesoid X receptor (FXR). Activation of FXR inhibits bile acid synthesis and protects against toxic accumulation in models of cholestasis and facilitates hepatic regeneration in preclinical studies. Data from recent Phase II and III controlled trials suggest a therapeutic impact of OCA in PBC biochemical nonresponders, as evidenced by change in proven laboratory surrogates of long-term outcome. Dose-dependent pruritus is a common adverse effect, but may be overcome through dose-titration. Longer term studies are needed with focus on safety and long-term clinical efficacy. PMID:26549695

  9. ESPGHAN Committee on Nutrition Position Paper. Intravenous lipid emulsions and risk of hepatotoxicity in infants and children

    DEFF Research Database (Denmark)

    Hojsak, Iva; Colomb, Virginie; Braegger, Christian;

    2016-01-01

    The aim of this paper was to perform a systematic review with meta-analysis of available scientific evidence regarding the role of different intravenous lipid emulsions (ILE) in the pathogenesis of cholestasis and parenteral nutrition associated liver disease (PNALD).A systematic review of the...... literature (up to March 2015) identified 23 randomized controlled trials (RCT). Of these, 17 were performed in preterm infants or critically ill neonates with a short duration of intervention, 2 in older children with short term use (following surgery or bone marrow transplantation), 1 in neonates with long...... term use and 3 in infants and children receiving long term parenteral nutrition (PN).Meta-analysis showed no differences in the rate of cholestasis or bilirubin levels associated with short term use of different ILEs. Due to high heterogeneity of the long-term studies no meta-analysis could be...

  10. Acute liver failure in a patient with sickle cell/β+ thalassaemia

    International Nuclear Information System (INIS)

    We describe a rare, severe, vaso-occlusive presentation of sickle cell disease, named sickle cell intrahepatic cholestasis (SCIC). Patients with sickle cell/β+ thalassaemia frequently have mild vaso-occlusive symptoms and only one case of SCIC developing in a patient with sickle cell/β+ thalassaemia has been previously described in the world literature. The present report represents only the second described case of SCIC in a patient with sickle cell/β+ thalassaemia. An abdominal computed tomography scan and Doppler ultrasound studies demonstrated massive hepatomegaly (25 cm span). Liver biopsy was performed and demonstrated dilatation and congestion of erythrocytes, severe cholestasis and fibrosis. The case demonstrates the importance of early recognition and institution of adequate therapy. Initial and correct diagnosis does not require biopsy or surgery which carry substantial risks of bleeding and mortality

  11. Quantitative Evaluation of Liver Function Using 99mTc-DISIDA Cholescintigraphy

    International Nuclear Information System (INIS)

    Since hepatocyte clearance, leading edge parenchymal transit time and biliary excretion can be evaluated separately with hepatobiliary scan using 99mTc-DISIDA, hepatobiliary scan may be useful in differentiating intrahepatic cholestasis from extrahepatic cholestasis. Excretory liver function was analysed in 13 healthy subjects and 11 patients with clinically suspected hepatocellular disease and 9 patients with extrahepatic biliary obstruction confirmed by surgery, radiological and clinical evidence. Indices of total liver activity (% TLA), liver parenchymal uptake (% LPU), heart pool clearance (% HPC) and liver-heart rate (% LHR) were calculated from time activity curve over heart and liver. Compared with healthy subjects, significant reduction(p<0.05) in total liver activity (% TLA) and liver-heart rate (% LHR) was observed in all patients group. But no useful indices was demonstrated in differentiating hepatocellular disease from extrahepatic biliary obstruction.

  12. The Pitfalls of Febrile Jaundice. A Case Report

    Directory of Open Access Journals (Sweden)

    Obreja Maria

    2016-04-01

    Full Text Available Jaundice in sepsis is usually caused by cholestasis, and its onset can precede other manifestations of the infection. Inflammation-induced cholestasis is a common complication in patients with an extrahepatic infection or those with inflammatory processes. We describe the case of a 47 years old female who presented with low back pain and paravertebral muscular contracture. She subsequently developed a cholestatic syndrome with clinical manifestations such as jaundice, followed by fever and sepsis with multiple organ dysfunction. Initially labeled as biliary sepsis, the diagnosis was crucially reoriented as the blood cultures were positive for Streptococcus pyogenes and the magnetic resonance imaging (MRI findings suggested spondylodiscitis as well as a paravertebral abscess.

  13. Biochemical characterization of P4-ATPase mutations associated with Intrahepatic Cholestatic Disease

    DEFF Research Database (Denmark)

    Gantzel, Rasmus; Vestergaard, Anna Lindeløv; Mikkelsen, Stine; Molday, Robert S.; Andersen, Jens Peter

    Progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) are caused by mutation of the P4-ATPase ATP8B1 that flips phospholipid from the exoplasmic leaflet to the cytoplasmic leaflet of canalicular membranes. It is hypothesized that...... PFIC1 mutations are the most disturbing with respect to expression, structural stability and/or function. Although recent data indicates that the specific phospholipid substrate of ATP8B1 is phosphatidylcholine (PC) [1] whereas ATP8A2 flips phosphatidylserine (PS) and phosphatidylethanolamine (PE......), there may be several mechanistic similarities between ATP8B1 and ATP8A2, and here we investigate known disease mutations using our well-functioning methodology for expression, affinity purification and assay of the partial reactions of ATP8A2. Mutations I91P (L127P in ATP8B1) and L308F (I344F) are...

  14. Biochemical Characterization of P4-ATPase Mutations Associated with Intrahepatic Cholestatic Disease

    DEFF Research Database (Denmark)

    Gantzel, Rasmus; Vestergaard, Anna Lindeløv; Mikkelsen, Stine; Molday, Robert S.; Andersen, Jens Peter

    The cholestatic disorders progressive familial intrahepatic cholestasis type 1 (PFIC1, also referred to as Byler’s disease) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) are caused by mutation of the P4-ATPase ATP8B1. The substrate of ATP8B1 is very likely to be phosphatidylserine...... families have been investigated, and more than 50 distinct disease mutations have been identified, with roughly half being missense mutations. In this project we try to answer the question whether PFIC1 mutations are generally more disturbing than BRIC1 mutations with respect to expression, structural...... stability and function. We investigate the mutations in our well functioning system of ATP8A2, being expressed in mammalian HEK293T cells, affinity-purified, and reconstituted in lipid vesicles. Well-known mutations from both groups of patients have been selected for study. I91P in ATP8A2 (L127P in ATP8B1...

  15. Flagging Drugs That Inhibit the Bile Salt Export Pump.

    Science.gov (United States)

    Montanari, Floriane; Pinto, Marta; Khunweeraphong, Narakorn; Wlcek, Katrin; Sohail, M Imran; Noeske, Tobias; Boyer, Scott; Chiba, Peter; Stieger, Bruno; Kuchler, Karl; Ecker, Gerhard F

    2016-01-01

    The bile salt export pump (BSEP) is an ABC-transporter expressed at the canalicular membrane of hepatocytes. Its physiological role is to expel bile salts into the canaliculi from where they drain into the bile duct. Inhibition of this transporter may lead to intrahepatic cholestasis. Predictive computational models of BSEP inhibition may allow for fast identification of potentially harmful compounds in large databases. This article presents a predictive in silico model based on physicochemical descriptors that is able to flag compounds as potential BSEP inhibitors. This model was built using a training set of 670 compounds with available BSEP inhibition potencies. It successfully predicted BSEP inhibition for two independent test sets and was in a further step used for a virtual screening experiment. After in vitro testing of selected candidates, a marketed drug, bromocriptin, was identified for the first time as BSEP inhibitor. This demonstrates the usefulness of the model to identify new BSEP inhibitors and therefore potential cholestasis perpetrators. PMID:26642869

  16. Acute liver failure due to primary amyloidosis in a nephrotic syndrome: a swiftly progressive course.

    Science.gov (United States)

    Cardoso, Brigite Aguiar; Leal, Rita; Sá, Helena; Campos, Mário

    2016-01-01

    AL amyloidosis is a clonal plasma cell proliferative disorder characterised by extracellular tissue deposits of insoluble fibrils derived from κ or λ immunoglobulin light chains. The most common organs affected by AL amyloidosis are the kidney, presenting with nephrotic syndrome and/or progressive renal dysfunction, and the heart, with restrictive cardiomyopathy. Hepatic deposition of fibrils occurs in half the cases but the liver is rarely the predominantly affected organ. The most common presentation of hepatic amyloidosis is hepatomegaly with elevated alkaline phosphatase. Acute liver failure with cholestasis and jaundice is a rare complication, with a prevalence of approximately 5%, and is usually associated with a worse prognosis. We report a case of a 39-year-old man admitted to our nephrology department with an unusual presentation of primary amyloidosis with nephrotic syndrome and acute liver failure, complicated by obstructive cholestasis resulting in death 2 months after diagnosis. PMID:26965175

  17. Neonatal Giant Cell Hepatitis in an Infant with Cystic Fibrosis

    Directory of Open Access Journals (Sweden)

    Maedeh Ahmadi

    2009-04-01

    Full Text Available Background: Cystic fibrosis is a hereditary disease of mucus and sweat glands characterized by respiratory infections and pancreatic insufficiency. Case presentation: We describe a girl infant with cholestasis as of the first clinical presentation at the age of 1 month. She developed severe anemia which required transfusion for several times. High level of direct bilirubin, low level of albumin and positive sweat tests were detected in laboratory tests. Histopathology report of liver biopsy indicated giant cell neonatal hepatitis. Conclusion: Although neonatal hepatitis is common cause of neonatal cholestasis, such condition is quite rare in cystic fibrosis, which easily could be misdiagnosed. Early diagnosis and appropriate treatment could prevent further complications of the disease.

  18. The dermatoses of pregnancy

    Directory of Open Access Journals (Sweden)

    Sachdeva Silonie

    2008-01-01

    Full Text Available The skin changes in pregnancy can be either physiological (hormonal, changes in pre-existing skin diseases or development of new pregnancy specific dermatoses. Pregnancy-specific skin dermatoses include an ill-defined heterogeneous group of pruritic skin eruptions which are seen only in pregnancy. These include atopic eruption of pregnancy, polymorphic eruption of pregnancy, pemphigoid gestationis and intrahepatic cholestasis of pregnancy. Atopic eruption of pregnancy is the most common of these disorders. Most skin eruptions resolve postpartum and require only symptomatic treatment. Antepartum surveillance is recommended for patients with pemphigoid gestationis and intrahepatic cholestasis of pregnancy as they carry fetal risk. This article deals with the classification, clinical features and treatment of the specific dermatoses of pregnancy.

  19. Technical Pitfalls and Improvements for High-speed Screening and QSAR Analysis to Predict Inhibitors of the Human Bile Salt Export Pump (ABCB11/BSEP)

    OpenAIRE

    Saito, Hikaru; Osumi, Masako; Hirano, Hiroyuki; Shin, Wangsoo; Nakamura, Ryota; Ishikawa, Toshihisa

    2009-01-01

    Drug-induced hepatotoxicity is one of the major problems encountered in drug discovery and development. Selection of a candidate compound for pre-clinical studies in the drug discovery process is a critical step that can determine the speed and expenditure of clinical development. Because inhibition of human adenosine triphosphate-binding cassette transporter ABCB11 (SPGP/bile salt export pump) has severe consequences, which include intrahepatic cholestasis and hepatotoxicity, resulting from ...

  20. Nitric oxide-mediated inhibition of taurocholate uptake involves S-nitrosylation of NTCP

    OpenAIRE

    Schonhoff, Christopher M.; Ramasamy, Umadevi; Anwer, M. Sawkat

    2010-01-01

    The sodium-taurocholate (TC) cotransporting polypeptide (NTCP) facilitates bile formation by mediating sinusoidal Na+-TC cotransport. During sepsis-induced cholestasis, there is a decrease in NTCP-dependent uptake of bile acids and an increase in nitric oxide (NO) levels in hepatocytes. In rat hepatocytes NO inhibits Na+-dependent uptake of taurocholate. The aim of this study was to extend these findings to human NTCP and to further investigate the mechanism by which NO inhibits TC uptake. Us...

  1. What Causes Biliary Atresia? Unique Aspects of the Neonatal Immune System Provide Clues to Disease Pathogenesis

    OpenAIRE

    Mack, Cara L.

    2015-01-01

    Biliary atresia (BA) is the most frequent identifiable cause of neonatal cholestasis and the majority of patients will need liver transplantation for survival. Despite surgical intervention with the Kasai portoenterostomy, significant fibrosis and cirrhosis develops early in life. An increased understanding of what causes this inflammatory fibrosing cholangiopathy will lead to therapies aimed at protecting the intrahepatic biliary system from immune-mediated damage. This review focuses on stu...

  2. Effects of Bile Acids and the Bile Acid Receptor FXR Agonist on the Respiratory Rhythm in the In Vitro Brainstem Medulla Slice of Neonatal Sprague-Dawley Rats

    OpenAIRE

    Cong Zhao; Xianbao Wang; Yuling Cong; Yi Deng; Yijun Xu; Aihua Chen; Yanru Yin

    2014-01-01

    Intrahepatic cholestasis of pregnancy is always accompanied by adverse fetal outcomes such as malfunctions of respiration. Farnesoid X receptor (FXR) plays a critical role in the homeostasis of bile acids. Thus, we are determined to explore the effects of farnesoid X receptor (FXR) and five bile acids on respiratory rhythm generation and modulation of neonatal rats. Spontaneous periodic respiratory-related rhythmical discharge activity (RRDA) was recorded from hypoglossal nerves during the pe...

  3. Bile Acid-Induced Arrhythmia Is Mediated by Muscarinic M2 Receptors in Neonatal Rat Cardiomyocytes

    OpenAIRE

    Sheikh Abdul Kadir, Siti H; Michele Miragoli; Shadi Abu-Hayyeh; Moshkov, Alexey V.; Qilian Xie; Verena Keitel; Viacheslav O. Nikolaev; Catherine Williamson; Julia Gorelik

    2010-01-01

    BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is a common disease affecting up to 5% of pregnancies and which can cause fetal arrhythmia and sudden intrauterine death. We previously demonstrated that bile acid taurocholate (TC), which is raised in the bloodstream of ICP, can acutely alter the rate and rhythm of contraction and induce abnormal calcium destabilization in cultured neonatal rat cardiomyocytes (NRCM). Apart from their hepatic functions bile acids are ubiquitous signallin...

  4. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance

    OpenAIRE

    Fang, Sungsoon; Suh, Jae Myoung; Reilly, Shannon M; Yu, Elizabeth; Osborn, Olivia; Lackey, Denise; Yoshihara, Eiji; Perino, Alessia; Jacinto, Sandra; Lukasheva, Yelizaveta; Atkins, Annette R.; Khvat, Alexander; Schnabl, Bernd; Yu, Ruth T.; Brenner, David A

    2015-01-01

    The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations i...

  5. Bile acid-activated nuclear receptor FXR suppresses apolipoprotein A-I transcription via a negative FXR response element

    OpenAIRE

    Claudel, Thierry; Sturm, Ekkehard; Duez, Hélène; Torra, Inés Pineda; Sirvent, Audrey; Kosykh, Vladimir; Fruchart, Jean-Charles; Dallongeville, Jean; Hum, Dean W; Kuipers, Folkert; Staels, Bart

    2002-01-01

    Serum levels of HDL are inversely correlated with the risk of coronary heart disease. The anti-atherogenic effect of HDL is partially mediated by its major protein constituent apoA-I. In this study, we identify bile acids that are activators of the nuclear receptor farnesoid X receptor (FXR) as negative regulators of human apoA-I expression. Intrahepatocellular accumulation of bile acids, as seen in patients with progressive familial intrahepatic cholestasis and biliary atresia, was associate...

  6. Activation of PPAR-gamma signaling as a novel target to limit nfkb-dependet in flammation in cystic fibrosis biliar epithelium

    OpenAIRE

    Scirpo,

    2014-01-01

    Cystic fibrosis-associated liver disease (CFLD) is a chronic cholangiopathy that negatively impacts the quality of life and survival of patients with Cystic Fibrosis (CF). CF is a disease of secretory epithelia caused by genetically-determined defective function of CFTR (cystic fibrosis conductance regulator), a cAMP-activated Cl- channel that, in the liver, is uniquely expressed in the biliary epithelium. The pathogenesis of CFLD is thought to be related to the ductal cholestasis caused by t...

  7. Modulation of farnesoid X receptor results in post-translational modification of poly (ADP-ribose) polymerase 1 in the liver

    OpenAIRE

    Zhu, Yan; Li, Guodong; Dong, Yafeng; Zhou, Helen H.; Kong, Bo; Aleksunes, Lauren M.; Richardson, Jason R.; Li, Fei; Guo, Grace L.

    2012-01-01

    The farnesoid X receptor (FXR) is a bile acid-activated transcription factor belonging to the nuclear receptor superfamily. FXR deficiency in mice results in cholestasis, metabolic disorders, and tumorigenesis in liver and intestine. FXR is known to contribute to pathogenesis by regulating gene transcription; however, changes in the post-transcriptional modification of proteins associated with FXR modulation have not been determined. In the current study, proteomic analysis of the livers of w...

  8. A case of amoxicillin-induced hepatocellular liver injury with bile-duct damage

    OpenAIRE

    Kim, Ju Seung; Jang, Young Rock; Lee, Ji Won; Kim, Jin Yong; Jung, Young Kul; Chung, Dong Hae; Kwon, Oh Sang; Kim, Yun Soo; Choi, Duck Joo; Kim, Ju Hyun

    2011-01-01

    Amoxicillin, an antibiotic that is widely prescribed for various infections, is associated with a very low rate of drug-induced liver injury; hepatitis and cholestasis are rare complications. Here we present a case of a 39-year-old woman who was diagnosed with abdominal actinomycosis and received amoxicillin treatment. The patient displayed hepatocellular and bile-duct injury, in addition to elevated levels of liver enzymes. The patient was diagnosed with amoxicillin-induced cholestatic hepat...

  9. Endoscopic Treatment of Biliary Stenosis in Patients with Alveolar Echinococcosis – Report of 7 Consecutive Patients with Serial ERC Approach

    OpenAIRE

    Marija Stojkovic; Thomas Junghanss; Mira Veeser; Tim F Weber; Peter Sauer

    2016-01-01

    Background and Aims Biliary vessel pathology due to alveolar echicococcosis (AE) results in variable combinations of stenosis, necrosis and inflammation. Modern management strategies for patients with cholestasis are desperately needed. The aim is proof of principle of serial ERC (endoscopic retrograde cholangiography) balloon dilation for AE biliary pathology. Methods Retrospective case series of seven consecutive patients with AE-associated biliary pathology and ERC treatment in an interdis...

  10. Alagille Syndrome: A Review

    OpenAIRE

    Callea, Michele; Bahsi, Emrullah; Montanari, Marco; Ince, Bayram; Mancini, Giovanni E.; YAVUZ, Yasemin; Radovich, Franco; Gunay, Ayse; Piana, Gabriela; Unal, Mehmet; D’Alessandro, Giovanni; Caselli, Mauro; Clarich, Gabriella

    2013-01-01

    Alagille Syndrome (AGS) is a genetically determined multisystem disorder affecting liver, hearth, eyes, skeleton and facies, less commonly kidney and CNS. The prognosis depends on the severity of the associated anomalies. The liver pathology plays a central role in that most clinical complications are due to long standing cholestasis as a consequence of lack of bile excretion secondary to paucity/absence of interlobular bile ducts. That results in hyperbilirubinemia, hypercholesterolemia, hyp...

  11. Tissue factor contributes to neutrophil CD11b expression in alpha-naphthylisothiocyanate-treated mice

    International Nuclear Information System (INIS)

    Cholestatic liver injury induced by alpha-naphthylisothiocyanate (ANIT) is provoked by injury to intrahepatic bile ducts and the progression of hepatic necrosis requires the procoagulant protein tissue factor (TF) and extrahepatic cells including neutrophils. Recent studies have shown that myeloid cell TF contributes to neutrophil activation. We tested the hypothesis that myeloid cell TF contributes to neutrophil activation in ANIT-treated mice. TF activity in liver homogenates increased significantly in TFflox/flox mice treated with ANIT, but not in TFflox/flox/LysMCre mice (TFΔMyeloid mice), which have reduced TF expression in monocytes/macrophages and neutrophils. Myeloid cell-specific TF deficiency did not alter expression of the chemokines KC or MIP-2 but reduced hepatic neutrophil accumulation in ANIT-treated mice at 48 h as indicated by tissue myeloperoxidase (MPO) activity. Myeloid cell TF deficiency significantly reduced CD11b expression by blood neutrophils in ANIT-treated mice, and this was associated with reduced plasma MPO protein levels, an index of neutrophil degranulation. However, myeloid cell-specific TF deficiency had no effect on ANIT-induced coagulation cascade activation. The increase in serum ALT and ALP activities in ANIT-treated mice was reduced by myeloid cell TF deficiency (p < 0.05), but the myeloid cell TF deficiency did not reduce hepatic necrosis at 48 h, as determined by histopathology and morphometry. The results suggest that myeloid cell TF contributes to neutrophil CD11b expression during cholestasis by a coagulation-independent pathway. However, the resultant reduction in neutrophil accumulation/activation is insufficient to substantially reduce ANIT hepatotoxicity, suggesting that myeloid cell TF is only one of many factors modulating hepatic necrosis during cholestasis. - Research Highlights: → Myeloid cell tissue factor contributes to liver procoagulant activity during acute cholestasis. → ANIT-induced coagulation cascade

  12. Ondansetron to Treat Pruritus Due to Cholestatic Jaundice

    OpenAIRE

    Dillon, Sarah; Tobias, Joseph D

    2013-01-01

    Intractable itching is a symptom of cholestatic liver disease of various causes that is bothersome and difficult to manage. Although treatment of the primary cause of cholestasis is paramount in resolving the issue, given the debilitating consequences of pruritus, symptomatic treatment is frequently necessary. Although many medications including cholestyramine, rifampin, opioid antagonists (i.e., naloxone, naltrexone), phenobarbital, and antihistamines have been used to treat cholestatic-indu...

  13. Constitutive Androstane Receptor-Mediated Changes in Bile Acid Composition Contributes to Hepatoprotection from Lithocholic Acid-Induced Liver Injury in MiceS⃞

    OpenAIRE

    Beilke, Lisa D.; Aleksunes, Lauren M.; Holland, Ricky D; Besselsen, David G; Beger, Rick D.; Klaassen, Curtis D.; Cherrington, Nathan J.

    2009-01-01

    Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice ...

  14. Protective Action of Antioxidants on Hepatic Damage Induced by Griseofulvin

    OpenAIRE

    Martinez, M. del C.; Afonso, S. G.; Buzaleh, A. M.; Batlle, A.

    2014-01-01

    Erythropoietic protoporphyria (EPP) is a disease associated with ferrochelatase deficiency and characterized by the accumulation of protoporphyrin IX (PROTO IX) in erythrocytes, liver, and skin. In some cases, a severe hepatic failure and cholestasis were observed. Griseofulvin (Gris) develops an experimental EPP with hepatic manifestations in mice such as PROTO IX accumulation followed by cellular damage as wells as necrotic and inflammatory processes. The antioxidant defense system was also...

  15. Clinical evaluation of a new serum tumour marker CA 242 in pancreatic carcinoma.

    OpenAIRE

    Pasanen, P. A.; Eskelinen, M.; Partanen, K.; Pikkarainen, P; Penttilä, I.; Alhava, E

    1992-01-01

    The aim of this study was to evaluate the new monoclonal tumour marker CA 242 in the diagnosis of pancreatic carcinoma and to compare it with the established markers CA 50 and CEA. Serum concentrations were determined in 113 patients with jaundice, in 20 patients with laboratory values suggesting cholestasis, and in 60 patients with a suspicion to have chronic pancreatitis. Twenty-four of these 193 patients had pancreatic carcinoma and two patients had carcinoma of papilla of Vater. The sensi...

  16. A prospective study of serum tumour markers carcinoembryonic antigen, carbohydrate antigens 50 and 242, tissue polypeptide antigen and tissue polypeptide specific antigen in the diagnosis of pancreatic cancer with special reference to multivariate diagnostic score.

    OpenAIRE

    Pasanen, P. A.; Eskelinen, M.; Partanen, K.; Pikkarainen, P; Penttilä, I.; Alhava, E

    1994-01-01

    The aim of this study was to assess by a stepwise multivariate discriminant analysis the value of four current serum tumour markers - carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 50 and CA 242 and tissue polypeptide antigen (TPA) - and a new serum tumour marker, tissue polypeptide specific antigen (TPS), in the diagnosis of pancreatic cancer. The serum values were measured in a prospective series of patients with jaundice, with unjaundiced cholestasis and with a suspicion of chro...

  17. Disseminated Langerhans Cell Histiocytosis Presenting as Cholestatic Jaundice

    OpenAIRE

    Kapoor, Rohit; Loizides, Anthony M; Sachdeva, Soumya; Paul, Premila

    2015-01-01

    Langerhans cell histiocytosis (LCH) is a disorder associated with proliferation of Langerhans cells in various organs. LCH secondary to multisystem involvement can present in a variety of ways. Because of its infiltrative nature, LCH can involve the skin, lymph nodes, the lung or the liver. Jaundice in LCH is a manifestation of liver disease; biliary dilatation secondary to lithiasis or may be due to coexistent Niemann-Pick disease. However, a case of cholestasis has been very rarely describe...

  18. Liver protective effect of ursodeoxycholic acid includes regulation of ADAM17 activity

    Czech Academy of Sciences Publication Activity Database

    Buryová, Halka; Chalupský, Karel; Žbodáková, Olga; Kanchev, Ivan; Jiroušková, Markéta; Gregor, Martin; Sedláček, Radislav

    2013-01-01

    Roč. 13, 30.10.2013 (2013), s. 155-155. ISSN 1471-230X R&D Projects: GA ČR GAP305/10/2143; GA ČR GAP303/10/2044; GA AV ČR IAA500520812; GA MŠk ED1.1.00/02.0109 Institutional support: RVO:68378050 Keywords : ursodeoxycholic acid * ADAM17 * shedding * cholestasis * liver Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 2.113, year: 2013

  19. The Association between Bile Salt Export Pump Single-Nucleotide Polymorphisms and Primary Biliary Cirrhosis Susceptibility and Ursodeoxycholic Acid Response

    OpenAIRE

    Rui-rui Chen; Yuan-jun Li; Xin-min Zhou; Lu Wang; Juan Xing; Shuang Han; Li-na Cui; Lin-hua Zheng; Kai-chun Wu; Yong-quan Shi; Zhe-yi Han; Ying Han; Dai-ming Fan

    2014-01-01

    Background. Primary biliary cirrhosis (PBC) is a chronic and progressive cholestasis liver disease. Bile salt export pump (BSEP) is the predominant bile salt efflux system of hepatocytes. BSEP gene has been attached great importance in the susceptibility of PBC and the response rate of ursodeoxycholic acid (UDCA) treatment of PBC patients. Methods. In this study, TaqMan assay was used to genotype four variants of BSEP, and the Barcelona criteria were used for evaluating the response rate of U...

  20. Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families

    OpenAIRE

    Strautnieks, S S; Byrne, J A; Pawlikowska, L.; Cebecauerova, D; Rayner, A; Dutton, L; Meier, Y; Antoniou, A; Stieger, B; Arnell, H; Ozcay, F; Al-Hussaini, H F; Bassas, A F; Verkade , H.J.; Fischler, B

    2008-01-01

    BACKGROUND & AIMS: Patients with severe bile salt export pump (BSEP) deficiency present as infants with progressive cholestatic liver disease. We characterized mutations of ABCB11 (encoding BSEP) in such patients and correlated genotypes with residual protein detection and risk of malignancy. METHODS: Patients with intrahepatic cholestasis suggestive of BSEP deficiency were investigated by single-strand conformation polymorphism analysis and sequencing of ABCB11. Genotypes sorted by likely ph...

  1. Bile Salt Export Pump is Dysregulated with Altered Farnesoid X Receptor Isoform Expression in Patients with Hepatocellular Carcinoma

    OpenAIRE

    Chen, Yuan; Song, Xiulong; Valanejad, Leila; Vasilenko, Alexander; More, Vijay; Qiu, Xi; Chen, Weikang; Lai, Yurong; Slitt, Angela; Stoner, Matthew; Yan, Bingfang; Deng, Ruitang

    2013-01-01

    As a canalicular bile acid effluxer, bile salt export pump (BSEP) plays a vital role in maintaining bile acid homeostasis. BSEP deficiency leads to severe cholestasis and hepatocellular carcinoma (HCC) in young children. Regardless of the etiology, chronic inflammation is the common pathological process for HCC development. Clinical studies showed that bile acid homeostasis is disrupted in HCC patients with elevated serum bile acid level as a proposed marker for HCC. However, the underlying m...

  2. Recent insights into the function and regulation of the bile salt export pump (ABCB11)

    OpenAIRE

    Stieger, B

    2009-01-01

    PURPOSE OF REVIEW: Generation of bile is an important function of the liver. Its impairment can be caused by inherited mutations or by acquired factors and leads to cholestasis. Bile salts are an important constituent of bile and are secreted by the bile salt export pump (BSEP) from hepatocytes. RECENT FINDINGS: Significant progress was made in the understanding of mechanisms and consequences of malfunctioning BSEP. This information was gained from extensive characterization of patients with ...

  3. ATPase Class I Type 8B Member 1 and Protein Kinase C-ζ Induce the Expression of the Canalicular Bile Salt Export Pump in Human Hepatocytes

    OpenAIRE

    Chen, Frank; Ellis, Ewa; Strom, Stephen C.; Shneider, Benjamin L.

    2010-01-01

    The exact molecular mechanism(s) of the disease that results from defects in the ATPase Class I Type 8B Member 1 gene remains controversial. Prior investigations of human ileum and in intestinal and ovarian cell lines have suggested that Familial Intrahepatic Cholestasis 1 (FIC1) activates the Farnesoid X-Receptor (FXR) via a pathway involving Protein Kinase C ζ (PKCζ). Translational investigations of human liver from individuals with FIC1 disease have been confounded by secondary affects of ...

  4. Hepatic bile acids and bile acid-related gene expression in pregnant and lactating rats

    OpenAIRE

    Zhu, Qiong N.; Xie, Hong M.; Dan Zhang; Jie Liu; Yuan F. Lu

    2013-01-01

    Background. Significant physiological changes occur during pregnancy and lactation. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease closely related to disruption of bile acid homeostasis. The objective of this study was to examine the regulation of bile acid synthesis and transport in normal pregnant and lactating rats. Materials and Methods. Livers from timed pregnant SD rats were collected on gestational days (GD) 10, 14 and 19, and postnatal days (PND) 1, 7, 14 and 21. T...

  5. ДИСЛИПИДЕМИЯ И АССОЦИИРОВАНЫЕ МЕТАБОЛИЧЕСКИЕ ЗАБОЛЕВАНИЯ

    Directory of Open Access Journals (Sweden)

    О. Ш. Ойноткинова

    2011-01-01

    Full Text Available This article presents the pathogenesis of dyslipidemia and associated metabolic disorders with the position of lipid metabolism. The role of natural mechanism of cholesterol homeostasis changing was showed, functional disorders of the enterohepatic circulation of bile acids and intrahepatic cholestasis due to violation of the reticuloendothelial system, entailing disruption of a specific target organ, on the one hand, and the development of atherosclerosis with ischemic syndromes — on the other, were demonstrated. Diagnostic and treatment algorithm is presented.

  6. Acute liver function decompensation in a patient with sickle cell disease managed with exchange transfusion and endoscopic retrograde cholangiography

    OpenAIRE

    Papafragkakis, Haris; Mel A. Ona; Changela, Kinesh; Sadanandan, Swayamprabha; Jelin, Abraham; Anand, Sury; Duddempudi, Sushil

    2014-01-01

    Sickle cell intrahepatic cholestasis is a relatively uncommon complication of homozygous sickle cell anemia, which may lead to acute hepatic failure and death. Treatment is mainly supportive, but exchange transfusion is used as salvage therapy in life threatening situations. We describe a case of a 16-year-old female with homozygous sickle cell anemia who presented to the emergency room with fatigue, malaise, dark urine, lower back pain, scleral icterus and jaundice. She was found to have mar...

  7. ESPGHAN Committee on Nutrition Position Paper. Intravenous Lipid Emulsions and Risk of Hepatotoxicity in Infants and Children: a Systematic Review and Meta-analysis.

    Science.gov (United States)

    Hojsak, Iva; Colomb, Virginie; Braegger, Christian; Bronsky, Jiri; Campoy, Cristina; Domellöf, Magnus; Embleton, Nicholas; Fidler Mis, Nataša; Hulst, Jessie M; Indrio, Flavia; Lapillonne, Alexandre; Mihatsch, Walter; Molgaard, Christian; van Goudoever, Johannes; Fewtrell, Mary

    2016-05-01

    The aim of the present article was to perform a systematic review with meta-analysis of available scientific evidence regarding the role of different intravenous lipid emulsions (ILE) in the pathogenesis of cholestasis and parenteral nutrition-associated liver disease. A systematic review of the literature (up to March 2015) identified 23 randomized controlled trials (RCTs). Of these, 17 were performed in preterm infants or critically ill neonates with a short duration of intervention, 2 in older children with short-term use (following surgery or bone marrow transplantation), 1 in neonates with long-term use, and 3 in infants and children receiving long-term parenteral nutrition (PN). Meta-analysis showed no differences in the rate of cholestasis or bilirubin levels associated with short-term use of different ILEs. Because of high heterogeneity of the long-term studies no meta-analysis could be performed. Available studies found that the use of multicomponent fish oil (FO)-containing ILE compared with pure soya bean oil (SO), ILE-reduced liver enzymes, and bilirubin levels in noncholestatic children on long-term PN and one other RCT found that FO-based ILE-reversed cholestasis in a proportion of patients. The ESPGHAN Committee on Nutrition concludes that there is no evidence of a difference in rates of cholestasis or bilirubin levels between different ILE for short-term use in neonates. The use of multicomponent FO-containing ILE may contribute to a decrease in total bilirubin levels in children with IF on prolonged PN. Well-designed RCTs are, however, lacking and long-term effects have not been determined. PMID:26825766

  8. Le cas clinique du mois. Sclérose hepato-portale chez un patient traité par azathioprine

    OpenAIRE

    Roland, S.; Delwaide, Jean; Cornet, G.; Mahieu, Ph; Jacquet, N.; Belaiche, Jacques

    1998-01-01

    We report a case of hepatoportal sclerosis in a renal transplant patient treated with azathioprine. The initial symptom was ascites. On the biochemical level, there were cholestasis without cytolysis or hepatocellular insufficiency. A presinusoidal portal hypertension was found on haemodynamic studies, without portal thrombosis at CT-scan. A diagnosis of hepatoportal sclerosis was evoked on histology and attributed to azathioprine. This case gives an illustration of a classical albeit rare co...

  9. Cystic diseases of the biliary tract and liver

    OpenAIRE

    Nafiye Urgancı

    2008-01-01

    Cystic diseases of liver are recognized in infancy and childhood initially. Cystic diseases of liver and biliary tract are choledocal cysts, autosomal recessive and autosomal dominant polycystic kidney disease, congenital hepatic fibrosis and Caroli disease (cystic dilatation of intrahepatic bile ducts). Choledochal cysts and Caroli disease do not allow biliary flow, cause chronic or obstructive cholestasis and progressive liver disease. In congenital hepatic fibrosis and polycystic kidney di...

  10. When the Turkish word exists Other

    OpenAIRE

    Varken, Türkçesi

    2008-01-01

    Cystic diseases of liver are recognized in infancy and childhood initially Cystic diseases of liver and biliary tract are choledocal cysts autosomal recessive and autosomal dominant polycystic kidney disease congenital hepatic fibrosis and Caroli disease cystic dilatation of intrahepatic bile ducts Choledochal cysts and Caroli disease do not allow biliary flow cause chronic or obstructive cholestasis and progressive liver disease In congenital hepatic fibrosis and polycystic kidney disease th...

  11. Cystic diseases of the biliary tract and liver Invited Editor

    OpenAIRE

    Urgancı, Nafiye

    2008-01-01

    Cystic diseases of liver are recognized in infancy and childhood initially Cystic diseases of liver and biliary tract are choledocal cysts autosomal recessive and autosomal dominant polycystic kidney disease congenital hepatic fibrosis and Caroli disease cystic dilatation of intrahepatic bile ducts Choledochal cysts and Caroli disease do not allow biliary flow cause chronic or obstructive cholestasis and progressive liver disease In congenital hepatic fibrosis and polycystic kidney disease th...

  12. Editorial

    OpenAIRE

    Apak, Hilmi

    2008-01-01

    Cystic diseases of liver are recognized in infancy and childhood initially Cystic diseases of liver and biliary tract are choledocal cysts autosomal recessive and autosomal dominant polycystic kidney disease congenital hepatic fibrosis and Caroli disease cystic dilatation of intrahepatic bile ducts Choledochal cysts and Caroli disease do not allow biliary flow cause chronic or obstructive cholestasis and progressive liver disease In congenital hepatic fibrosis and polycystic kidney disease th...

  13. 12 month old girl with womiting Case of the Month

    OpenAIRE

    Öztürk, Erkut; Önal, Zerrin; Aldemir, Hüseyin; Sander, Serdar

    2008-01-01

    Cystic diseases of liver are recognized in infancy and childhood initially Cystic diseases of liver and biliary tract are choledocal cysts autosomal recessive and autosomal dominant polycystic kidney disease congenital hepatic fibrosis and Caroli disease cystic dilatation of intrahepatic bile ducts Choledochal cysts and Caroli disease do not allow biliary flow cause chronic or obstructive cholestasis and progressive liver disease In congenital hepatic fibrosis and polycystic kidney disease th...

  14. Groove Pancreatitis with Biliary and Duodenal Stricture: An Unusual Cause of Obstructive Jaundice

    OpenAIRE

    Marta Gravito-Soares; Elisa Gravito-Soares; Ana Alves; Dário Gomes; Nuno Almeida; Guilherme Tralhão; Carlos Sofia

    2016-01-01

    Introduction: Groove pancreatitis is an uncommon cause of chronic pancreatitis that affects the groove anatomical area between the head of the pancreas, duodenum, and common bile duct. Clinical case: A 67-year-old man with frequent biliary colic and an alcohol consumption of 30–40 g/day was admitted to the hospital complaining of jaundice and pruritus. Laboratory analysis revealed cholestasis and the ultrasound scan showed intra-hepatic biliary ducts dilatation, middle third cystic dilatat...

  15. Association of lipid peroxidation with hepatocellular injury in preterm infants

    OpenAIRE

    Weinberger, Barry; Watorek, Kazimierz; Strauss, Richard; Witz, Gisela; Hiatt, Mark; Hegyi, Thomas

    2002-01-01

    Introduction We wished to determine whether cholestasis induced by total parenteral nutrition (TPN) in preterm newborn infants is associated with increased oxidative stress secondary to increased reactive oxygen intermediates. We hypothesized that elevated urinary thiobarbituric-acid-reacting substances (TBARS), a marker of oxidative stress, would be associated with hepatocellular injury as measured by serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. Materials and met...

  16. Liver dysfunction associated with artificial nutrition in critically ill patients

    OpenAIRE

    Grau, Teodoro; Bonet, Alfonso; Rubio, Mercedes; Mateo, Dolores; Farré, Mercé; Acosta, José Antonio; Blesa, Antonio; Montejo, Juan Carlos; de Lorenzo, Abelardo García; Mesejo, Alfonso; ,

    2007-01-01

    Introduction Liver dysfunction associated with artificial nutrition in critically ill patients is a complication that seems to be frequent, but it has not been assessed previously in a large cohort of critically ill patients. Methods We conducted a prospective cohort study of incidence in 40 intensive care units. Different liver dysfunction patterns were defined: (a) cholestasis: alkaline phosphatase of more than 280 IU/l, gamma-glutamyl-transferase of more than 50 IU/l, or bilirubin of more ...

  17. Resolution of biliary stricture after living donor liver transplantation in a child by percutaneous trans-hepatic cholangiography and drainage: a case report

    OpenAIRE

    Putzer, Gabriel; Paal, Peter; Chemelli, Andreas P; Mark, Walter; Lederer, Wolfgang; Wiedermann, Franz J.

    2013-01-01

    Introduction Intra-hepatic cholestasis arising from biliary strictures is a frequent complication in pediatric patients after liver transplantation. Minimally invasive procedures such as percutaneous drainage placement and balloon dilation are the preferred diagnostic and therapeutic modalities. Case presentation We report the case of a 12-month-old Caucasian boy with biliary atresia who was initially treated with hepatoportoenterostomy. In the following months, he developed biliary cirrhosis...

  18. Methods and timing of biliary drainage for acute cholangitis: Tokyo Guidelines

    OpenAIRE

    Nagino, Masato; Takada, Tadahiro; Kawarada, Yoshifumi; Nimura, Yuji; Yamashita, Yuichi; Tsuyuguchi, Toshio; Wada, Keita; Mayumi, Toshihiko; Yoshida, Masahiro; Miura, Fumihiko; Steven M. Strasberg; Henry A. Pitt; Belghiti, Jacques; Fan, Sheung-Tat; Liau, Kui-Hin

    2007-01-01

    Biliary drainage is a radical method to relieve cholestasis, a cause of acute cholangitis, and takes a central part in the treatment of acute cholangitis. Emergent drainage is essential for severe cases, whereas patients with moderate and mild disease should also receive drainage as soon as possible if they do not respond to conservative treatment, and their condition has not improved. Biliary drainage can be achieved via three different routes/procedures: endoscopic, percutaneous transhepati...

  19. Platycodin D attenuates bile duct ligation-induced hepatic injury and fibrosis in mice.

    Science.gov (United States)

    Kim, Tae-Won; Lee, Hong-Ki; Song, In-Bae; Lim, Jong-Hwan; Cho, Eun-Sang; Son, Hwa-Young; Jung, Ju-Young; Yun, Hyo-In

    2013-01-01

    Platycodin D (PD) is the major triterpene saponin in the root of Platycodon grandiflorum. The aim of the present study was to evaluate the protective effects of PD on bile duct ligation (BDL)-induced cholestasis in mice. Mice were allocated to five groups: sham, BDL alone, and BDL with PD treatment at 1, 2, and 4mg/kg. PD was administered to the mice for 28 consecutive days after the BDL operation. PD treatment of BDL-operated mice decreased serum alanine aminotransferase, serum aspartate aminotransferase, and total bilirubin levels by up to 37%, 31%, and 41%, respectively, in comparison with the levels in mice that underwent BDL alone. PD treatment attenuated oxidative stress, as evidenced by an increase in anti-oxidative enzyme levels glutathione and superoxide dismutase together with a decrease in lipid peroxidation and oxidative stress indices levels of malondialdehyde and nitric oxide. Histopathological studies further confirmed the protective effects of PD on cholestasis-induced hepatic injury and liver fibrosis in mice. In addition, nuclear factor-kappa B and inducible nitric oxide synthase levels significantly decreased after PD treatment, as did the levels of hepatocyte apoptosis. Taken together, these results suggest that PD treatment might be beneficial in cholestasis-induced hepatotoxicity. PMID:23116642

  20. Development of animal models for hepatobiliary nuclear imaging

    Energy Technology Data Exchange (ETDEWEB)

    Park, Jin Hee; Park, Yun Hee; Ryu, Yeon Mi; Shin, Eun Kyung; Kim, Meyoung Kon [Korea University Medical College, Seoul (Korea, Republic of)

    2002-07-01

    Animal models for hepatobiliary disorders were classified into 2 different types: parenchymal hepatotoxicity and biliary-tract cholestasis. The purpose of this study was to develop animal models for hepatobiliary scintigraphy in evaluating a novel agents, such as {sup 99m}Tc-mercaptoacetyl triglycine(MAG3)-biocytin. Animal models were prepared by use of female Balb/c mice. Those were treated with 0.1, 0.5, and 2.5 ml/kg of carbon tetrachloride (CCl4) intraperitoneally for hepatotoxicity and with 30, 150, and 750 mg/kg of {alpha}-naphthylisothiocyanate (ANIT) to induce cholestasis. Dose of optimum was 0.5 ml/kg and 150 mg/kg for each model but lower (0.1 ml/kg and 30 mg/kg) and higher (2.5ml/kg and 750 mg/kg)were not be compatible for hepatobiliary models. Using these hepatobiliary models, {sup 99m}Tc-MAG3-biocytin scintigraphy was successfully carried out by using 4 parameters, e.g., peak liver/heat ratio (Rmax), peak ratio time (Tmax), half clearance time (HCT), and hepatic extraction fraction (HEF) for hepatotoxicity and cholestasis. Additionally, biochemical and histological analysis also resulted in confirming these animal models. Thus, we concluded that these animal models were highly likely to be efficient in evaluating hepatobiliary scintigraphic agent such as {sup 99m}Tc-MAG3-biocytin.

  1. Evaluation of two experimental models of hepatic encephalopathy in rats

    Directory of Open Access Journals (Sweden)

    García-Moreno L.M.

    2005-01-01

    Full Text Available The serious neuropsychological repercussions of hepatic encephalopathy have led to the creation of several experimental models in order to better understand the pathogenesis of the disease. In the present investigation, two possible causes of hepatic encephalopathy, cholestasis and portal hypertension, were chosen to study the behavioral impairments caused by the disease using an object recognition task. This working memory test is based on a paradigm of spontaneous delayed non-matching to sample and was performed 60 days after surgery. Male Wistar rats (225-250 g were divided into three groups: two experimental groups, microsurgical cholestasis (N = 20 and extrahepatic portal hypertension (N = 20, and a control group (N = 20. A mild alteration of the recognition memory occurred in rats with cholestasis compared to control rats and portal hypertensive rats. The latter group showed the poorest performance on the basis of the behavioral indexes tested. In particular, only the control group spent significantly more time exploring novel objects compared to familiar ones (P < 0.001. In addition, the portal hypertension group spent the shortest time exploring both the novel and familiar objects (P < 0.001. These results suggest that the existence of portosystemic collateral circulation per se may be responsible for subclinical encephalopathy.

  2. Genetic variants in adult liver diseases.

    Science.gov (United States)

    Dröge, C; Häussinger, D; Keitel, V

    2015-12-01

    In the last decades, understanding of genetic variants contributing to liver disease development has considerably improved through novel genotyping techniques. Genetic variants of single genes are known to be decisive for the development of monogenetic liver diseases of varying severity. Identification of genetic variants is an important part of the diagnostic process, e. g. the majority of patients with high iron [Fe] (HFE)-associated hemochromatosis carry the homozygous mutation p.C282Y. Detection of mutations in genes encoding hepatobiliary transport proteins like familial intrahepatic cholestasis 1 (FIC1), bile salt export pump (BSEP), or multidrug resistance protein 3 (MDR3) is the basis to differentiate various forms of intrahepatic cholestasis. Moreover, genetic variants in a variety of genes are known to act as disease modifiers and represent risk factors for disease progression and the development of cirrhosis or even hepatocellular carcinoma. Success of drug treatment or appearance of severe side effects can also be influenced by specific genetic variants. All these aspects underscore the increasing importance of genetic variants, which in the future may help to identify patients at risk for disease progression or help to guide treatment decisions. In the present overview, specific frequent genetic variants are summarized that play roles in monogenetic liver diseases, forms of intrahepatic cholestasis, gallstone development, fatty liver disease, drug-induced liver injury, and liver disease progression as well as hepatocellular carcinoma development. PMID:26666282

  3. Distinct Plasma Bile Acid Profiles of Biliary Atresia and Neonatal Hepatitis Syndrome.

    Science.gov (United States)

    Zhou, Kejun; Wang, Jun; Xie, Guoxiang; Zhou, Ying; Yan, Weihui; Pan, Weihua; Che, Yanran; Zhang, Ting; Wong, Linda; Kwee, Sandi; Xiao, Yongtao; Wen, Jie; Cai, Wei; Jia, Wei

    2015-11-01

    Biliary atresia (BA) is a severe chronic cholestasis disorder of infants that leads to death if not treated on time. Neonatal hepatitis syndrome (NHS) is another leading cause of neonatal cholestasis confounding the diagnosis of BA. Recent studies indicate that altered bile acid metabolism is closely associated with liver injury and cholestasis. In this study, we systematically measured the bile acid metabolome in plasma of BA, NHS, and healthy controls. Liver bile acids were also measured using biopsy samples from 48 BA and 16 NHS infants undergoing operative cholangiography as well as 5 normal adjacent nontumor liver tissues taken from hepatoblastoma patients as controls. Both BA and NHS samples had significantly elevated bile acid levels in plasma compared to normal controls. BA patients showed a distinct bile acid profile characterized by the higher taurochenodeoxycholic acid (TCDCA) level and lower chenodeoxycholic acid (CDCA) level than those in NHS patients. The ratio of TCDCA to CDCA in plasma was significantly higher in BA compared to healthy infants (p BSEP), and multidrug resistant protein 3 (MDR3) in BA compared to NHS. Taken together, the plasma bile acid profiles are distinct in BA, NHS, and normal infants, as characterized by the ratio of TCDCA/CDCA differentially distributed among the three groups of infants. PMID:26449593

  4. Development of animal models for hepatobiliary nuclear imaging

    International Nuclear Information System (INIS)

    Animal models for hepatobiliary disorders were classified into 2 different types: parenchymal hepatotoxicity and biliary-tract cholestasis. The purpose of this study was to develop animal models for hepatobiliary scintigraphy in evaluating a novel agents, such as 99mTc-mercaptoacetyl triglycine(MAG3)-biocytin. Animal models were prepared by use of female Balb/c mice. Those were treated with 0.1, 0.5, and 2.5 ml/kg of carbon tetrachloride (CCl4) intraperitoneally for hepatotoxicity and with 30, 150, and 750 mg/kg of α-naphthylisothiocyanate (ANIT) to induce cholestasis. Dose of optimum was 0.5 ml/kg and 150 mg/kg for each model but lower (0.1 ml/kg and 30 mg/kg) and higher (2.5ml/kg and 750 mg/kg)were not be compatible for hepatobiliary models. Using these hepatobiliary models, 99mTc-MAG3-biocytin scintigraphy was successfully carried out by using 4 parameters, e.g., peak liver/heat ratio (Rmax), peak ratio time (Tmax), half clearance time (HCT), and hepatic extraction fraction (HEF) for hepatotoxicity and cholestasis. Additionally, biochemical and histological analysis also resulted in confirming these animal models. Thus, we concluded that these animal models were highly likely to be efficient in evaluating hepatobiliary scintigraphic agent such as 99mTc-MAG3-biocytin

  5. Nucleolar localization of cirhin, the protein mutated in North American Indian childhood cirrhosis

    International Nuclear Information System (INIS)

    Cirhin (NP116219), the product of the CIRH1A gene is mutated in North American Indian childhood cirrhosis (NAIC/CIRH1A, OMIM 604901), a severe autosomal recessive intrahepatic cholestasis. It is a 686-amino-acid WD40-repeat containing protein of unknown function that is predicted to contain multiple targeting signals, including an N-terminal mitochondrial targeting signal, a C-terminal monopartite nuclear localization signal (NLS) and a bipartite nuclear localization signal (BNLS). We performed the direct determination of subcellular localization of cirhin as a crucial first step in unraveling its biological function. Using EGFP and His-tagged cirhin fusion proteins expressed in HeLa and HepG2, cells we show that cirhin is a nucleolar protein and that the R565W mutation, for which all NAIC patients are homozygous, has no effect on subcellular localization. Cirhin has an active C-terminal monopartite nuclear localization signal (NLS) and a unique nucleolar localization signal (NrLS) between residues 315 and 432. The nucleolus is not known to be important specifically for intrahepatic cholestasis. These observations provide a new dimension in the study of hereditary cholestasis

  6. {sup 99m}Tc sestamibi imaging. Can it be a useful substitute for hepatobiliary scintigraphy in infantile jaundice?

    Energy Technology Data Exchange (ETDEWEB)

    Sadeghi, R.; Kakhki, V.R.D.; Zakavi, R. [Mashhad Univ. of Medical Sciences (Iran). Nuclear Medicine Dept.; Kianifar, H.R. [Mashhad Univ. of Medical Sciences (Iran). Paediatric Dept.; Ansari, K. [Tehran Univ. of Medical Sciences (Iran). Nuclear Medicine Dept.

    2009-07-01

    Hepatobiliary scintigraphy is an integral part in the diagnostic work-up of the neonatal cholestasis syndrome. However, less than optimal specificity is its major disadvantage. Differentiation between biliary atresia and neonatal hepatitis is nearly impossible in some cases with poor hepatocellular function. {sup 99m}Tc sestamibi (MIBI) is a cationic lipophilic agent which is a substrate of P-glycoprotein. This glycoprotein is normally expressed in biliary canalicular surfaces of hepatocytes. This property provides a hepatic excretory mechanism which is different from bilirubin excretion. In this study we evaluated the value of {sup 99m}Tc MIBI in differential diagnosis of neonatal cholestasis. 20 infants with a mean age of 2.41 months (range, 0.1-5 months) were included in the study. Ten infants turned out to have extrahepatic biliary atresia and the other ten had neonatal hepatitis. Hepatobiliary (with {sup 99m}Tc BrIDA) and {sup 99m}Tc MIBI scintigraphy were performed for all the patients. {sup 99m}Tc MIBI scintigraphy has shown bowel activity in all patients, including the patients with biliary atresia. Hepatobiliary scintigraphy revealed bowel activity only in five patients with neonatal hepatitis. Bowel visualization with {sup 99m}Tc MIBI may be seen in patients with biliary atresia and {sup 99m}Tc MIBI has limited value in differential diagnosis of neonatal cholestasis. (orig.)

  7. Naproxen-induced liver injury

    Institute of Scientific and Technical Information of China (English)

    Sharif Ali; Jason D Pimentel; Chan Ma

    2011-01-01

    BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to induce liver injury. Patterns of the injury usually range from mild elevations of liver enzymes to sometimes severe fulminant hepatic failure. Likewise, naproxen is a propionic acid derivative NSAID that was introduced in 1980 and has been available as an over-the-counter medication since 1994, but has rarely been reported to cause liver injury. METHODS: We treated a 30-year-old woman with jaundice and intractablepruritusthatdevelopedshortlyaftertakingnaproxen. We reviewed the medical history and liver histopathology of the patient as well as all previously published case reports of naproxen-associated liver toxicity in the English language literature. RESULTS: The liver biochemical profile of the patient revealed a mixed cholestasis and hepatitis pattern. Consecutive liver biopsies demonstrated focal lobular inflammation, hepatocyte drop-out, and a progressive loss of the small interlobular bile ducts (ductopenia). The biopsy performed two years after onset of the disease showed partial recovery of a small number of bile ducts; however, 10 years passed before the biochemical profile returned to near normal. CONCLUSIONS:  Naproxen-associated liver toxicity remains a rare entity, but should be considered in any patient presenting with cholestasis shortly after its use. Liver injury is most commonly seen in a mixed pattern characterized by cholestasis and hepatitis. The resulting liver damage may take years to resolve.

  8. Diagnostic and therapeutic approach to cholestatic liver disease Abordaje diagnóstico y terapéutico del síndrome colestásico

    Directory of Open Access Journals (Sweden)

    T. Pérez Fernández

    2004-01-01

    Full Text Available When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatiic. If bile ducts appear dilated and the probability of interventional treatment is high, endoscopic retrograde cholagio-pancreatography (ERCP or trans-hepatic cholangiography (THC should be the next step. If the probability of interventional therapeutics is low, cholangio-MRI should be performed. Once bile duct dilation and space occupying lesions are excluded, a work up for intrahepatic cholestasis should be started. Some especific clinical situations may be helpful in the diagnostic strategy. If cholestasis occurs in the elderly, drug-induced cholestatic disease should be suspected, whereas if it occurs in young people with risk factors, cholestatic viral hepatitis is the most likely diagnosis. During the first trimester of pregnancy cholestasis may occur in hiperemesis gravidorum, and in the third trimester of gestation cholestasis of pregnancy should be suspected. A familial history of recurrent cholestasis points to benign recurrent intrahepatic cholestasis. The occurrence of intrahepatic cholestasis in a mid-dle-aged woman is a frequent presentation of primary biliary cirrhosis, whereas primary sclerosing cholangitis should be suspected in young males with inflammatory bowel disease. The presence of vascular spider nevi, ascites, and a history of alcohol abuse should point to alcoholic hepatitis. Neonatal cholestasis syndromes include CMV, toxoplasma and rubinfections or metabolic defects such as cystic fibrosis, α1-antitripsin deficiency, bile acid synthesis defects, or biliary atresia. The treatment of cholestasis should include a management of complications such as pruritus, osteopenia and correction of fat soluble vitamin deficiencies. When hepatocellular failure or portal hypertension-related complications occur, liver transplantation should be considered.Ante la presencia de colestasis, se debe

  9. Effects of structural injure in the bile bacterial contamination after balloon transduodenal sphincteroplasty (papillary dilation in dogs

    Directory of Open Access Journals (Sweden)

    Zavadinack Netto Martin

    2006-01-01

    Full Text Available PURPOSE: To evaluate, in dogs, the biliary sphincter subjected to dilation by hydrostatic balloon by the point of view of structural alterations of the papilla and the biochemestry and bacterial contamination of the bile. METHODS: Twenty dogs were submitted to laparotomy, duodenotomy, and enlargement of the major duodenal papilla- GA(n=10 - with balloon of 8mm inflated with pressure of 0,5atm, during 2 minutes or to the sham procedure - GB(n=10. Blood samples collected on times t(0day, t(7days and t(28days were subjected to dosages of alkaline phosphatase (ALP and gamma-glutamyltransferase (GGT for cholestasis evaluation. The collected material from the gall bladder at the same times were registered and numbered to be submitted to culture in BHI, blood agar (rich, non-selective element and Mac Conkey (selective element for Gram-negative bacillus. On the 28th day three fragments of the papilla were tranversally cut by the choledoc axis 3mm from the duodenal papilla and the cuts, stained with hematoxylin-eosin and Masson's tricome, were evaluated according to their inflammatory reaction. RESULTS: The GGT and ALP averages on the three periods in the groups A and B did not show significant differences, not being characterizes the cholestasis. The bacterian contamination was significantly higher in GA (2,19 than in GB (1,96; the contamination was lower in the initial time compared with 7 and 28 days (t0cholestasis. The morphologic lesions are more intense in the late phase, not associated with an eventual papilla esthenosis.

  10. AP-1 Inhibition by SR 11302 Protects Human Hepatoma HepG2 Cells from Bile Acid-Induced Cytotoxicity by Restoring the NOS-3 Expression

    Science.gov (United States)

    González-Rubio, Sandra; Linares, Clara I.; Aguilar-Melero, Patricia; Rodríguez-Perálvarez, Manuel; Montero-Álvarez, José L.

    2016-01-01

    The harmful effects of bile acid accumulation occurring during cholestatic liver diseases have been associated with oxidative stress increase and endothelial nitric oxide synthase (NOS-3) expression decrease in liver cells. We have previously reported that glycochenodeoxycholic acid (GCDCA) down-regulates gene expression by increasing SP1 binding to the NOS-3 promoter in an oxidative stress dependent manner. In the present study, we aimed to investigate the role of transcription factor (TF) AP-1 on the NOS-3 deregulation during GCDCA-induced cholestasis. The cytotoxic response to GCDCA was characterized by 1) the increased expression and activation of TFs cJun and c-Fos; 2) a higher binding capability of these at position -666 of the NOS-3 promoter; 3) a decrease of the transcriptional activity of the promoter and the expression and activity of NOS-3; and 4) the expression increase of cyclin D1. Specific inhibition of AP-1 by the retinoid SR 11302 counteracted the cytotoxic effects induced by GCDCA while promoting NOS-3 expression recovery and cyclin D1 reduction. NOS activity inhibition by L-NAME inhibited the protective effect of SR 11302. Inducible NOS isoform was no detected in this experimental model of cholestasis. Our data provide direct evidence for the involvement of AP-1 in the NOS-3 expression regulation during cholestasis and define a critical role for NOS-3 in regulating the expression of cyclin D1 during the cell damage induced by bile acids. AP-1 appears as a potential therapeutic target in cholestatic liver diseases given its role as a transcriptional repressor of NOS-3. PMID:27490694

  11. Characterization of the role of ABCG2 as a bile acid transporter in liver and placenta.

    Science.gov (United States)

    Blazquez, Alba G; Briz, Oscar; Romero, Marta R; Rosales, Ruben; Monte, Maria J; Vaquero, Javier; Macias, Rocio I R; Cassio, Doris; Marin, Jose J G

    2012-02-01

    ABCG2 is involved in epithelial transport/barrier functions. Here, we have investigated its ability to transport bile acids in liver and placenta. Cholylglycylamido fluorescein (CGamF) was exported by WIF-B9/R cells, which do not express the bile salt export pump (BSEP). Sensitivity to typical inhibitors suggested that CGamF export was mainly mediated by ABCG2. In Chinese hamster ovary (CHO cells), coexpression of rat Oatp1a1 and human ABCG2 enhanced the uptake and efflux, respectively, of CGamF, cholic acid (CA), glycoCA (GCA), tauroCA, and taurolithocholic acid-3-sulfate. The ability of ABCG2 to export these bile acids was confirmed by microinjecting them together with inulin in Xenopus laevis oocytes expressing this pump. ABCG2-mediated bile acid transport was inhibited by estradiol 17β-d-glucuronide and fumitremorgin C. Placental barrier for bile acids accounted for 14-fold increased maternal cholanemia induced by obstructive cholestasis in pregnant rats. In rat placenta, the expression of Abcg2, which was much higher than that of Bsep, was not affected by short-term cholestasis. In pregnant rats, fumitremorgin C did not affect uptake/secretion of GCA by the liver but inhibited its fetal-maternal transfer. Compared with wild-type mice, obstructive cholestasis in pregnant Abcg2(-/-) knockout mice induced similar bile acid accumulation in maternal serum but higher accumulation in placenta, fetal serum, and liver. In conclusion, ABCG2 is able to transport bile acids. The importance of this function depends on the relative expression in the same epithelium of other bile acid exporters. Thus, ABCG2 may play a key role in bile acid transport in placenta, as BSEP does in liver. PMID:22096226

  12. Investigation of Homocystein Plasma Level in Cholestatic Rat and Its Effect on Nitric Oxide Secretion in Liver

    Directory of Open Access Journals (Sweden)

    N. Mirazi

    2005-04-01

    Full Text Available Homocystein (Hcy,one of the thio-amino acid is known as a risk factor in some cardiovascular diseases with releasing O2 radical . It has also been reported that; there is oxidative stress effects of Hcy in cholestasis. The aim of this study is to determine plasma Hcy alteration and nitric oxide (NO in liver and its effects on pathologic disfunction.In this study , 150 Spraque – Dawley male rats with 200 ± 20g body weight were used in the experiments and they were randomly divided in three control, SHAM and bile duct ligation (BDL groups (n= 10-12 . In 7th,14th,21st and 28th days cholestasis was observed in BDL group,the animal were anesthetized with ether and then blood samples were taken from heart directly and analysed for cystein , methionine by HPLC and HPLC-UV. Two hours before blood sampling , 40 and 100 mg/kg methionine were injected (I.P .All data are expressed as mean  SEM. Statistical evaluation of data performed by SPSS soft ware using analysis of variance (ANOVA followed by post hoc test. P-values less than 0.05 were considered statistically significant .The results suggest that billirubin and hepatic enzymes were significantly elevated in BDL rats compared with SHAM and controls (P<0.05. Homocystein concentration was significantly rised in 14th day in BDL group (P<0.05. The plasma cystein and methionine level were significantly elevated in BDL rats compared with SHAM and control groups ( p = 0.01 . Plasma nitrate / nitrite ratio were significantly increased in BDL rats compared with SHAM and control rats (P<0.05. With these data we suppose that some of the systemic oxidative stresses in BDL rat model of cholestasis contributes possibly through NO-dependent mechanisms disorders.

  13. Use of a low-density microarray for studying gene expression patterns induced by hepatotoxicants on primary cultures of rat hepatocytes.

    Science.gov (United States)

    de Longueville, Francoise; Atienzar, Franck A; Marcq, Laurence; Dufrane, Simon; Evrard, Stéphanie; Wouters, Lydia; Leroux, Florence; Bertholet, Vincent; Gerin, Brigitte; Whomsley, Rhys; Arnould, Thierry; Remacle, José; Canning, Mickael

    2003-10-01

    In the field of gene expression analysis, DNA microarray technology is having a major impact on many different areas including toxicology. For instance, a number of studies have shown that transcription profiling can generate the information needed to assign a compound to a mode-of-action class. In this study, we investigated whether compounds inducing similar toxicological endpoints produce similar changes in gene expression. In vitro primary rat hepatocytes were exposed to 11 different hepatotoxicants: acetaminophen, amiodarone, clofibrate, erythromycin estolate, isoniazid, alpha-naphtylylisothiocyanate, beta-naphtoflavone, 4-pentenoic acid, phenobarbital, tetracycline, and zileuton. These molecules were selected on the basis of their variety of hepatocellular effects observed such as necrosis, cholestasis, steatosis, and induction of CYP P450 enzymes. We used a low-density DNA microarray containing 59 genes chosen as relevant toxic and metabolic markers. The in vitro gene expression data generated in this study were generally in good agreement with the literature, which mainly concerns in vivo data. Furthermore, gene expression profiles observed in this study have been confirmed for several genes by real-time PCR assays. All the tested drugs generated a specific gene expression profile. Our results show that even with a relatively limited gene set, gene expression profiling allows a certain degree of classification of compounds with similar hepatocellular toxicities such as cholestasis, necrosis. The clustering analysis revealed that the compounds known to cause steatosis were linked, suggesting that they functionally regulate similar genes and possibly act through the same mechanisms of action. On the other hand, the drugs inducing necrosis and cholestasis were pooled in the same cluster. The drugs arbitrarily classified as the CYP450 inducers formed individual clusters. In conclusion, this study suggests that low-density microarrays could be useful in

  14. Ostα depletion protects liver from oral bile acid load.

    Science.gov (United States)

    Soroka, Carol J; Velazquez, Heino; Mennone, Albert; Ballatori, Nazzareno; Boyer, James L

    2011-09-01

    Bile acid homeostasis is tightly maintained through interactions between the liver, intestine, and kidney. During cholestasis, the liver is incapable of properly clearing bile acids from the circulation, and alternative excretory pathways are utilized. In obstructive cholestasis, urinary elimination is often increased, and this pathway is further enhanced after bile duct ligation in mice that are genetically deficient in the heteromeric, basolateral organic solute transporter alpha-beta (Ostα-Ostβ). In this study, we examined renal and intestinal function in Ostα-deficient and wild-type mice in a model of bile acid overload. After 1% cholic acid feeding, Ostα-deficient mice had significantly lower serum ALT levels compared with wild-type controls, indicating partial protection from liver injury. Urinary clearance of bile acids, but not clearance of [(3)H]inulin, was significantly higher in cholic acid-fed Ostα-deficient mice compared with wild-type mice but was not sufficient to account for the protection. Fecal excretion of bile acids over the 5 days of cholic acid feeding was responsible for almost all of the bile acid loss in Ostα-deficient mice, suggesting that intestinal losses of bile acids accounted for the protection from liver injury. Thus fecal loss of bile acids after bile acid overload reduced the need for the kidney to filter and excrete the excess bile acids. In conclusion, Ostα-deficient mice efficiently eliminate excess bile acids via the feces. Inhibition of intestinal bile acid absorption might be an effective therapeutic target in early stages of cholestasis when bile acids are still excreted into bile. PMID:21719738

  15. Pyrazinamide Induced Rat Cholestatic Liver Injury through Inhibition of FXR Regulatory Effect on Bile Acid Synthesis and Transport.

    Science.gov (United States)

    Guo, Hong-Li; Hassan, Hozeifa M; Zhang, Yun; Dong, Si-Zhe; Ding, Ping-Ping; Wang, Tao; Sun, Li-Xin; Zhang, Lu-Yong; Jiang, Zhen-Zhou

    2016-08-01

    Pyrazinamide (PZA) is an indispensable first-line drug used for the treatment of tuberculosis which may cause serious hepatotoxicity; however, the mechanisms underlying these toxicities are poorly understood. Cholestasis plays an important role in drug-induced liver injury. Since there were no previous published works reported cholestasis and PZA hepatotoxicity relationship, this study aimed to identify whether PZA can induce liver injury with characterized evidences of cholestasis and to clarify expression changes of proteins related to both bile acid synthesis and transport in PZA-induced liver injury. PZA (2 g/kg) was administered for 7 consecutive days by oral gavage. Results showed there were 2-fold elevation in both ALT and AST serum levels in PZA-treated rats. In addition, a 10-fold increment in serum total bile acid was observed after PZA administration. The mRNA and protein expressions of bile acid synthesis and transport parameters were markedly altered, in which FXR, Bsep, Mrp2, Mdr2, Ostα/β, Oatp1a1, Oatp1b2, and Cyp8b1 were decreased (P < .05), while Mrp3, Ntcp, Oatp1a4, and Cyp7a1 were increased (P < .05). Moreover, treatment with the FXR agonist obeticholic acid (OCA) generated obvious reductions in serum ALT, AST, and TBA levels in PZA-treated rats. Those effects were due to transcriptional regulation of pre-mentioned target genes by OCA. Taken together, these results suggested that PZA-induced cholestatic liver injury was related to FXR inhibition, leading to the dysfunction in bile acid synthesis and transport. PMID:27255380

  16. Extrahepatic bile duct atresia from the pathologist’s perspective: pathological features and differential diagnosis

    Directory of Open Access Journals (Sweden)

    Peter Van Eyken

    2014-06-01

    Full Text Available Extrahepatic biliary atresia (EHBA refers to stenosis or atresia of the extrahepatic biliary tree. It accounts for 25-30% of cases of neonatal cholestasis. If left untreated, EHBA progresses to biliary cirrhosis and is universally fatal within the first 2 years of life. Early diagnosis is crucial since surgical treatment (Kasai procedure is the only treatment option. Histopathologic examination of liver biopsy specimens is a key element in the diagnostic work-up of infants with suspected EHBA. Pathologic diagnosis aims at excluding non-surgically correctable causes of neonatal cholestasis thereby leading to surgical exploration for confirmation of the diagnosis. All published data indicate that pathologists can diagnose EHBA with high sensitivity, high specificity and reasonable interobserver agreement. The most useful histologic features in the diagnosis of EHBA are portal tract changes including ductular proliferation and bile plugs in ducts and ductules. These lesions are not pathognomonic but can be seen in extrahepatic obstruction of any cause. Total parenteral nutrition (TPN-associated cholestasis and alpha1-antitrypsin (A1AT deficiency cannot be differentiated from EHBA without access to clinical data and may lead to false-positive diagnosis. False-negative interpretation may be caused by early age at diagnosis or by small/indequate specimens. The pathologist also plays a role in the examination of the resected fibrotic segment and of explant specimens. Histopathology can yield prognostic information, being also an indispensable tool in research for the possible pathogenesis of this disease. A well-coordinated, multidisciplinary approach is required in the assessment of suspected cases of EHBA.  Proceedings of the International Course on Perinatal Pathology (part of the 10th International Workshop on Neonatology · October 22nd-25th, 2014 · Cagliari (Italy · October 25th, 2014 · The role of the clinical pathological dialogue in

  17. The enhanced value of combining conventional and 'omics' analyses in early assessment of drug-induced hepatobiliary injury

    International Nuclear Information System (INIS)

    The InnoMed PredTox consortium was formed to evaluate whether conventional preclinical safety assessment can be significantly enhanced by incorporation of molecular profiling ('omics') technologies. In short-term toxicological studies in rats, transcriptomics, proteomics and metabolomics data were collected and analyzed in relation to routine clinical chemistry and histopathology. Four of the sixteen hepato- and/or nephrotoxicants given to rats for 1, 3, or 14 days at two dose levels induced similar histopathological effects. These were characterized by bile duct necrosis and hyperplasia and/or increased bilirubin and cholestasis, in addition to hepatocyte necrosis and regeneration, hepatocyte hypertrophy, and hepatic inflammation. Combined analysis of liver transcriptomics data from these studies revealed common gene expression changes which allowed the development of a potential sequence of events on a mechanistic level in accordance with classical endpoint observations. This included genes implicated in early stress responses, regenerative processes, inflammation with inflammatory cell immigration, fibrotic processes, and cholestasis encompassing deregulation of certain membrane transporters. Furthermore, a preliminary classification analysis using transcriptomics data suggested that prediction of cholestasis may be possible based on gene expression changes seen at earlier time-points. Targeted bile acid analysis, based on LC-MS metabonomics data demonstrating increased levels of conjugated or unconjugated bile acids in response to individual compounds, did not provide earlier detection of toxicity as compared to conventional parameters, but may allow distinction of different types of hepatobiliary toxicity. Overall, liver transcriptomics data delivered mechanistic and molecular details in addition to the classical endpoint observations which were further enhanced by targeted bile acid analysis using LC/MS metabonomics.

  18. A case of infantile Dubin-Johnson syndrome with high CT attenuation in the liver

    International Nuclear Information System (INIS)

    We report a case of Dubin-Johnson syndrome (DJS) with severe infantile cholestasis and elevated computed tomography (CT) attenuation of the liver. Increased levels of urinary coproporphyrin I were found as well as pigment granules in the hepatocytes and hepatosteatosis. The CT attenuation was markedly higher in the liver of this patient at the ages of 3 and 7 months than in the spleen or kidneys. This high attenuation may be a finding specific to infantile DJS and, therefore, abdominal CT may be helpful in the diagnosis. (orig.). With 3 figs

  19. Ultrasound as a decision-making tool in abdominal surgery in cows.

    Science.gov (United States)

    Braun, Ueli

    2005-03-01

    In many patients, abdominal ultrasonography is an excellent diagnostic and prognostic tool. It aids in deciding whether the animal should undergo surgical or medical treatment or be slaughtered. This is particularly true in cattle with traumatic reticuloperitonitis (in combination with radiography of the reticulum) or with a tentative diagnosis of left or right displacement of the abomasum. Ultrasound also is an excellent aid for identification of ileus of the small and large intestine, liver abscesses, cholestasis, various urinary tract disorders, and the different forms of ascites. PMID:15718086

  20. Cephalexin induced cholestatic jaundice.

    Science.gov (United States)

    Agrawal, Abhinav; Rao, Mana; Jasdanwala, Sarfaraz; Mathur, Ajay; Eng, Margaret

    2014-01-01

    Cephalexin is a very commonly prescribed orally administered antibiotic which has many potential side effects. Amongst these cholestatic jaundice has been infrequently reported as an adverse reaction. We present a case of a 57-year-old male who exhibited features of cholestatic jaundice including elevated liver function tests (LFTs) after taking cephalexin and showed improvement on removal of the offending agent. During this time he was symptomatically treated with cholestyramine. Complete resolution of LFTs was seen in four weeks. Cephalexin induced cholestasis is rare and hence requires a high degree of clinical suspicion for prompt diagnosis and treatment. PMID:25180107

  1. LITHOCHOLIC ACID FEEDING RESULTS IN DIRECT HEPATO-TOXICITY INDEPENDENT OF NEUTROPHIL FUNCTION IN MICE

    OpenAIRE

    Woolbright, Benjamin L.; Li, Feng; Xie, Yuchao; Farhood, Anwar; Fickert, Peter; Trauner, Michael; Jaeschke, Hartmut

    2014-01-01

    Lithocholic acid (LCA) supplementation in the diet results in intrahepatic cholestasis and bile infarcts. Previously we showed that an innate immune response is critical for cholestatic liver injury in the bile duct ligated mice. Thus, the purpose of this study was to investigate the role of neutrophils in the mechanism of liver injury caused by feeding mice a diet containing LCA. C57BL/6 mice were given control or 1% LCA containing diet for 24–96h and then examined for parameters of hepatoto...

  2. DECREASED APOPTOSIS DURING CAR-MEDIATED HEPATOPROTECTION AGAINST LITHOCHOLIC ACID-INDUCED LIVER INJURY IN MICE

    OpenAIRE

    Beilke, Lisa D.; Aleksunes, Lauren M.; Olson, Erik R.; Besselsen, David G; Klaassen, Curtis D.; Dvorak, Katerina; Cherrington, Nathan J.

    2009-01-01

    Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR+/+ (WT) and CAR−/−...

  3. Antibodies against p53 protein in serum of patients with benign or malignant pancreatic and biliary diseases.

    OpenAIRE

    Laurent-Puig, P.; Lubin, R; Semhoun-Ducloux, S; Pelletier, G.; Fourre, C; Ducreux, M.; Briantais, M J; Buffet, C; Soussi, T

    1995-01-01

    Specific markers for pancreatic or biliary cancer have been developed in the past few years. Ca 19-9 has a good sensitivity but it is also increased in benign cholestasis. Mutations in the p53 gene are commonly reported in pancreatic cancer and can be detected by a serological analysis. The aim of this work was to find out the sensitivity and specificity of this new assay in diagnosing cancer of the pancreas or of the bile ducts. The presence of antibodies against p53 was determined by an enz...

  4. Exon-skipping and mRNA decay in human liver tissue: molecular consequences of pathogenic bile salt export pump mutations

    OpenAIRE

    Carola Dröge; Heiner Schaal; Guido Engelmann; Daniel Wenning; Dieter Häussinger; Ralf Kubitz

    2016-01-01

    The bile salt export pump BSEP mediates bile formation. Over 150 BSEP mutations are associated with progressive familial intrahepatic cholestasis type 2 (PFIC-2), with few characterised specifically. We examined liver tissues from two PFIC-2 patients compound heterozygous for the splice-site mutation c.150 + 3A > C and either c.2783_2787dup5 resulting in a frameshift with a premature termination codon (child 1) or p.R832C (child 2). Splicing was analysed with a minigene system and mRNA sequen...

  5. The feline bile salt export pump: a structural and functional comparison with canine and human Bsep/BSEP

    OpenAIRE

    Beusekom, C.D. van; Heuvel, J.J.M.W. van den; Koenderink, J.B.; Schrickx, J.A.; Russel, F G M

    2013-01-01

    Background The bile salt export pump (BSEP/ABCB11) is the primary transporter for the excretion of bile acids from hepatocytes into bile. In human, inhibition of BSEP by drugs has been related to drug-induced cholestasis and subsequent cytotoxic effects. The role of BSEP in canine and feline liver diseases has not been studied in detail, but the same mechanism of inhibition by drugs as in humans could play a role in veterinary medicine. The aim of this study was to investigate the functional ...

  6. POSTOPERATIVE COMPLICATIONS IN LIVER TRANSPLANT RECIPIENTS: MODERN СCONSIDERATIONS OF PATHOGENESIS AND MAIN AREAS OF PROPHYLAXIS AND TREATMENT

    Directory of Open Access Journals (Sweden)

    M. Sh. Khubutia

    2009-05-01

    Full Text Available The article presents analysis of scientific literature of the last 15 years about complications after orthotopic liver transplantation, depending on the severity of the initial status of recipient and expression of metabolic and functional disorders. Factors affecting the development of vascular complications (arterial and venous thrombosis, biliary complications (cholestasis, cholangitis, immune response (acute rejection, and also surgical and infectious complications and functional insufficiency of the graft are analyzed in this review. The necessity to improve monitoring in the immediate post transplant period is considered. 

  7. Diagnosis of Caroli's disease by technetium-99m DISIDA cholescintigraphy. Report of three cases

    International Nuclear Information System (INIS)

    Three patients in whom Caroli's disease was diagnosed by cholangiographic methods were studied by scintigraphy with Tc-99m DISIDA. Cholescintigrams showed an intense concentration of the radionuclide in the form of round spots near the hepatic hilus in late images. In two patients with cholestasis, a delayed hepatic clearance of the radionuclide was observed, which improved when the exploration was performed after a choledocoduodenostomy. Tc-99m DISIDA is not only a good noninvasive method to diagnose Caroli's disease, but also a useful technique to evaluate the patency of the biliary tree during the follow-up of such patients

  8. THE DIAGNOSIS OF ACUTE GALLSTONE PANCREATITIS

    Directory of Open Access Journals (Sweden)

    Elena Gologan

    2009-05-01

    Full Text Available Acute gallstone pancreatitis is a severe form of pancreatitis caused by an ampullary blocked gallstone. The clinical course combines elements of severe pancreatitis and obstructive jaundice with angiocolitis. Complications are very frequent in the absence of spontaneous, interventional or surgical desobstruction. The diagnosis is based upon clinical features, biochemical paramethers with cholestasis, hyperamilasemia, hyperamilasuria, hyperlipasemia, metabolic disorders. Imagistic assay is undoubtful necessary for the diagnosis; it allows identifying most of the complications, and some of these investigations are very useful in the desobstruction procedures, done at proper moment.

  9. [Correction of hepatic dysfunction as pre-treatment before systemic chemotherapy in patients with bile duct neoplasms].

    Science.gov (United States)

    Iakovlev, A Iu; Chichkanova, A S; Ulitin, D N; Mokrov, K V; Akulenko, S V

    2012-01-01

    This prospective randomized study incorporates 141 surgical department patients with hepatobiliary tumors. The 1st group patients received 800 ml/day of remaxol. The 2nd1 group patients received Ringer solution and 10% glucose at 1:1 ratio. The subgroups included: 1 subgroup-with pre-operative cholecysto- or choledochostomia and B-subgroup-without pre-operative interventions. The combined surgical and pharmaceutical correction of bile passage, bilirubinemia, cholestasis and cytolysis by remaxole leads to better hepatic dysfunction correction and allows better timing of chemotherapy in bile passage tumors. PMID:23607215

  10. [Endoscopic ultrasound-guided choledocho-duodenostomy in advanced pancreatic cancer with duodenal obstruction].

    Science.gov (United States)

    Mella, José Manuel; Guidi, Martín; De María, Julio; Hwang, Hui-Jer; Curvale, Cecilia R; Matano, Raúl

    2015-01-01

    Endoscopic retrograde cholangiopancreatography (ERCP) is considered the first-approach for biliary drainage. In cases of ERCP failure, patients are usually referred for percutaneous transhepatic biliary drainage or surgical biliary bypass. In the last decade, the indications of endoscopic ultrasound (EUS) in the management of patients with pancreatic cancer have increased, and numerous cases of EUS-guided biliary drainage have been reported in patients with failures during the ERCP. Our goal is to report a patient with locally advanced pancreatic cancer who presented with painless jaundice and cholestasis with biliary and duodenal obstruction. A EUS-guided choledochoduodenostomy was performed by placement of a self-expanding metal stent. PMID:26502467

  11. Mechanism of Vitamin D Receptor Inhibition of Cholesterol 7α-Hydroxylase Gene Transcription in Human HepatocytesS⃞

    OpenAIRE

    Han, Shuxin; Chiang, John Y. L.

    2008-01-01

    Lithocholic acid (LCA) is a potent endogenous vitamin D receptor (VDR) ligand. In cholestasis, LCA levels increase in the liver and intestine. The objective of this study is to test the hypothesis that VDR plays a role in inhibiting cholesterol 7α-hydroxylase (CYP7A1) gene expression and bile acid synthesis in human hepatocytes. Immunoblot analysis has detected VDR proteins in the nucleus of the human hepatoma cell line HepG2 and human primary hepatocytes. 1α, 25-Dihyd...

  12. Vanishing bile duct and Stevens-Johnson syndrome associated with ciprofloxacin treated with tacrolimus

    Institute of Scientific and Technical Information of China (English)

    Gokhan Okan; Serpil Yaylaci; Onder Peker; Sabahattin Kaymakoglu; Murat Saruc

    2008-01-01

    Stevens-Johnson syndrome (SJS) is a serious and potentially life-threatening disease. Vanishing bile duct syndrome (VBDS) is a rare cause of progressive cholestasis. Both syndromes are mostly related with drugs. We report a case of a patient withciprofloxacin-induced SJS and acute onset of VBDS,and reviewed the related literature. It is the first case of ciprofloxacin-induced VBDS successfully treatedwith tacrolimus. This case reminds physicians of the importance of drug reactions, their severity, techniques for diagnosis and methods of management.

  13. Ultrasound-guided percutaneous cholecysto-cholangiography for the exclusion of biliary atresia in infants

    Energy Technology Data Exchange (ETDEWEB)

    Shin, Kyung Min; Ryeom, Hun Kyu; Choe, Byung Ho; Kim, Kap Cheol; Kim, Jong Yeol; Lee, Jong Min; Kim, Hye Jeong; Lee, Hee Jung [Kyungpook National University Hospital, Daegu (Korea, Republic of)

    2006-08-15

    The aim of this study is to determine the feasibility and effectiveness of performing an ultrasound-guided percutaneous cholecysto-cholangiogram (PCC) for excluding biliary atresia as the cause of neonatal jaundice. Between Oct. 2003 and Feb. 2005, six ultrasound-guided PCC procedures were performed to five jaundiced infants (4 females and 1 male; mean age: 60 days old) for whom possibility of biliary atresia could not be ruled out by the DISIDA scan as the cause of their neonatal jaundice. Gallbladder puncture was performed under ultrasound guidance with a 23-gauge needle. Contrast material injection during fluoroscopic examination was performed after dilatation of the gallbladder lumen with normal saline under ultrasound guidance. The criteria used for excluding biliary atresia were complete visualization of the extrahepatic biliary trees and/or contrast excretion into the duodenum. The complications and final diagnosis was assessed according to the clinical and laboratory findings. The procedures were successful in all the patients without any complication. Biliary atresia could be ruled out in all the patients. The final diagnosis was neonatal cytomegalovirus hepatitis in two patients, total parenteral nutrition-associated cholestasis in two patients, and combined cytomegalovirus hepatitis and total parenteral nutrition-associated cholestasis in one patient. Ultrasound-guided PCC is a feasible and effective method for the early definitive exclusion of biliary atresia as the cause of neonatal jaundice. By the technique of injecting normal saline before contrast injection, PCC can be done even in a totally collapsed or very small gallbladder.

  14. Endoscopic management of biliary fascioliasis: a case report

    Directory of Open Access Journals (Sweden)

    Kasnazani Kalandar A

    2010-03-01

    Full Text Available Abstract Introduction Fasciola hepatica, an endemic parasite common in Iraq and its neighboring countries, is a very rare cause of cholestasis worldwide. Humans can become definitive hosts of this parasite through their ingestion of a contaminated water plant, for example, contaminated watercress. Symptoms of cholestasis may appear suddenly and, in some cases, are preceded by long periods of fever, eosinophilia, and vague gastrointestinal symptoms. Here we report the case of a woman with a sudden onset of symptoms of cholangitis. Her infection was proved by endoscopic retrograde cholangiography to be due to Fasciola hepatica infestation. Case presentation A 38-year-old Kurdish woman from the northern region of Iraq presented with fever, right upper quadrant abdominal pain, and jaundice. An examination of the patient revealed elevated total serum bilirubin and liver enzymes. An ultrasonography also showed a dilatation of her common bile duct. During endoscopic retrograde cholangiopancreatography, a filling defect was identified in her common bile duct. After sphincterotomy and balloon extraction, one live Fasiola hepatica was extracted and physically removed. Conclusion Fasciola hepatica should be a part of the differential diagnosis of common bile duct obstruction. When endoscopic retrograde cholangiopancreatography is available, the disease can be easily diagnosed and treated.

  15. Marked Direct Hyperbilirubinemia due to Ceftriaxone in an Adult with Sickle Cell Disease

    Directory of Open Access Journals (Sweden)

    Daniyeh Khurram

    2015-01-01

    Full Text Available Drugs are a significant cause of liver injury. Drug-induced liver injury (DILI can cause acute hepatitis, cholestasis, or a mixed pattern. Ceftriaxone is a commonly used antibiotic and has been associated with reversible biliary sludge, pseudolithiasis, and cholestasis. A 32-year-old male with sickle cell disease was admitted to the hospital for acute sickle cell crisis. On the second day of hospitalization, he developed cough and rhonchi with chest X-ray revealing right middle lobe infiltrates. Ceftriaxone and azithromycin were initiated. Subsequently, he developed conjugated hyperbilirubinemia and mild transaminitis. His total bilirubin trended upwards from 3.3 mg/dL on admission to 17 mg/dL. It was predominantly conjugated bilirubin, with preadmission bilirubin levels of 3-4 mg/dL. His transaminases were mildly elevated as well compared to previous levels. Extensive workup for bilirubin elevation was unremarkable. Ceftriaxone was switched to levofloxacin and the hyperbilirubinemia improved. On ambulatory follow-up, his bilirubin remained below 4 mg/dL. Ceftriaxone may be associated with marked direct hyperbilirubinemia particularly in sickle cell patients with chronic liver chemistry abnormalities. In the case of elevated bilirubin with concomitant ceftriaxone use, elimination of the offending agent should be considered.

  16. MR cholangio-pancreatography using an open, low magnetic field of 0.2 Tesla. Early clinical results and comparison with a higher magnetic field (1.5 Tesla) and with ERCP

    International Nuclear Information System (INIS)

    Aim: To evaluate MR cholangio-pancreatography (MRCP) using an open low magnetic field apparatus in normals and in patients with mechanical cholestasis. Methods: MRCP was performed on five normals and on 30 patients, using both an 0.2 Tesla and 1.5 Tesla apparatus. With the low field system, rapid acquisition by relaxation enhancement was used, for the high field system, half Fourier acquisition single shot turbo spin-echo sequences were used. In all patients, sonography and ERCP of PTC was performed; 23 underwent surgery. Results: In all normals it was possible to show the bile duct, hepatic duct, gall bladder and intrahepatic ducts of the first order. Using the high field system, second order ducts could be shown and sometimes third order ducts. In the patients, MRCP, using either system, demonstrated all 21 obstructive sites due to tumours or stenoses. Stones were shown in 69% by the low field system and in 88% by the high field system. Conclusion: MRCP can be successfully carried out using the low field system. In the presence of mechanical cholestasis, image quality is adequate for the localisation of stenoses and occlusions, and using an open magnet, is suitable for planning further intervention. (orig.)

  17. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    Energy Technology Data Exchange (ETDEWEB)

    Wu, Weibin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China); Zhu, Bo; Peng, Xiaomin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Zhou, Meiling, E-mail: meilingzhou2012@gmail.com [Department of Radiology, Zhongshan Hospital of Fudan University and Shanghai Institute of Medical Imaging, Shanghai 200032 (China); Jia, Dongwei, E-mail: jiadongwei@fudan.edu.cn [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Gu, Jianxin [Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032 (China); Institutes of Biomedical Science, Fudan University, Shanghai 200032 (China)

    2014-01-03

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients.

  18. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease

    International Nuclear Information System (INIS)

    Highlights: •FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. •Activation of FXR attenuated alcohol-induced liver injury and steatosis. •Activation of FXR attenuated cholestasis and oxidative stress in mouse liver. -- Abstract: Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients

  19. Metformin interferes with bile acid homeostasis through AMPK-FXR crosstalk.

    Science.gov (United States)

    Lien, Fleur; Berthier, Alexandre; Bouchaert, Emmanuel; Gheeraert, Céline; Alexandre, Jeremy; Porez, Geoffrey; Prawitt, Janne; Dehondt, Hélène; Ploton, Maheul; Colin, Sophie; Lucas, Anthony; Patrice, Alexandre; Pattou, François; Diemer, Hélène; Van Dorsselaer, Alain; Rachez, Christophe; Kamilic, Jelena; Groen, Albert K; Staels, Bart; Lefebvre, Philippe

    2014-03-01

    The nuclear bile acid receptor farnesoid X receptor (FXR) is an important transcriptional regulator of bile acid, lipid, and glucose metabolism. FXR is highly expressed in the liver and intestine and controls the synthesis and enterohepatic circulation of bile acids. However, little is known about FXR-associated proteins that contribute to metabolic regulation. Here, we performed a mass spectrometry-based search for FXR-interacting proteins in human hepatoma cells and identified AMPK as a coregulator of FXR. FXR interacted with the nutrient-sensitive kinase AMPK in the cytoplasm of target cells and was phosphorylated in its hinge domain. In cultured human and murine hepatocytes and enterocytes, pharmacological activation of AMPK inhibited FXR transcriptional activity and prevented FXR coactivator recruitment to promoters of FXR-regulated genes. Furthermore, treatment with AMPK activators, including the antidiabetic biguanide metformin, inhibited FXR agonist induction of FXR target genes in mouse liver and intestine. In a mouse model of intrahepatic cholestasis, metformin treatment induced FXR phosphorylation, perturbed bile acid homeostasis, and worsened liver injury. Together, our data indicate that AMPK directly phosphorylates and regulates FXR transcriptional activity to precipitate liver injury under conditions favoring cholestasis. PMID:24531544

  20. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats.

    Science.gov (United States)

    Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko; Masutomi, Naoya; Tsutsui, Naohisa; Adam, Klaus-Peter; Alexander, Danny C; Lawton, Kay A; Milburn, Michael V; Ryals, John A; Wulff, Jacob E; Guo, Lining

    2013-04-01

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. PMID:23360887

  1. Ultrasound-guided percutaneous cholecysto-cholangiography for the exclusion of biliary atresia in infants

    International Nuclear Information System (INIS)

    The aim of this study is to determine the feasibility and effectiveness of performing an ultrasound-guided percutaneous cholecysto-cholangiogram (PCC) for excluding biliary atresia as the cause of neonatal jaundice. Between Oct. 2003 and Feb. 2005, six ultrasound-guided PCC procedures were performed to five jaundiced infants (4 females and 1 male; mean age: 60 days old) for whom possibility of biliary atresia could not be ruled out by the DISIDA scan as the cause of their neonatal jaundice. Gallbladder puncture was performed under ultrasound guidance with a 23-gauge needle. Contrast material injection during fluoroscopic examination was performed after dilatation of the gallbladder lumen with normal saline under ultrasound guidance. The criteria used for excluding biliary atresia were complete visualization of the extrahepatic biliary trees and/or contrast excretion into the duodenum. The complications and final diagnosis was assessed according to the clinical and laboratory findings. The procedures were successful in all the patients without any complication. Biliary atresia could be ruled out in all the patients. The final diagnosis was neonatal cytomegalovirus hepatitis in two patients, total parenteral nutrition-associated cholestasis in two patients, and combined cytomegalovirus hepatitis and total parenteral nutrition-associated cholestasis in one patient. Ultrasound-guided PCC is a feasible and effective method for the early definitive exclusion of biliary atresia as the cause of neonatal jaundice. By the technique of injecting normal saline before contrast injection, PCC can be done even in a totally collapsed or very small gallbladder

  2. Xenobiotic-sensing nuclear receptors CAR and PXR as drug targets in cholestatic liver disease.

    Science.gov (United States)

    Kakizaki, Satoru; Takizawa, Daichi; Tojima, Hiroki; Yamazaki, Yuichi; Mori, Masatomo

    2009-11-01

    Cholestasis results in the intrahepatic retention of cytotoxic bile acid and it can thus lead to liver injury and/or liver fibrosis. Cholestatic liver damage is counteracted by a variety of intrinsic hepatoprotective mechanisms including a complex network of drug metabolizing enzymes and transporters. During the last decade, much progress has been made in dissecting the mechanisms which regulate the hepatic xeno- and endobiotic metabolism by nuclear receptors. The xenobiotic receptors CAR and PXR are two important members of the NR1I nuclear receptor family. They function as sensors of toxic byproducts derived from the endogenous metabolism and of exogenous chemicals, in order to enhance their elimination. Ligands for both receptors, including phenobarbital, have already been used to treat cholestatic liver diseases before the mechanisms of these receptors were revealed. Furthermore, Yin Zhi Huang, a traditional Chinese herbal medicine, which has been used to prevent and treat neonatal jaundice, was identified to be a CAR ligand which also accelerates bilirubin clearance. Therefore, CAR and PXR have a protective effect on cholestasis by activating both detoxification enzymes and transporters. As a result, novel compounds targeting CAR and PXR with specific effects and fewer side effects will therefore be useful for the treatment of cholestatic liver diseases. This article will review the current knowledge on xenobiotic-sensing nuclear receptors CAR and PXR, while also discussing their potential role in the treatment of cholestatic liver diseases. PMID:19925451

  3. TGF-β-SMAD3 signaling mediates hepatic bile acid and phospholipid metabolism following lithocholic acid-induced liver injury.

    Science.gov (United States)

    Matsubara, Tsutomu; Tanaka, Naoki; Sato, Misako; Kang, Dong Wook; Krausz, Kristopher W; Flanders, Kathleen C; Ikeda, Kazuo; Luecke, Hans; Wakefield, Lalage M; Gonzalez, Frank J

    2012-12-01

    Transforming growth factor-β (TGFβ) is activated as a result of liver injury, such as cholestasis. However, its influence on endogenous metabolism is not known. This study demonstrated that TGFβ regulates hepatic phospholipid and bile acid homeostasis through MAD homolog 3 (SMAD3) activation as revealed by lithocholic acid-induced experimental intrahepatic cholestasis. Lithocholic acid (LCA) induced expression of TGFB1 and the receptors TGFBR1 and TGFBR2 in the liver. In addition, immunohistochemistry revealed higher TGFβ expression around the portal vein after LCA exposure and diminished SMAD3 phosphorylation in hepatocytes from Smad3-null mice. Serum metabolomics indicated increased bile acids and decreased lysophosphatidylcholine (LPC) after LCA exposure. Interestingly, in Smad3-null mice, the metabolic alteration was attenuated. LCA-induced lysophosphatidylcholine acyltransferase 4 (LPCAT4) and organic solute transporter β (OSTβ) expression were markedly decreased in Smad3-null mice, whereas TGFβ induced LPCAT4 and OSTβ expression in primary mouse hepatocytes. In addition, introduction of SMAD3 enhanced the TGFβ-induced LPCAT4 and OSTβ expression in the human hepatocellular carcinoma cell line HepG2. In conclusion, considering that Smad3-null mice showed attenuated serum ALP activity, a diagnostic indicator of cholangiocyte injury, these results strongly support the view that TGFβ-SMAD3 signaling mediates an alteration in phospholipid and bile acid metabolism following hepatic inflammation with the biliary injury. PMID:23034213

  4. Lithocholic acid feeding results in direct hepato-toxicity independent of neutrophil function in mice.

    Science.gov (United States)

    Woolbright, Benjamin L; Li, Feng; Xie, Yuchao; Farhood, Anwar; Fickert, Peter; Trauner, Michael; Jaeschke, Hartmut

    2014-07-01

    Lithocholic acid (LCA) supplementation in the diet results in intrahepatic cholestasis and bile infarcts. Previously we showed that an innate immune response is critical for cholestatic liver injury in the bile duct ligated mice. Thus, the purpose of this study was to investigate the role of neutrophils in the mechanism of liver injury caused by feeding mice a diet containing LCA. C57BL/6 mice were given control or 1% LCA containing diet for 24-96 h and then examined for parameters of hepatotoxicity. Plasma ALT levels were significantly increased by 48 h after LCA feeding, which correlated with both neutrophil recruitment to the liver and upregulation of numerous pro-inflammatory genes. The injury was confirmed by histology. Deficiency in intercellular adhesion molecule-1 (ICAM-1) expression or inhibition of neutrophil function failed to protect against the injury. Bile acid levels were quantified in plasma and bile of LCA-fed mice after 48 and 96 h. Only the observed biliary levels of taurochenodeoxycholic acid and potentially tauro-LCA caused direct cytotoxicity in mouse hepatocytes. These data support the conclusion that neutrophil recruitment occurs after the onset of bile acid-induced necrosis in LCA-fed animals, and is not a primary mechanism of cell death when cholestasis occurs through accumulation of hydrophobic bile acids. PMID:24742700

  5. Cholescintigraphy, ultrasonography and computerized tomography in the evaluation of biliary tract disorders

    International Nuclear Information System (INIS)

    Newer modalities available for the evaluation of hepatobiliary disease include cholescintigraphy, ultrasonography, and computerized tomography. We have examined the relative strengths and weaknesses of each of these noninvasive techniques and developed a rational diagnostic approach for the evaluation of acute cholecystitis, chronic cholecystitis, and cholestasis. The procedure of choice for suspected acute cholecystitis is /sup 99m/Tc-HIDA cholescintigraphy because it is a highly accurate method for obtaining functional information with regard to cystic duct patency. In suspected chronic cholecystitis, the oral cholecystogram is the best screening procedure, followed by ultrasound for confirmation of gallbladder disease as the cause of nonvisualizaion. The role of /sup 99m/Tc-HIDA cholescintigraphy in suspected chronic cholecystitis is limited to those cases where the oral cholecystogram and sonogram yield disparate results, or where a patient is known to have chronic gallbladder disease and super-imposed acute exacerbation is suspected. Ultrasonography is recommended as the initial procedure for evaluation of the patient with cholestasis. It is highly accurate in distinguishing hepatocellular disease from obstructive jaundice, and when dilated biliary radicles are visualized, ultrasonography is frequently capable of identifying the cause of obstruction. If the patient's body habitus or gaseous distention makes ultrasonographic evaluation difficult, then computerized tomography is recommended, followed by endoscopic retrograde cholangiopancreatography or transhepatic cholangiography, when needed

  6. Efficacy of extracorporeal albumin dialysis for acute kidney injury due to cholestatic jaundice nephrotoxicity.

    Science.gov (United States)

    Sens, Florence; Bacchetta, Justine; Rabeyrin, Maud; Juillard, Laurent

    2016-01-01

    We report a case of a 37-year-old man with Maturity Onset Diabetes of the Youth (MODY) type 5, admitted for an episode of cholestasis and a simultaneous acute kidney injury (AKI). Chronic liver disease was due to a mutation in the transcription factor 2 (TCF2) gene, thus highlighting the need for a close liver follow-up in these patients. AKI was attributed to a cholemic nephropathy based on the following rationale: (1) alternative diagnoses were actively ruled out; (2) the onset of AKI coincided with the onset of severe hyperbilirubinaemia; (3) renal pathology showed large bile tubular casts and a marked tubular necrosis and (4) creatinine serum dramatically decreased when bilirubin levels improved after the first sessions of extracorporeal albumin dialysis (ECAD), thus suggesting its role in renal recovery. Even though cholestasis can precipitate renal injury, the diagnosis of cholemic nephropathy could require a renal biopsy at times. Future studies should confirm the benefits of ECAD in cholemic nephropathy. PMID:27389722

  7. Biochemical Characterization of P4-ATPase Mutations Associated with Intrahepatic Cholestatic Disease

    DEFF Research Database (Denmark)

    Gantzel, Rasmus; Vestergaard, Anna Lindeløv; Mikkelsen, Stine; S. Molday, Robert; Andersen, Jens Peter

    . Mutations I91P in ATP8A2 (L127P in ATP8B1) and L308F (I344F) are located in TM1 and TM3, respectively, and E897K (E891K) is located in the exoplasmic loop between TM5 and TM6. Our experiments are focusing on the ATPase activity, rate of phosphorylation and dephosphorylation, and affinities for vanadate and......The cholestatic disorders progressive familial intrahepatic cholestasis type 1 (PFIC1) and benign recurrent intrahepatic cholestasis type 1 (BRIC1) are caused by mutation of the P4-ATPase ATP8B1 that flips phospholipid from the exoplasmic leaflet to the cytoplasmic leaflet of canalicular membranes....... It is hypothesized that PFIC1 mutations are generally more disturbing than BRIC1 mutations with respect to expression, structural stability and/or function. Although recent data have indicated that the specific phospholipid substrate of ATP8B1 is phosphatidylcholine (PC) [1] whereas ATP8A2 flips...

  8. Bile composition in Alagille Syndrome and PFIC patients having Partial External Biliary Diversion

    Directory of Open Access Journals (Sweden)

    Thompson Richard J

    2008-10-01

    Full Text Available Abstract Background Partial External Biliary Diversion (PEBD is a surgical intervention to treat children with Progressive Familial Intrahepatic Cholestasis (PFIC and Alagille syndrome (AGS. PEBD can reduce disease progression, and examining the alterations in biliary lipid composition may be a prognostic factor for outcome. Methods Biliary lipid composition and the clinical course of AGS and PFIC patients were examined before and after PEBD. Results Pre-PEBD bile from AGS patients had greater chenodeoxycholic/cholic acid (CDCA/CA, bile salt, cholesterol and phospholipid concentrations than PFIC patients. AGS patients, and PFIC patients with familial intrahepatic cholestasis 1 (FIC1 genotype, responded better to PEBD than PFIC patients with bile salt export protein (BSEP genotype. After successful PEBD, AGS patients have higher biliary lipid concentrations than PFIC patients and PEBD also increases biliary phospholipid concentrations in FIC1 patients. Conclusion Both AGS and FIC1 patients can benefit from PEBD, and preserved biliary phospholipid concentrations may be associated with better outcomes post-PEBD.

  9. Repeated Oral Administration of Oleanolic Acid Produces Cholestatic Liver Injury in Mice

    Directory of Open Access Journals (Sweden)

    Yasha Xu

    2013-03-01

    Full Text Available Oleanolic acid (OA is a triterpenoid and a fantastic molecule with many beneficial effects. However, high-doses and long-term use can produce adverse effects. This study aimed to characterize the hepatotoxic potential of OA. Mice were given OA at doses of 100–3,000 µmol/kg (45–1,350 mg/kg, po for 10 days, and the hepatotoxicity was determined by serum biochemistry, histopathology, and toxicity-related gene expression via real-time RT-PCR. Animal body weight loss was evident at OA doses of 1,000 µmol/kg and above. Serum alanine aminotransferase activities were increased in a dose-dependent manner, indicative of hepatotoxicity. Serum total bilirubin concentrations were increased, indicative of cholestasis. OA administration produced dose-dependent pathological lesions to the liver, including inflammation, hepatocellular apoptosis, necrosis, and feathery degeneration indicative of cholestasis. These lesions were evident at OA doses of 500 µmol/kg and above. Real-time RT-PCR revealed that OA produced dose-dependent increases in acute phase proteins (MT-1, Ho-1, Nrf2 and Nqo1, decreases in bile acid synthesis genes (Cyp7a1 and Cyp8b1, and decreases in liver bile acid transporters (Ntcp, Bsep, Oatp1a1, Oatp1b2, and Ostβ. Thus, the clinical use of OA and OA-type triterpenoids should balance the beneficial effects and toxicity potentials.

  10. Successful orthotopic liver transplantation in an adult patient with sickle cell disease and review of the literature

    Directory of Open Access Journals (Sweden)

    Morey Blinder

    2013-05-01

    Full Text Available Sickle cell disease can lead to hepatic complications ranging from acute hepatic crises to chronic liver disease including intrahepatic cholestasis, and iron overload. Although uncommon, intrahepatic cholestasis may be severe and medical treatment of this complication is often ineffective. We report a case of a 37 year-old male patient with sickle cell anemia, who developed liver failure and underwent successful orthotopic liver transplantation. Both pre and post-operatively, he was maintained on red cell transfusions. He remains stable with improved liver function 42 months post transplant. The role for orthotopic liver transplantation is not well defined in patients with sickle cell disease, and the experience remains limited. Although considerable challenges of post-transplant graft complications remain, orthotopic liver transplantation should be considered as a treatment option for sickle cell disease patients with end-stage liver disease who have progressed despite conventional medical therapy. An extended period of red cell transfusion support may lessen the post-operative complications.

  11. Evaluation of liver enzyme levels in workers exposed to vinyl chloride vapors in a petrochemical complex: a cross-sectional study

    Directory of Open Access Journals (Sweden)

    Dolati Mandana

    2007-08-01

    Full Text Available Abstract Background Polyvinyl chloride is used in production and manufacturing of many essential tools (e.g. plastic pipes, photography films, etc.. Its production is impossible without the use of vinyl chloride monomer (VCM, which can cause liver damage in long-term. In this study we intend to assess the effects of mild to moderate long term exposure to VCM on liver and to assess the importance of liver enzyme measurements as a screening tool. Methods In this study, liver enzyme levels of 52 workers were compared to 48 control workers using the T-test. The cases all worked in a PVC production unit in a petrochemical complex and the controls were randomly selected from office personnel of the same complex. A questionnaire was also filled in about information such as age, weight, work history, etc. in both groups. Results Mean comparisons for ALP and GGT using T-test showed statistically significant differences between the two groups. For AST, ALT and bilirubin (total, direct the mean was higher in the case group but this difference was not statistically significant. Discussion This study showed that mild exposure to VCM can cause mild liver cholestasis. So, using cholestasis assessment tests such as ALP and GGT should be considered in periodic assessment of liver function in PVC producing units.

  12. Concept on the pathogenesis and treatment of primary biliary cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Vasiliy Ivanovich Reshetnyak

    2006-01-01

    Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic, progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis, leading to liver failure in the absence of treatment. Little is known about the etiology of PBC. PBC is characterized by anti-mitochondrial antibodies and destruction of intrahepatic bile ducts. The serologic hallmark of PBC is the presence of auto-antibodies to mitochondria, especially to the E2 component of the pyruvate dehydrogenase complex (PDC). Current theories on the pathogenesis of PBC favor the hypothesis that the disease develops as a result of an inappropriate immune response following stimulation by an environmental or infectious agent. Some reports suggest that xenobiotics and viral infections may induce PBC. The pathogenetic mechanism is believed to be caused by a defect in immunologic tolerance, resulting in the activation and expansion of self-antigen specific T and B lymphocyte clones and the production of circulating autoantibodies in addition to a myriad of cytokines and other inflammatory mediators.This leads to ductulopenia and persistent cholestasis, by developing end-stage hepatic-cell failure. In this review are given our own and literary data about mechanisms of development of intrahepatic cholestasis and possible ways of its correction.

  13. Percutaneous transpapillary extraction of biliary calculus for symptomatic choledocholithiasis after unsuccessfully endoscopic treatment

    International Nuclear Information System (INIS)

    Purpose: Evaluation of a percutaneous transhepatic treatment of symptomatic choledocholithiasis in bile ducts that cannot be reached with the endoscope. Methods: From January 1996 to August 2000 a transhepatic extraction of biliary calculus was performed in four patients. Endoscopic retrograde cholangiography (ERC) was not successful in any of the cases. Clinical symptoms were icterus in four cases, additional cholangitis or colics in two cases. First, a ballon dilation of the papilla was performed by a percutaneous transhepatic approach. For removal of bile duct stones, occlusion catheters and Dormia baskets were used. Technical success was defined as complete removal of bile duct stones. Clinical success was defined as normalization of cholestasis and inflammation parameters. In the follow-up an ultrasound examination was performed and blood samples were taken for control of cholestasis parameters. Results: In all four cases treatment was technically and clinically successful. For complete removal of biliary calculus a second intervention was necessary in two cases. In each case an internal to external drainage was left over a mean of 7 days (3 - 13 days). In the mean follow-up of 30.5 months (6 - 50 months) all patients had persistent relief of symptoms. No further interventions were necessary. No complications were present. Conclusion: Percutaneous transpapillary extraction of biliary calculus is an effective alternative to surgery in patients with bile ducts, that cannot be reached with the endoscope. (orig.)

  14. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity.

    Directory of Open Access Journals (Sweden)

    Esther M Verhaag

    Full Text Available Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis.To investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions.HepG2.rNtcp cells were preconditioned (24 h with sub-apoptotic concentrations (0.1-50 μM of various bile acids, the superoxide donor menadione, TNF-α or the Farsenoid X Receptor agonist GW4064, followed by a challenge with the apoptosis-inducing bile acid glycochenodeoxycholic acid (GCDCA; 200 μM for 4 h, menadione (50 μM, 6 h or cytokine mixture (CM; 6 h. Levels of apoptotic and necrotic cell death, mRNA expression of the bile salt export pump (ABCB11 and bile acid sensors, as well as intracellular GCDCA levels were analyzed.Preconditioning with the pro-apoptotic bile acids GCDCA, taurocholic acid, or the protective bile acids (tauroursodeoxycholic acid reduced GCDCA-induced caspase-3/7 activity in HepG2.rNtcp cells. Bile acid preconditioning did not induce significant levels of necrosis in GCDCA-challenged HepG2.rNtcp cells. In contrast, preconditioning with cholic acid, menadione or TNF-α potentiated GCDCA-induced apoptosis. GCDCA preconditioning specifically reduced GCDCA-induced cell death and not CM- or menadione-induced apoptosis. The hormetic effect of GCDCA preconditioning was concentration- and time-dependent. GCDCA-, CDCA- and GW4064- preconditioning enhanced ABCB11 mRNA levels, but in contrast to the bile acids, GW4064 did not significantly reduce GCDCA-induced caspase-3/7 activity. The GCDCA challenge strongly increased intracellular levels of this bile acid, which was not lowered by GCDCA

  15. Hormesis in Cholestatic Liver Disease; Preconditioning with Low Bile Acid Concentrations Protects against Bile Acid-Induced Toxicity

    Science.gov (United States)

    Verhaag, Esther M.; Buist-Homan, Manon; Koehorst, Martijn; Groen, Albert K.; Moshage, Han; Faber, Klaas Nico

    2016-01-01

    Introduction Cholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis. Aim To investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions. Methods HepG2.rNtcp cells were preconditioned (24 h) with sub-apoptotic concentrations (0.1–50 μM) of various bile acids, the superoxide donor menadione, TNF-α or the Farsenoid X Receptor agonist GW4064, followed by a challenge with the apoptosis-inducing bile acid glycochenodeoxycholic acid (GCDCA; 200 μM for 4 h), menadione (50 μM, 6 h) or cytokine mixture (CM; 6 h). Levels of apoptotic and necrotic cell death, mRNA expression of the bile salt export pump (ABCB11) and bile acid sensors, as well as intracellular GCDCA levels were analyzed. Results Preconditioning with the pro-apoptotic bile acids GCDCA, taurocholic acid, or the protective bile acids (tauro)ursodeoxycholic acid reduced GCDCA-induced caspase-3/7 activity in HepG2.rNtcp cells. Bile acid preconditioning did not induce significant levels of necrosis in GCDCA-challenged HepG2.rNtcp cells. In contrast, preconditioning with cholic acid, menadione or TNF-α potentiated GCDCA-induced apoptosis. GCDCA preconditioning specifically reduced GCDCA-induced cell death and not CM- or menadione-induced apoptosis. The hormetic effect of GCDCA preconditioning was concentration- and time-dependent. GCDCA-, CDCA- and GW4064- preconditioning enhanced ABCB11 mRNA levels, but in contrast to the bile acids, GW4064 did not significantly reduce GCDCA-induced caspase-3/7 activity. The GCDCA challenge strongly increased intracellular levels of this bile acid, which was not lowered by GCDCA

  16. Evaluation Of Gonadotropin And Testosterone Hormons In Adult Male Cholestatic Rats

    Directory of Open Access Journals (Sweden)

    Nasiri E

    2003-11-01

    Full Text Available Obstructive cholestasis is associated with overproduction of endogenous opioids (EOP, nitric oxide (NO, and cytokins in the blood streams. Therefore we investigated the relationship between obstructive cholestasis and function of germ cells in adult male rats."nMaterial and Methods: To study this, we used three groups of animals: No-surgery, Sham-surgery, and surgical ligation of the bile duct. After 3 weeks all animal were killed by ether, serum concentrations of FSH, LH and testosterone were determined by Radioimmunoassay, apoptosis was evaluated by DNA fragmentation detected by in situ terminal deoxynucloetidyl Transfrase-mediated dUTP nike end labeling (TUNEL."nResults: The mean of FSH level in cholestatic, control and sham groups were 13.22+ 1.038, 18.14+ 1.276, and 16.92+ 1.072 ng/ml, respectively. The mean of LH level in cholestatic, control and sham groups were 0.83 + 0.21, 2.058 ± 0.26, and 1.84 + 0.17 ng/ml, respectively. In addition, the mean of testosterone level in cholestatic, control and sham groups were 1.52 ± 0.16, 2.41 ± 0.18, and 2.31 + 0.14 ng/ml, respectively. The results of this study were indicated that serum FSH, LH and testosterone were significantly lower in cholestatic than control and sham groups (p=0.0195, P= 0.0029, and P=0.0023, respectively. However there was no significant difference in apoptotic index between all of groups (P=0.195. The apoptotic index in cholestatic, control and sham rats were 9.897± 1.374, 7.086 + 0.91, and 7.729 + 1.101, respectively. "nConclusion: These findings have been shown which as obstructive cholestasis was decreased the levels of serum gonadotropins and testosterone but it has no significant effector testicular germinal cells apoptosis."n"n"n"n 

  17. Scrub typhus hepatitis confirmed by immunohistochemical staining

    Institute of Scientific and Technical Information of China (English)

    Jong-Hoon Chung; Sung-Chul Lim; Na-Ra Yun; Sung-Heui Shin; Choon-Mee Kim; Dong-Min Kim

    2012-01-01

    Scrub typhus is an acute febrile disease caused by Orientia tsutsugamushi (O.tsutsugamushi).We report herein the case of a woman who presented with fever and elevated serum levels of liver enzymes and who was definitively diagnosed with scrub typhus by histopathological examination of liver biopsy specimens,serological tests and nested polymerase chain reaction.Immunohistochemical staining using a monoclonal anti-O.tsutsugamushi antibody showed focally scattered positive immunoreactions in the cytoplasm of some hepatocytes.This case suggests that scrub typhus hepatitis causes mild focal inflammation due to direct liver damage without causing piecemeal necrosis or interface hepatitis.Thus,scrub typhus hepatitis differs from acute viral hepatitis secondary to liver damage due to host immune responses,which causes severe Iobular disarray with diffuse hepatocytic degeneration,necrosis and apoptosis as well as findings indicative of hepatic cholestasis,such as hepatic bile plugs or brown pigmentation of hepatocytes.

  18. Clinical findings, dental treatment, and improvement in quality of life for a child with Rothmund-Thomson syndrome

    Science.gov (United States)

    De Oliveira, Katharina Morant Holanda; Silva, Raquel Assed Bezerra; Carvalho, Fabricio Kitazono; Silva, Lea Assed Bezerra; Nelson-Filho, Paulo; Queiroz, Alexandra Mussolino

    2016-01-01

    The purpose of this study was to report the clinical findings, dental treatment, and improvement in quality of life for a child with Rothmund-Thomson syndrome. The patient had alopecia, delayed speech, low weight and height, cholestasis, and iron deficiency anemia. Furthermore, there were carious lesions and darkened spots on all primary molars. Microdontia of a premolar was observed at the radiographic examination. The patient and family had no commitment to her oral health and dental treatment at first appointments. Oral hygiene instructions, composite restorations, endodontic treatments, teeth extractions, and stainless steel crown installations were performed. The patient was followed up for 7 years through the present due to other possible future clinical findings associated with the syndrome. An improvement in social aspects was observed after removal of toothache and improved esthetics. Such patients need continuous periodic services, which contributes to improving the quality of life in both buccal and general aspects. PMID:27307676

  19. Peribiliary hepatic cysts presenting as hilar cholangiocarcinoma in a patient with end-stage liver disease

    Science.gov (United States)

    Lim, Jane; Nissen, Nicholas N.; McPhaul, Christopher; Annamalai, Alagappan; Klein, Andrew S.; Sundaram, Vinay

    2016-01-01

    Peribiliary cysts are cystic dilatations of peribiliary glands in the liver. They are present in ~50% of cirrhotic patients, but are underrecognized because they are usually asymptomatic and rarely present as obstructive jaundice. A 63-year-old male with hepatitis C cirrhosis, awaiting liver transplantation, had a new finding of intrahepatic dilatation on magnetic resonance imaging. This was initially concerning for cholangiocarcinoma, but was ultimately diagnosed as peribiliary cysts. Peribiliary cysts can imitate cholangiocarcinoma on imaging. Therefore, awareness of this condition is essential because misdiagnosis may lead to inappropriate delay or denial for liver transplantation. The ideal imaging modalities to identify peribiliary cysts are magnetic resonance cholangiography and drip infusion cholangiographic computed tomography, though hepatic dysfunction may limit the usefulness of the latter. Peribiliary cysts should be considered in cirrhotic patients with cholestasis, biliary dilatations and negative biopsy of the biliary system for malignancy. PMID:27511912

  20. Activity of gammaglutamiltransferase in addicts of Dnipropetrovsk province

    Directory of Open Access Journals (Sweden)

    E. B. Motorya

    2012-07-01

    Full Text Available Change of GGT activity is studied in patients using alcohol and narcotic substances. 2878 residents of the Dnipropetrovsk province are examined. The increase of GGT activity is marked in 528 cases (18.3 %. It may be caused by increasing synthesis as a result of activating enzymes which ensure this process. The activation may be initiated by alcohol and medicines, by the damage of cellular membranes under the action of toxic agents, under ischemia and infection-induced liver injury, and by the detachment of enzymes from cellular membranes affected by detergent bile acids under the cholestasis. Ordinary values for major part of examined patients (81.7 % may be explained by only episodic taking alcohol and narcotic drugs, which was not affect the liver parenchyma, and also by effective treatment normalized the enzyme’s activity.

  1. 131I rose bengal: Its use in the evaluation of infantile jaundice

    International Nuclear Information System (INIS)

    One-hundred ten 131I-rose bengal studies (RBI) were performed in infants suspected of having biliary atresia. Fecal RBI excretion of less than 10% was observed in 72 of 73 cases of extrahepatic biliary atresia, but also in 10 of 37 cases of intrahepatic cholestasis of various origins. One-hundred twenty-two RBI tests were performed in children operated on for extrahepatic biliary atresia and 71 tests were performed between postsurgical weeks 3 and 8, and 51 tests were done later. Prognostically, early tests show that fecal RBI excretion of more than 15% was observed in 2 of 34 cases who were later completely jaundice-free and in only 1 of 37 cases where no bile flow restoration occurred. (orig.)

  2. Rapid diagnosis of Zellweger syndrome and infantile Refsum's disease by fast atom bombardment-mass spectrometry of urine bile salts

    International Nuclear Information System (INIS)

    A method is described for the rapid determination of urinary bile salt profiles by fast atom bombardment-mass spectrometry (FAB-MS). Negative ion FAB spectra could be obtained from the equivalent of 10 μl of urine loaded onto the target probe with glycerol as matrix. In samples from infants and children with cholestasis the major peaks were produced by the taurine and glycine conjugates of di-, tri- and tetrahydroxycholanoic acids. In samples from patients with Zellweger syndrome and infantile Refsum's disease, a unique ion at m/z 572 indicated the presence of taurine-conjugated tetrahydroxycholestanoic acid(s). Capillary gas chromatography-mass spectrometry (GC-MS) of the bile acids liberated by alkaline hydrolysis indicated the presence of at least two nuclear-tetrahydroxylated cholestanoic acids, probably the 6α- and 1β-hydroxylated derivatives of 3α, 7α, 12α-trihydroxy-5β-cholestan-26-oic acid. (Auth.)

  3. Pathomorphological findings in preterm infants

    International Nuclear Information System (INIS)

    Pathomorphology in the preterm infant represents an interaction of morphological organ immaturity and neonatal management with their respective sequelae. Pathomorphological examples include the modification in the morphology of hyaline membrane disease and bronchopulmonary dysplasia as a consequence of modern neonatal therapy. Hemorrhagic and ischemic/hypoxic lesions of the central nervous system may occur in age- and agent-related distributional patterns, with subependymal hemorrhage and periventricular leukomalacia representing the most important examples. The most common intestinal finding, namely, necrotizing enterocolitis, typically shows segmental alterations, the morphology of which largely depends on the dominating causative agent. Hepatic cholestasis and fatty change are mostly consequences of parenteral nutrition or hypoxic/ischemic stress. Hepatic necrosis can be associated with the latter, but may also indicate disseminated intravascular coagulation. Vascular pathomorphology is represented by thromembolic lesions, in most instances corresponding to sequelae of neonatal management. (orig.)

  4. MR-assisted bile duct drainage: a study of passive catheter visualization in an animal model

    International Nuclear Information System (INIS)

    Purpose: To investigate interactive MR-assisted bile duct drainage in pigs with the passive visualization technique using near real-time imaging. Methods: 8 bile duct drainages were placed in an open low-field MR system (0.2 Tesla) in 4 pigs with surgically induced cholestasis. After planning the intervention with magnetic resonance cholangiography (MRC), both the puncture and catheter placement were interactively guided using a fast T2-weighted true FISP sequence. Results: MRC enabled interventional planning in all puncture attempts. Punctures were unproblematic in all attempts, the bile ducts were punctured 6 times after the first and twice after the second attempt. Placement of the passively visible catheter was successful in all animals. The applied sequence enables interactive fluoroscopy-like positioning of the devices. Conclusion: The procedure introduced here enables reliable and fast placement of a bile duct drainage in an animal model using a low-field MR system. (orig.)

  5. PIPIDA scintigraphy for cholecystitis: false positives in alcoholism and total parenteral nutrition

    International Nuclear Information System (INIS)

    A review of gallbladder scintigraphy in patients with potentially compromised hepatobiliary function revealed two groups in whom cholecystitis might be mistakenly diagnosed. In 200 consecutive hospitalized patients studied with technetium-99m-PIPIDA for acute cholecystitis or cholestasis, there were 41 alcoholics and 17 patients on total parenteral nutrition. In 60% of the alcoholics and 92% of those on parenteral nutrition, absent or delayed visualization of the gallbladder occurred without physical or clinical evidence of cholecystitis. A cholecystagogue, sincalide, did not prevent the false-positive features which presumably are due to altered bile flow kinetics related to alcoholism and parenteral nutrition. Four patients on parenteral nutrition undergoing cholecystectomy for suspected cholecystitis had normal gallbladders filled with jellylike viscous thick bile. A positive (nonvisualized or delayed visualized) gallbladder PIPIDA scintigram in these two populations should not be interpreted as indicating a need for cholecystectomy

  6. Intestinal FXR agonism promotes adipose tissue browning and reduces obesity and insulin resistance.

    Science.gov (United States)

    Fang, Sungsoon; Suh, Jae Myoung; Reilly, Shannon M; Yu, Elizabeth; Osborn, Olivia; Lackey, Denise; Yoshihara, Eiji; Perino, Alessia; Jacinto, Sandra; Lukasheva, Yelizaveta; Atkins, Annette R; Khvat, Alexander; Schnabl, Bernd; Yu, Ruth T; Brenner, David A; Coulter, Sally; Liddle, Christopher; Schoonjans, Kristina; Olefsky, Jerrold M; Saltiel, Alan R; Downes, Michael; Evans, Ronald M

    2015-02-01

    The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver. However, unlike systemic agonism, we find that Fex reduces diet-induced weight gain, body-wide inflammation and hepatic glucose production, while enhancing thermogenesis and browning of white adipose tissue (WAT). These pronounced metabolic improvements suggest tissue-restricted FXR activation as a new approach in the treatment of obesity and metabolic syndrome. PMID:25559344

  7. Heavy flow autochtonic case of hepatitis E in elderly men

    Directory of Open Access Journals (Sweden)

    S. V. Baramzina

    2016-01-01

    Full Text Available The article presents an analysis of the first clinical cases of acute hepatitis E autochtonic on the territory of the Kirov region. HEV-infection was diagnosed in 76 year old male, not to travel outside the region and the country for a long time, eat a lot of fresh fruit. A feature of the disease in non-endemic region was: severe course of hepatitis E in the elderly, with the development of clinic of acute liver failure and encephalopathy, the presence of the expressed syndrome cytolysis, cholestasis, hepatic-cell failure.Timely treatment of a patient for medical care, the lack of severe somatic diseases, chronic liver disease and adequate pathogenetic therapy helped to keep the patient’s life. In deciphering undifferentiated acute hepatitis in the elderly should be included in the scheme of examination and determination HEV RNA, a/HEV IgM and G.

  8. Congenital cystic dilations of the choledoco; cases reports and literature revision

    International Nuclear Information System (INIS)

    Congenital bile duct cyst (CBC) are anomalies with higher risk of biliary stone, chronic cholestasis, and biliary tree cancer. In this work, we report 12 cases 2,4% of 1500 endoscopic retrograde cholangiopancreatography (ERCP) done in last 18 month the mean age was 44,6 years and women predominant (75%). The main clinical diagnosis was, biliary tract obstruction in 5 patients (42%)An Initial CBC diagnosis, was not done in any of the cases. Eight cases, were CBC type 1,3 were type V and one type ll. In 8 patients an endoscopic sphincterotomy was done and 5 remotion in 6. CBC must be in the differential diagnosis of biliary litiasic disease, ERCP and resonance cholangiography have an important role in this diagnosis. Bibliography has been reviewed

  9. Selective screening of 650 high risk Iranian patients for detection of inborn error of metabolism

    Directory of Open Access Journals (Sweden)

    Narges Pishva

    2015-02-01

    Full Text Available Objective: Although metabolic diseases individually are rare ,but overall have an incidence of 1/2000 and can cause devastating and irreversible effect if not diagnosed early and treated promptly. selective screening is an acceptable method for detection of these multi presentation diseases.Method: using panel neonatal screening for detection of metabolic diseases in 650 high risk Iranian patients in Fars province. The following clinical features were used as inclusion criteria for investigation of the patients.Lethargy, poor feeding ,persistent vomiting, cholestasis, intractable seizure ,decreased level of consciousness ,persistent hypoglycemia, unexplained acid base disturbance and unexplained neonatal death.Result: Organic acidemia with 40 cases (42% was the most frequent disorder diagnosed in our high risk populations, followed by disorder of galactose metabolism(30%, 15 patient had classic galactosemia(GALT

  10. Cholestatic Jaundice Associated with Carnitine Palmitoyltransferase IA Deficiency.

    Science.gov (United States)

    Morris, A A M; Olpin, S E; Bennett, M J; Santani, A; Stahlschmidt, J; McClean, P

    2013-01-01

    Liver dysfunction usually accompanies metabolic decompensation in fatty acid oxidation disorders, including carnitine palmitoyltransferase (CPT) Ia deficiency. Typically, the liver is enlarged with raised plasma transaminase activities and steatosis on histological examination. In contrast, cholestatic jaundice is rare, having only been reported in long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. We report a 3-year-old boy with CPT Ia deficiency who developed hepatomegaly and cholestatic jaundice following a viral illness. No cause for the jaundice could be found, apart from the fatty acid oxidation disorder. Liver histology showed diffuse, predominately macrovesicular steatosis, hepatocellular and canalicular cholestasis but no bile duct paucity or evidence of large duct obstruction. The liver dysfunction resolved in 4-7 weeks. PMID:23430491

  11. Reversion of severe hepatopulmonary syndrome in a non cirrhotic patient after corticosteroid treatment for granulomatous hepatitis: A case report and review of the literature

    Institute of Scientific and Technical Information of China (English)

    Nikolaos Tzovaras; Aggelos Stefos; Sarah P Georgiadou; Nikolaos Gatselis; Georgia Papadamou; Eirini Rigopoulou; Maria Ioannou; Ioannis Skoularigis; Georgios N Dalekos

    2006-01-01

    Hepatopulmonary syndrome (HPS) is defined as a clinical triad including liver disease, abnormal pulmonary gas exchange and evidence of intrapulmonary vascular dilatations. We report a 61-year-old male presented with fatigue, long-lasting fever, loss of weight, signs of portal hypertension, hepatosplenomegaly, cholestasis and progressive dyspnoea over the last year. Clinical, laboratory and histological findings confirmed the diagnosis of granulomatous hepatitis. HPS due to hepatic granulomainduced portal hypertension was proved to be the cause of severe hypoxemia of the patient as confirmed by contrast-enhanced echocardiography. Reversion of HPS after corticosteroid therapy was confirmed by a new contrastenhanced echocardiography along with the normalization of cholestatic enzymes and improvement of the patient's conditions. This is the first case of complete reversion of HPS in a non-cirrhotic patient with hepatic granuloma,indicating that intrapulmonary shunt in liver diseases is a functional phenomenon and HPS can be developed even in miscellaneous liver involvement as in this case.

  12. Combined endoscopic and ursodeoxycholic acid treatment of biliary cast syndrome in a non-transplant patient

    Institute of Scientific and Technical Information of China (English)

    Panagiotis Katsinelos; Grigoris Chatzimavroudis; Ioannis Pilpilidis; George Paroutoglou; Jannis Kountouras; Christos Zavos

    2008-01-01

    A 76-year-old diabetic man underwent cholecystectomy for gangrenous calculous cholecystitis.His postoperative course was complicated by the development of Candida albicans esophagitis necessitating antifungal therapy,and total parenteral nutrition(TPN)for 15 d.Seven weeks after cholecystectomy,he presented with cholangitis.Endoscopic retrograde ch0Iangiopancreatography(ERCP)demonstrated extrahepatic filling defects.Despite endoscopic extraction of a biliary cast,cholestasis remained unchanged.Oral administration of ursodeoxycholic acid(UDCA),750 mg/d,resulted in normalization of liver function tests.We,therefore,propose for the first time,combined endoscopic plus UDCA treatment for the management of biliary cast syndrome.(C)2008 The WJG Press.All righis reserved.

  13. Functional and histopathologic changes in the liver during sepsis.

    Science.gov (United States)

    Caruana, J A; Montes, M; Camara, D S; Ummer, A; Potmesil, S H; Gage, A A

    1982-05-01

    Although liver failure from sepsis is a frequent occurrence in serious ill, hospitalized patients, little information is available on the histologic changes of the liver. We examined the histopathology of the liver of 19 patients who died of clinical sepsis and attempted to relate certain features of the illness or treatment to the observed histopathologic changes. The most striking finding was midzonal and peripheral necrosis of a moderate to marked degree in 11 of 19 patients. Other important changes were acute inflammation and cholestasis. The severity of hepatocellular necrosis did not appear to be influenced by the premortem circulating pathogen, by the nutritional support administered or by the arterial blood pressure. It is suggested that hepatocellular necrosis is characteristic of sepsis and may be caused by loss of specific factors which normally maintain liver function and structure. PMID:6803371

  14. Selective screening of 650 high risk Iranian patients for detection of inborn error of metabolism

    Directory of Open Access Journals (Sweden)

    Narges Pishva

    2015-02-01

    Full Text Available Objective: Although metabolic diseases individually are rare ,but overall have an incidence of 1/2000 and can cause devastating and irreversible effect if not diagnosed early and treated promptly. selective screening is an acceptable method for detection of these multi presentation diseases. Method: using panel neonatal screening for detection of metabolic diseases in 650 high risk Iranian patients in Fars province. The following clinical features were used as inclusion criteria for investigation of the patients. Lethargy, poor feeding ,persistent vomiting, cholestasis, intractable seizure ,decreased level of consciousness ,persistent hypoglycemia, unexplained acid base disturbance and unexplained neonatal death. Result: Organic acidemia with 40 cases (42% was the most frequent disorder diagnosed in our high risk populations, followed by disorder of galactose metabolism(30%, 15 patient had classic galactosemia(GALT

  15. Chemotherapy in patients with hepatic failure

    International Nuclear Information System (INIS)

    The toxicity of chemotherapy in the liver may manifest as hepatocyte dysfunction with chemical hepatitis, veno-occlusive disease or chronic fibrosis. The hepatocyte dysfunction is caused by direct effect of the drug or its metabolites evidencing by increased bilirubin and liver enzymes (Sgot, SGPT). Prolonged effect leads to cholestasis and fatty infiltration. This dysfunction is concomitant enhanced by viral infection, liver metastases and other drugs as antiemetics. The vast majority of the indicated drugs in a cancer patient, cytostatics, antiemetics, analgésios, anticonvulsants, etc, are metabolized in the liver. The evidence of abnormal hepatocyte function in a patient in which involves chemotherapy raises the need for dose modification indicated and / or discontinuation. The aim of this paper is to review existing information on the use of cytostatics in cancer patients with hepatic impairment, classifying drugs according to their potential hepato toxicity and recommended dose modification in patients with hepatic dysfunction

  16. Neonatal haemochromatosis associated with gastroschisis.

    Science.gov (United States)

    Thornton, M P; Marven, S S; Tanner, M S; Gürtl-Lackner, B

    2008-05-01

    We describe, to our knowledge, the first case of progressive neonatal liver failure due to neonatal haemochromatosis (NH) occurring in an infant with a gastroschisis and review the literature regarding these two conditions. A 1,665 g male infant with antenatally diagnosed gastroschisis was born with a severe coagulopathy, anaemia, thrombocytopenia, hypoglycaemia and jaundice. He developed progressive liver failure, complicated by necrotising enterocolitis. Serum ferritin was elevated at 1,459 microg/L. He died on day 40 and a limited post-mortem examination confirmed significant hepatic siderosis with fibrosis and cholestasis, and siderosis of the pancreas. Although no genetic aetiology for gastroschisis has been identified, an occasional inherited tendency has been observed. There is also evidence to support an autosomal recessive inheritance in NH. PMID:18338135

  17. CT and MRI of diffuse lobar involvement pattern in liver pathology.

    Science.gov (United States)

    Karçaaltincaba, Muşturay; Sirlin, Claude B

    2011-12-01

    Focal, segmental, and diffuse liver pathologies have been described in the literature. This article describes a pattern in which liver pathology is confined to a lobe. This lobar pattern has not been described previously to our knowledge. Herein, we illustrate computed tomography (CT) and magnetic resonance imaging (MRI) findings of diffuse lobar involvement patterns in various liver conditions. Diffuse lobar involvement can be observed in benign (steatosis, hepatic iron overload, cholestasis, perfusion alterations, infarction, alveolar hydatid cysts, trauma, and hemangiomas) and primary malignant (hepatocellular carcinoma) pathologies. Diffuse lobar involvement in metastatic disease appears to be rare. Due in part to their potentially unusual appearances, the diagnosis of lobar pathologies using imaging can be challenging, and entities with lobar patterns can cause diagnostic confusion. Liver MRI can be used as a problem-solving tool for diffuse lobar pathologies detected on ultrasonography and CT. Inand out-of-phase MRI can help in the assessment of lobar fat accumulation. PMID:21053176

  18. Low-fat, high calorie parenteral nutrition (PN), reverses liver affection in long term PN dependent infants

    DEFF Research Database (Denmark)

    Jakobsen, Marianne Skytte; Hørby Jørgensen, Marianne; Husby, Steffen;

    2015-01-01

    INTRODUCTION: Parenteral nutrition-associated cholestasis (PNAC) is a complication of long-term parenteral nutrition (PN). Removal of lipids may reverse PNAC but compromises the energy to ensure infant growth. The purpose of this study was to test whether a low-fat, high-carbohydrate PN regimen......, which prevents and reverses PNAC in adults, could do the same in infants. This regimen could potentially avoid the problem of diminished energy input after removing nutritional lipids. METHODS: Infants developing PNAC over a 2-year period were started on a low-fat PN regimen with calories primarily from......-fat, high-carbohydrate PN regimen together with enteral feeding is well tolerated and may be used in reversing liver disease in PN-dependent infants without compromising growth....

  19. Prevention of vitamin K deficiency bleeding in breastfed infants: lessons from the Dutch and Danish biliary atresia registries

    DEFF Research Database (Denmark)

    Hasselt, P.M. van; Koning, T.J. de; Vries, E. de; Lundin, C.R.; Berger, R.; Kimpen, J.L.; Houwen, R.H.; Jorgensen, M.H.; Verkade, H.J.; Kvist, Nina Eva

    2008-01-01

    vitamin K at birth followed by 1 mg of weekly oral prophylaxis (Denmark, 1994 to May 2000), or 2 mg of intramuscular prophylaxis at birth (Denmark, June 2000-2005) or were fed by formula. We determined the absolute and relative risk of severe vitamin K deficiency and vitamin K deficiency bleeding on...... prophylaxis at birth, and in 1 of 98 formula-fed infants (P < .001). The relative risk of a bleeding in breastfed compared with formula-fed infants was 77.5 for 25 microg of daily oral prophylaxis, 7.2 for 1 mg of weekly oral prophylaxis, and 9.3 for 2 mg of intramuscular prophylaxis at birth. CONCLUSIONS: A......OBJECTIVE: Newborns routinely receive vitamin K to prevent vitamin K deficiency bleeding. The efficacy of oral vitamin K administration may be compromised in infants with unrecognized cholestasis. We aimed to compare the risk of vitamin K deficiency bleeding under different prophylactic regimens in...

  20. Relationship between serum heat-stable alkaline phosphatase level and pregnancy

    International Nuclear Information System (INIS)

    Serum heat-stable alkaline phosphatase (HSAP) level in 649 cases of normal pregnancy and 164 cases of high-risk pregnancy is measured by radioimmunoassay (RIA). The results indicate that the HSAP level in normal pregnancy increased proportionally with gestation weeks (r = 0.9843). In 33 cases of pregnancy induced hypertension and 21 cases of intrauterine fetal growth retardation, the HSAP level is significantly low. In 7 cases of neonatal asphyxia and 26 cases of fetal distress, the HSAP level in the mother's serum is also low. In 53 cases of intrahepatic cholestasis of pregnancy, the HSAP level is similar to those of normal pregnancy. This study illustrates that HSAP RIA can play an important role in the evaluation of placental function and fetal prognosis for cases of high-risk pregnancy

  1. Diagnostic imaging of digestive tract involvement in cystic fibrosis. Part 1: hepatobiliary disease

    International Nuclear Information System (INIS)

    Cystic fibrosis is a severe hereditary disease characterized by epithelial chloride channel dysfunction, leading to the production of abnormally thick secretions. The abnormal gene is located on the long arm of chromosome 7. Hepatobiliary involvement derives from ductal obstruction causing cholestasis, steatosis, cirrhosis and portal hypertension. Biliary sludge, cholelithiasis and gallbladder sclerosis and atrophy are common findings. As the correlation between the hepatobiliary changes and their clinical and analytical impact is very limited, imaging techniques are essential in this disease. Ultrasound is the basic imaging tool, both for initial evaluation and follow-up of the hepatic and biliary involvement, although other techniques such as radionuclide imaging, magnetic resonance and computed tomography can be highly useful. Given the long-term, chronic nature of this disease, the use of aggressive techniques or irradiation should be carefully weighed. (Author) 38 refs

  2. Mycophenolate mofetil for drug-induced vanishing bile duct syndrome

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    Amoxicillin/clavulanate is associated with liver injury,mostly of a cholestatic pattern. While outcomes are usually benign, progression to cirrhosis and death has been reported. The role of immunosuppressive therapy for patients with a protracted course is unclear. We report the case of an elderly patient who developed prolonged cholestasis secondary to amoxicillin/clavulanate. Vanishing bile duct syndrome was confirmed by sequential liver biopsies. The patient responded to prednisone treatment,but could not be weaned off corticosteroids, even when azathioprine was added. Complete withdrawal of both prednisone and azathioprine was possible by using mycophenolate mofetil, an inosine monophosphate dehydrogenase inhibitor. Sustained remission has been maintained for more than 3 years with low-dose mycophenolate mofetil.

  3. Role of farnesoid X receptor and bile acids in alcoholic liver disease

    Directory of Open Access Journals (Sweden)

    Sharon Manley

    2015-03-01

    Full Text Available Alcoholic liver disease (ALD is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a and PPARα (peroxisome proliferator-activated receptor alpha in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.

  4. Hepatobiliary Disposition of 3α,6α,7α,12α-Tetrahydroxy-Cholanoyl Taurine: A Substrate for Multiple Canalicular Transporters

    OpenAIRE

    Megaraj, Vandana; Iida, Takashi; Jungsuwadee, Paiboon; Hofmann, Alan F.; Vore, Mary

    2010-01-01

    Tetrahydroxy bile acids become major biliary bile acids in Bsep(−/−) mice and Fxr(−/−) mice fed cholic acid; we characterized disposition of these novel bile acids that also occur in patients with cholestasis. We investigated mouse Mrp2 (mMrp2) and P-glycoprotein [(P-gp) mMdr1a]-mediated transport of a tetrahydroxy bile acid, 6α-OH-taurocholic acid (6α-OH-TC), and its biliary excretion in wild-type and Mrp2(−/−) mice in the presence or absence of N-(4-[2-(1,2,3,4-tetrahydro-6,7-dimethoxy-2-is...

  5. 胆盐输出泵基因多态性与妊娠期肝内胆汁淤积症相关性研究

    Institute of Scientific and Technical Information of China (English)

    罗振宇; 刘淮

    2008-01-01

    妊娠肝内胆汁淤积症(intrahepatic cholestasis of pregnancy,ICP)是发生在妊娠晚期特有的并发症,多发生于妊娠最后的3个月。文献报道ICP有家族性倾向,Reyes发现智利Arancanian印第安混血人种发病率最高,提示本病可能与种族、遗传有关。胆盐输出泵(bile salt export pump,BSEP)仅在肝细胞胆小管侧膜上特异性表达,介导单价胆盐的跨毛细胆管转运,

  6. Primary sclerosing cholangitis and pregnancy

    Directory of Open Access Journals (Sweden)

    Casper Q. Kammeijer

    2011-08-01

    Full Text Available Primary sclerosing cholangitis is a progressive disease, and coincidentally in pregnancy it is rare. It is characterized by progressive inflammation and destruction of bile ducts finally resulting in liver failure. A rare case of primary sclerosing cholangitis in pregnancy is presented. The course of the pregnancy was marked by threatened preterm delivery and exacerbation of cholestasis. She was successfully treated with ursodeoxycholic acid (UDCA. Although, primary sclerosing cholangitis has both maternal and fetal effects on pregnancy, the overall outcome is favorable. Only few cases have been reported using high dose ursodeoxycholic acid for primary sclerosing cholangitis in pregnancy, it often improves pruritus but has no protection against stillbirth. Data on the safety to the fetus or neonate and long-term outcome are scarce.

  7. Hepatic failure caused by plasma cell infiltration in multiple Myeloma

    Institute of Scientific and Technical Information of China (English)

    Fadi E Rahhal; Robert R Schade; Asha Nayak; Teresa A Coleman

    2009-01-01

    Although plasma cell infiltration is not rare in autopsy of patients with multiple myeloma (MM), it is very rarely detected in living patients. This is because MM rarely causes significant liver dysfunction that requires further evaluation. A 49-year-old man presented with acute renal failure and was diagnosed with kappa light chain MM stage ?B. Thalidomide and dexamethasone were initiated. The patient developed a continuous increase in bilirubin that led to severe cholestasis. A liver biopsy revealed plasma cell infiltration. He then rapidly progressed to liver failure and died. Treatment options are limited in MM with significant liver dysfunction.Despite new drug therapies in MM, those patients with rapidly progressive liver failure appear to have a dismal outcome.

  8. Clinical characteristics of caroli's disease

    Institute of Scientific and Technical Information of China (English)

    Ozlem Yonem; Yusuf Bayraktar

    2007-01-01

    Caroli's disease is a rare congenital condition characterized by non-obstructive saccular or fusiform dilatation of larger intrahepatic bile ducts. Cholangitis,liver cirrhosis, and cholangiocarcinoma are its potential complications. The diagnosis of Caroli's disease depends on demonstrating that the cystic lesions are in continuity with the biliary tree which can be showed by ultrasonography, computerized tomography, endoscopic retrograde cholangiopancreatography, percutaneous transhepatic cholangiography or magnetic resonance cholangiopancreatography. Treatment of Caroli's disease relies on the location of the biliary abnormalities. While localized forms confined to one lobe can be treated with surgery, liver transplantation is the only effective modality for diffuse forms. Although a rare disorder;Caroli's disease should always be considered in the differential diagnosis of chronic cholestasis of unknown cause.

  9. Nuclear receptors, bile acids and cholesterol homeostasis series - bile acids and pregnancy.

    Science.gov (United States)

    Abu-Hayyeh, Shadi; Papacleovoulou, Georgia; Williamson, Catherine

    2013-04-10

    Bile acids have been traditionally thought of as having an important role in fat emulsification. It is now emerging that they act as important signalling molecules that not only autoregulate their own synthesis but also influence lipid and glucose metabolism. Although, the mechanisms that underlie the regulation of bile acid homeostasis have been well characterised in normal physiology, the impact of pregnancy on bile acid regulation is still poorly understood. This review summarises the main regulatory mechanisms underlying bile acid homeostasis and discusses how pregnancy, a unique physiological state, can modify them. The fetoplacental adaptations that protect against fetal bile acid toxicity are reviewed. We highlight the importance of bile acid regulation during gestation by discussing the liver disease of pregnancy, intrahepatic cholestasis of pregnancy (ICP) and how genetic, endocrine and environmental factors contribute to the disease aetiology at a cellular and molecular level. PMID:23159988

  10. Influence of the Gut Microflora and of Biliary Constituents on Morphological Changes in the Small Intestine in Obstructive Jaundice

    Directory of Open Access Journals (Sweden)

    M. Saeed Quraishy

    1996-01-01

    Full Text Available Increased amounts of intestinal endotoxin are absorbed in obstructive jaundice. The precise mechanism is not known but the increased absorption may arise from alterations in the luminal contents, in the intestinal flora, in the gut wall or in interactions between all three. To examine the effects of the intestinal flora we have compared the morphological changes in the small intestine in obstructive jaundice in germ free and conventional rats while the effects of bile constituents have been examined by addition of bile constituents to the diet of bile duct ligated rats. Changes in the intestine were examined, histologically, by enzyme histochemistry, and by transmission and scanning electron microscopy. The results showed no differences in response between germ free and conventional rats. Feeding of diets containing bile salts exacerbated the lesion. Feeding of diets containing cholesterol, however, reduced the degree of intestinal changes produced by cholestasis and completely antagonised the increase in damage caused by feeding of bile salts.

  11. Liver Hydatid Cyst and Acute Cholangitis: a Case Report.

    Science.gov (United States)

    Nemati Honar, Behzad; Hayatollah, Gholamhossein; Nikshoar, Mohammadreza; Forootan, Mojgan; Feizi, Ali Mohammad

    2016-04-01

    Amongst the cause of cystic hepatic disease, hydatid cyst is common in the Asia, South America, and Africa. The definitive therapy for hepatic hydatid disease is surgical resection. Rupture of the hydatid cyst into the biliary tree can lead to serious cholangitis. In this report, a 22-year-old man is presented with the signs and symptoms of obstructive jaundice and cholangitis. Ultrasonography reported dilated common bile duct (CBD) with sludge and stones, a hydatid cyst adjacent to the gall bladder and mild thickening of gallbladder wall without a stone. MRCP revealed dilated CBD with a cyst in segment fifth of liver. Due to signs and symptoms of obstructive jaundice in addition to lab data and imaging modalities, the ruptured hydatid cyst into a biliary tree was considered, and surgical intervention was performed to extract daughter vesicles from the CBD. Post intervention, signs and symptoms and cholestasis enzymes were subsided. PMID:27309273

  12. Abdominal complications following neutropenia and haematopoietic stem cell transplantation: CT findings

    International Nuclear Information System (INIS)

    In haematology units, acute abdominal symptoms are common and often challenging for the clinician in charge. Two haematological conditions that may induce specific diagnoses are of particular concern: neutropenia and haematopoietic stem cell transplantation. Clinical and biological manifestations, including abdominal pain, fever, diarrhoea, hepatic cytolysis, or cholestasis are often non-specific. Computed tomography is often the primary imaging screening technique performed in such patients, as it is widely available, performs well for this indication, and may demonstrate evocative findings. The aim of this review is to provide the spectrum of specific diagnoses encountered and the corresponding key CT features in patients presenting with acute abdominal disorders following neutropenia and/or haematopoietic stem cell transplantation

  13. Regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis

    Science.gov (United States)

    Banushi, Blerida; Forneris, Federico; Straatman-Iwanowska, Anna; Strange, Adam; Lyne, Anne-Marie; Rogerson, Clare; Burden, Jemima J.; Heywood, Wendy E.; Hanley, Joanna; Doykov, Ivan; Straatman, Kornelis R.; Smith, Holly; Bem, Danai; Kriston-Vizi, Janos; Ariceta, Gema; Risteli, Maija; Wang, Chunguang; Ardill, Rosalyn E.; Zaniew, Marcin; Latka-Grot, Julita; Waddington, Simon N.; Howe, S. J.; Ferraro, Francesco; Gjinovci, Asllan; Lawrence, Scott; Marsh, Mark; Girolami, Mark; Bozec, Laurent; Mills, Kevin; Gissen, Paul

    2016-01-01

    Post-translational modifications are necessary for collagen precursor molecules (procollagens) to acquire final shape and function. However, the mechanism and contribution of collagen modifications that occur outside the endoplasmic reticulum and Golgi are not understood. We discovered that VIPAR, with its partner proteins, regulate sorting of lysyl hydroxylase 3 (LH3, also known as PLOD3) into newly identified post-Golgi collagen IV carriers and that VIPAR-dependent sorting is essential for modification of lysines in multiple collagen types. Identification of structural and functional collagen abnormalities in cells and tissues from patients and murine models of the autosomal recessive multisystem disorder Arthrogryposis, Renal dysfunction and Cholestasis syndrome caused by VIPAR and VPS33B deficiencies confirmed our findings. Thus, regulation of post-Golgi LH3 trafficking is essential for collagen homeostasis and for the development and function of multiple organs and tissues. PMID:27435297

  14. Severe iron overload and hyporegenerative anemia in a case with rhesus hemolytic disease: therapeutic approach to rare complications

    Directory of Open Access Journals (Sweden)

    Fatih Demircioğlu

    2010-09-01

    Full Text Available A 33 weeks’ gestation, a baby with rhesus hemolytic disease (RHD, who had received intrauterine transfusions twice, developed cholestatic hepatic disease and late hyporegenerative anemia. Her serum ferritin and bilirubin levels increased to 8842 ng/ml and 17.9 mg/dl, respectively. Liver biopsy showed cholestasis and severe iron overload. Treatment with recombinant erythropoietin (rHuEPO decreased the transfusion need, and intravenous deferoxamine resulted in a marked decreased in serum ferritin levels and normalization of liver function. In patients who have undergone intrauterine transfusions due to RHD, hyperferritinemia and late hyporegenerative anemia should be kept in mind. Chelation therapy in cases with symptomatic hyperferritinemia and rHuEPO treatment in cases with severe hyporegenerative anemia should be considered.

  15. An incidental case of biliary fascioliasis with subtle clinical findings: US and MRCP findings

    International Nuclear Information System (INIS)

    Fascioliasis is a disease caused by the trematode Fasciola hepatica. Cholangitis is a common clinical manifestation. Although fascioliasis may show various radiological and clinical features, cases without biliary dilatation are rare. We present unique ultrasound (US) and magnetic resonance cholangiopancreatography (MRCP) findings of a biliary fascioliasis case which doesn’t have biliary obstruction or cholestasis. Radiologically, curvilinear parasites compatible with juvenile and mature Fasciola hepatica within the gallbladder and common bile duct were found. The parasites appear as bright echogenic structures with no acoustic shadow on US and hypo-intense curvilinear lesions on T2 weighted MRCP images. Imaging studies may significantly contribute to the diagnosis of patients with subtle clinical and laboratory findings, particularly in endemic regions

  16. Imaging of Drug-induced Complications in the Gastrointestinal System.

    Science.gov (United States)

    McGettigan, Melissa J; Menias, Christine O; Gao, Zhenqiang J; Mellnick, Vincent M; Hara, Amy K

    2016-01-01

    Drug-induced injury commonly affects the gastrointestinal and hepatobiliary systems because of the mechanisms of absorption and metabolism. In pill esophagitis, injury is frequently related to direct contact with the esophageal mucosa, resulting in small superficial ulcers in the mid esophagus. Nonsteroidal anti-inflammatory drugs can lead to gastrointestinal tract ulcers and small bowel mucosal diaphragms (thin weblike strictures). Injury to the pancreatic and hepatobiliary systems can manifest as pancreatitis, acute or chronic hepatitis, cholestasis, or steatosis and steatohepatitis (which may progress to cirrhosis). Various drugs may also insult the hepatic vasculature, resulting in Budd-Chiari and sinusoidal obstructive syndromes. Focal lesions such as hepatic adenomas may develop after use of oral contraceptives or anabolic steroids. Ultrasonography, computed tomography, and magnetic resonance imaging can aid in diagnosis of drug-induced injuries and often are necessary to exclude other causes. PMID:26761532

  17. Adenosine kinase deficiency with neurodevelopemental delay and recurrent hepatic dysfunction: A case report

    Science.gov (United States)

    Shakiba, Marjan; Mahjoub, Fatemeh; Fazilaty, Hassan; Rezagholizadeh, Fereshteh; Shakiba, Arghavan; Ziadlou, Maryam; Gahl, William A.; Behnam, Babak

    2016-01-01

    Hypermethioninemia may be benign, present as a nonspecific sign of nongenetic conditions such as liver failure and prematurity, or a severe, progressive inborn error of metabolism. Genetic causes of hypermethioninemia include mitochondrial depletion syndromes caused by mutations in the MPV17 and DGUOK genes and deficiencies of cystathionine β-synthase, methionine adenosyltransferase types I and III, glycine N-methyltransferase, S-adenosylhomocysteine hydrolase, citrin, fumarylacetoacetate hydrolase, and adenosine kinase. Here we present a 3-year old girl with a history of poor feeding, irritability, respiratory infections, cholestasis, congenital heart disease, neurodevelopmental delay, hypotonia, sparse hair, facial dysmorphisms, liver dysfunction, severe hypermethioninemia and mild homocystinemia. Genetic analysis of the adenosine kinase (ADK) gene revealed a previously unreported variant (c.479–480 GA>TG) resulting in a stop codon (p.E160X) in ADK. A methionine-restricted diet normalized the liver function test results and improved her hypotonia. PMID:27500280

  18. Compounds of Natural Origin and Acupuncture for the Treatment of Diseases Caused by Estrogen Deficiency.

    Science.gov (United States)

    Thakur, Abhishek; Mandal, Subhash C; Banerjee, Sugato

    2016-06-01

    A predominant number of diseases affecting women are related to female hormones. In most of the cases, these diseases are reported to be associated with menstrual problems. These diseases affect female reproductive organs such as the breast, uterus, and ovaries. Estrogen is the main hormone responsible for the menstrual cycle, so irregular menstruation is primarily due to a disturbance in estrogen levels. Estrogen imbalance leads to various pathological conditions in premenopausal women, such as endometriosis, breast cancer, colorectal cancer, prostate cancer, poly cysts, intrahepatic cholestasis of pregnancy, osteoporosis, cardiovascular diseases, obesity, etc. In this review, we discuss common drug targets and therapeutic strategies, including acupuncture and compounds of natural origin, for the treatment of diseases caused by estrogen deficiency. PMID:27342884

  19. Sclerosing angiomatoid nodular transformation of the spleen during pregnancy: Diagnostic challenges and clinical management.

    Science.gov (United States)

    Corrado, Giacomo; Tabanelli, Valentina; Biffi, Roberto; Petralia, Giuseppe; Tinelli, Andrea; Peccatori, Fedro A

    2016-08-01

    We report the first case of sclerosing angiomatoid nodular transformation (SANT) of the spleen diagnosed during pregnancy, discussing differential diagnosis, immunohistochemical profile and treatment. A G2P1 37-year-old woman presented during the 19th week of gestation because of pruritus at lower limbs. To exclude cholestasis, an abdominal ultrasound and whole body magnetic resonance were performed and a single solid lesion with intrinsic vascularization was identified. Therefore, at 22 weeks gestation, after normal fetal assessment, the patient was referred for a splenectomy. No further treatment was suggested and the patient gave birth at 42 weeks gestation with a spontaneous delivery. Distinguishing SANT from other vascular neoplasms of the spleen during pregnancy is a difficult task. Surgical excision should be performed to exclude malignancy and to resolve symptoms, if present. PMID:27080826

  20. Definitive exclusion of biliary atresia in infants with cholestatic jaundice: the role of percutaneous cholecysto-cholangiography.

    Science.gov (United States)

    Nwomeh, Benedict C; Caniano, Donna A; Hogan, Mark

    2007-09-01

    Definitive exclusion of biliary atresia in the infant with cholestatic jaundice usually requires operative cholangiography. This approach suffers from the disadvantage that sick infants are subjected to a time-consuming and potentially negative surgical exploration. The purpose of this study was to determine if percutaneous cholecystocholangiography (PCC) prevents unnecessary laparotomy in infants whose cholestasis is caused by diseases other than biliary atresia. This study is a 10 year retrospective review of all infants with persistent direct hyperbilirubinemia and inconclusive biliary nuclear scans who underwent further evaluation for suspected biliary atresia. A gallbladder ultrasound (US) was obtained in all patients. When the gallbladder was visualized, further imaging by PCC was done under intravenous sedation; otherwise, the standard operative cholangiogram (OCG) was performed, with liver biopsy as indicated. The primary outcome was the diagnostic accuracy of PCC, especially with respect to preventing a laparotomy. There were 35 infants with suspected biliary atresia, with a mean age of 8 weeks (range 1-14 weeks). Nine infants whose gallbladder was visualized by ultrasound underwent PCC that definitively excluded biliary atresia. Of this group, the most frequent diagnosis (five patients) was total parenteral nutrition-associated cholestasis. The other 26 infants with absent or decompressed gallbladder had laparotomy and OCG, which identified biliary atresia in 16 patients (61%). Laparotomy was avoided in all 9 patients who underwent PCC, thus reducing the negative laparotomy rate by 47%. There were no complications associated with PCC. Several alternative techniques to operative cholangiogram have been described for the definitive exclusion of biliary atresia, but many of these have distinct drawbacks. Advances in interventional radiology techniques have permitted safe percutaneous contrast evaluation of the biliary tree. Identification of a normal gall

  1. EU Framework 6 Project: Predictive Toxicology (PredTox)-overview and outcome

    International Nuclear Information System (INIS)

    In this publication, we report the outcome of the integrated EU Framework 6 Project: Predictive Toxicology (PredTox), including methodological aspects and overall conclusions. Specific details including data analysis and interpretation are reported in separate articles in this issue. The project, partly funded by the EU, was carried out by a consortium of 15 pharmaceutical companies, 2 SMEs, and 3 universities. The effects of 16 test compounds were characterized using conventional toxicological parameters and 'omics' technologies. The three major observed toxicities, liver hypertrophy, bile duct necrosis and/or cholestasis, and kidney proximal tubular damage were analyzed in detail. The combined approach of 'omics' and conventional toxicology proved a useful tool for mechanistic investigations and the identification of putative biomarkers. In our hands and in combination with histopathological assessment, target organ transcriptomics was the most prolific approach for the generation of mechanistic hypotheses. Proteomics approaches were relatively time-consuming and required careful standardization. NMR-based metabolomics detected metabolite changes accompanying histopathological findings, providing limited additional mechanistic information. Conversely, targeted metabolite profiling with LC/GC-MS was very useful for the investigation of bile duct necrosis/cholestasis. In general, both proteomics and metabolomics were supportive of other findings. Thus, the outcome of this program indicates that 'omics' technologies can help toxicologists to make better informed decisions during exploratory toxicological studies. The data support that hypothesis on mode of action and discovery of putative biomarkers are tangible outcomes of integrated 'omics' analysis. Qualification of biomarkers remains challenging, in particular in terms of identification, mechanistic anchoring, appropriate specificity, and sensitivity.

  2. microRNA-222 modulates liver fibrosis in a murine model of biliary atresia

    Energy Technology Data Exchange (ETDEWEB)

    Shen, Wen-jun; Dong, Rui; Chen, Gong, E-mail: chengongzlp@hotmail.com; Zheng, Shan

    2014-03-28

    Highlights: • The RRV infected group showed cholestasis, retardation and extrahepatic biliary atresia. • miR-222 was highly expressed, and PPP2R2A was inhibited in the murine biliary atresia model. • miR-222 profoundly modulated the process of fibrosis in the murine biliary atresia model. • miR-222 might represent a potential target for improving biliary atresia prognosis. - Abstract: microRNA-222 (miR-222) has been shown to initiate the activation of hepatic stellate cells, which plays an important role in the pathogenesis of liver fibrosis. The aim of our study was to evaluate the role of miR-22 in a mouse model of biliary atresia (BA) induced by Rhesus Rotavirus (RRV) infection. New-born Balb/c mice were randomized into control and RRV infected groups. The extrahepatic bile ducts were evaluated. The experimental group was divided into BA group and negative group based on histology. The expression of miR-222, protein phosphatase 2 regulatory subunit B alpha (PPP2R2A), proliferating cell nuclear antigen (PCNA) and phospho-Akt were detected. We found that the experimental group showed signs of cholestasis, retardation and extrahepatic biliary atresia. No abnormalities were found in the control group. In the BA group, miR-222, PCNA and Akt were highly expressed, and PPP2R2A expression was significantly inhibited. Our findings suggest that miR-222 profoundly modulated the process of fibrosis in the murine BA model, which might represent a potential target for improving BA prognosis.

  3. Protective effect of the roots extract of Platycodon grandiflorum on bile duct ligation-induced hepatic fibrosis in rats.

    Science.gov (United States)

    Lim, J-H; Kim, T-W; Song, I-B; Park, S-J; Kim, M-S; Cho, E-S; Jung, J-Y; Son, H-Y; Kim, J-W; Yun, H-I

    2013-11-01

    The aim of the present study was to evaluate the protective effect of aqueous extract from Platycodon grandiflorum (BC703) on bile duct ligation (BDL)-induced hepatic fibrosis in rats. BDL rats were divided into three groups, which orally received distilled water or BC703 (10 or 50 mg/kg/day) for consecutive 28 days. Antifibrotic effects of BC703 on BDL-induced hepatic fibrosis in rats were estimated by assessing serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), blood urea nitrogen (BUN), transforming growth factor-beta 1 (TGF-β1) and hepatic levels of malondialdehyde (MDA), glutathione (GSH), total superoxide dismutase (SOD) and nitric oxide (NO). The biochemical observations were supplemented by histopathological examination of liver samples stained with hematoxylin and eosin and Masson's trichrome stain. ALT, AST, TBIL and BUN were elevated in the group treated with BDL alone than in the sham-operated group. These elevations were significantly decreased by BC703 treatment. Hepatic GSH and SOD levels, depressed by BDL, were also increased in the BC703 group. In addition, increases in hepatic MDA and NO levels in the BDL-induced cholestasis were attenuated by BC703 treatment. Furthermore, BC703 treatment significantly reduced the serum level of fibrogenic cytokine, TGF-β1. Histopathological studies further substantiated the protective effect of BC703 on BDL-induced hepatic fibrosis in rat. BC703 may have beneficial effects not only on hepatic fibrosis by cholestasis but also on hepatic fibrosis development in patients with chronic hepatic disease. PMID:23424213

  4. Changes in GM1 ganglioside content and localization in cholestatic rat liver.

    Science.gov (United States)

    Jirkovská, Marie; Majer, Filip; Smídová, Jaroslava; Stríteský, Jan; Shaik, Gouse Mohiddin; Dráber, Petr; Vítek, Libor; Marecek, Zdenek; Smíd, Frantisek

    2007-07-01

    (Glyco)sphingolipids (GSL) are believed to protect the cell against harmful environmental factors by increasing the rigidity of plasma membrane. Marked decrease of membrane fluidity in cholestatic hepatocytes was described but the role of GSL therein has not been investigated so far. In this study, localization in hepatocytes of a representative of GSL, the GM1 ganglioside, was compared between of rats with cholestasis induced by 17alpha-ethinylestradiol (EE) and vehicle propanediol treated or untreated animals. GM1 was monitored by histochemical reaction employing cholera toxin B-subunit. Our findings in normal rat liver tissue showed that GM1 was localized in sinusoidal and canalicular hepatocyte membranes in both peripheral and intermediate zones of the hepatic lobules, and was nearly absent in central zones. On the contrary, in EE-treated animals GM1 was also expressed in central lobular zones. Moreover, detailed densitometry analysis at high magnification showed greater difference of GM1 expression between sinusoidal surface areas and areas of adjacent cytoplasm, caused as well by increased sinusoidal staining in central lobular zone as by decreased staining in cytoplasm in peripheral zone. These differences correlated with serum bile acids as documented by linear regression analyses. Both GM1 content and mRNA corresponding to GM1-synthase remained unchanged in livers; the enhanced expression of GM1 at sinusoidal membrane thus seems to be due to re-distribution of cellular GM1 at limited biosynthesis and could be responsible for protection of hepatocytes against harmful effects of bile acids accumulated during cholestasis. PMID:17333356

  5. Endoscopic Treatment of Biliary Stenosis in Patients with Alveolar Echinococcosis--Report of 7 Consecutive Patients with Serial ERC Approach.

    Directory of Open Access Journals (Sweden)

    Marija Stojkovic

    2016-02-01

    Full Text Available Biliary vessel pathology due to alveolar echicococcosis (AE results in variable combinations of stenosis, necrosis and inflammation. Modern management strategies for patients with cholestasis are desperately needed. The aim is proof of principle of serial ERC (endoscopic retrograde cholangiography balloon dilation for AE biliary pathology.Retrospective case series of seven consecutive patients with AE-associated biliary pathology and ERC treatment in an interdisciplinary endoscopy unit at a University Hospital which hosts a national echinococcosis treatment center. The AE patient cohort consists of 106 patients with AE of the liver of which 13 presented with cholestasis. 6/13 received bilio-digestive anastomosis and 7/13 patients were treated by ERC and are reported here. Biliary stricture balloon dilation was performed with 18-Fr balloons at the initial and with 24-Fr balloons at subsequent interventions. If indicated 10 Fr plastic stents were placed.Six patients were treated by repeated balloon dilation and stenting, one by stenting only. After an acute phase of 6 months with repeated balloon dilation, three patients showed "sustained clinical success" and four patients "assisted therapeutic success," of which one has not yet reached the six month endpoint. In one patient, sustained success could not be achieved despite repeated insertion of plastic stents and balloon dilation, but with temporary insertion of a fully covered self-expanding metal stent (FCSEMS. There was no loss to follow up. No major complications were observed.Serial endoscopic dilation is a standard tool in the treatment of benign biliary strictures. Serial endoscopic intervention with balloon dilation combined with benzimidazole treatment can re-establish and maintain biliary duct patency in AE associated pathology and probably contributes to avoid or postpone bilio-digestive anastomosis. This approach is in accordance with current ERC guidelines and is minimally disruptive

  6. Endoscopic Treatment of Biliary Stenosis in Patients with Alveolar Echinococcosis – Report of 7 Consecutive Patients with Serial ERC Approach

    Science.gov (United States)

    Stojkovic, Marija; Junghanss, Thomas; Veeser, Mira; Weber, Tim F.; Sauer, Peter

    2016-01-01

    Background and Aims Biliary vessel pathology due to alveolar echicococcosis (AE) results in variable combinations of stenosis, necrosis and inflammation. Modern management strategies for patients with cholestasis are desperately needed. The aim is proof of principle of serial ERC (endoscopic retrograde cholangiography) balloon dilation for AE biliary pathology. Methods Retrospective case series of seven consecutive patients with AE-associated biliary pathology and ERC treatment in an interdisciplinary endoscopy unit at a University Hospital which hosts a national echinococcosis treatment center. The AE patient cohort consists of 106 patients with AE of the liver of which 13 presented with cholestasis. 6/13 received bilio-digestive anastomosis and 7/13 patients were treated by ERC and are reported here. Biliary stricture balloon dilation was performed with 18-Fr balloons at the initial and with 24-Fr balloons at subsequent interventions. If indicated 10 Fr plastic stents were placed. Results Six patients were treated by repeated balloon dilation and stenting, one by stenting only. After an acute phase of 6 months with repeated balloon dilation, three patients showed “sustained clinical success” and four patients “assisted therapeutic success,” of which one has not yet reached the six month endpoint. In one patient, sustained success could not be achieved despite repeated insertion of plastic stents and balloon dilation, but with temporary insertion of a fully covered self-expanding metal stent (FCSEMS). There was no loss to follow up. No major complications were observed. Conclusions Serial endoscopic dilation is a standard tool in the treatment of benign biliary strictures. Serial endoscopic intervention with balloon dilation combined with benzimidazole treatment can re-establish and maintain biliary duct patency in AE associated pathology and probably contributes to avoid or postpone bilio-digestive anastomosis. This approach is in accordance with current

  7. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

    International Nuclear Information System (INIS)

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ► We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ► We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ► The toxins decreased the

  8. Pregnancy outcomes associated with viral hepatitis.

    Science.gov (United States)

    Reddick, K L B; Jhaveri, R; Gandhi, M; James, A H; Swamy, G K

    2011-07-01

    The aim of this study was to examine the contribution of hepatitis B virus (HBV) and hepatitis C virus (HCV) to pregnancy-related complications including gestational diabetes mellitus (GDM), preterm birth (PTB), intrauterine growth restriction (IUGR), pre-eclampsia, antepartum haemorrhage and cholestasis. The Nationwide Inpatient Sample was queried for all pregnancy-related discharges, pregnancy complications and viral hepatitis from 1995 to 2005. Logistic regression was used to examine the association between HBV, HCV, HBV + HCV and pregnancy-related complications including GDM, PTB, IUGR, pre-eclampsia, antepartum haemorrhage, cholestasis and caesarean delivery. Model covariates included maternal age, race, insurance status, substance use and medical complications including liver complication, hypertension, HIV, anaemia, thrombocytopenia and sexually transmitted infections. Of 297 664 pregnant women data available for analysis, 1446 had a coded diagnosis of HBV, HCV or both. High-risk behaviours, such as smoking, alcohol and substance use were higher in women with either HBV or HCV. Women with HBV had an increased risk for PTB (aOR 1.65, CI [1.3, 2.0]) but a decreased risk for caesarean delivery (aOR 0.686, CI [0.53, 0.88]). Individuals with HCV had an increased risk for GDM (aOR 1.6, CI [1.0, 2.6]). Individuals with both HBV and HCV co-infection had an increased risk for antepartum haemorrhage (aOR 2.82, CI [1.1, 7.2]). There was no association of viral hepatitis with IUGR or pre-eclampsia. Women with hepatitis have an increased risk for complications during pregnancy. Research to determine the efficacy and cost-effectiveness of counselling patients about potential risks for adverse outcomes is warranted. PMID:21692952

  9. Mitochondrial genome depletion in human liver cells abolishes bile acid-induced apoptosis: role of the Akt/mTOR survival pathway and Bcl-2 family proteins.

    Science.gov (United States)

    Marin, Jose J G; Hernandez, Alicia; Revuelta, Isabel E; Gonzalez-Sanchez, Ester; Gonzalez-Buitrago, Jose M; Perez, Maria J

    2013-08-01

    Acute accumulation of bile acids in hepatocytes may cause cell death. However, during long-term exposure due to prolonged cholestasis, hepatocytes may develop a certain degree of chemoresistance to these compounds. Because mitochondrial adaptation to persistent oxidative stress may be involved in this process, here we have investigated the effects of complete mitochondrial genome depletion on the response to bile acid-induced hepatocellular injury. A subline (Rho) of human hepatoma SK-Hep-1 cells totally depleted of mitochondrial DNA (mtDNA) was obtained, and bile acid-induced concentration-dependent activation of apoptosis/necrosis and survival signaling pathways was studied. In the absence of changes in intracellular ATP content, Rho cells were highly resistant to bile acid-induced apoptosis and partially resistant to bile acid-induced necrosis. In Rho cells, both basal and bile acid-induced generation of reactive oxygen species (ROS), such as hydrogen peroxide and superoxide anion, was decreased. Bile acid-induced proapoptotic signals were also decreased, as evidenced by a reduction in the expression ratios Bax-α/Bcl-2, Bcl-xS/Bcl-2, and Bcl-xS/Bcl-xL. This was mainly due to a downregulation of Bax-α and Bcl-xS. Moreover, in these cells the Akt/mTOR pathway was constitutively activated in a ROS-independent manner and remained similarly activated in the presence of bile acid treatment. In contrast, ERK1/2 activation was constitutively reduced and was not activated by incubation with bile acids. In conclusion, these results suggest that impaired mitochondrial function associated with mtDNA alterations, which may occur in liver cells during prolonged cholestasis, may activate mechanisms of cell survival accounting for an enhanced resistance of hepatocytes to bile acid-induced apoptosis. PMID:23597504

  10. Dynamic localization of hepatocellular transporters in health and disease

    Institute of Scientific and Technical Information of China (English)

    Marcelo G Roma; Fernando A Crocenzi; Aldo D Mottino

    2008-01-01

    Vesicle-based trafficking of hepatocellular transporters involves delivery of the newly-synthesized carriers from the rough endoplasmic reticulum to either the plasma membrane domain or to an endosomal, submembrane compartment, followed by exocytic targeting to the plasma membrane. Once delivered to the plasma membrane, the transporters usually undergo recycling between the plasma membrane and the endosomal compartment, which usually serves as a reservoir of pre-existing transporters available on demand. The balance between exocytic targeting and endocytic internalization from/to this recycling compartment is therefore a chief determinant of the overall capability of the liver epithelium to secrete bile and to detoxify endo and xenobiotics. Hence, it is a highly regulated process. Impaired regulation of this balance may lead to abnormal localization of these transporters, which results in bile secretory failure due to endocytic internalization of key transporters involved in bile formation. This occurs in several experimental models of hepatocellular cholestasis, and in most human cholestatic liver diseases. This review describes the molecular bases involved in the biology of the dynamic localization of hepatocellular transporters and its regulation, with a focus on the involvement of signaling pathways in this process. Their alterations in different experimental models of cholestasis and in human cholestatic liver disease are reviewed. In addition, the causes explaining the pathological condition (e.g. disorganization of actin or actin-transporter linkers) and the mediators involved (e.g. activation of cholestatic signaling transduction pathways) are also discussed. Finally, several experimental therapeutic approaches based upon the administration of compounds known to stimulate exocytic insertion of canalicular transporters (e.g. cAMP, tauroursodeoxycholate) are described.

  11. Constitutive androstane receptor-mediated changes in bile acid composition contributes to hepatoprotection from lithocholic acid-induced liver injury in mice.

    Science.gov (United States)

    Beilke, Lisa D; Aleksunes, Lauren M; Holland, Ricky D; Besselsen, David G; Beger, Rick D; Klaassen, Curtis D; Cherrington, Nathan J

    2009-05-01

    Pharmacological activation of the constitutive androstane receptor (CAR) protects the liver during cholestasis. The current study evaluates how activation of CAR influences genes involved in bile acid biosynthesis as a mechanism of hepatoprotection during bile acid-induced liver injury. CAR activators phenobarbital (PB) and 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or corn oil (CO) were administered to C57BL/6 wild-type (WT) and CAR knockout (CAR-null) mice before and during induction of intrahepatic cholestasis using the secondary bile acid, lithocholic acid (LCA). In LCA-treated WT and all the CAR-null groups (excluding controls), histology revealed severe multifocal necrosis. This pathology was absent in WT mice pretreated with PB and TCPOBOP, indicating CAR-dependent hepatoprotection. Decreases in total hepatic bile acids and hepatic monohydroxy, dihydroxy, and trihydroxy bile acids in PB- and TCPOBOP-pretreated WT mice correlated with hepatoprotection. In comparison, concentrations of monohydroxylated and dihydroxylated bile acids were increased in all the treated CAR-null mice compared with CO controls. Along with several other enzymes (Cyp7b1, Cyp27a1, Cyp39a1), Cyp8b1 expression was increased in hepatoprotected mice, which could be suggestive of a shift in the bile acid biosynthesis pathway toward the formation of less toxic bile acids. In CAR-null mice, these changes in gene expression were not different among treatment groups. These results suggest CAR mediates a shift in bile acid biosynthesis toward the formation of less toxic bile acids, as well as a decrease in hepatic bile acid concentrations. We propose that these combined CAR-mediated effects may contribute to the hepatoprotection observed during LCA-induced liver injury. PMID:19196849

  12. Feed-forward regulation of bile acid detoxification by CYP3A4: studies in humanized transgenic mice.

    Science.gov (United States)

    Stedman, Catherine; Robertson, Graham; Coulter, Sally; Liddle, Christopher

    2004-03-19

    Bile acids are potentially toxic end products of cholesterol metabolism and their concentrations must be tightly regulated. Homeostasis is maintained by both feed-forward regulation and feedback regulation. We used humanized transgenic mice incorporating 13 kb of the 5' regulatory flanking sequence of CYP3A4 linked to a lacZ reporter gene to explore the in vivo relationship between bile acids and physiological adaptive CYP3A gene regulation in acute cholestasis after bile duct ligation (BDL). Male transgenic mice were subjected to BDL or sham surgery prior to sacrifice on days 3, 6, and 10, and others were injected with intraperitoneal lithocholic acid (LCA) or vehicle alone. BDL resulted in marked hepatic activation of the CYP3A4/lacZ transgene in pericentral hepatocytes, with an 80-fold increase in transgene activation by day 10. Individual bile acids were quantified by liquid chromatography/mass spectrometry. Serum 6beta-hydroxylated bile acids were increased following BDL, confirming the physiological relevance of endogenous Cyp3a induction to bile acid detoxification. Although concentrations of conjugated primary bile acids increased after BDL, there was no increase in LCA, a putative PXR ligand, indicating that this cannot be the only endogenous bile acid mediating this protective response. Moreover, in LCA-treated animals, 5-bromo-4-chloro-3-indolyl-beta-d-galactopyranoside staining showed hepatic activation of the CYP3A4 transgene only on the liver capsular surface, and minimal parenchymal induction, despite significant liver injury. This study demonstrates that CYP3A up-regulation is a significant in vivo adaptive response to cholestasis. However, this up-regulation is not dependent on increases in circulating LCA and the role of other bile acids as regulatory molecules requires further exploration. PMID:14681232

  13. Decreased apoptosis during CAR-mediated hepatoprotection against lithocholic acid-induced liver injury in mice.

    Science.gov (United States)

    Beilke, Lisa D; Aleksunes, Lauren M; Olson, Erik R; Besselsen, David G; Klaassen, Curtis D; Dvorak, Katerina; Cherrington, Nathan J

    2009-07-10

    Myeloid cell leukemia-1 (Mcl-1) is an anti-apoptotic protein that is regulated by the constitutive androstane receptor (CAR). Activation of CAR can protect the liver against bile acid-induced toxicity and it may have a role in cell death via apoptosis by altering expression of Bcl-2 family proteins such as myeloid cell leukemia-1 (Mcl-1). Our aim was to determine if activation of CAR reduces hepatocellular apoptosis during cholestasis as a mechanism of hepatoprotection. CAR(+/+) (WT) and CAR(-/-) (CAR-null) mice were pre-treated with compounds known to activate CAR prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Pre-treatment with the CAR activators phenobarbital (PB) and TCPOBOP (TC), as well as the non-CAR activator pregnenolone 16alpha-carbontrile (PCN), protected against LCA-induced liver injury in WT mice, whereas liver injury was more extensive without CAR (CAR-null). Unexpectedly, expression of anti-apoptotic Mcl-1 and Bcl-x(L) was not increased in hepatoprotected mice. Compared to unprotected groups, apoptosis was decreased in hepatoprotected mice as evidenced by the absence of cleaved caspase 3 (cCasp3). In contrast to the cytoplasmic localization in the injured livers (LCA and oltipraz), Mcl-1 protein was localized in the nucleus of hepatoprotected livers to potentially promote cell survival. This study demonstrates that although apoptosis is reduced in hepatoprotected mice pre-treated with CAR and non-CAR activators; hepatoprotection is not directly a result of CAR-induced Mcl-1 expression. PMID:19433268

  14. Sustained Isoprostane E2 Elevation, Inflammation and Fibrosis after Acute Ischaemia-Reperfusion Injury Are Reduced by Pregnane X Receptor Activation.

    Directory of Open Access Journals (Sweden)

    Aimen O Amer

    Full Text Available Liver grafts donated after cardiac death are increasingly used to expand the donor pool but are prone to ischaemic-type biliary lesions. The anti-inflammatory effects of the activated pregnane X receptor have previously been shown to be beneficial in a number of inflammatory liver conditions. However, its role in reducing peri-portal inflammation and fibrosis following ischaemia-reperfusion injury has not been investigated. Hepatic injury and its response to pregnane X receptor activation was examined after partial hepatic ischaemia-reperfusion injury induced by surgically clamping the left and middle lobar blood vessels in rats. Molecular and pathological changes in the liver were examined over the following 28 days. Ischaemia-reperfusion injury resulted in transient cholestasis associated with microvillar changes in biliary epithelial cell membranes and hepatocellular injury which resolved within days after reperfusion. However, in contrast to chemically-induced acute liver injuries, this was followed by sustained elevation in isoprostane E2, peri-portal inflammation and fibrosis that remained unresolved in the ischaemic reperfused lobe for at least 28 days after clamping. Administration of pregnenolone-16α-carbonitrile--a rodent-specific pregnane X receptor activator--resulted in significant reductions in cholestasis, hepatic injury, ischaemic lobe isoprostane E2 levels, peri-portal inflammation and fibrosis. Hepatic ischaemia-reperfusion injury therefore results in inflammatory and fibrotic changes that persist well beyond the initial ischaemic insult. Drug-mediated activation of the pregnane X receptor reduced these adverse changes in rats, suggesting that the pregnane X receptor is a viable drug target to reduce ischaemic-type biliary lesions in recipients of liver transplants donated after cardiac death.

  15. Estrogen and Estrogen Receptor-α-Mediated Transrepression of Bile Salt Export Pump.

    Science.gov (United States)

    Chen, Yuan; Vasilenko, Alex; Song, Xiulong; Valanejad, Leila; Verma, Ruchi; You, Sangmin; Yan, Bingfang; Shiffka, Stephanie; Hargreaves, Leeza; Nadolny, Christina; Deng, Ruitang

    2015-04-01

    Among diseases unique to pregnancy, intrahepatic cholestasis of pregnancy is the most prevalent disorder with elevated serum bile acid levels. We have previously shown that estrogen 17β-estradiol (E2) transrepresses bile salt export pump (BSEP) through an interaction between estrogen receptor (ER)-α and farnesoid X receptor (FXR) and transrepression of BSEP by E2/ERα is an etiological contributing factor to intrahepatic cholestasis of pregnancy. Currently the mechanistic insights into such transrepression are not fully understood. In this study, the dynamics of coregulator recruitment to BSEP promoter after FXR activation and E2 treatment were established with quantitative chromatin immunoprecipitation assays. Coactivator peroxisome proliferator-activated receptor-γ coactivator-1 was predominantly recruited to the BSEP promoter upon FXR activation, and its recruitment was decreased by E2 treatment. Meanwhile, recruitment of nuclear receptor corepressor was markedly increased upon E2 treatment. Functional evaluation of ERα and ERβ chimeras revealed that domains AC of ERα are the determinants for ERα-specific transrepression on BSEP. Further studies with various truncated ERα proteins identified the domains in ERα responsible for ligand-dependent and ligand-independent transrepression. Truncated ERα-AD exhibited potent ligand-independent transrepressive activity, whereas ERα-CF was fully capable of transrepressing BSEP ligand dependently in vitro in Huh 7 cells and in vivo in mice. Both ERα-AD and ERα-CF proteins were associated with FXR in the coimmunoprecipitation assays. In conclusion, E2 repressed BSEP expression through diminishing peroxisome proliferator-activated receptor-γ coactivator-1 recruitment with a concurrent increase in nuclear receptor corepressor recruitment to the BSEP promoter. Domains AD and CF in ERα mediated ligand-independent and ligand-dependent transrepression on BSEP, respectively, through interacting with FXR. PMID:25675114

  16. A nested case-control study of maternal-neonatal transmission of hepatitis B virus in a Chinese population

    Institute of Scientific and Technical Information of China (English)

    Li-Zhang Chen; Wen-Qi Zhou; Shu-Shan Zhao; Zhi-Yu Liu; Shi-Wu Wen

    2011-01-01

    AIM: To examine the determinants of maternal-neo?natal transmission of hepatitis B virus (HBV).METHODS: A nested case-control study was conducted in Changsha, Hunan, People's Republic of China from January 1, 2005 to September 31, 2006. To avoid po?tential maternal blood contamination, we collected vein blood of newborns immediately after birth and before initial hepatitis B vaccination to determine the HBV in?fection status of the newborn. For each HBsAg-positive infant, one HBsAg-negative infant born to an HBsAg-positive mother was matched by hospital at birth (same), gender (same), and date of birth (within 1 mo). A face-to-face interview was conducted to collect clinical and epidemiological data. Conditional logistic regression analysis was used to estimate the independent effects of various determinants on maternal-neonatal transmis?sion of HBV.RESULTS: A total of 141 HBsAg-positive infants and 141 individually matched HBsAg-negative infants were included in the final analysis. Maternal first-degree family history of HBV infection, intrahepatic cholesta-sis, and premature rupture of membranes were risk factors for perinatal transmission of HBV, whereas sys?tematic treatment and HBV immunoglobulin injections for mothers with HBV infection were protective factors for maternal-neonatal transmission of HBV, after ad?justment for potential confounding factors.CONCLUSION: For HBsAg-positive mothers, system?atic treatment, HBV immunoglobulin administration, and controlling intrahepatic cholestasis and pregnancy complications may reduce the incidence of perinatal transmission of HBV.

  17. microRNA-222 modulates liver fibrosis in a murine model of biliary atresia

    International Nuclear Information System (INIS)

    Highlights: • The RRV infected group showed cholestasis, retardation and extrahepatic biliary atresia. • miR-222 was highly expressed, and PPP2R2A was inhibited in the murine biliary atresia model. • miR-222 profoundly modulated the process of fibrosis in the murine biliary atresia model. • miR-222 might represent a potential target for improving biliary atresia prognosis. - Abstract: microRNA-222 (miR-222) has been shown to initiate the activation of hepatic stellate cells, which plays an important role in the pathogenesis of liver fibrosis. The aim of our study was to evaluate the role of miR-22 in a mouse model of biliary atresia (BA) induced by Rhesus Rotavirus (RRV) infection. New-born Balb/c mice were randomized into control and RRV infected groups. The extrahepatic bile ducts were evaluated. The experimental group was divided into BA group and negative group based on histology. The expression of miR-222, protein phosphatase 2 regulatory subunit B alpha (PPP2R2A), proliferating cell nuclear antigen (PCNA) and phospho-Akt were detected. We found that the experimental group showed signs of cholestasis, retardation and extrahepatic biliary atresia. No abnormalities were found in the control group. In the BA group, miR-222, PCNA and Akt were highly expressed, and PPP2R2A expression was significantly inhibited. Our findings suggest that miR-222 profoundly modulated the process of fibrosis in the murine BA model, which might represent a potential target for improving BA prognosis

  18. Etiological spectrum of recurrent jaundice in adults: A retrospective observational study from a tertiary care center

    Directory of Open Access Journals (Sweden)

    Gouranga Santra

    2016-01-01

    Full Text Available Introduction: Studies regarding etiological spectrum of recurrent jaundice are rare. We conducted this study to identify the causes of recurrent jaundice in a tertiary care center. Materials and Methods: Frequency of different causes of recurrent jaundice was assessed from 130 patients attended General Medicine Department over a period of 3 years. Recurrent jaundice was considered when patients had more than one episodes of jaundice with serum bilirubin ≥3 mg/dl since childhood. Recurrent jaundice was diagnosed from past medical records, records of follow-up visits, and current clinical presentation. Causes were identified from past and present medical records of history, clinical and laboratory examinations. Results: Causes of recurrent jaundice included prehepatic (30%, hepatic (59.23%, and posthepatic (10.77 % disorders. Prehepatic disorders were Gilbert′s syndrome (GS, megaloblastic anemia, autoimmune haemolytic anemia, Wilson′s disease, G6PD deficiency, etc. Hepatic disorders were exacerbations of alcoholic hepatitis, hepatitis B and C, autoimmune hepatitis, congestive cardiac failure, sarcoidosis, benign recurrent intrahepatic cholestasis, eclampsia, pregnancy induced cholestasis, falciparum malaria, drug induced liver injury (DILI, etc. Posthepatic causes were choledocholithiasis, recurrent pancreatitis, periampullary carcinoma, choledochal cyst, ascariasis, hemobilia, HIV cholangiopathy, autoimmune pancreatitis, etc. Prehepatic jaundice cases were younger. The highest level of total bilirubin was seen in alcoholic hepatitis, DILI, and hepatitis B. Alcoholic hepatitis was the most common cause of recurrent jaundice (19.23%. GS was the most common prehepatic cause. Mean age was lowest in GS and highest in DILI. Conclusion: Etiological spectrum of recurrent jaundice includes many prehepatic, hepatic or posthepatic disorders. A larger study may enlarge the spectrum.

  19. Portal Vein Embolization Before Liver Resection: A Systematic Review

    Energy Technology Data Exchange (ETDEWEB)

    Lienden, K. P. van, E-mail: k.p.vanlienden@amc.uva.nl [Academic Medical Center, Department of Radiology (Netherlands); Esschert, J. W. van den; Graaf, W. de [Academic Medical Center, Department of Surgery (Netherlands); Bipat, S.; Lameris, J. S. [Academic Medical Center, Department of Radiology (Netherlands); Gulik, T. M. van [Academic Medical Center, Department of Surgery (Netherlands); Delden, O. M. van [Academic Medical Center, Department of Radiology (Netherlands)

    2013-02-15

    This is a review of literature on the indications, technique, and outcome of portal vein embolization (PVE). A systematic literature search on outcome of PVE from 1990 to 2011 was performed in Medline, Cochrane, and Embase databases. Forty-four articles were selected, including 1,791 patients with a mean age of 61 {+-} 4.1 years. Overall technical success rate was 99.3 %. The mean hypertrophy rate of the FRL after PVE was 37.9 {+-} 0.1 %. In 70 patients (3.9 %), surgery was not performed because of failure of PVE (clinical success rate 96.1 %). In 51 patients (2.8 %), the hypertrophy response was insufficient to perform liver resection. In the other 17 cases, 12 did not technically succeed (0.7 %) and 7 caused a complication leading to unresectability (0.4 %). In 6.1 %, resection was cancelled because of local tumor progression after PVE. Major complications were seen in 2.5 %, and the mortality rate was 0.1 %. A head-to-head comparison shows a negative effect of liver cirrhosis on hypertrophy response. The use of n-butyl cyanoacrylate seems to have a greater effect on hypertrophy, but the difference with other embolization materials did not reach statistical significance. No difference in regeneration is seen in patients with cholestasis or chemotherapy. Preoperative PVE has a high technical and clinical success rate. Liver cirrhosis has a negative effect on regeneration, but cholestasis and chemotherapy do not seem to have an influence on the hypertrophy response. The use of n-butyl cyanoacrylate may result in a greater hypertrophy response compared with other embolization materials used.

  20. Long-term outcome of endoscopic metallic stenting for benign biliary stenosis associated with chronic pancreatitis

    Institute of Scientific and Technical Information of China (English)

    Taketo Yamaguchi; Takeshi Ishihara; Katsutoshi Seza; Akihiko Nakagawa; Kentarou Sudo; Katsuyuki Tawada; Teruo Kouzu; Hiromitsu Saisho

    2006-01-01

    AIM: Endoscopic metal stenting (EMS) offers good results in short to medium term follow-up for bile duct stenosis associated with chronic pancreatitis (CP);however, longer follow-up is needed to determine if EMS has the potential to become the treatment of first choice.METHODS: EMS was performed in eight patients with severe common bile duct stenosis due to CR After the resolution of cholestasis by endoscopic naso-biliary drainage three patients were subjected to EMS while,the other five underwent EMS following plastic tube stenting. The patients were followed up for more than5 years through periodical laboratory tests and imaging techniques.RESULTS: EMS was successfully performed in all the patients. Two patients died due to causes unrelated to the procedure: one with an acute myocardial infarction and the other with maxillary carcinoma at 2.8 and 5.5years after EMS, respectively. One patient died with cholangitis because of EMS clogging 3.6 years after EMS.None of these three patients had showed symptoms of cholestasis during the follow-up period. Two patients developed choledocholithiasis and two suffered from duodenal ulcers due to dislodgement of the stent between 4.8 and 7.3 years after stenting; however, they were successfully treated endoscopically. Thus, five of eight patients are alive at present after a mean follow-up period of 7.4 years.CONCLUSION: EMS is evidently one of the very promising treatment options for bile duct stenosis associated with CP, provided the patients are closely followed up; thus setting a system for their prompt management on emergency is desirable.

  1. Portal Vein Embolization Before Liver Resection: A Systematic Review

    International Nuclear Information System (INIS)

    This is a review of literature on the indications, technique, and outcome of portal vein embolization (PVE). A systematic literature search on outcome of PVE from 1990 to 2011 was performed in Medline, Cochrane, and Embase databases. Forty-four articles were selected, including 1,791 patients with a mean age of 61 ± 4.1 years. Overall technical success rate was 99.3 %. The mean hypertrophy rate of the FRL after PVE was 37.9 ± 0.1 %. In 70 patients (3.9 %), surgery was not performed because of failure of PVE (clinical success rate 96.1 %). In 51 patients (2.8 %), the hypertrophy response was insufficient to perform liver resection. In the other 17 cases, 12 did not technically succeed (0.7 %) and 7 caused a complication leading to unresectability (0.4 %). In 6.1 %, resection was cancelled because of local tumor progression after PVE. Major complications were seen in 2.5 %, and the mortality rate was 0.1 %. A head-to-head comparison shows a negative effect of liver cirrhosis on hypertrophy response. The use of n-butyl cyanoacrylate seems to have a greater effect on hypertrophy, but the difference with other embolization materials did not reach statistical significance. No difference in regeneration is seen in patients with cholestasis or chemotherapy. Preoperative PVE has a high technical and clinical success rate. Liver cirrhosis has a negative effect on regeneration, but cholestasis and chemotherapy do not seem to have an influence on the hypertrophy response. The use of n-butyl cyanoacrylate may result in a greater hypertrophy response compared with other embolization materials used.

  2. Diagnosis of alpha-1-antitrypsin deficiency by DNA analysis of children with liver disease

    Directory of Open Access Journals (Sweden)

    De TOMMASO Adriana Maria Alves

    2001-01-01

    Full Text Available Background - Alpha-1-antitrypsin deficiency is a genetic disorder which is transmitted in a co-dominant, autosomal form. Alpha-1-antitrypsin deficiency affects mainly the lungs and the liver leading, in the latter case, to neonatal cholestasis, chronic hepatitis or cirrhosis. A precise diagnosis of Alpha-1-antitrypsin deficiency may be obtained by biochemical or molecular analysis. Objective - The purpose of this study was to use DNA analysis to examine the presence of an alpha-1-antitrypsin deficiency in 12 children suspected of having this deficiency and who showed laboratory and clinical characteristics of the disease. Patients and Methods - Twelve patients, aged 3 months to 19 years, who had serum alpha-1-antitrypsin levels lower than normal and/or had hepatic disease of undefined etiology were studied. The mutant alleles S and Z of the alpha-1-antitrypsin gene were investigated in the 12 children. Alpha-1-antitrypsin gene organization was analyzed by amplification of genoma through the polymerase chain reaction and digestion with the restriction enzymes Xmnl (S allele and Taq 1 (Z allele. Results - Seven of the 12 patients had chronic liver disease of undefined etiology and the other five patients had low serum levels of alpha-1-antitrypsin as well as a diagnosis of neonatal cholestasis and/or chronic liver disease of undefined etiology. Five of the 12 patients were homozygous for the Z allele (ZZ and two had the S allele with another allele (*S different from Z. Conclusion - These results show that alpha-1-antitrypsin deficiency is relatively frequent in children with chronic hepatic disease of undefined etiology and/or low alpha-1-antitrypsin levels (41.6%. A correct diagnosis is important for effective clinical follow-up and for genetic counseling.

  3. Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients.

    Science.gov (United States)

    Hogan, William J; Maris, Michael; Storer, Barry; Sandmaier, Brenda M; Maloney, David G; Schoch, H Gary; Woolfrey, Ann E; Shulman, Howard M; Storb, Rainer; McDonald, George B

    2004-01-01

    Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 microM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P =.04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P =.07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 microM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 microM (4-6.9 mg/dL; 20%), 119.7 to 169.29 microM (7.0-9.9 mg/dL; 17%), and 171.0 microM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival. PMID:12969980

  4. Aktivitas Antifibrotik Ekstrak Buah Delima Terstandar 40% Ellagic Acid pada Tikus Putih (Rattus norvegicus sebagai Hewan Model (ANTIFIBROTIC ACTIVITY OF POMEGRANATE FRUIT EXTRACT STANDARDIZED 40% ELLAGIC ACID ON RATS (RATTUS NORVEGICUS AS ANIMAL MODEL

    Directory of Open Access Journals (Sweden)

    Wiwik Misaco Yuniarti

    2014-08-01

    Full Text Available The number of patients with chronic liver disease (fibrosis or cirrhosis of the liver is increasing fromtime to time. However, until now there is no therapy that really effective to overcome that disease. Therapyfor liver fibrosis typically use substance that have antioxidant activity, anti-inflammatory or anti fibrotic.Various efforts always done to find alternative therapies for liver fibrosis. One of them is the use ofpotential plants that suspected having such activity. Various parts of pomegranate have been shown tohave various activities that beneficial for health. This study was conducted to determine the effect ofpomegranate fruit extract standardized 40% ellagic acid on the improvement degree of liver fibrosis causedby cholestasis by measuring of serum alkaline phosphatase levels (ALP and gamma-glutamyl transferase(GGT, as a specific indicator of liver damage becaused of cholestasis. The research was conducted by using32 male rats, wistar strain, 2.5 month old, weighing between 150-200 grams. Animal models of liver fibrosis obtained by using BDL technique. Subjects were divided into a control group (P0 = without BDLand giving of pomegranate extract and treatment groups (P1 = BDL with administration of CMC, P2 =BDL with ellagic acid 90% and P3 = BDL with pomegranate fruit extract standardized 40% ellagic acid.CMC, extract (150 mg / kg BW / PO and ellagic acid (60 mg / kg BW / PO administered for 21 consecutivedays in the same volume. At the end of 21 days periods, biochemical evaluation was performed to measureserum levels of GGT and ALP. The result indicated that administration of pomegranate fruit extract ( P3significantly reduced GGT ( 10.5±9.2 mg/dl and ALP level ( 509.0±4.2 mg/dl close to normal level of GGTand ALP ( P0, GGT : 2.8 ± 1.4; ALP : 449.0±62.3 (p<0.05. The level of GGT and ALP in P3 group were lowercompared to the group ellagic acid (P2, GGT=48.5±4.8 and ALP = 691.0± 29.7 and group which only begiven CMC (P1, GGT

  5. Perturbation of bile acid homeostasis is an early pathogenesis event of drug induced liver injury in rats

    Energy Technology Data Exchange (ETDEWEB)

    Yamazaki, Makoto; Miyake, Manami; Sato, Hiroko; Masutomi, Naoya; Tsutsui, Naohisa [Mitsubishi Tanabe Pharma Corporation, Kisarazu, Chiba 292-0818 (Japan); Adam, Klaus-Peter; Alexander, Danny C.; Lawton, Kay A.; Milburn, Michael V.; Ryals, John A.; Wulff, Jacob E. [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States); Guo, Lining, E-mail: lguo@metabolon.com [Metabolon Inc., 617 Davis Drive, Suite 400, Durham, NC 27713 (United States)

    2013-04-01

    Drug-induced liver injury (DILI) is a significant consideration for drug development. Current preclinical DILI assessment relying on histopathology and clinical chemistry has limitations in sensitivity and discordance with human. To gain insights on DILI pathogenesis and identify potential biomarkers for improved DILI detection, we performed untargeted metabolomic analyses on rats treated with thirteen known hepatotoxins causing various types of DILI: necrosis (acetaminophen, bendazac, cyclosporine A, carbon tetrachloride, ethionine), cholestasis (methapyrilene and naphthylisothiocyanate), steatosis (tetracycline and ticlopidine), and idiosyncratic (carbamazepine, chlorzoxasone, flutamide, and nimesulide) at two doses and two time points. Statistical analysis and pathway mapping of the nearly 1900 metabolites profiled in the plasma, urine, and liver revealed diverse time and dose dependent metabolic cascades leading to DILI by the hepatotoxins. The most consistent change induced by the hepatotoxins, detectable even at the early time point/low dose, was the significant elevations of a panel of bile acids in the plasma and urine, suggesting that DILI impaired hepatic bile acid uptake from the circulation. Furthermore, bile acid amidation in the hepatocytes was altered depending on the severity of the hepatotoxin-induced oxidative stress. The alteration of the bile acids was most evident by the necrosis and cholestasis hepatotoxins, with more subtle effects by the steatosis and idiosyncratic hepatotoxins. Taking together, our data suggest that the perturbation of bile acid homeostasis is an early event of DILI. Upon further validation, selected bile acids in the circulation could be potentially used as sensitive and early DILI preclinical biomarkers. - Highlights: ► We used metabolomics to gain insights on drug induced liver injury (DILI) in rats. ► We profiled rats treated with thirteen hepatotoxins at two doses and two time points. ► The toxins decreased the

  6. Pregnane X receptor mediated-transcription regulation of CYP3A by glycyrrhizin: a possible mechanism for its hepatoprotective property against lithocholic acid-induced injury.

    Science.gov (United States)

    Wang, Yu-Guang; Zhou, Jian-Ming; Ma, Zeng-Chun; Li, Hua; Liang, Qian-De; Tan, Hong-Ling; Xiao, Cheng-Rong; Zhang, Bo-Li; Gao, Yue

    2012-10-25

    Licorice (LE) has been commonly used in traditional Chinese medicine (TCM) for over 4000 years to reconcile various drugs and for hepatic disorders. Glycyrrhizin is the main bioactive component isolated from LE herbs. In the present study we examined the effects of glycyrrhizin on pregnane X receptor (PXR)-mediated CYP3A expression and its hepatoprotective activity. Treatment of HepG2 cells with glycyrrhizin resulted in marked increase in both CYP3A4 mRNA and protein levels. The transcriptional activation of the CYP3A4 gene through glycyrrhizin is PXR-dependent, as shown in transient transfection experiments. Glycyrrhizin activates the DNA-binding capacity of the PXR for the CYP3A4 element responding to xenobiotic signals, as measured by the electrophoretic-mobility shift assay (EMSA). These results indicate that the induction of the hepatic CYP3A4 by glycyrrhizin is mediated through the activation of PXR. The next aim of the current study was to determine whether the activation of PXR and induction of CYP3A by glycyrrhizin prevents hepatotoxicity during cholestasis as a mechanism of hepatoprotection. Mice were pretreated with glycyrrhizin prior to induction of intrahepatic cholestasis using lithocholic acid (LCA). Pre-treatment with glycyrrhizin, as well as the PXR activator pregnenolone 16α-carbontrile (PCN), prevents the increase in plasma ALT and AST activity, multifocal necrosis and prevents an increase in a level of serum LCA level in mice, as compared with the results in the mice treated with LCA alone. Activation of the PXR by glycyrrhizin results in induction of CYP3A11 (CYP3A4 for human) expression and inhibition of CYP7A1 through an increase in small heterodimer partner (SHP) expression. Glycyrrhizin regulates the expression of the gene mentioned above to prevent toxic accumulation of bile acids in the liver and it also protects mouse livers from the harmful effects of LCA. In conclusion, PXR-mediated effects on CYP3A and CYP7A may contribute to the

  7. Protective effect of low dose of melatonin against cholestatic oxidative stress after common bile duct ligation in rats

    Institute of Scientific and Technical Information of China (English)

    Mukaddes Esrefoglu; Mehmet Gül; Memet Hanifi Emre; Alaattin Polat; Mukadder Ayse Selimoglu

    2005-01-01

    AIM: To investigate the role of oxidative injury and the effect of exogenous melatonin administration on liver damage induced by bile duct ligation (BDL), and second,to evaluate the role of nitric oxide (NO), a free oxygen radical, in oxidative injury.METHODS: Thirty-two Sprague-Dawley rats were assigned to four groups: sham operation (SO), BDL, BDL+melatonin,and BDL+vehicle. Cholestasis was achieved by double ligature of the common bile duct. Melatonin was injected intraperitoneally 500 μg/(kg.d) for 8 d. Hepatic oxidative stress markers were evaluated by changes in the amount of lipid peroxides, measured as malondialdehyde (MDA),and reduced GSH. Total nitrite (NOx) concentrations were determined in hepatic homogenates. Histopathological examination was performed using a histological scoring system.RESULTS: The histopathological changes including portal inflammation, necrosis, apoptosis, focal inflammation and fibrosis were severe in the BDL and BDL+vehicle groups. There were numerous large areas of coagulation necrosis. Histological Activity Index scores of these groups were significantly higher than that of the SO group. Treatment with melatonin reduced these alterations significantly. The degree of necro-infiammation and fibrosis showed significant difference between the BDL and BDL+melatonin groups. BDL was accompanied by a significant increase in MDA and NOx, and a significant decrease in GSH levels. Mean±SE values of MDA, GSH and NOx levels of SO group were 147.47±6.69, 0.88±0.33 μmol/g and 180.70±6.58 nm/g, respectively. The values of BDL group were 200.14±21.30, 0.65±0.02 μmol/g, and 400.46±48.89 nm/g, respectively, whereas the values of BDL+melatonin group were 115.93±6.8, 0.74±0.02 μmol/g,and 290.38±32.32 nm/g, respectively. Melatonin treatment was associated with a significant recovery of MDA, GSH and NOx levels.CONCLUSION: We have concluded that oxidative stress is associated with the pathogenesis of cholestatic liver damage and NO

  8. Detection of hepatitis in children with idiopathic cholestatic bile salt export pump gene mutations%特发性胆汁淤积性肝炎患儿胆盐输出泵基因突变的检测

    Institute of Scientific and Technical Information of China (English)

    高国鹏; 王琳琳; 唐清; 单庆文; 云翔; 董淳强

    2012-01-01

    目的 对特发性胆汁淤积性肝炎患儿的胆盐输出泵(BSEP)基因进行突变筛查.方法 特发性胆汁淤积性肝炎患儿90例,采用聚合酶链反应—单链构象多态性(PCR-SSCP)检查结合DNA测序技术,检测BSEP基因的第7、8、11、12、14、15、18、21、26号外显子的突变情况.针对发现的突变位点,在71例健康婴儿中进行筛查以排除基因多态性.结果 在2例患儿BSEP基因的第7外显子上检测到相同的杂合突变c.499G >T,导致基因编码的BSEP蛋白的第167位丙氨酸(Ala)被丝氨酸(Ser)所替代(p.A167S).该位点的突变未在71例健康婴儿中发现,排除了BSEP基因的多态性.结论 在特发性胆汁淤积性肝炎患儿中,发现一种新的BSEP基因突变,位点为c.499G> T.%Objective To evaluate bile salt export pump gene ( BSEP) mutation in children with cholestasis in idio-pathic infantile hepatitis. Methods 90 cases of cholestasis in idiopathic infantile hepatitis (case group) were studied by polymerase chain reaction-single strand conformation polymorphism ( PCR - SSCP) and DNA sequencing technology to detect BSEP gene mutation in exon7, 8, 11, 12, 14, 15, 18, 21, 26 in idiopathic infantile hepatitis. 71 cases of healthy babies without infantile hepatitis (control group) by DNA sequencing technology to exclude gene polymorphism. Results Exon 7 of BSEP gene in two cases was found the same heterozygous mutation c. 499G > T, and BSEP protein lead to the gene encoding the 167 alanine (Ala) , serine ( Ser) replaced (p. A167S). The sites of mutation is not found in 71 cases of healthy infants, excluding the BSEP gene polymorphism. Conclusion A new BSEP gene mutation is found in children with idiopathic infantile cholestatic hepatitis, sites for the c.499G > T.

  9. Organic anion transporting polypeptide 1a1 null mice are sensitive to cholestatic liver injury.

    Science.gov (United States)

    Zhang, Youcai; Csanaky, Iván L; Cheng, Xingguo; Lehman-McKeeman, Lois D; Klaassen, Curtis D

    2012-06-01

    Organic anion transporting polypeptide 1a1 (Oatp1a1) is predominantly expressed in livers of mice and is thought to transport bile acids (BAs) from blood into liver. Because Oatp1a1 expression is markedly decreased in mice after bile duct ligation (BDL). We hypothesized that Oatp1a1-null mice would be protected against liver injury during BDL-induced cholestasis due largely to reduced hepatic uptake of BAs. To evaluate this hypothesis, BDL surgeries were performed in both male wild-type (WT) and Oatp1a1-null mice. At 24 h after BDL, Oatp1a1-null mice showed higher serum alanine aminotransferase levels and more severe liver injury than WT mice, and all Oatp1a1-null mice died within 4 days after BDL, whereas all WT mice survived. At 24 h after BDL, surprisingly Oatp1a1-null mice had higher total BA concentrations in livers than WT mice, suggesting that loss of Oatp1a1 did not prevent BA accumulation in the liver. In addition, secondary BAs dramatically increased in serum of Oatp1a1-null BDL mice but not in WT BDL mice. Oatp1a1-null BDL mice had similar basolateral BA uptake (Na(+)-taurocholate cotransporting polypeptide and Oatp1b2) and BA-efflux (multidrug resistance-associated protein [Mrp]-3, Mrp4, and organic solute transporter α/β) transporters, as well as BA-synthetic enzyme (Cyp7a1) in livers as WT BDL mice. Hepatic expression of small heterodimer partner Cyp3a11, Cyp4a14, and Nqo1, which are target genes of farnesoid X receptor, pregnane X receptor, peroxisome proliferator-activated receptor alpha, and NF-E2-related factor 2, respectively, were increased in WT BDL mice but not in Oatp1a1-null BDL mice. These results demonstrate that loss of Oatp1a1 function exacerbates cholestatic liver injury in mice and suggest that Oatp1a1 plays a unique role in liver adaptive responses to obstructive cholestasis. PMID:22461449

  10. Percutaneous transpapillary extraction of biliary calculus for symptomatic choledocholithiasis after unsuccessfully endoscopic treatment; Perkutane transpapillaere Gallensteinextraktion bei symptomatischer Choledocholithiasis nach frustranem endoskopischen Behandlungsversuch

    Energy Technology Data Exchange (ETDEWEB)

    Zorger, N.; Manke, C.; Lenhart, M.; Voelk, M.; Link, J.; Feuerbach, S. [Klinikum der Univ. Regensburg (Germany). Inst. fuer Roentgendiagnostik

    2001-02-01

    Purpose: Evaluation of a percutaneous transhepatic treatment of symptomatic choledocholithiasis in bile ducts that cannot be reached with the endoscope. Methods: From January 1996 to August 2000 a transhepatic extraction of biliary calculus was performed in four patients. Endoscopic retrograde cholangiography (ERC) was not successful in any of the cases. Clinical symptoms were icterus in four cases, additional cholangitis or colics in two cases. First, a ballon dilation of the papilla was performed by a percutaneous transhepatic approach. For removal of bile duct stones, occlusion catheters and Dormia baskets were used. Technical success was defined as complete removal of bile duct stones. Clinical success was defined as normalization of cholestasis and inflammation parameters. In the follow-up an ultrasound examination was performed and blood samples were taken for control of cholestasis parameters. Results: In all four cases treatment was technically and clinically successful. For complete removal of biliary calculus a second intervention was necessary in two cases. In each case an internal to external drainage was left over a mean of 7 days (3 - 13 days). In the mean follow-up of 30.5 months (6 - 50 months) all patients had persistent relief of symptoms. No further interventions were necessary. No complications were present. Conclusion: Percutaneous transpapillary extraction of biliary calculus is an effective alternative to surgery in patients with bile ducts, that cannot be reached with the endoscope. (orig.) [German] Ziel: Untersuchung der perkutanen transhepatischen Therapie der symptomatischen Choledocholithiasis bei endoskopisch nicht sondierbarem Gallengangssystem. Methoden: Von Januar 1996 bis August 2000 wurde bei 4 Patienten eine transhepatische Gallengangsstein-Entfernung durchgefuehrt. Die Endoskopisch Retrograde Cholangiographie (ERC) war in allen Faellen aufgrund einer vorangegangenen Magenresektion (B II) technisch nicht erfolgreich gewesen. In 4

  11. Interleukin-13 Activates Distinct Cellular Pathways Leading to Ductular Reaction, Steatosis, and Fibrosis.

    Science.gov (United States)

    Gieseck, Richard L; Ramalingam, Thirumalai R; Hart, Kevin M; Vannella, Kevin M; Cantu, David A; Lu, Wei-Yu; Ferreira-González, Sofía; Forbes, Stuart J; Vallier, Ludovic; Wynn, Thomas A

    2016-07-19

    Fibroproliferative diseases are driven by dysregulated tissue repair responses and are a major cause of morbidity and mortality because they affect nearly every organ system. Type 2 cytokine responses are critically involved in tissue repair; however, the mechanisms that regulate beneficial regeneration versus pathological fibrosis are not well understood. Here, we have shown that the type 2 effector cytokine interleukin-13 simultaneously, yet independently, directed hepatic fibrosis and the compensatory proliferation of hepatocytes and biliary cells in progressive models of liver disease induced by interleukin-13 overexpression or after infection with Schistosoma mansoni. Using transgenic mice with interleukin-13 signaling genetically disrupted in hepatocytes, cholangiocytes, or resident tissue fibroblasts, we have revealed direct and distinct roles for interleukin-13 in fibrosis, steatosis, cholestasis, and ductular reaction. Together, these studies show that these mechanisms are simultaneously controlled but distinctly regulated by interleukin-13 signaling. Thus, it may be possible to promote interleukin-13-dependent hepatobiliary expansion without generating pathological fibrosis. VIDEO ABSTRACT. PMID:27421703

  12. Clinical diagnostics of hepatopathies in small mammals: evaluation of importance of individual methods

    International Nuclear Information System (INIS)

    The aim of this review article was to summarise different methods of intravital diagnostics of hepathopathies in small mammals and to evaluate their practical use. Anamnestic data evaluation, palpation of the liver, and collection of fluid from the abdominal cavity for the purpose of laboratory examination play an irreplaceable role in the diagnostics of liver diseases. Biochemical blood indices analyses include concentrations of enzymes indicating hepatocellular damage (ALT, AST, LDH), cholestasis or enzymatic activity alteration (ALP, GGT), values monitoring the liver synthesis (albumin, glucose, urea, coagulation factors, bilirubin, bile acids, ammonium). Cytological and histological examination of biopsy samples enables to evaluate the liver state precisely. The biopsy includes: fine needle aspiration biopsy, percutaneous biopsy, biopsy under the guidance of ultrasonography, biopsy under endoscopic or otoscopic guidance, and biopsy during exploratory laparotomy. In very small mammals (hamsters, mice, and others), these methods are not indicated. Nevertheless, we can use a modification of the percutaneous biopsy using a key-hole technique and biopsy during laparotomy

  13. Effects of bile acids and the bile acid receptor FXR agonist on the respiratory rhythm in the in vitro brainstem medulla slice of neonatal Sprague-Dawley rats.

    Directory of Open Access Journals (Sweden)

    Cong Zhao

    Full Text Available Intrahepatic cholestasis of pregnancy is always accompanied by adverse fetal outcomes such as malfunctions of respiration. Farnesoid X receptor (FXR plays a critical role in the homeostasis of bile acids. Thus, we are determined to explore the effects of farnesoid X receptor (FXR and five bile acids on respiratory rhythm generation and modulation of neonatal rats. Spontaneous periodic respiratory-related rhythmical discharge activity (RRDA was recorded from hypoglossal nerves during the perfusion of modified Krebs solution. Group 1-6 was each given GW4064 and five bile acids of chenodeoxycholic acid (CDCA, deoxycholic acid (DCA, lithocholic acid (LCA, cholic acid (CA as well as ursodeoxycholic acid (UDCA at different concentrations to identify their specific functions on respiratory rhythm modulations. Group 7 was applied to receive FXR blocker Z-guggulsterone and Z-guggulsterone with the above bile acids separately to explore the role of FXR in the respiratory rhythm modulation. Group 8 was given dimethyl sulfoxide (DMSO as controls. Apart from UDCA, CDCA, DCA LCA and CA all exerted effects on RRDA recorded from hypoglossal nerves in a concentration-dependent manner. Respiratory cycle (RC, Inspiratory time (TI, Expiratory Time (TE and Integral Amplitude (IA were influenced and such effects could be reversed by Z-guggulsterone. FXR may contribute to the effects on the modulation of respiratory rhythm exerted by bile acids.

  14. Complications and Monitoring – Guidelines on Parenteral Nutrition, Chapter 11

    Directory of Open Access Journals (Sweden)

    Working group for developing the guidelines for parenteral nutrition of The German Association for Nutritional Medicine

    2009-11-01

    Full Text Available Compared to enteral or hypocaloric oral nutrition, the use of PN (parenteral nutrition is not associated with increased mortality, overall frequency of complications, or longer length of hospital stay (LOS. The risk of PN complications (e.g. refeeding-syndrome, hyperglycaemia, bone demineralisation, catheter infections can be minimised by carefully monitoring patients and the use of nutrition support teams particularly during long-term PN. Occuring complications are e.g. the refeeding-syndrome in patients suffering from severe malnutrition with the initiation of refeeding or metabolic, hypertriglyceridemia, hyperglycaemia, osteomalacia and osteoporosis, and hepatic complications including fatty liver, non-alcoholic fatty liver disease, cholestasis, cholecystitis, and cholelithiasis. Efficient monitoring in all types of PN can result in reduced PN-associated complications and reduced costs. Water and electrolyte balance, blood sugar, and cardiovascular function should regularly be monitored during PN. Regular checks of serum electrolytes and triglycerides as well as additional monitoring measures are necessary in patients with altered renal function, electrolyte-free substrate intake, lipid infusions, and in intensive care patients. The metabolic monitoring of patients under long-term PN should be carried out according to standardised procedures. Monitoring metabolic determinants of bone metabolism is particularly important in patients receiving long-term PN. Markers of intermediary, electrolyte and trace element metabolism require regular checks.

  15. Pharmacovigilance and Moroccan Tuberculosis Public Program: Current Situation

    Directory of Open Access Journals (Sweden)

    Driss Soussi Tanani

    2014-01-01

    Full Text Available The objective of this work is to demonstrate the interest of integration of pharmacovigilance in Moroccan Tuberculosis Control Program (MTCP. Design and Data Collection. The integration of pharmacovigilance in MTCP was conducted in October 2012 with the Global Fund support. We compared the reports notified before and after this integration (period 1: January 2010–October 2012; period 2: October 2012–December 2013. The detection of signals was based on the Information Component available in VigiMine. We used the SPSS version 10.0 and MedCalc version 7.3 for data analysis. Results. The average number of spontaneous reports increased from 3.6 to 37.4 cases/month (P<10-3. The average age was 40.7±17.5 years; the sex ratio was 0.8. Hepatic reactions (32.7% predominated during the first period, while skin reactions (24.1% were in the second period (P=10-4, and 40.9% of cases in the first period were serious against 15.8% in second period (P=0.003. Nine signals were generated (hepatic enzyme increase, cholestasis, jaundice, arthralgia, acne, lower limb edema, pruritus, skin rashes, and vomiting. Conclusion. The integration of pharmacovigilance in Moroccan Tuberculosis Control Program improved the management of ADRs and detected new signals of antituberculosis drugs.

  16. Assessment of hepatotoxic liabilities by transcript profiling

    International Nuclear Information System (INIS)

    Male Wistar rats were treated with various model compounds or the appropriate vehicle controls in order to create a reference database for toxicogenomics assessment of novel compounds. Hepatotoxic compounds in the database were either known hepatotoxicants or showed hepatotoxicity during preclinical testing. Histopathology and clinical chemistry data were used to anchor the transcript profiles to an established endpoint (steatosis, cholestasis, direct acting, peroxisomal proliferation or nontoxic/control). These reference data were analyzed using a supervised learning method (support vector machines, SVM) to generate classification rules. This predictive model was subsequently used to assess compounds with regard to a potential hepatotoxic liability. A steatotic and a non-hepatotoxic 5HT6 receptor antagonist compound from the same series were successfully discriminated by this toxicogenomics model. Additionally, an example is shown where a hepatotoxic liability was correctly recognized in the absence of pathological findings. In vitro experiments and a dog study confirmed the correctness of the toxicogenomics alert. Another interesting observation was that transcript profiles indicate toxicologically relevant changes at an earlier timepoint than routinely used methods. Together, these results support the useful application of toxicogenomics in raising alerts for adverse effects and generating mechanistic hypotheses that can be followed up by confirmatory experiments

  17. Metformin-induced mixed hepatocellular and cholestatic hepatic injury: case report and literature review

    Directory of Open Access Journals (Sweden)

    Saadi T

    2013-08-01

    Full Text Available Tarek Saadi,1–3 Matti Waterman,1–4 Heba Yassin,3 Yaacov Baruch1,41Liver Unit, 2Department of Gastroenterology, 3Department of Internal Medicine A, Rambam Health Care Campus, Haifa, Israel; 4The Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelIntroduction: Metformin is a first-line drug choice for the treatment of type 2 diabetes mellitus (DM-2. Metformin-induced hepatotoxicity has rarely been reported. We report on a case of metformin-induced mixed hepatocellular and cholestatic liver injury in an elderly patient with DM-2 as well as review and summarize case reports of metformin hepatotoxicity available in English on the PubMed database.Case: After receiving metformin 850 mg/day for 2 weeks, a 78-year-old male presented with a 10-day history of abdominal pain, vomiting, diarrhea, and jaundice. Laboratory analysis showed severe hepatocellular and cholestatic hepatic injury. Other causes for acute liver injury were ruled out. Discontinuation of metformin treatment led to significant subjective improvement after 1 week, and all hepatic abnormalities resolved by 2 months.Conclusion: Metformin is an important drug for the treatment of DM-2, which is also used for treatment of patients with fatty liver. It can, however, induce hepatocellular and cholestatic hepatic injury; both physicians and patients should be aware of this potential side effect.Keywords: metformin, hepatocellular liver injury, cholestasis, hepatotoxicity

  18. Microarray Study of Pathway Analysis Expression Profile Associated with MicroRNA-29a with Regard to Murine Cholestatic Liver Injuries

    Directory of Open Access Journals (Sweden)

    Sung-Chou Li

    2016-03-01

    Full Text Available Accumulating evidence demonstrates that microRNA-29 (miR-29 expression is prominently decreased in patients with hepatic fibrosis, which consequently stimulates hepatic stellate cells’ (HSCs activation. We used a cDNA microarray study to gain a more comprehensive understanding of genome-wide gene expressions by adjusting miR-29a expression in a bile duct-ligation (BDL animal model. Methods: Using miR-29a transgenic mice and wild-type littermates and applying the BDL mouse model, we characterized the function of miR-29a with regard to cholestatic liver fibrosis. Pathway enrichment analysis and/or specific validation were performed for differentially expressed genes found within the comparisons. Results: Analysis of the microarray data identified a number of differentially expressed genes due to the miR-29a transgene, BDL, or both. Additional pathway enrichment analysis revealed that TGF-β signaling had a significantly differential activated pathway depending on the occurrence of miR-29a overexpression or the lack thereof. Furthermore, overexpression was found to elicit changes in Wnt/β-catenin after BDL. Conclusion: This study verified that an elevated miR-29a level could alleviate liver fibrosis caused by cholestasis. Furthermore, the protective effects of miR-29a correlate with the downregulation of TGF-β and associated with Wnt/β-catenin signal pathway following BDL.

  19. Modification on ursodeoxycholic acid (UDCA) scaffold. discovery of bile acid derivatives as selective agonists of cell-surface G-protein coupled bile acid receptor 1 (GP-BAR1).

    Science.gov (United States)

    Sepe, Valentina; Renga, Barbara; Festa, Carmen; D'Amore, Claudio; Masullo, Dario; Cipriani, Sabrina; Di Leva, Francesco Saverio; Monti, Maria Chiara; Novellino, Ettore; Limongelli, Vittorio; Zampella, Angela; Fiorucci, Stefano

    2014-09-25

    Bile acids are signaling molecules interacting with the nuclear receptor FXR and the G-protein coupled receptor 1 (GP-BAR1/TGR5). GP-BAR1 is a promising pharmacological target for the treatment of steatohepatitis, type 2 diabetes, and obesity. Endogenous bile acids and currently available semisynthetic bile acids are poorly selective toward GP-BAR1 and FXR. Thus, in the present study we have investigated around the structure of UDCA, a clinically used bile acid devoid of FXR agonist activity, to develop a large family of side chain modified 3α,7β-dihydroxyl cholanoids that selectively activate GP-BAR1. In vivo and in vitro pharmacological evaluation demonstrated that administration of compound 16 selectively increases the expression of pro-glucagon 1, a GP-BAR1 target, in the small intestine, while it had no effect on FXR target genes in the liver. Further, compound 16 results in a significant reshaping of bile acid pool in a rodent model of cholestasis. These data demonstrate that UDCA is a useful scaffold to generate novel and selective steroidal ligands for GP-BAR1. PMID:25162837

  20. Newly Identified Mechanisms of Total Parenteral Nutrition Related Liver Injury

    Directory of Open Access Journals (Sweden)

    Ajay Kumar Jain

    2014-01-01

    Full Text Available Total parenteral nutrition (TPN, a lifesaving therapy, involves providing nutrition by bypassing the gut. Unfortunately it is associated with significant complications including gut atrophy and parenteral nutrition associated liver disease (PNALD. PNALD includes steatosis, cholestasis, disrupted glucose metabolism, disrupted lipid metabolism, cirrhosis, and liver failure. The etiopathogenesis remains poorly defined; however, an altered enterohepatic circulation, disrupting nuclear receptor signaling, is emerging as a promising mechanism. Rodent models and our piglet TPN model have shown that, during regular feeding, bile acids activate farnesoid X receptor (FXR in the gut and enhance fibroblast growth factor 19 (FGF19 level. FGF19 regulates bile acid, lipid, and glucose metabolism. We noted reduced FGF19 with TPN use and substantial improvement in FGF19, bilirubin, and metabolic profiles with the FXR agonist chenodeoxycholic acid (CDCA. Additionally, CDCA caused gut growth and enhanced expression of glucagon like peptides (GLPs. GLPs regulate gut trophic effects, insulin, glucose homeostasis, and hepatic steatosis. GLP secretion is regulated by the CDCA activated receptor TGR5. This leads to an important conclusion that, in addition to a disrupted FXR-FGF19 axis, a disrupted TGR5-GLP axis may contribute to TPN related pathologies. Thus modulators of FXR-FGF19 and the TGR5-GLP axis could help bring forward novel treatment strategies.

  1. The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.

    Science.gov (United States)

    Verbeke, Len; Farre, Ricard; Verbinnen, Bert; Covens, Kris; Vanuytsel, Tim; Verhaegen, Jan; Komuta, Mina; Roskams, Tania; Chatterjee, Sagnik; Annaert, Pieter; Vander Elst, Ingrid; Windmolders, Petra; Trebicka, Jonel; Nevens, Frederik; Laleman, Wim

    2015-02-01

    Bacterial translocation (BTL) drives pathogenesis and complications of cirrhosis. Farnesoid X-activated receptor (FXR) is a key transcription regulator in hepatic and intestinal bile metabolism. We studied potential intestinal FXR dysfunction in a rat model of cholestatic liver injury and evaluated effects of obeticholic acid (INT-747), an FXR agonist, on gut permeability, inflammation, and BTL. Rats were gavaged with INT-747 or vehicle during 10 days after bile-duct ligation and then were assessed for changes in gut permeability, BTL, and tight-junction protein expression, immune cell recruitment, and cytokine expression in ileum, mesenteric lymph nodes, and spleen. Auxiliary in vitro BTL-mimicking experiments were performed with Transwell supports. Vehicle-treated bile duct-ligated rats exhibited decreased FXR pathway expression in both jejunum and ileum, in association with increased gut permeability through increased claudin-2 expression and related to local and systemic recruitment of natural killer cells resulting in increased interferon-γ expression and BTL. After INT-747 treatment, natural killer cells and interferon-γ expression markedly decreased, in association with normalized permeability selectively in ileum (up-regulated claudin-1 and occludin) and a significant reduction in BTL. In vitro, interferon-γ induced increased Escherichia coli translocation, which remained unaffected by INT-747. In experimental cholestasis, FXR agonism improved ileal barrier function by attenuating intestinal inflammation, leading to reduced BTL and thus demonstrating a crucial protective role for FXR in the gut-liver axis. PMID:25592258

  2. Activation of farnesoid X receptor attenuates hepatic injury in a murine model of alcoholic liver disease.

    Science.gov (United States)

    Wu, Weibin; Zhu, Bo; Peng, Xiaomin; Zhou, Meiling; Jia, Dongwei; Gu, Jianxin

    2014-01-01

    Alcoholic liver disease (ALD) is a common cause of advanced liver disease, and considered as a major risk factor of morbidity and mortality worldwide. Hepatic cholestasis is a pathophysiological feature observed in all stages of ALD. The farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily, and plays an essential role in the regulation of bile acid, lipid and glucose homeostasis. However, the role of FXR in the pathogenesis and progression of ALD remains largely unknown. Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet. We used a specific agonist of FXR WAY-362450 to study the effect of pharmacological activation of FXR in alcoholic liver disease. In this study, we demonstrated that FXR activity was impaired by chronic ethanol ingestion in a murine model of ALD. Activation of FXR by specific agonist WAY-362450 protected mice from the development of ALD. We also found that WAY-362450 treatment rescued FXR activity, suppressed ethanol-induced Cyp2e1 up-regulation and attenuated oxidative stress in liver. Our results highlight a key role of FXR in the modulation of ALD development, and propose specific FXR agonists for the treatment of ALD patients. PMID:24269813

  3. A fatal case of bupropion (Zyban hepatotoxicity with autoimmune features: Case report

    Directory of Open Access Journals (Sweden)

    Humayun Fawwaz

    2007-09-01

    Full Text Available Abstract Background Bupropion is approved for the treatment of mood disorders and as an adjuvant medication for smoking cessation. Bupropion is generally well tolerated and considered safe. Two randomized controlled trials of bupropion therapy for smoking cessation did not report any hepatic adverse events. However, there are three reports of severe but non-fatal bupropion hepatotoxicity published in the literature. Case Presentation We present the case of a 55-year old man who presented with jaundice and severe hepatic injury approximately 6 months after starting bupropion for smoking cessation. Laboratory evaluation demonstrated a mixed picture of hepatocellular injury and cholestasis. Liver biopsy demonstrated findings consistent with severe hepatotoxic injury due to drug induced liver injury. Laboratory testing was also notable for positive autoimmune markers. The patient initially had clinical improvement with steroid therapy but eventually died of infectious complications. Conclusion This report represents the first fatal report of bupropion related hepatotoxicity and the second case of bupropion related liver injury demonstrating autoimmune features. The common use of this medication for multiple indications makes it important for physicians to consider this medication as an etiologic agent in patients with otherwise unexplained hepatocellular jaundice.

  4. Distribution of electrophoretically separated serum high density lipoprotein subfraction levels among healthy students and its alteration in patients with liver diseases.

    Directory of Open Access Journals (Sweden)

    Ikeda,Satoru

    1986-06-01

    Full Text Available In an attempt to evaluate high density lipoprotein (HDL subfraction levels in liver diseases, HDL was separated by a precipitation method with dextran sulfate-Mg2+ from sera of 289 healthy adults and 50 patients with liver diseases. The HDL was subdivided into HDL2e and HDL3e by Utermann's polyacrylamide gel electrophoresis with lauric acid. Ultracentrifugally separated HDL2 and HDL3 roughly corresponded to HDL2e and HDL3e, respectively. Male and female groups had different distributions of HDL2e/HDL3e ratios. Among healthy males, 121 cases had ratios less than 1.0 (mean +/- SD = 0.72 +/- 0.39, n = 150, while among healthy females, the ratios were generally larger than those of males and varied widely from 0.2 to 6.6 (mean +/- SD = 1.77 +/- 1.05, n = 139. Low levels of HDL-cholesterol were found in patients with liver diseases, except those with mild alcoholic liver injury and intrahepatic cholestasis. Apparent decreases in HDL3e, but not in HDL2e, were found in all cases with liver diseases investigated, even in those who did not show decreases in the total HDL level, when male and female patients were analyzed separately. The analysis of HDL subfractions by the present method is simple and useful for the study on altered lipid metabolism in liver diseases.

  5. Application of Cell-Based Assay Systems for the Early Screening of Human Drug Hepatotoxicity in the Discovery Phase of Drug Development

    Directory of Open Access Journals (Sweden)

    Jalal Pourahmad

    2005-01-01

    Full Text Available While drug toxicity (especially hepatotoxicity is the most frequent reason cited for withdrawal of an approved drug, no simple solution exists to adequately predict such adverse events. Simple cytotoxicity assays in HepG2 cells are relatively insensitive to human hepatotoxic drugs in a retrospective analysis of marketed pharmaceuticals. In comparison, a panel of pre-lethal mechanistic cellular assays hold the promise to deliver a more sensitiveapproach to detect endpoint-specific drug toxicities. The panel of assays covered by this review includes steatosis, cholestasis, phospholipidosis, reactive intermediates, mitochondria membrane function, oxidative stress, and drug interactions. In addition, the use of metabolically competent cells or the introduction of major human hepatocytes in these in-vitro studies allow a more complete picture of potential drug side effect. Since inter-individual therapeutic index (TI may differ from patient to patient, the rational use of one or more of these cellular assay and targeted in-vivo exposure data may allow pharmaceutical scientists to select drugcandidates with a higher TI potential in the drug discovery phase.

  6. Citrin deficiency: A treatable cause of acute psychosis in adults

    Directory of Open Access Journals (Sweden)

    Sunita Bijarnia-Mahay

    2015-01-01

    Full Text Available Citrin deficiency is an autosomal recessive genetic disorder caused by a defect in the mitochondrial aspartate/glutamate antiporter, citrin. The disorder manifests either as neonatal intra-hepatic cholestasis or occurs in adulthood with recurrent hyperammonemia and neuropsychiatric disturbances. It has a high prevalence in the East Asian population, but is actually pan-ethnic. We report the case of a 26-year-old male patient presenting with episodes of abnormal neuro-psychiatric behavior associated with hyperammonemia, who was diagnosed to be having citrin deficiency. Sequencing of the SLC25A13 gene revealed two novel mutations, a single base pair deletion, c. 650delT (p.Phe217SerfsFNx0133 in exon 7, and a missense mutation, c. 869T>C (p.Ile290Thr in exon 9. Confirmation of the diagnosis allowed establishment of the appropriate management. The latter is an essential pre-requisite for obtaining a good prognosis as well as for family counseling.

  7. EUS-guided biliary drainage with placement of a new partially covered biliary stent for palliation of malignant biliary obstruction: a case series.

    Science.gov (United States)

    Fabbri, C; Luigiano, C; Fuccio, L; Polifemo, A M; Ferrara, F; Ghersi, S; Bassi, M; Billi, P; Maimone, A; Cennamo, V; Masetti, M; Jovine, E; D'Imperio, N

    2011-05-01

    Endoscopic ultrasonography-guided biliary drainage (EUS-BD) has been developed as an alternative drainage technique in patients with obstructive jaundice where endoscopic retrograde cholangiopancreatography (ERCP) has failed. Between July 2008 and December 2009, 16 patients (9 men; median age 79 years) with biliopancreatic malignancy, who were candidates for alternative techniques of biliary decompression because ERCP had been unsuccessful, underwent EUS-BD with placement of a transmural or transpapillary partially covered nitinol self-expandable metal stent (SEMS). EUS-assisted cholangiography was successful in all patients, with definition of the relevant anatomy, but biliary drainage was successfully performed in only 12 (75 %) of the 16 patients (9 choledochoduodenostomies with SEMS placement and 3 biliary rendezvous procedures with papillary SEMS placement), with regression of the cholestasis. No major complications and no procedure-related deaths occurred. There was one case of pneumoperitoneum which was managed conservatively. The median follow-up was 170 days. During the follow-up, eight patients of the 12 patients in whom biliary draining was successful died; four are currently alive. None of the patients required endoscopic reintervention. This series demonstrated that EUS-BD with a partially covered SEMS has a high rate of clinical success and low complication rates, and could represent an alternative choice for biliary decompression. PMID:21271507

  8. Portal hypertensive biliopathy: A single center experience and literature review.

    Science.gov (United States)

    Suárez, Vanessa; Puerta, Andrés; Santos, Luisa Fernanda; Pérez, Juan Manuel; Varón, Adriana; Botero, Rafael Claudino

    2013-03-27

    Portal hypertensive biliopathy (PHB) is characterized by anatomical and functional abnormalities of the intrahepatic, extrahepatic and pancreatic ducts, in patients with portal hypertension associated to extrahepatic portal vein obstruction and less frequently to cirrhosis. These morphological changes, consisting in dilatation and stenosis of the biliary tree, are due to extensive venous collaterals occurring in an attempt to decompress the portal venous blockage. It is usually asymptomatic until it progresses to more advanced stages with cholestasis, jaundice, biliary sludge, gallstones, cholangitis and finally biliary cirrhosis. Imaging modalities of the biliary tree such as Doppler ultrasound, computed tomography, magnetic resonance cholangiopancreatography and endoscopic retrograde cholangiopancreatography are essential to establish the diagnosis and the need of therapeutical interventions. Once the diagnosis is established, treatment with ursodesoxycholic acid seems to be beneficial. Decompression of the biliary tree to dilate, remove stones or implant biliary prosthesis by endoscopic or surgical procedures (hepato-yeyunostomy) usually resolves the cholestatic picture and prevents septic complications. The ideal treatment is the decompression of the portal system, with transjugular intrahepatic porto-systemic shunt or a surgical porto-systemic shunt. Unfortunately, few patients will be candidates for these procedures due to the extension of the thrombotic process. The purpose of this paper is to report the first 3 cases of PHB seen in a Colombian center and to review the literature. PMID:23556047

  9. Effect of short-term physical exercise on foetal heart rate and uterine activity in normal and abnormal pregnancies.

    Science.gov (United States)

    Rauramo, I

    1987-01-01

    The response of a short-term submaximal bicycle ergometer test on foetal heart rate (FHR) and on uterine activity was studied in 61 pregnant women between pregnancy weeks 32 and 40. 28 of the women had uncomplicated pregnancies, 13 were hypertensive, 11 were diabetic, and 9 had intrahepatic cholestasis of pregnancy. After exercise, FHR declined in healthy subjects in pregnancy weeks past 35, whereas no significant change was found in such subjects before week 35 of pregnancy. Analysis of variance revealed a difference of FHR between subjects with umcomplicated and pre-eclamptic pregnancies in relation to time (p = 0.021). Exercise induced uterine contractions in hypertensive subjects. Foetal bradycardia was found in 2 healthy, in 2 pre-eclamptic, and in one cholestatic subject. In healthy pregnant women a non-reactive FHR with concomitant reduced FHR variability was found after exercise (P less than 0.01). The FHR variability of patients with pathologic pregnancies was less affected. These results suggest that, after a relatively strenuous short-term exercise, foetuses of mothers with uneventful pregnancies can be at risk of hypoxia in late pregnancy, but the clinical significance remains uncertain. PMID:3435001

  10. Cholescintigraphy

    International Nuclear Information System (INIS)

    This thesis describes the clinical application of cholescintigraphy with sup(99m)Technetium-diethyl-IDA as hepato-biliary radiopharmaceutical. After a review of some anatomical and physiological properties of liver and biliary tract the conceptions jaundice and cholestasis are defined. Various clinical investigations in patients with liver and biliary tract disorders are discussed such as biochemical blood examinations, liver biopsy and radiological investigations. The applications and limitations of colloid liver scintigraphy in patients with focal or diffuse liver diseases are reviewed. Furthermore the diagnostic value of this investigation in jaundiced patients is discussed. The literature study ends with a review of the application of various hepato-biliary radiopharmaceuticals and the development, properties and first application of IDA-derivates. The synthesis, preparation and quality control of diethyl-IDA which is available as an 'instant labelling kit' (Solco-HIDAsup(R)) is described. The biological properties of the radiopharmaceutical are studied by means of kinetic and autoradiographic investigations in rat. As introduction to the clinical studies the technical basis of cholescintigraphy is described that encompasses the performance of the serial scintigrams and the generation of time-activity curves and functional images by a computer. Cholescintigraphic patterns in individuals without liver or biliary tract disorders are shown. (Auth.)

  11. Mechanisms of STAT3 activation in the liver of FXR knockout mice.

    Science.gov (United States)

    Li, Guodong; Zhu, Yan; Tawfik, Ossama; Kong, Bo; Williams, Jessica A; Zhan, Le; Kassel, Karen M; Luyendyk, James P; Wang, Li; Guo, Grace L

    2013-12-01

    Farnesoid X receptor (FXR, Nr1h4) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is essential in maintaining bile acid (BA) homeostasis, and FXR(-/-) mice develop cholestasis, inflammation, and spontaneous liver tumors. The signal transducer and activator of transcription 3 (STAT3) is well known to regulate liver growth, and STAT3 is feedback inhibited by its target gene, the suppressor of cytokine signaling 3 (SOCS3). Strong activation of STAT3 was detected in FXR(-/-) mouse livers. However, the mechanism of STAT3 activation with FXR deficiency remains elusive. Wild-type (WT) and FXR(-/-) mice were used to detect STAT3 pathway activation in the liver. In vivo BA feeding or deprivation was used to determine the role of BAs in STAT3 activation, and in vitro molecular approaches were used to determine the direct transcriptional regulation of SOCS3 by FXR. STAT3 was activated in FXR(-/-) but not WT mice. BA feeding increased, but deprivation by cholestyramine reduced, serum inflammatory markers and STAT3 activation. Furthermore, the Socs3 gene was determined as a direct FXR target gene. The elevated BAs and inflammation, along with reduced SOCS3, collectively contribute to the activation of the STAT3 signaling pathway in the liver of FXR(-/-) mice. This study suggests that the constitutive activation of STAT3 may be a mechanism of liver carcinogenesis in FXR(-/-) mice. PMID:24091600

  12. [Klatskin tumors--diagnostic and interventional therapy].

    Science.gov (United States)

    Ortner, M A

    2006-10-18

    Klatskin tumors are defined as malignant tumors of the bile duct involving the bifurcation and intrahepatic bile ducts. The most common presenting clinical feature, obstructive jaundice, usually occurs with advanced disease. Diagnostic tools currently available are therefore either performed too late or are not able to detect early disease stage. Imaging procedures for diagnosis and staging are ultrasonography, magnetic resonance imaging with cholangiopancreaticography, intravenous bolus-enhanced spiral computed tomography and endoscopic retrograde cholangiopancreaticography. Before initiating any palliative measure, a proper staging and a surgical consultation at a hepatobiliary center is necessary. To assess resectability, additional diagnostic methods like angiography, positron emission tomography, cholangioscopy, endoscopic or intraluminal ultrasonography and finally even explorative laparoscopy may be required. At time of diagnosis only a small percentage of Klatskin tumors is curative resectable. Therefore, palliative treatment options play an important role. Endoprostheses insertion is the method of choice to relieve jaundice. Although it improves quality of life, it does not seem to improve survival time. Definitive evidence for a benefit of additional radio and/or chemotherapy is still missing. Photodynamic therapy, a light therapy, is the first approach leading to an improvement of cholestasis and quality of life as well as to a prolongation of survival time. PDT should therefore be offered to all patients with nonresectable cholangiocarcinoma. PMID:17111849

  13. Genotypic and phenotypic features of citrin deficiency: five-year experience in a Chinese pediatric center.

    Science.gov (United States)

    Song, Yuan-Zong; Deng, Mei; Chen, Feng-Ping; Wen, Fang; Guo, Li; Cao, Shui-Liang; Gong, Jian; Xu, Hao; Jiang, Guang-Yu; Zhong, Le; Kobayashi, Keiko; Saheki, Takeyori; Wang, Zi-Neng

    2011-07-01

    Citrin is a liver-type aspartate/glutamate carrier (AGC) encoded by the gene SLC25A13. Two phenotypes for human citrin deficiency have been described, namely the adult-onset citrullinemia type II (CTLN2) and the neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). However, citrin deficiency currently remains a perplexing and poorly recognized disorder. In particular, description of post-NICCD clinical presentations before CTLN2 onset is rather limited. Analysis of SLC25A13 mutations, identification of dysmorphic erythrocytes, hepatobiliary scintigraphic imaging and investigation of post-NICCD clinical presentations were performed in a citrin-deficient cohort comprised of 51 cases of children diagnosed with citrin deficiency in a Chinese pediatric center. Twelve SLC25A13 mutations were detected in this cohort, including the novel V411M and G283X mutations. Among the 51 citrin-deficient subjects, 7 cases had echinocytosis, which was associated with more severe biochemical abnormalities. Delayed hepatic discharge and bile duct/bowel visualization were common scintigraphic findings. Moreover, 9 of the 34 post-NICCD cases demonstrated concurrent failure to thrive and dyslipidemia, constituting a clinical phenotype different from NICCD and CTLN2. The novel mutations, echinocytosis, hepatobiliary scintigraphic features and the novel clinical phenotype in this study expanded the genotypic and phenotypic spectrum of citrin deficiency, and challenge the traditionally-assumed 'apparently healthy' period after the NICCD state for this disease entity. PMID:21424115

  14. The role of hepatobiliary scintigraphy in cystic fibrosis.

    Science.gov (United States)

    O'Connor, P J; Southern, K W; Bowler, I M; Irving, H C; Robinson, P J; Littlewood, J M

    1996-02-01

    This was a prospective open study that examined the quantitative and qualitative analysis of hepatobiliary scintigraphy (DISIDA) in detecting liver involvement in cystic fibrosis (CF). Forty-four adult and pediatric patients (median age, 12.1 years; range, 1.1-36.3 years) were divided into three groups: group 1, no evidence of liver involvement (n = 8); group 2, biochemical evidence of liver involvement on two or more occasions (n = 26); and group 3, clinical evidence of liver disease (n = 10). In groups 1 and 2, the most common qualitative scintigraphic finding was focal intrahepatic retention of tracer (26/34 patients, 12 of whom had normal findings on ultrasonography). This finding corresponds to focal cholestasis and may warrant treatment with the choleretic agent ursodeoxycholic acid (UDCA). In the group 3 patients, the abnormal qualitative scintigraphic appearances (heterogeneous uptake of tracer and nodular liver outline) added little to the findings on ultrasonography; however, these patients had a prolonged mean hepatic clearance time compared with those in groups 1 and 2 (one-way ANOVA; P < .015). It is proposed that scintigraphy with DISIDA has a role in the detection of early liver involvement in cystic fibrosis. PMID:8591853

  15. Clinical features and management of primary biliary cirrhosis

    Institute of Scientific and Technical Information of China (English)

    Andrea Crosignani; Pier Maria Battezzati; Pietro Invernizzi; Carlo Selmi; Elena Prina; Mauro Podda

    2008-01-01

    Primary biliary cirrhosis (PBC),which is characterised by progressive destruction of intrahepatic bile ducts,is not a rare disease since both prevalence and incidence are increasing during the last years mainly due to the improvement of case finding strategies.The prognosis of the disease has improved due to both the recognition of earlier and indolent cases,and to the wide use of ursodeoxycholic acid (UDCA).New indicators of prognosis are available that will be useful especially for the growing number of patients with less severe disease.Most patients are asymptomatic at presentation.Pruritus may represent the most distressing symptom and,when UDCA is ineffective,cholestyramine represents the mainstay of treatment.Complications of long-standing cholestasis may be clinically relevant only in very advanced stages.Available data on the effects of UDCA on clinically relevant end points clearly indicate that the drug is able to slow but not to halt the progression of the disease while,in advanced stages,the only therapeutic option remains liver transplantation.

  16. Dermatoses of pregnancy: Nomenclature, misnomers, and myths.

    Science.gov (United States)

    Danesh, Melissa; Pomeranz, Miriam Keltz; McMeniman, Erin; Murase, Jenny E

    2016-01-01

    The most recent reclassification of dermatoses of pregnancy includes polymorphic eruption of pregnancy, atopic eruption of pregnancy, and pemphigoid gestationis; intrahepatic cholestasis of pregnancy, strictly not a dermatosis, was included in specific dermatoses of pregnancy for working purposes. Another dermatosis, pustular psoriasis of pregnancy, could be included for similar reasons. The nomenclature of these pregnancy-specific eruptions has been revised several times, generating potential confusion among practitioners. Clouding the picture further are misnomers that have been used to describe dermatoses of pregnancy. In addition, several cutaneous conditions that are associated with, but not specific to, pregnancy, have been misunderstood, which has resulted in certain myths among patients and physicians. In this contribution, we describe how the nomenclature of each dermatosis of pregnancy has evolved to fit the current classification scheme. We then identify several misnomers that have generated confusion within the scheme. Finally, we debunk several myths that have developed around cutaneous conditions outside of this scheme, in both mother and newborn. PMID:27265068

  17. Medical and dental management of Alagille syndrome: A review

    Science.gov (United States)

    Berniczei-Royko, Adam; Chałas, Renata; Mitura, Iwona; Nagy, Katalin; Prussak, Elżbieta

    2014-01-01

    Alagille syndrome is a rare, autosomal, complex, dominant disorder associated with dysfunction of the liver, heart, skeleton, and eyes, as well as characteristic facial appearance. It is associated with the defect in component of the Notch signalling pathway. Here, we review the main features of Alagille syndrome with special focus on oro-facial manifestations like prominent forehead, moderate hypertelorism with deep-set eyes, a saddle or straight nose with a flattened, bulbous tip, and large ears. The article is based on the most recent and significant literature available from the Medline database. Contrary to healthy children, patients with Alagille syndrome have many problems, depending on several factors like the severity of cholestasis and scarring in the liver, heart or lung problems, presence of infections, or other problems related to poor nutrition that can manifest in their oral cavity in the dental and periodontal tissues, as well as oral mucosa. From the dentist’s view, the most important elements are careful observation, accurate diagnosis, and planned management of such patients, especially during the patient’s formative years, to prevent complications. Aggressive preventive oral care and consultations with medical specialists before any invasive procedure are obligatory. All this can improve quality of life in patients with Alagille syndrome. PMID:24658020

  18. [Is it possible to reduce the incidence of aminoglycoside-induced nephrotoxicity?].

    Science.gov (United States)

    Fillastre, J P

    1999-01-01

    The incidence of nephrotoxicity due to aminoglycosides should be sharply reduced. The indications for prescribing these antibiotics should be limited to infectious disorders induced by aerobic Gram-negative bacteria and by some Gram-positive bacteria requiring treatment in specialized hospital units using an association of aminoglycosides and another antibiotic. Daily doses should not exceed those indicated by the manufacturer, and the length of treatment should be as short as possible, with a relay to other antibiotics that are not or are less nephrotoxic. The possibilities for reducing the incidence of nephrotoxicity are few. It is not possible to prevent the antibiotic from entering the renal tubular cell or from producing deleterious effects therein. However, by using short-term intravenous infusion as the administration route, prolonged contact between the antibiotic and its receptors on the brush borders of the proximal tubular cells can be avoided, particularly since the process of cellular absorption is saturable. Essentially, doses should be adapted according to the age and the glomerular filtration of the patient, since renal function usually decreases with age. Volemic and hydroelectrolytic disorders favour nephrotoxicity and should be corrected. Associations with other nephrotoxic drugs should either be avoided or used with increased caution. The same is true in special situations such as endotoxaemia, severe renal parenchymatous infections and cholestasis. In any case, given the well-known insidious onset of nephropathy, aminoglycoside treatment always requires laboratory follow-up consisting of repeated testing of creatinemia during the two weeks of treatment. PMID:10465001

  19. Colangiohidatidosis: Una complicación evolutiva de la hidatidosis hepática Cholangiohydatidosis: An evolutive complication of hepatic hydatidosis

    Directory of Open Access Journals (Sweden)

    Carlos Manterola

    2001-01-01

    Full Text Available Hydatidosis is and endemic disease in the south of Chile, especially in Region IX where remain rates of high prevalence. Cholangiohydatidosis is an infrequent complication of liver hydatidosis. The objective of this paper is to describe clinical features of a series of patients with cholangiohydatidosis. Series of cases of cholangiohydatidosis treated consecutively and the corresponding follow-up is reported. Clinical, laboratory and images characteristics are described. Descriptive statistic was used and its incidence was calculated. In the studied period, 13 patients with cholangiohydatidosis were recruited, 9 men (69.2% and 4 women (30.7%. Observed laboratory abnormalities were an increment of leukocytes in 8 patients (61.5% and hepatic cholestasis with hepatocyte signs of cytolysis in 11 patients (84.6%. Choledocus diameter average measured by ultrasonography was 24,7 mm. All the patients had at least one liver cyst whose diameter average was of 12.1 cm. At surgery, evidence of biliary communications was detected in all patients and biliary decompression was carried out through a choledocostomy in 12 patients (92.3% and by choledocoduodenal anastomoses in one case (7.7%. With a mean follow-up of 38.7 months morbility was 23% and mortality 7.7%. Accumulated incidence of this entity was of 0.07 cases in 5 years. Cholangiohydatidosis is an uncommon complication of liver hydatidosis that presents considerable morbidity and mortality rates.

  20. Pathogenesis and treatment of pruritus.

    Science.gov (United States)

    Greaves, Malcolm W

    2010-07-01

    Classification of itch into four categories-pruritoceptive, neurogenic, neuropathic, and psychogenic-has proven to be of utility to clinicians and investigators. Itch is recognized to be transmitted by dedicated afferent neurons, and a matrix of cerebral cortical loci involved in perception and the desire to scratch has been recognized. This highlights the multidimensional nature of the itch sensation. Some of the many mediators of itch, especially relevant in pruritogenic itch, are the result of cross-talk between dermal mast cells and adjacent cutaneous afferents. Keratinocytes of the epidermis express many neuropeptides, and their receptors are far from passive bystanders in the neurophysiology of itch. Mediators can also act centrally (eg, opioid peptides that act on micro receptors in the central nervous system). The pathophysiology of pruritus in neurogenic itch caused by common systemic diseases is gradually being elucidated, especially in the itch of cholestasis, although the molecular basis of itching in chronic renal failure remains elusive. Better understanding of the mediators of itch and their receptors has led to the imminent development of novel anti-itch compounds, including interleukin-31 inhibitors, histamine H4-receptor antagonists, and neurokinin-1 receptor antagonists. PMID:20428977