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Roderick H.j. Houwen - One of the best experts on this subject based on the ideXlab platform.
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Familial Cholestasis: Progressive familial intrahepatic Cholestasis, benign recurrent intrahepatic Cholestasis and intrahepatic Cholestasis of pregnancy
Best Practice & Research in Clinical Gastroenterology, 2010Co-Authors: Wendy L. Van Der Woerd, Janneke M Stapelbroek, Stan F J Van De Graaf, Leo W. J. Klomp, Roderick H.j. HouwenAbstract:Progressive familial intrahepatic Cholestasis (PFIC) type 1, 2 and 3 are due to mutations in ATP8B1, ABCB11 and ABCB4, respectively. Each of these genes encodes a hepatocanalicular transporter, which is essential for the proper formation of bile. Mutations in ABCB4 can result in progressive cholestatic disease, while mutations in ATP8B1 and ABCB11 can result both in episodic Cholestasis, referred to as benign recurrent intrahepatic Cholestasis (BRIC) type 1 and 2, as well as in progressive cholestatic disease. This suggests a clinical continuum and these diseases are therefore preferably referred to as ATP8B1 deficiency and ABCB11 deficiency. Similarly PFIC type 3 is designated as ABCB4 deficiency. Heterozygous mutations in each of these transporters can also be associated with intrahepatic Cholestasis of pregnancy. This review summarizes the pathophysiology, clinical features and current as well as future therapeutic options for progressive familial- and benign recurrent intrahepatic Cholestasis as well as intrahepatic Cholestasis of pregnancy.
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benign recurrent intrahepatic Cholestasis progressing to progressive familial intrahepatic Cholestasis low ggt Cholestasis is a clinical continuum
Journal of Hepatology, 2002Co-Authors: Nancy A M Van Ooteghem, Leo W. J. Klomp, Gerard P Van Bergehenegouwen, Roderick H.j. HouwenAbstract:Benign recurrent intrahepatic Cholestasis (BRIC) is an autosomal recessive liver disease, characterised by intermittent attacks of Cholestasis, which can start at any age and last for several weeks to months. Characteristically serum GGT activity is low and normal liver structure is preserved. Progressive familial intrahepatic Cholestasis (PFIC) is another liver disease, characterised by severe Cholestasis, starting almost invariably before 6 months of age. All patients progress to cirrhosis, liver failure and death, unless a liver transplantation is performed. We now identified four patients who presented in childhood with recurrent attacks of Cholestasis, while in the course of the disease the Cholestasis gradually became permanent. Although liver biopsies performed in the early stages of the disease showed normal liver architecture, late stage biopsies revealed evident fibrosis with porto-portal septa formation. In conclusion, the disease of these patients started with the clinical and histopathological characteristics of BRIC but progressed to PFIC.
Bruno Stieger - One of the best experts on this subject based on the ideXlab platform.
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role of the bile salt export pump bsep in acquired forms of Cholestasis
Drug Metabolism Reviews, 2010Co-Authors: Bruno StiegerAbstract: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 or drugs, aberrant bile salt metabolites, or pregnancy. This inhibition will lead to acquired Cholestasis. Some drugs are now known to be competitive inhibitors of Bsep. In addition, a polymorphism in the gene coding for BSEP has been identified as a potential susceptibility factor for acquired Cholestasis.
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Genetic Determinants of Drug-induced Cholestasis and Intrahepatic Cholestasis of Pregnancy
Seminars in liver disease, 2010Co-Authors: Christiane Pauli-magnus, Peter J. Meier, Bruno StiegerAbstract: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 impair the bile salt export pump (BSEP) function by an indirect mechanism. In addition, genetic variants (as well as mutants) of the genes coding for the phosphatidylcholine translocator MDR3 and BSEP and for the farnesoid X receptor, which is critical in the transcriptional activation of MDR3 ( ABCB4) and BSEP ( ABCB11) have been associated with intrahepatic Cholestasis of pregnancy. The pathogenesis of drug-induced liver injury encompasses a wide spectrum of mechanisms, some of which are still poorly understood. BSEP is now known to be subject to drug inhibition in susceptible patients. Information on genetic factors rendering individuals susceptible to inhibition of BSEP by drugs or their metabolites is still scarce. Besides rare mutations that have been linked to drug-induced Cholestasis, the common p.V444A polymorphism of BSEP has been identified as a potential risk factor. In this review, the authors summarize key concepts of physiology of bile formation, diagnostic principles to indentify these forms of acquired Cholestasis, as well as pathogenetic mechanisms leading to intrahepatic Cholestasis of pregnancy or drug-induced Cholestasis. In addition, they review the current knowledge on genetic susceptibility factors for these two forms of Cholestasis.
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mutations and polymorphisms in the bile salt export pump and the multidrug resistance protein 3 associated with drug induced liver injury
Pharmacogenetics and Genomics, 2007Co-Authors: Carmen Lang, Bruno Stieger, Peter J. Meier, Yvonne Meier, Ulrich Beuers, Thomas Lang, Reinhold Kerb, Gerd A Kullakublick, Christiane PaulimagnusAbstract:OBJECTIVES: Increasing evidence suggests that a genetically determined functional impairment of the hepatocellular efflux transporters bile salt export pump (BSEP, ABCB11) and multidrug resistance protein 3 (MDR3, ABCB4) play a pathophysiological role in the development of drug-induced liver injury. The aim of this study was therefore to describe the extent of genetic variability in ABCB11 and ABCB4 in patients with drug-induced liver injury and to in vitro functionally characterize newly detected ABCB11 mutations and polymorphisms. METHODS: ABCB11 and ABCB4 were sequenced in 23 patients with drug-induced Cholestasis and 13 patients with drug-induced hepatocellular injury. Ninety-five healthy Caucasians served as the control group. Reference and mutant BSEP were expressed in Sf9 cells and ATP-dependent transport of [H]-taurocholate was measured in a rapid filtration assay. RESULTS: Four highly conserved nonsynonymous mutations were specific for drug-induced liver injury [ABCB11: D676Y (drug-induced Cholestasis) and G855R (drug-induced Cholestasis); ABCB4: I764L (drug-induced Cholestasis) and L1082Q (drug-induced hepatocellular injury)]. Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced Cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced Cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P Furthermore, a polymorphism in exon 13 of ABCB11 (V444A), which is associated with decreased hepatic BSEP expression was significantly more frequent in drug-induced Cholestasis patients than in drug-induced hepatocellular injury patients and healthy controls (76 versus 50 and 59% in drug-induced Cholestasis patients, drug-induced hepatocellular injury patients and healthy controls, respectively; P>0.05). The in-vitro transport activity of the V444A and the D676Y BSEP constructs was similar, whereas the G855R mutation was nonfunctional. CONCLUSION: In summary, our data support a role of ABCB11 and ABCB4 mutations and polymorphisms in drug-induced Cholestasis. Genotyping of selected patients with acquired Cholestasis might help to identify individuals with a genetic predisposition.
Michael Trauner - One of the best experts on this subject based on the ideXlab platform.
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Mechanisms of Cholestasis.
Clinics in liver disease, 2008Co-Authors: Gernot Zollner, Michael TraunerAbstract:This article gives an overview of the molecular and cellular mechanisms of Cholestasis. Topics reviewed include the pathomechanisms of hereditary Cholestasis syndromes, such as progressive familial intrahepatic Cholestasis, and hepatocellular transporter defects encountered in various acquired cholestatic disorders, such as intrahepatic Cholestasis of pregnancy, drug-induced Cholestasis, inflammatory Cholestasis, primary sclerosing cholangitis, and primary biliary cirrhosis. In addition, current concepts regarding adaptive hepatocellular mechanisms counteracting cholestatic liver damage are discussed.
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Mechanisms of Disease: mechanisms and clinical implications of Cholestasis in sepsis
Nature Clinical Practice Gastroenterology & Hepatology, 2006Co-Authors: Andreas Geier, Peter Fickert, Michael TraunerAbstract:Over the past decade, inflammation-induced alterations at the hepatocellular, bile ductular and ductal level have been linked to different clinical presentations of Cholestasis in sepsis. In this Review, the authors give a comprehensive overview of the molecular and cellular mechanisms that underlie sepsis-associated Cholestasis and the potential clinical and therapeutic implications that these mechanisms have for critically ill patients. Cholestasis is a common complication in patients with extrahepatic bacterial infection and sepsis. This article gives a comprehensive overview of the molecular and cellular mechanisms of sepsis-associated Cholestasis. Recent advances in the understanding of intrahepatic Cholestasis have allowed us to delineate the molecular mechanisms that underlie sepsis-associated Cholestasis and to describe their potential clinical and therapeutic applications. The mechanisms and clinical presentation of sepsis-associated liver injury vary according to the severity of the bacterial infection. Proinflammatory cytokines and nitric oxide cause Cholestasis by impairing hepatocellular and ductal bile formation. Ischemic liver injury and, rarely, progressive sclerosing cholangitis can also be found in patients with septic shock, or major trauma with systemic inflammatory response syndrome. Treatment is mainly focused on eradication of the underlying infection and managing the sepsis. The use of ursodeoxycholic acid or extracorporeal liver support as treatments for sepsis-associated Cholestasis is under investigation, but neither can be recommended in routine clinical practice at present. Patients with progressive sclerosing cholangitis should be considered for orthotopic liver transplantation. Cholestasis is a common complication in patients with extrahepatic bacterial infection and sepsis, predominantly associated with Gram-negative bacteria Cholestasis in sepsis results from either a functional defect in bile formation at the hepatocellular level or an impairment in bile secretion at the level of the small or large bile ducts caused by proinflammatory cytokines and nitric oxide The clinical presentation of sepsis-associated liver injury varies according to the severity of the bacterial infection Functional hepatocellular Cholestasis (sepsis-associated Cholestasis) predominates in patients with sepsis, whereas ischemic liver injury (shock liver) and, occasionally, progressive sclerosing cholangitis can be found in patients with septic shock or major trauma with systemic inflammatory response syndrome Treatment is focused mainly on eradicating the underlying infection and managing the sepsis Patients with progressive sclerosing cholangitis should be considered for orthotopic liver transplantation
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transcriptional regulation of hepatobiliary transport systems in health and disease implications for a rationale approach to the treatment of intrahepatic Cholestasis
Annals of Hepatology, 2005Co-Authors: Martin Wagner, Michael TraunerAbstract:Hepatobiliary transport systems mediate hepatic uptake and biliary excretion of bile acids, bilirubin and other biliary constituents. Hereditary or acquired defects of these transporters may cause or maintain Cholestasis and jaundice under various clinical conditions including progressive familial intrahepatic Cholestasis (PFIC) 1-3 or its milder forms, benign recurrent intrahepatic Cholestasis (BRIC) 1 and 2 , DubinJohnson syndrome, drug and inflammation-induced Cholestasis and intrahepatic Cholestasis of pregnancy. Moreover, induction of alternative efflux pumps for bile acids/bilirubin and phase I/II detoxifying enzymes may counteract hepatic accumulation of potentially
Irwin M. Arias - One of the best experts on this subject based on the ideXlab platform.
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Progressive familial intrahepatic Cholestasis: genetic disorders of biliary transporters.
Journal of Gastroenterology and Hepatology, 2005Co-Authors: Matthew J Harris, David G. Le Couteur, Irwin M. AriasAbstract:Progressive familial intrahepatic Cholestasis types 1, 2 and 3 are childhood diseases of the liver. Benign recurrent intrahepatic Cholestasis is predominantly an adult form with similar clinical symptoms that spontaneously resolve. These genetic disorders have significantly helped to unravel the basic mechanisms of the canalicular bile transport processes. Progressive familial intrahepatic Cholestasis type 1 involves a gene also linked to benign recurrent intrahepatic Cholestasis. The gene codes for an aminophospholipid translocase protein that maintains the integrity of the membrane. How a mutation in this protein causes Cholestasis is unknown but is thought to involve the enterohepatic recirculation of bile acids. Progressive familial intrahepatic Cholestasis types 2 and 3 involve the canalicular bile salt export pump and a phospholipid translocase, respectively, both of which are fundamental to bile secretion. This review covers the clinical manifestations, genetics, treatment and mechanism of each disease.
Leo W. J. Klomp - One of the best experts on this subject based on the ideXlab platform.
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Familial Cholestasis: Progressive familial intrahepatic Cholestasis, benign recurrent intrahepatic Cholestasis and intrahepatic Cholestasis of pregnancy
Best Practice & Research in Clinical Gastroenterology, 2010Co-Authors: Wendy L. Van Der Woerd, Janneke M Stapelbroek, Stan F J Van De Graaf, Leo W. J. Klomp, Roderick H.j. HouwenAbstract:Progressive familial intrahepatic Cholestasis (PFIC) type 1, 2 and 3 are due to mutations in ATP8B1, ABCB11 and ABCB4, respectively. Each of these genes encodes a hepatocanalicular transporter, which is essential for the proper formation of bile. Mutations in ABCB4 can result in progressive cholestatic disease, while mutations in ATP8B1 and ABCB11 can result both in episodic Cholestasis, referred to as benign recurrent intrahepatic Cholestasis (BRIC) type 1 and 2, as well as in progressive cholestatic disease. This suggests a clinical continuum and these diseases are therefore preferably referred to as ATP8B1 deficiency and ABCB11 deficiency. Similarly PFIC type 3 is designated as ABCB4 deficiency. Heterozygous mutations in each of these transporters can also be associated with intrahepatic Cholestasis of pregnancy. This review summarizes the pathophysiology, clinical features and current as well as future therapeutic options for progressive familial- and benign recurrent intrahepatic Cholestasis as well as intrahepatic Cholestasis of pregnancy.
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benign recurrent intrahepatic Cholestasis progressing to progressive familial intrahepatic Cholestasis low ggt Cholestasis is a clinical continuum
Journal of Hepatology, 2002Co-Authors: Nancy A M Van Ooteghem, Leo W. J. Klomp, Gerard P Van Bergehenegouwen, Roderick H.j. HouwenAbstract:Benign recurrent intrahepatic Cholestasis (BRIC) is an autosomal recessive liver disease, characterised by intermittent attacks of Cholestasis, which can start at any age and last for several weeks to months. Characteristically serum GGT activity is low and normal liver structure is preserved. Progressive familial intrahepatic Cholestasis (PFIC) is another liver disease, characterised by severe Cholestasis, starting almost invariably before 6 months of age. All patients progress to cirrhosis, liver failure and death, unless a liver transplantation is performed. We now identified four patients who presented in childhood with recurrent attacks of Cholestasis, while in the course of the disease the Cholestasis gradually became permanent. Although liver biopsies performed in the early stages of the disease showed normal liver architecture, late stage biopsies revealed evident fibrosis with porto-portal septa formation. In conclusion, the disease of these patients started with the clinical and histopathological characteristics of BRIC but progressed to PFIC.