Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0008370 (cholestasis)
 9,378 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Hepatobiliary transport systems are responsible for hepatic uptake and excretion of bile salts and other biliary constituents (eg, bilirubin) into bile. Hereditary transport defects can result in progressive familial and benign recurrent intrahepatic cholestasis. Exposure to acquired cholestatic injury (eg, drugs, hormones, proinflammatory cytokines, biliary obstruction or destruction) also results in altered expression and function of hepatic uptake and excretory systems, changes that may maintain and contribute to cholestasis and jaundice. Recruitment of alternative efflux pumps and induction of phase I and II detoxifying enzymes may limit hepatic accumulation of potentially toxic biliary constituents in cholestasis by providing alternative metabolic and escape routes. These molecular changes are mediated by bile salts, proinflammatory cytokines, drugs, and hormones at a transcriptional and posttranscriptional level. Alterations of hepatobiliary transporters and enzymes are not only relevant for a better understanding of the pathophysiology of cholestatic liver diseases, but may also represent important targets for pharmacotherapy. Drugs (eg, ursodeoxycholic acid, rifampicin) used to treat cholestatic liver diseases and pruritus may counteract cholestasis via stimulation of defective transporter expression and function. In addition, therapeutic strategies may be aimed at supporting and stimulating alternative detoxification pathways and elimination routes for bile salts in cholestasis.
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PMID:Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. 1575 46

Intrahepatic cholestasis, or impairment of bile flow, is an important manifestation of inherited and acquired liver disease. In recent years, human genetic and molecular studies have identified several genes, the disruption of which results in cholestasis. ATP8B1 (FIC1), ABCB11 (BSEP), and ABCB4 (MDR3) are disrupted in forms of progressive familial intrahepatic cholestasis (PFIC) and related disorders. Mutations in BAAT, TJP2 (ZO-2), and EPHX1 have been identified in patients with hypercholanemia. A CLDN1 mutation was recently reported in patients with ichthyosis, leukocyte vacuoles, alopecia and sclerosing cholangitis (ILVASC), and North American Indian childhood cirrhosis (NAIC) is associated with a missense mutation in CIRH1A. Alagille syndrome patients carry mutations in JAG1, and mutations in VPS33B have been identified in patients with arthrogryposis, renal dysfunction and cholestasis syndrome (ARC). Identification of these genes, and characterization of the proteins they encode, is enhancing our understanding of the biology of the enterohepatic circulation in health and disease.
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PMID:Molecular basis of intrahepatic cholestasis. 1576 32

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.
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PMID:Progressive familial intrahepatic cholestasis: genetic disorders of biliary transporters. 1594 26

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 , Dubin-Johnson 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 toxic biliary constituents in cholestasis by providing alternative escape routes. Transcriptional and post-transcriptional regulation of hepatobiliary transporters in health and disease is mediated by multiple factors such as bile acids, proinflammatory cytokines, drugs and hormones. Ligand-activated nuclear receptors (NR) and hepatocyte-enriched transcription factors play a critical role in transcriptional transporter regulation. Many hepatobiliary transporter alterations in cholestatic liver disease can now be explained by ligand binding of accumulating cholephiles to NRs. Moreover, NR-mediated actions may be targeted by pharmacological ligands. Understanding the transcriptional mechanisms leading to transporter changes therefore not only represents a key for understanding the pathophysiology of the cholestatic liver disease, but also represents a prerequisite for designing novel therapeutic strategies.
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PMID:Transcriptional regulation of hepatobiliary transport systems in health and disease: implications for a rationale approach to the treatment of intrahepatic cholestasis. 1601 Feb 41

Identification of the transport systems involved in bile secretion and of the genes codifying these systems has allowed the etiology of familial intrahepatic cholestasis to be determined in most affected children. Mutations in ATP8B1 cause a defect in FIC1, an aminophospholipid flipase, and give rise to a variable spectrum of disease, ranging from progressive intrahepatic cholestasis to benign recurrent cholestasis, due to alterations in the lipid composition of the membranes and decreased expression of the nuclear factor FXR. Mutations in ABCB11 cause a defect of the canalicular bile salt export pump (BSEP), with early clinical manifestations and progression to hepatocellular failure in childhood. Mutations in ABCB4 cause an alteration in the MDR3 phospholipid transporter, and a variable spectrum of disease from progressive ductal injury to cirrhosis in children, and gallstones, cholestasis of pregnancy, or late cirrhosis in adults.
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PMID:[Childhood cholestasis and bile transporters]. 1613 74

This is a case report of a 36 years old man who has been suffering for 20 years from benign recurrent intrahepatic cholestasis (BRIC). BRIC is a rare autosomal recessive disease characterised by prolonged episodes of intrahepatic cholestasis and pruritus alternating with periods of nearly normal liver function, and does not progress to cirrhosis. Since all former approaches to medical treatment of the patients severe pruritus were ineffective, the patient was treated by 3 sessions of albumin dialysis (MARS, Molecular Adsorbents Recirculating System). MARS dialysis decreased serum bilirubin levels by more than 60 % and effectively lowered serum bile acid levels by 45 %. The course of serum parameters was accompanied by a dramatic clinical improvement of the patients symptoms (pruritus, jaundice, fatigue etc.). MARS therapy appeared to shorten the duration of the cholestatic attack.
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PMID:Successful clinical application of extracorporal albumin dialysis in a patient with benign recurrent intrahepatic cholestasis (BRIC). 1621 86

ICP (intrahepatic cholestasis of pregnancy) is characterized by pruritus and biochemical cholestasis, including raised SBAs (serum bile acids) and, usually, elevated aminotransferases levels. However, AHP (asymptomatic hypercholanaemia of pregnancy) is defined as the presence of total SBA levels above the cut-off value (11 microM) in healthy pregnant women, thus elevation of total SBAs do not necessarily reflect an ICP condition. The aim of the present study was to describe clinical, obstetric, perinatal and biochemical findings, as well as the SBA profile, in pregnant women studied in the third trimester of pregnancy in order to define characteristic patterns of individual bile acids that enable women with ICP to be distinguished from AHP and healthy pregnancies. Free and conjugated ursodeoxycholic (UDCA), cholic (CA), lithocholic (LCA), deoxycholic (DCA) and chenodeoxycholic (CDCA) acids were evaluated by CE (capillary electrophoresis) in 41 patients (15 of them simultaneously by HPLC), in 30 healthy pregnant women and in 10 non-pregnant women. A highly significant correlation between CE and HPLC for total SBAs (r=0.990) and for individual SBAs was found. Normal pregnant women had higher total SBA levels than non-pregnant women (due to an increase in taurine-conjugated dihydroxy SBAs). Women with ICP had higher levels of total SBAs, the free/conjugated ratio, LCA, CA, CDCA and DCA than normal pregnant women. Newborns from women with ICP had lower birth weight and gestational age. Women with AHP had higher levels of conjugated dihydroxy SBAs than normocholanaemic patients, without any evidence of a clinical difference. In conclusion, the present study has shown a clear difference in SBA profiles between ICP and normal pregnancies (including AHP), involving a shift towards a characteristic hydrophobic composition in women with ICP.
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PMID:Bile acid profiles by capillary electrophoresis in intrahepatic cholestasis of pregnancy. 1635 62

A young patient with recurrent attacks of intrahepatic cholestasis is described. On the basis of clinical presentation, laboratory findings and genetic analysis, the diagnosis of benign recurrent intrahepatic cholestasis type 2 (BRIC-2) was established. By the use of BSEP-specific antibodies, almost complete absence of BSEP from the canalicular membrane of liver cells was detected in the patient. Two different BSEP mutations were found. One mutation (E186G) had been described in one BRIC-2 case; the second mutation (V444A) is more frequent and has been linked to intrahepatic cholestasis of pregnancy. It is concluded that this form of compound heterozygosity of the BSEP gene reduces the amount of BSEP protein due to protein instability or mis-targeting, which is the underlying reason for reduced bile salt excretion and cholemia.
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PMID:Benign recurrent intrahepatic cholestasis associated with mutations of the bile salt export pump. 1639 81

Cholestatic syndromes are inborn or acquired disorders of bile formation. In recent years, several inherited cholestatic syndromes were characterized at the molecular level: progressive familial intrahepatic cholestasis (PFIC) and benign recurrent intrahepatic cholestasis (BRIC). Both PFIC and BRIC were divided phenotypically in distinct subtypes; however, at the genotype level, these clinical entities overlap. PFIC starts in early childhood and progresses toward liver cirrhosis, which often requires liver transplantation within the first decade of life. The diagnosis of PFIC is usually made on the basis of clinical and laboratory findings but needs to be confirmed by genetic and histological analysis. Only recently was it recognized that BRIC, which was estimated as a milder form of PFIC-1, may be caused by more than one gene.
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PMID:Inborn errors of biliary canalicular transport systems. 1639 70

Definitive medical treatment for benign recurrent intrahepatic cholestasis (BRIC) is not available and the significance of surgical treatment is a matter of debate. It has been postulated that BRIC may progress to progressive familial intrahepatic cholestasis (PFIC), which leads to liver insufficiency and cirrhosis. External biliary diversion represents an option for both conditions and we recently introduced a new laparoscopic technique for infants with PFIC. However, limited umbilical incision may interfere with creating a jejunal conduit by infraumbilical exteriorisation, in particular in obese adolescents. Therefore, we modified our technique by exteriorising a small bowel loop via the right midabdominal trocar incision at the position of the jejunostomy. The technique was used in a 17-year-old obese patient with BRIC. This is the first report on a patient with BRIC undergoing laparoscopic external biliary diversion.
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PMID:Modified laparoscopic external biliary diversion for benign recurrent intrahepatic cholestasis in obese adolescents. 1673 28


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