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)

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.
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PMID:A case of infantile Dubin-Johnson syndrome with high CT attenuation in the liver. 979 30

The liver converts endogenous and xenobiotic lipophilic compounds into anionic conjugates with glutathione, glucuronate, or sulfate. These conjugates are transported across the canalicular (apical) membrane into bile by a 190 kDa membrane glycoprotein that has been cloned recently. This apical conjugate-transporting ATPase has been termed canalicular multidrug resistance protein (cMRP) because of the similarity in substrate specificity and sequence with the multidrug resistance protein (MRP1), canalicular multispecific organic anion transporter (cMOAT), or multidrug resistance protein 2 (MRP2). The amino acid sequence identity of human MRP2 and MRP1 is 49%. MRP2 is predominantly expressed in hepatocytes and localized to apical membrane domains. MRP2 is not expressed in the human Dubin-Johnson syndrome, which is therefore associated with an inherited deficiency in the secretion of amphiphilic anionic conjugates into the bile. The rat homolog Mrp2 is absent in two mutant strains of rats with different point mutations in the corresponding gene. These mutant rats are hyperbilirubinemic and deficient in the ATP-dependent transport of conjugates from hepatocytes into bile. Impairment of bile flow (cholestasis) can be associated with a down-regulation of the expression of the conjugate export pump, and MRP2 contributes to bile flow as an important driving force.
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PMID:Hepatic canalicular membrane 5: Expression and localization of the conjugate export pump encoded by the MRP2 (cMRP/cMOAT) gene in liver. 921 74

In distinguishing normal from abnormal hepatic changes, the author described the expected changes in liver tests that occur during complicated pregnancy. This article reviews the forms of pre-existing liver disease that may affect or be affected by pregnancy, as well as liver diseases that tend to arise during pregnancy. Among the pre-existing liver diseases are autoimmune chronic active hepatitis, which may be activated by pregnancy and tends to be associated with an increased risk of still and premature births. Worsening of chronic hepatitis B and C has occasionally been observed. While some women with cirrhosis can sustain a normal pregnancy without any worsening of hepatic function, others develop liver failure; plus, women with cirrhosis are less fertile and have higher rates of both stillbirths and premature infants. Other liver disorders that may or may not be affected by pregnancy include Dubin-Johnson syndrome, Gilbert syndrome, benign recurrent intrahepatic cholestasis, Wilson's disease, hepatic adenomas, and focal nodular hyperplasia. Among the hepatic disorders that occur during pregnancy in normally healthy women and then resolve after delivery is intrahepatic cholestasis of pregnancy (also known as pruritus gravidarum, recurrent intrahepatic cholestasis of pregnancy, and obstetric hepatosis). Others include acute fatty liver of pregnancy and HELLP syndrome (hemolysis, elevated liver enzymes, and low platelet count), which may be part of the spectrum of disorders associated with pre-eclampsia/eclampsia. Pregnancy may also trigger the dissemination of herpes infection to the liver.
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PMID:Liver problems in pregnancy: part 2--managing pre-existing and pregnancy-induced liver disease. 973 96

Progressive familial intrahepatic cholestasis (PFIC) is a group of severe genetic cholestatic liver diseases of early life. PFIC types 1 and 2 are characterized by cholestasis and a low to normal serum gamma-glutamyltransferase (GGT) activity, whereas in PFIC type 3, the serum GGT activity is elevated. PFIC types 1 and 2 occur due to mutations in loci at chromosome 18 and chromosome 2, respectively. The pathophysiology of PFIC type 1 is not well understood. PFIC types 2 and 3 are caused by transport defects in the liver affecting the hepatobiliary secretion of bile acids and phospholipids, respectively. Benign recurrent intrahepatic cholestasis (BRIC) is linked to a mutation in the same familial intrahepatic cholestasis 1 locus at chromosome 18. Defects of bile acid synthesis may be difficult to differentiate from these transport defects. Intrahepatic cholestasis of pregnancy (ICP) appears to be related to these cholestatic diseases. For example, heterozygosity in families with PFIC type 3 is associated with ICP, but ICP has also been reported in families with BRIC. In Dubin-Johnson syndrome there is no cholestasis; only the hepatobiliary transport of conjugated bilirubin is affected. This, therefore, is a mild disease, and patients have a normal lifespan.
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PMID:Genetic cholestasis: lessons from the molecular physiology of bile formation. 1075 20

Uptake of drugs and metabolites from the circulation into the liver is facilitated by transporter proteins in the basolateral membrane of the hepatocyte. Among these proteins are the sodium taurocholate cotransporting protein, various multispecific transporters for organic anions and cations, transporters for glucose, amino acids, and prostaglandins. The canalicular membrane contains a number of ATP-dependent transporters belonging to the families of P-glycoproteins and multidrug resistance-associated proteins. Transport across the canalicular membrane represents the rate-determining step in the secretion of compounds from blood to bile. Mutations of genes encoding these canalicular transporters are associated with liver diseases such as progressive familial intrahepatic cholestasis and Dubin-Johnson syndrome. Wilson's disease appears to be due to a defect of a copper-transporting P-type ATPase. Also, bile ductuli contribute to bile formation. Mutations in the CFTR gene, encoding a chloride channel in bile duct epithelial cells, leads to the hepatic component of cystic fibrosis.
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PMID:Foreword: from classic bile physiology to cloned transporters. 1107 93

Conjugate export pumps of the multidrug resistance protein (MRP) family mediate the ATP-dependent secretion of anionic conjugates across the canalicular and the basolateral hepatocyte membrane into bile and sinusoidal blood, respectively. Xenobiotic and endogenous lipophilic substances may be conjugated with glutathione, glucuronate, sulfate, or other negatively charged groups and thus become substrates for export pumps of the MRP family. The apical isoform, MRP2 (gene symbol ABCC2), has been localized to the apical membrane of several polarized epithelia and particularly to the canalicular membrane of hepatocytes. Absence of functionally active MRP2 glycoprotein from this membrane domain prevents the secretion of many anionic conjugates into bile. Prototypic endogenous substrates of high affinity for recombinant human MRP2 include bisglucuronosyl bilirubin, monoglucuronosyl bilirubin, and the glutathione S-conjugate leukotriene C4. Several mutations in the human MRP2 gene have been identified that lead to the absence of MRP2 from the canalicular membrane and to the conjugated hyperbilirubinemia of Dubin-Johnson syndrome. MRP2-mediated conjugate export represents a decisive final step in the detoxification of drugs, toxins, and endogenous substances. The basolateral isoform, MRP3 (gene symbol ABCC3), is upregulated in MRP2 deficiency and in extrahepatic cholestasis. MRP3 mediates the ATP-dependent transport of anionic conjugates, particularly of glucuronides and sulfoconjugates, across the basolateral hepatocyte membrane into sinusoidal blood. The inverse regulation of MRP3 and MRP2 expression under many conditions is consistent with their distinct localization and with a compensatory role of MRP3 in the hepatic secretion of anionic conjugates during impaired transport into bile.
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PMID:Hepatic secretion of conjugated drugs and endogenous substances. 1107 95

A 65-year-old man presented with multiple liver tumours. Imaging techniques could not differentiate between adenomas and hepatocellular carcinomas. He had no relevant past medical history. Liver function tests were normal except for a 1.5-fold rise in GGT. AFP was normal. Viral markers were negative. During laparoscopy, numerous black tumours of different sizes were seen. These tumours were adenomas without malignant transformation. Tumoral hepatocytes contained a brown pigment in the canalicular area without evidence of cholestasis. This pigment was Fontana positive and looked like Dubin-Johnson pigment by electron microscopy. The expression of the canalicular multispecific organic anion transporter (cMOAT) was decreased in the tumours but normal in the non-tumoral liver ruling out the diagnosis of Dubin-Johnson syndrome. There was mild iron deposition possibly related to an homozygous H63D mutation in the HFE gene. Three years after their discovery, the size of the tumours remained stable. It is concluded that this male patient with multiple adenomas and mild iron overload is at risk of developing an hepatocellular carcinoma and that the black colour of adenomas is probably due to a partial defect in excretion of organic anions.
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PMID:Multiple black hepatocellular adenomas in a male patient. 1111 85

Transport proteins in hepatocytes and bile duct epithelium mediate uptake and secretion of cholephilic compounds in the liver and are involved in bile formation. Many of these proteins have recently been cloned and characterized and appear to belong to large gene families. Apart from the liver these proteins are expressed in the blood-brain barrier, placenta, kidneys, lungs, intestine and seminiferous tubules. Prokaryotes and yeasts contain similar proteins. In cancer cells they are involved in multidrug resistance. Some genetic cholestatic liver diseases, including progressive familial intrahepatic cholestasis, Dubin-Johnson syndrome, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy result from mutations in transport protein genes. These proteins also play a role in drug-induced liver disease and in primary biliary cirrhosis. Cyclosporine and oestradiol (glucuronide) for instance inhibit bile salt export protein (BSEP).
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PMID:[Bile formation and cholestasis]. 1114 92

ABC transporters are found in all known organisms, and approximately 1,100 different transporters belonging to this family have been described in the literature. The family is defined by homology within the ATP-binding cassette (ABC) region, which extends outside of the more typical Walker motifs found in all ATP-binding proteins. Most family members also contain transmembrane domains involved in recognition of substrates, which are transported across, into, and out of cell membranes, but some members utilize ABCs as engines to regulate ion channels. There are approximately 50 known ABC transporters in the human, and there are currently 13 genetic diseases associated with defects in 14 of these transporters. The most common genetic disease conditions include cystic fibrosis, Stargardt disease, age-related macular degeneration, adrenoleukodystrophy, Tangier disease, Dubin-Johnson syndrome and progressive familial intrahepatic cholestasis. At least 8 members of this family are involved in the transport of a variety of amphipathic compounds, including anticancer drugs, and some appear to contribute to the resistance of cancer cells to chemotherapy.
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PMID:Overview: ABC transporters and human disease. 1180 86

ATP-binding cassette (ABC) transporter genes are ubiquitously present in most organisms from bacteria to man. This gene family is the largest one known as of yet. Still growing, the number of human ABC transporters counts currently 47 members which belong to seven subfamilies. ABC transporters share a similar molecular architecture: (1) Full-structured transporters harbor two symmetric halves each consisting of one nucleotide binding domain (NBD) and one transmembrane domain (TMD). (2) Half-transporters with one NBD and one TMD homo- or heterodimerize to functional transporter complexes. ABC transporters are "traffic ATPases" which hydrolyze ATP and which transport a wide array of molecules or conduct the transport of molecules by stimulating other translocation mechanisms. Many ABC transporters are involved in human inherited or sporadic diseases such as cystic fibrosis, adrenoleukodystrophy, Stargardt's disease, drug-resistant tumors, Dubin-Johnson syndrome, Byler's disease, progressive familiar intrahepatic cholestasis, X-linked sideroblastic anemia and ataxia, persistent hyperinsulimenic hypoglycemia of infancy, and others. The present review summarizes the current findings in basic research and the efforts for bridging the gap to clinical applications in therapy and diagnostics.
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PMID:The human ATP-binding cassette transporter genes: from the bench to the bedside. 1189 42


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