Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

MDR3 P-glycoprotein mediates canalicular phospholipid transport in hepatocytes. Defects in the MDR3 gene have been found to cause a subtype of progressive familial intrahepatic cholestasis (PFIC) with high gamma-glutamyltranspeptidase (GGT) levels. Affected children develop proliferation of biliary epithelium, portal inflammation, and biliary cirrhosis. The frequency of MDR3 mutations in patients with high GGT-PFIC is unclear. There have been no Asian patients reported to carry MDR3 mutations. To determine the role of MDR3 defects in chronic cholestatic patients, we studied six Taiwanese children from five families who presented high GGT-PFIC among 47 patients with infantile onset chronic intrahepatic cholestasis. Sequence analysis of MDR3 cDNA from liver tissues was performed. Only one patient had mutation in the MDR3 gene. This patient had a homozygous 719-bp deletion (nucleotide 287 to 1005) of liver cDNA encompassing exon 5 to 9 and leading to protein truncation. The onset age was 1 y in contrast with the other five patients who presented neonatal cholestasis. Four patients without mutation, including one sibling pair, exhibited histologic features of prominent portal fibrosis leading to advanced biliary cirrhosis that were indistinguishable from the case of MDR3 mutation. We concluded that mutations in MDR3 accounted for approximately 2% (1/47) of infantile onset chronic cholestasis in Taiwan. Those patients presenting high GGT-PFIC with early onset cholestasis but without MDR3 mutation probably had inheritable disorders remaining to be clarified.
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PMID:Progressive familial intrahepatic cholestasis with high gamma-glutamyltranspeptidase levels in Taiwanese infants: role of MDR3 gene defect? 1142 Apr 18

Class III multidrug resistance P-glycoproteins, mdr2 in mice and MDR3 in humans, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion. The role of an MDR3 gene defect in liver disease was initially suspected in a subtype of progressive familial intrahepatic cholestasis called PFIC3. Several MDR3 mutations have been identified in children with PFIC3 and are associated with a low level of phospholipids in bile, leading to a high biliary cholesterol saturation index. Mutations leading to a truncated protein are associated with an absence of canalicular MDR3 protein. The phenotypic spectrum of PFIC3 ranges from neonatal cholestasis to cirrhosis in young adults. There is now strong evidence that in addition to PFIC3, an MDR3 defect can be involved in intrahepatic cholestasis of pregnancy and in cholesterol gallstone disease. Therefore, at least three human liver diseases are due to a single gene deficiency. Patients with PFIC3 due to MDR3 deficiency may benefit from ursodeoxycholic acid therapy and could be good candidates for cell therapy in the future.
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PMID:Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases. 1174 43

We describe a 47-year-old patient who developed cholelithiasis in adolescence, followed by recurrent intrahepatic cholestasis of pregnancy, and finally biliary cirrhosis in adulthood. In our patient, the consecutive presentation of the 3 mentioned disorders raised the suspicion of a defect of MDR3, the canalicular protein involved in the transport of phospatidylcholine to bile. Mutational analysis in our patient showed a heterozygous missense mutation of the MDR3 gene that has not been described previously, which occurs in exon 14 at codon 535, and results in the substitution of glycine for aspartic acid. Further analysis of 7 members of the family showed the same mutation in her daughter who, on follow-up, developed cholestasis of pregnancy and persisting high serum levels of gamma-glutamyl transpeptidase and alkaline phosphatase after delivery. Although biliary cirrhosis associated with MDR3 deficiency typically appears before the age of 25 years, in our case, the relatively mild MDR3 dysfunction allowed for a slower progression of the disease with established, well-advanced cirrhosis in the fifth decade of life. The present case, which accumulates the 3 clinical disorders assocaited with MDR3 deficiency, shows that this condition should be suspected not only in children or young people with high gamma-glutamyl transpeptidase cholestasis but also in middle-aged or older patients with chronic idiopathic cholestasis, especially when there is a previous history of cholestasis of pregnancy or juvenile cholelithiasis.
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PMID:A multidrug resistance 3 gene mutation causing cholelithiasis, cholestasis of pregnancy, and adulthood biliary cirrhosis. 1472 40

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

Mutations in multidrug resistance 3 gene (MDR3 or ABCB4) underlie progressive familial intrahepatic cholestasis type 3 (PFIC3), a severe pediatric liver disease progressing to cirrhosis. Abcb4-/- mice exhibit slowly developing hepatic lesions that can be accelerated by feeding a cholic acid (CA)-supplemented diet. We investigated the beneficial effects of a soybean lecithin (L)-supplemented diet in this model of liver disease. Abcb4-/- mice and wild-type (WT) controls were divided in four groups by the diet they were fed: control (C) diet, L-supplemented diet, CA-supplemented diet, and L- and CA-supplemented (L+CA) diet. After 2 wk on these regimens, liver enzymes and bilirubin were measured in serum with bile flow, total bile acids, and cholesterol (CHOL) and phospholipid (PL) concentrations in bile. Ductular hyperplasia, portal fibroblastic cell proliferation, myofibroblast activation, and hepatic fibrosis were quantified on liver sections. Abcb4-/- mice fed the C diet exhibited mild liver damage. CA produced very high elevations of serum liver enzymes and bilirubin with significant bile duct proliferation, peribiliary fibroblast activation, and fibrosis. The L-supplemented diet dramatically mitigated the hepatic damage in CA-supplemented diet animals. We conclude that L is protective against liver disease in Abcb4-/- mice and suggest that it could offer potential benefit in PFIC3.
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PMID:Dietary lecithin protects against cholestatic liver disease in cholic acid-fed Abcb4- deficient mice. 1723 20

Because ATP-binding cassette (ABC) transporters are important for normal bile secretion, hereditary and acquired ABC transporter defects play a central role in the pathogenesis of cholestasis. Defects of the phospholipid export pump MDR3 ( ABCC4) result in impaired biliary excretion of phosphatidylcholine and a variety of cholestatic syndromes ranging from progressive familial intrahepatic cholestasis in neonates to biliary cirrhosis in adults. Moreover, MDR3 mutations predispose to cholestasis of pregnancy and drug-induced cholestasis. Because MDR2 (rodent orthologue of human MDR3) knockout mice develop sclerosing cholangitis, it is attractive to speculate that MDR3 defects could also play an important role in cholangiopathies in humans. Indeed, MDR3 variants could play a role as modifier gene in primary biliary cirrhosis and primary sclerosing cholangitis, but their exact role needs further clarification. Impaired biliary phosphatidylcholine excretion has also been reported in total parenteral nutrition-induced cholestasis and bile duct injury following liver transplantation, but a genetic basis for these findings remains to be explored. Several drugs for the treatment of cholestatic liver diseases target MDR3 expression and function, further underscoring the clinical significance of this transport system.
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PMID:MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes. 1729 78

Primary metabolic disorders are a disparate group of diseases that may or may not be accompanied by hepatic manifestations. Those with liver involvement may show a range of histopathologic changes. Proper histologic diagnosis requires correlation with clinical and laboratory data, including evaluation for mutations either via serum protein electrophoresis or through formal genetic analysis. This article is a review of the three most common inherited metabolic disorders which may present with a hepatitic pattern. In alpha1-antitrypsin disorder, there is a broad range of clinical presentations, age at presentation, and histological features ranging from "neonatal hepatitis" to a chronic progressive hepatitis in later childhood and adulthood. Hence, this disorder must be in the differential diagnosis of liver disease of the very young, and in older children and adults, with or without coexistent overt pulmonary symptoms. In Wilson disease, presentation tends to be in older childhood or the adult, with a progressive chronic hepatitis. Cystic fibrosis may feature a characteristic obstructive biliary syndrome, coexisting with the many extrahepatic manifestations of this debilitating disease. Lastly, the progressive familial intrahepatic cholestasis (PFIC) syndromes are given as examples of inherited metabolic conditions in which relentlessly progressive cholestatic liver disease eventuates over years in end-stage cholestatic liver disease with cirrhosis. Distinguishing features include absence of elevated serum gamma-glutamyl transpeptidase (GGT) in PFIC-1 and PFIC-2, and elevated GGT in PFIC-3. However, molecular studies are required for a confident diagnosis of the rare PFIC syndromes.
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PMID:Hepatitic inherited metabolic disorders. 1735 91

ABCB4 (MDR3), a lipid translocator, moves phosphatidylcholine from the inner to the outer leaflet of the canalicular membrane. Genetic mutations of ABCB4 lead to three distinct but related hepatobiliary diseases. Progressive familial intrahepatic cholestasis (PFIC) type 3 is a chronic cholestatic syndrome characterized by a markedly elevated gamma-glutamyltranspeptidase. Patients present with jaundice, pruritus, and hepatosplenomegaly. Periportal inflammation progresses to biliary cirrhosis and causes portal hypertension. Ursodeoxycholic acid (UDCA) normalizes liver function tests in approximately one half of treated PFIC type 3 patients. Partial responders or nonresponders eventually will require liver transplantation. Gallstone patients with ABCB4 mutations may have low phospholipid-associated cholelithiasis syndrome, characterized by cholesterol gallstones and intrahepatic microlithiasis, along with recurrent biliary symptoms, despite cholecystectomy. Patients with ABCB4 mutations also may develop intrahepatic brown pigment stones. UDCA may improve biliary symptoms even before the dissolution of stones occurs. Additional therapies such as farnesoid X receptor ligands/agonists and benzfibrates show future therapeutic promise. Intrahepatic cholestasis of pregnancy affects pregnant women with abnormal ABCB4. These women suffer from disabling pruritus and also may experience steatorrhea. Fetuses are at high risk for prematurity and stillbirths. The definitive treatment is delivery of the baby. In the interim, limited fat intake, fat-soluble vitamin supplementation, and UDCA with or without S-adenosylmethionine can provide symptomatic relief. Additional hepatobiliary diseases related to ABCB4 mutations are likely to be identified. This may result in the discovery of additional therapies for PFIC type 3, gallstones, and intrahepatic cholestasis of pregnancy.
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PMID:The Multiple Facets of ABCB4 (MDR3) Deficiency. 1822 10

Alterations in bile secretion at the hepatocellular and cholangiocellular levels may cause cholestasis. Formation of 'toxic bile' may be the consequence of abnormal bile composition and can result in hepatocellular and/or bile duct injury. The canalicular phospholipid flippase (Mdr2/MDR3) normally mediates biliary excretion of phospholipids, which normally form mixed micelles with bile acids and cholesterol to protect the bile duct epithelium from the detergent properties of bile acids. Mdr2 knockout mice are not capable of excreting phospholipids into bile and spontaneously develop bile duct injury with macroscopic and microscopic features closely resembling human sclerosing cholangitis. MDR3 mutations have been linked to a broad spectrum of hepatobiliary disorders in humans ranging from progressive familial intrahepatic cholestasis in neonates to intrahepatic cholestasis of pregnancy, drug-induced cholestasis, intrahepatic cholelithiasis, sclerosing cholangitis and biliary cirrhosis in adults. Other examples for bile injury due to the formation of toxic bile include the cholangiopathy seen in cystic fibrosis, after lithocholate feeding (in mice) and vanishing bile duct syndromes induced by drugs and xenobiotics. Therapeutic strategies for cholangiopathies may target bile composition/toxicity and the affected bile duct epithelium itself, and ideally should also have anti-cholestatic, anti-fibrotic and anti-neoplastic properties. Ursodeoxycholic acid (UDCA) shows some of these properties, but is of limited efficacy in the treatment of human cholangiopathies. By contrast to UDCA, its side chain-shortened homologue norUDCA undergoes cholehepatic shunting leading to a bicarbonate-rich hypercholeresis. Moreover, norUDCA has anti-inflammatory, anti-fibrotic and anti-proliferative effects, and stimulates bile acid detoxification. Upcoming clinical trials will have to demonstrate whether norUDCA or other side chain-modified bile acids are also clinically effective in humans. Finally, drugs for the treatment of cholangiopathies may target bile toxicity via nuclear receptors (FXR, PPARalpha) regulating biliary phospholipid and bile acid excretion.
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PMID:Lessons from the toxic bile concept for the pathogenesis and treatment of cholestatic liver diseases. 1899 69

Class III multidrug resistance P-glycoproteins, mdr2 in mice and MDR3 in human, are canalicular phospholipid translocators involved in biliary phospholipid (phosphatidylcholine) excretion.The role of a MDR3 (ABCB4) gene defect in liver disease has been initially proven in a subtype of progressive familial intrahepatic cholestasis called PFIC3, a severe pediatric liver disease that may require liver transplantation.Several MDR3 mutations have been identified in children with PFIC3 and are associated to low level of phospholipids in bile leading to high biliary cholesterol saturation index.MDR3 mutations are associated to loss of canalicular MDR3 protein and /or to loss of protein function.There is evidence that biallelic or monoallelic MDR3 defect causes or predisposes to 6 human liver diseases (PFIC3, adult biliary cirrhosis, low phospholipid associated cholelithiasis syndrome, transient neonatal cholestasis, intrahepatic cholestasis of pregnancy, drug induced cholestasis).Some patients with MDR3 deficiency may benefit from ursodeoxycholic acid therapy and could be good candidates to a targeted pharmacological approach and/or to cell therapy in the future.
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PMID:Liver diseases related to MDR3 (ABCB4) gene deficiency. 1927 48


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