The multiple facets of ABCB4 (MDR3) deficiency |
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Authors: | Shikha S Sundaram Ronald J Sokol |
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Institution: | (1) Section of Pediatric Gastroenterology, Hepatology, and Nutrition, The Children’s Hospital, 1056 East 19th Avenue, B290, Denver, CO 80218-1088, USA |
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Abstract: | Opinion statement 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 γ-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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