Bile Pigment Metabolism and Its Disorders

Emery and Rimoin's Principles and Practice of Medical Genetics(2020)

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摘要
Bilirubin is the breakdown product of the heme moiety of hemoproteins, including hemoglobin, myoglobin, and several hepatic hemoproteins. About 80% of the 200–300 mg bilirubin is produced daily in reticuloendothelial cells from hemoglobin of senescent erythrocytes, the remainder being derived mostly from hepatic hemoproteins. Microsomal heme oxygenases cleave heme forming biliverdin, which is reduced to bilirubin by biliverdin reductase. At low concentrations, bilirubin is cytoprotective and provides metabolic benefits. However, bilirubin-induced neurological damage (BIND) caused by severe unconjugated hyperbilirubinemia is a major clinical concern. Physiologically, BIND is prevented by binding to plasma albumin, rapid uptake by hepatocytes, UGT1A1-mediated glucuronidation, and active canalicular excretion. A fraction of the bilirubin glucuronides is pumped out by ABCC3 through the sinusoidal surface of hepatocytes and undergoes reuptake by hepatocytes located downstream to sinusoidal blood flow. A small portion of bilirubin excreted in bile undergoes enterohepatic recycling, the remainder being degraded by bacteria to urobilinogen. Unconjugated hyperbilirubinemia can be caused by excessive bilirubin production, reduced hepatocellular uptake, or defective glucuronidation, whereas conjugated hyperbilirubinemia results from defective canalicular excretion or abnormal reuptake. Hyperbilirubinemia, which is universal in neonates, normally resolves in 1–2 weeks, but can be exacerbated or prolonged by breastfeeding or delayed UGT1A1 maturation (Lucey–Driscoll syndrome). In addition to acquired hepatobiliary diseases and hemolysis, a number of inherited liver disorders can cause lifelong hyperbilirubinemia. Coding region mutations of UGT1A1 can cause complete or partial loss of bilirubin glucuronidation (Crigler–Najjar syndrome, type 1 and type 2, respectively). A variant UGT1A1 promoter can reduce UGT1A1 expression, causing mild and innocuous unconjugated hyperbilirubinemia (Gilbert syndrome). Conjugated hyperbilirubinemia can result from mutations of the ABCC2 that reduce canalicular secretion of bilirubin glucuronides and many other organic anions causing Dubin–Johnson syndrome. Concurrent mutations of ABCB1 and ABCB3 disable reuptake of bilirubin glucuronides, causing mild conjugated hyperbilirubinemia (Rotor syndrome). Several other inherited defects of bile canalicular proteins cause four types of progressive familial intrahepatic cholestasis that cause mixed hyperbilirubinemia as well as liver injury.
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bile pigment metabolism,disorders
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