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Abstract

Abstract 

  1. Bilirubin is an orange pigment derived from the degradation of the heme moiety of hemoproteins, particularly the hemoglobin of mature circulating erythrocytes.

  2. Bilirubin is a potentially toxic waste product that is normally rendered harmless by binding to serum albumin, conjugation in the liver, and efficient excretion into bile by the liver. Bilirubin is an antioxidant, and a protective role of bilirubin against oxidant damage has been suggested. On the other hand, patients with profound unconjugated hyperbilirubinemia are at risk for bilirubin encephalopathy (kernicterus). Accumulation of bilirubin in plasma and tissues results in jaundice, which has attracted the attention of patients and clinicians since antiquity.

  3. Following formation in the reticuloendothelial system, bilirubin is released into the circulation, where it avidly binds to serum albumin and is rapidly cleared by the liver. Extraction of bilirubin from the circulation is a specific hepatic function involving facilitated diffusion. Within the hepatocyte, bilirubin binds to cytosolic proteins, primarily to glutathione-S-transferases. The water-insoluble bilirubin molecule is transformed into polar bilirubin monoglucuronide and diglucuronide by the action of bilirubin-UDP-glucuronosyltransferase (bilirubin-UGT) and is excreted into the bile canaliculus against a concentration gradient by energy-consuming mechanisms.

  4. Inherited disorders of bilirubin metabolism result in hyperbilirubinemia. These include disorders resulting in predominantly unconjugated hyperbilirubinemia (Crigler-Najjar syndrome types I and II, and Gilbert syndrome) and those resulting in predominantly conjugated hyperbilirubinemia (Dubin-Johnson syndrome, Rotor syndrome, and benign recurrent intrahepatic cholestasis).

  5. Bilirubin-UGT (protein/gene for UDP-glucuronosyltransferase 1, family member 1A equivalent to bilirubin-UGT (UGT1A1)) and several additional isoforms of the UGT1A subfamily that mediate the glucuronidation of other aglycone substrates are expressed from the locus UGT1A, located on chromosome 2q37. Genetic lesions in any of the five exons that encode UGT1A1 may lead to complete absence (Crigler-Najjar syndrome type I; MIM 218800) or incomplete deficiency (Crigler-Najjar syndrome type II) of bilirubin glucuronidation. In contrast, Gilbert syndrome (MIM 143500) is associated with an abnormality of the TATAA box within the promoter region upstream to exon 1 of UGT1A1 that results in reduced expression of structurally normal UGT1A1. Dubin-Johnson syndrome (MIM 237500) is caused by a genetic abnormality of bile canalicular multispecific organic anion transporter, which is involved in the excretion of many non–bile salt organic anions by an adenosine triphosphate (ATP)-requiring active process. Dubin-Johnson syndrome is associated with a characteristic accumulation of pigments in the liver and an abnormality of porphyrin metabolism in which over 80 percent of urinary coproporphyrin is coproporphyrin I, as compared with less than 35 percent in normal individuals. Rotor syndrome (MIM 237450) is primarily a disorder of hepatic storage and differs from Dubin-Johnson syndrome by the lack of hepatic pigmentation, urinary coproporphyrin excretion pattern, and hepatic sulfobromophthalein (BSP) metabolism. Dubin-Johnson syndrome is caused by genetic lesions of the gene MRP2 (also termed cMOAT ). Other genetic abnormalities can cause hyperbilirubinemia, secondary to structural abnormalities of the biliary system or derangement of specific excretory functions of the bile canaliculus. These include progressive familial intrahepatic cholestasis, type I (MIM 211600) and benign recurrent intrahepatic cholestasis (MIM 243300), both of which are associated with mutations of the protein/gene for familial intrahepatic cholestasis-1 (FIC1) gene on chromosome 18q21. Progressive familial intrahepatic cholestasis type II (MIM 601847) is characterized by abnormality of bile salt excretion and is associated with mutations of the gene SPGP , which is located on chromosome 2q24. A third type of progressive familial intrahepatic cholestasis (MIM 602347) involves mutations of the MDR3 gene, the products of which are needed for phospolipid excretion in bile. Several heritable developmental disorders of the biliary system have been described. Of these, Alagille syndrome (MIM 118450) has been found to be caused by lesions of JAG1, a gene located on chromosome 20p12.

  6. Crigler-Najjar syndrome types I and II have an autosomal-recessive pattern of inheritance. Patients with Gilbert syndrome are homozygous for the specific promoter abnormality, but all subjects homozygous for this genotype do not exhibit the clinical picture of Gilbert syndrome. Studies of urinary coproporphyrin excretion reveal autosomal-recessive patterns of inheritance for Dubin-Johnson and Rotor syndromes.

  7. Several animal models of inherited disorders of bilirubin metabolism are important in understanding the pathophysiology of their human counterparts. These models include the Gunn rat (Crigler-Najjar syndrome type I); the Bolivian population of squirrel monkeys (Gilbert syndrome); and mutant albino rats with organic anion excretion defect (TR −\−), golden lion tamarin monkeys, and mutant Corriedale sheep (Dubin-Johnson syndrome).

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