The hereditary hyperbilirubinemias (Wolkoff et al., 1983) include (1) those resulting in predominantly unconjugated hyperbilirubinemia: Gilbert or Arias syndrome, Crigler-Najjar syndrome type I (218800), and Crigler-Najjar syndrome type II (606785); and (2) those resulting in predominantly conjugated hyperbilirubinemia: ... The hereditary hyperbilirubinemias (Wolkoff et al., 1983) include (1) those resulting in predominantly unconjugated hyperbilirubinemia: Gilbert or Arias syndrome, Crigler-Najjar syndrome type I (218800), and Crigler-Najjar syndrome type II (606785); and (2) those resulting in predominantly conjugated hyperbilirubinemia: Dubin-Johnson syndrome (237500), Rotor syndrome (237450), and several forms of intrahepatic cholestasis (147480, 211600, 214950, 243300). Detailed studies show that patients with Gilbert syndrome have reduced activity of bilirubin glucuronosyltransferase (Bosma et al., 1995, Koiwai et al., 1995). - Genetic Heterogeneity of Hyperbilirubinemia See also Crigler-Najjar syndrome type I (HBLRCN1; 218800), Crigler-Najjar syndrome type II (HBLRCN2; 606785), and transient familial neonatal hyperbilirubinemia (HBLRTFN; 237900), all caused by mutation in the UGT1A1 gene (191740) on chromosome 2q37; Dubin-Johnson syndrome (DJS, HBLRDJ; 237500), caused by mutation in the ABCC2 gene (601107) on chromosome 10q24; and Rotor syndrome (HBLRR; 237450), caused by digenic mutation in the SLCO1B1 (604843) and SLCOB3 (605495) genes, both on chromosome 12p.
The characteristics of Gilbert syndrome are normal liver function tests of the usual type, normal liver histology, delayed clearance of bilirubin from the blood, and mild jaundice that tends to fluctuate in severity, particularly after fasting (Nixon and ... The characteristics of Gilbert syndrome are normal liver function tests of the usual type, normal liver histology, delayed clearance of bilirubin from the blood, and mild jaundice that tends to fluctuate in severity, particularly after fasting (Nixon and Monahan, 1967). This disorder is difficult to distinguish from prolonged posthepatic hyperbilirubinemia. Arias (1962) demonstrated glucuronyltransferase deficiency in 8 patients with chronic nonhemolytic jaundice and serum unconjugated bilirubin levels of 6.2 to 18.8 mg percent. Arias et al. (1969) concluded that this disorder is distinct from Crigler-Najjar syndrome type I (218800), which also has deficiency of hepatic glucuronyltransferase activity. In Crigler-Najjar syndrome type I, hyperbilirubinemia is severe, with total serum bilirubin levels ranging from 20 to 45 mg/dL, and is frequently accompanied by kernicterus. The bile is almost colorless and contains traces of unconjugated bilirubin only. Transmission is autosomal recessive and phenobarbital does not influence the hyperbilirubinemia. In the Arias type, hyperbilirubinemia is less severe without kernicterus. The bile is pigmented and contains bilirubin glucuronide. Phenobarbital administration causes prompt disappearance of jaundice. Since patients with the Arias type have a disorder almost only of cosmetic significance, long-term phenobarbital treatment is useful. Black and Sherlock (1970) found that all 13 patients treated with phenobarbitone showed a rapid fall in plasma bilirubin; in 3 of the 10 symptomatic patients, the symptoms improved. The reduction in plasma bilirubin was associated with an increase in hepatic bilirubin UDP-glucuronyltransferase activity. Dawson et al. (1979) presented evidence for 2 types of Gilbert disease. One group with normal distribution of neutral alpha-glucosidase, an endoplasmic reticulum marker, had normal endoplasmic reticulum by electron microscopy. Those with an abnormal distribution showed marked hypertrophy of the smooth endoplasmic reticulum by electron microscopy. Strassburg (2008) provided a review of the role of UGT1A1 variants in drug metabolism and noted that the variation of glucuronidation in patients with Gilbert syndrome impacts drug therapy, particularly with drugs that have a narrow therapeutic spectrum.
In 6 unrelated Japanese families with Gilbert syndrome, Koiwai et al. (1995) demonstrated that affected members were heterozygous for several different missense mutations in the UGT1 gene, including a G-to-A change at nucleotide 211 in exon 1, resulting ... In 6 unrelated Japanese families with Gilbert syndrome, Koiwai et al. (1995) demonstrated that affected members were heterozygous for several different missense mutations in the UGT1 gene, including a G-to-A change at nucleotide 211 in exon 1, resulting in a gly71-to-arg substitution (G71R; 191740.0016), and a C-to-A change at nucleotide 686, resulting in a pro229-to-gln substitution (P229Q; 191740.0010). Interestingly, in a Japanese girl with anorexia nervosa and unconjugated hyperbilirubinemia, Maruo et al. (1999) identified a homozygous G71R mutation. The parents were heterozygous for the mutation. Hsieh et al. (2001) studied 20 unrelated patients with Gilbert syndrome and found several combinations of mutations, including homozygous, heterozygous, and compound heterozygous, all of which led to differing levels of enzyme activity. Sugatani et al. (2002) presented evidence suggesting that a SNP, -3263T-G (191740.0024), in the UGT1A1 promoter, also known as the phenobarbital-responsive enhancer module NR3 region (gtPBREM NR3), may predispose patients to hyperbilirubinemia, particularly in patients with Gilbert syndrome and another mutation in the UGT1A1 gene. - TATAA Repeat Mutation Bosma et al. (1995) found that the coding region of the UGT1A1 gene was normal in 10 patients with Gilbert syndrome, but that these patients were homozygous for 2 extra bases (TA) in the TATAA element of the 5-prime promoter region of the gene; they found A(TA)7TAA (191740.0011) rather than the normal A(TA)6TAA. The presence of the longer TATAA element resulted in reduced expression of a reporter gene construct encoding firefly luciferase in a human hepatoma cell line. Schmid (1995) pointed out that this is another example of an expanded nucleotide repeat. The frequency of the abnormal allele reported by Bosma et al. (1995) was 40% among normal subjects. The 3 men in the control group who were homozygous for the longer TATAA element had significantly higher serum bilirubin levels than the other 52 normal subjects. In a kindred with a history of Crigler-Najjar syndrome type II, only the 6 heterozygous carriers who had a longer TATAA element on the structurally normal allele had mild hyperbilirubinemia characteristic of Gilbert syndrome. Bosma et al. (1995) concluded that reduced expression of the UGT1A1 gene due to abnormality in the promoter region is a necessary but not sufficient change for Gilbert syndrome. This made it necessary to search for ancillary factors that might modify the serum bilirubin concentration in persons homozygous for the promoter defect. These factors could include hepatic transport abnormalities, occult hemolysis, and stress-related induction of heme oxygenase. Using a novel PCR method termed fluorescence resonance energy transfer (FRET), Borlak et al. (2000) reported the (TA)6 and (TA)7 UGT1A1 genotypes of 265 unrelated healthy individuals from southern Germany. Genotype distribution was 43:45:12 for (TA)6/(TA)6, (TA)6/(TA)7, and (TA)7/(TA)7, respectively. Serum total bilirubin levels increased with presence of the (TA)7 allele; median micromoles per liter were 12.0, 14.0, and 20.5, respectively, which was a statistically significant difference. Prevalence for the homozygous (TA)7 genotype was 12.4%. Borlak et al. (2000) emphasized the clinical importance of the UGT1A1 genotype and function of the enzyme, particularly for drug metabolism. Hsieh et al. (2007) showed that mutant TA7 TATA-box-like sequence has reduced protein binding affinity compared to wildtype, and that binding affinity progressively decreases as the number of TA repeats in the UGT1A1 TATA-box-like sequence increases. The authors stated that this decrease in binding affinity underlies the reduced promoter activity of mutant UGT1A1 compared to wildtype and explains the pathogenesis of Gilbert syndrome.