What is the role of UGT mutations in the pathophysiology of Gilbert syndrome?

Updated: May 21, 2019
  • Author: Hisham Nazer, MBBCh, FRCP, DTM&H; Chief Editor: BS Anand, MD  more...
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Bilirubin-UGT, which is located primarily in the endoplasmic reticulum of hepatocytes, is responsible for conjugating bilirubin into bilirubin monoglucuronides and diglucuronides. It is one of several UGT enzyme isoforms responsible for the conjugation of a wide array of substrates, including carcinogens, drugs, hormones, and neurotransmitters.

Knowledge of these enzymes has been enhanced greatly by the characterization of the UGT1 gene locus in humans. The gene that expresses bilirubin-UGT has a complex structure and is located on chromosome 2. [25, 28, 29, 30, 31, 32, 33] There are 5 exons, of which exons 2-5, at the 3' end, are constant components of all isoforms of UGT, coding for the uridine diphosphate (UDP)-glucuronic acid binding site. Exon 1 encodes for a unique region within each UGT and confers substrate specificity; exon 1a encodes the variable region for bilirubin UGT1A1. Defects in the UGT1A1 enzyme are responsible for Gilbert syndrome and for Crigler-Najjar syndrome. [34, 35]

Expression of UGT1A1 depends on a promoter region in a 5' position relative to each exon 1 that contains a TATAA box. Impaired bilirubin glucuronidation therefore may result from mutations in exon 1a, its promoter, or the common exons.

A breakthrough in understanding the genetic basis of Gilbert syndrome was achieved in 1995, when abnormalities in the TATAA region of the promoter were identified. The addition of 2 extra bases (TA) in the TATAA region interferes with the binding of transcription factor IID and results in reduced expression of bilirubin-UGT1 (30% of normal). In the homozygous state, diminished bilirubin glucuronidation is observed, with bile containing an excess of bilirubin monoglucuronide over diglucuronide. [28, 36, 37, 38, 39]

Insertion of a homozygous TA dinucleotide in the regulatory TATA box in the UGT 1A1 gene promoter is the most common genetic defect in Gilbert syndrome. [8]

In Gilbert syndrome, the UGT1A1*28 variant reduces bilirubin conjugation by 70% and is associated with irinotecan and protease inhibitor side effects. In vivo research into the genotype, present in 76% of individuals with Gilbert syndrome, suggests that transcription and transcriptional activation of glucuronidation genes responsible for conjugation and detoxification are directly affected, leading to lower responsiveness. [33]

Additional mutations have since been identified. For example, some healthy Asian patients with Gilbert syndrome do not have mutations at the promoter level but are heterozygotes for missense mutations (Gly71Arg, Tyr486Asp, Pro364Leu) in the coding region. These individuals also have significantly higher bilirubin levels than do patients with the wild-type allele.

Whether reduced bilirubin-UGT activity results from a reduced number of enzyme molecules or from a qualitative enzyme defect is unknown. To compound this uncertainty, other factors (eg, occult hemolysis or hepatic transport abnormalities) may be involved in the clinical expression of Gilbert syndrome. For example, many individuals who are homozygous for the TATAA defect do not demonstrate unconjugated hyperbilirubinemia, and many patients with reduced levels of bilirubin-UGT, as observed in some granulomatous liver diseases, do not develop hyperbilirubinemia.

Because of the high frequency of mutations in the Gilbert promoter, heterozygous carriers of Crigler-Najjar syndromes types 1 and 2 can also carry the elongated Gilbert TATAA sequence on their normal allele. Such combined defects can lead to severe hyperbilirubinemia and help to explain the finding of intermediate levels of hyperbilirubinemia in family members of patients with Crigler-Najjar syndrome.

Gilbert syndrome can also frequently coexist with conditions associated with unconjugated hyperbilirubinemia, such as thalassemia [40] and glucose-6-phosphate deficiency (G6PD). [41, 42] Much of the observed unconjugated hyperbilirubinemia could be attributed to variation at the UGT 1A1 locus. [43]

Origa et al, in a study of 858 patients with transfusion-dependent thalassemia, found that in individuals with a combination of thalassemia and the Gilbert syndrome genotype (TA)7/(TA)7 UGT1A1, the latter effected the prevalence of cholelithiasis and influenced the age at which the condition arose. [44] The authors suggested that in patients with a combination of thalassemia and Gilbert syndrome, biliary ultrasonography should be performed, starting in childhood.

A Greek study of 198 adult patients with cholelithiasis, along with 152 controls, also found evidence of an association between Gilbert syndrome and the development of cholelithiasis. [45]

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