Gilbert’s Syndrome is a benign inherited condition causing mild, intermittent indirect hyperbilirubinemia.
Pathophysiology 2) BMJ Publishing Group Limited
Uridine-diphosphoglucuronate glucuronosyltransferase (UDPGT) is the enzyme responsible for conjugating bilirubin into bilirubin monoglucuronide and diglucuronide; it is therefore the rate limiting step of bilirubin conjugation. This occurs predominantly in the endoplasmic reticulum of hepatocytes. There are 5 exons that ultimately lead to production of UDPGT. Exon 1 determines substrate specificity. There are at least 13 different types of exon 1. Exon 1a encodes the variable region for UDPGT-1A1, the enzyme responsible for conjugating bilirubin. Upstream to exon 1a there is a TATAA box promoter region. The normal sequence of the TATAA region is A[TA]6TAA. People with Gilbert’s syndrome inherit a different sequence of the promoter region and predominantly express a longer sequence than A[TA]6TAA, known as A[TA]7TAA. Other mutations have been discovered within the coding regions of the UDPGT-1A1 leading to the Gilbert’s phenotype.
There is also evidence suggesting that patients with UDPGT-1A1 variants, mainly UDPGT-1A1*28, may have abnormal metabolism of protease inhibitors and thereby may develop severe irinotecan toxicity or icterus during treatment with atazanavir. There is evidence suggesting that these mutations provide a protective effect in the development of Hodgkin’s lymphoma and cardiovascular diseases.
This variant (UDPGT-1A1*28) has also been described as related with the development of indirect hyperbilirubinaemia in patients with rheumatoid arthritis receiving tocilizumab, a monoclonal antibody to the interleukin-6 receptor. No other evidence of severe liver toxicity has been demonstrated in these patients treated with this medication. One observation has been made regarding the UDPGT-1A1 variant specifically in patients receiving treatment for hepatitis C with pegylated interferon and ribavirin. It seems that these patients may develop a higher indirect bilirubin level due to ribavirin, when compared to patients that do not carry this variant. This phenomenon does not correlate with liver toxicity.
- Transient reduction in hepatic glucuronyl transferase activity to about one-third normal levels
- Mild jaundice during periods of stress, such as concurrent illness, strenuous exercise, or fasting
- Laboratory findings – Elevated serum indirect bilirubin (usually 2-3 times normal, almost always <6 mg/dL), Normal CBC, Normal liver enzymes.
- No treatment necessary; reassurance only
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