Gilbert’s Syndrome

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Summary 1) First Aid for the Basic Sciences: Organ Systems by Tao Le

Gilbert’s Syndrome is a benign inherited condition causing mild, intermittent indirect hyperbilirubinemia.

Pathophysiology 2) BMJ Publishing Group Limited

Gilbert Syndrome

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.

Causes 3) First Aid for the Basic Sciences: Organ Systems by Tao Le

  • Transient reduction in hepatic glucuronyl transferase activity to about one-third normal levels

Symptoms 4) First Aid for the Basic Sciences: Organ Systems by Tao Le

  • Mild jaundice during periods of stress, such as concurrent illness, strenuous exercise, or fasting

Decreased Bilirubin Uptake by Liver Cells

Diagnosis 5) First Aid for the Basic Sciences: Organ Systems by Tao Le

  • Laboratory findings – Elevated serum indirect bilirubin (usually 2-3 times normal, almost always <6 mg/dL), Normal CBC, Normal liver enzymes.

Treatment 6) First Aid for the Basic Sciences: Organ Systems by Tao Le

  • No treatment necessary; reassurance only

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