Aetiology

The genetic basis of GS was determined in 1995 with the discovery of alterations in the TATA box promoter region of the UGT1A1 gene.[12] This gene has been characterised and is found on chromosome 2.[13] Inheritance patterns of GS have been difficult to ascertain. Data suggest an autosomal recessive pattern of inheritance, whereas earlier studies report a possible autosomal dominant transmission with an incomplete penetrance pattern.[12] It is believed that when GS is caused by a missense mutation in the exon 1 of the UGT1A1 gene, the condition is conferred in an autosomal dominant manner with varying penetrance and results in defective enzymatic function. This is seen more commonly in Asian populations. When the promoter region for the gene is implicated, the condition is transmitted by autosomal recessive inheritance and leads to altered enzyme production. This promoter region mutation is seen more frequently in white people.[14]

Pathophysiology

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.[13] Upstream to exon 1a there is a TATA box promoter region. The normal sequence of the TATA region is A[TA]6TAA. People with GS inherit a different sequence of the promoter region and predominantly express a longer sequence than A[TA]6TAA, known as A[TA]7TAA.[12] Other mutations that lead to the Gilbert phenotype have been discovered within the coding regions of the UGT1A1 gene.[10][11][15]

Testosterone decreases the activity of uridine-diphosphoglucuronate glucuronosyltransferase (UDPGT) and consequently GS is more common in males and is usually diagnosed after puberty.[16] Patients with UGT1A1 gene variants, mainly UGT1A1*28, may have abnormal metabolism of certain drugs.[14] Evidence suggests that mutations in the UGT1A1 gene provide protective effects in the development of Hodgkin's lymphoma and cardiovascular diseases.[17][18]

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