What is Gilbert’s syndrome?
Gilbert’s syndrome or benign hereditary intermittent (with periodic exacerbations) hyperbilirubinaemia is the most common cause of hereditary increased levels of bilirubin. Gilbert’s syndrome is not a disease as such, but rather a hereditary metabolic pathology that can cause elevated bilirubin levels in the blood. Gilbert’s syndrome is not dangerous. The most obvious symptom is more or less marked jaundice that does not indicate a serious condition, but is only a temporary cosmetic affliction. The jaundice is not marked. Usually, it becomes more evident during stressful situations, after fasting, excessive use of alcohol or strenuous physical exertion. It is not an indication of hepatic damage, therefore therapy is unnecessary. Jaundice may not appear in some patients. The mean prevalence rate of Gilbert’s syndrome in the Caucasian population is 5–12% (Borlak at. al., 2000).
The main objective in diagnosing Gilbert’s syndrome is to exclude other serious hepatic conditions.
Description of the test
Performing a Gilbert’s syndrome test in our laboratory involves a simple “saliva sample” – a swab taken from oral mucosa. This test does not require a hospital stay as is the case with a biochemical urine test. Genetic testing provides the most accurate results. This has become the standard method for diagnosing Gilbert’s syndrome.
Gilbert’s syndrome is caused by mutations in the UGT1A1 gene that encodes bilirubin-UDP glucuronosyltransferase (UGT). The most common mutation in the case of Gilbert’s syndrome is TA insertion (homozygous) in the promoter region of the UGT1A1 gene (Monaghan G. et. al., 1996). This mutation reduces bilirubin-UDP glucuronosyltransferase expression by 30–50% (Hsieh et.al., 2007). Reduced bilirubin-UDP glucuronosyltransferase expression leads to an increased level of bilirubin in the blood, because bilirubin-UDP glucuronosyltransferase is the enzyme responsible for bilirubin glucuronidation.
It should also be noted that the metabolization of particular medicinal products (e.g., Irinotecan, Paracetamol, etc.) requires glucuronidation, and use of such medicines may cause intolerance in patients with Gilbert’s syndrome (Esteban A. et al., 1999; Innocenti F. et. al., 2004).
Interpretation of results
The most common cause of Gilbert’s syndrome is TA insertion in the promoter region of the UGT1A1 gene. Normally, both alleles in the promoter region of the UGT1A1 gene have six TA repeats – A(TA)6TAA. However, in the case of Gilbert’s syndrome, both alleles contain seven TA repeats – A(TA)7TAA.
A patient has an elevated level of bilirubin in the blood. The DNA test used to diagnose Gilbert’s syndrome, which detects TA insertion in the promoter region of the UGT1A1 gene, may have two results:
1. Hereditary Gilbert’s syndrome is confirmed
Genotype: homozygous (TA)7 – TA insertion is present in both alleles – A(TA)7TAA.
2. Hereditary Gilbert’s syndrome is not confirmed
homozygous (TA)6 – neither of the alleles have a TA insertion: A(TA)6TAA
heterozygous – one allele contains TA insertion, the other does not: A(TA) 6TAA/A(TA)7TAA
Another cause for the elevated bilirubin levels should be identified. In such cases, the existence of other mutations in the UGT1A1 gene that are not detected by this test cannot be excluded.