Gilbert Syndrome

Background

• Gilbert syndrome is a benign hereditary condition characterized by intermittent episodes of unconjugated hyperbilirubinemia.
• It is caused by autosomal recessive inheritance of a mutation in the promoter region of the uridine diphosphate (UDP)-glucuronosyltransferase gene (UGT1A1) on chromosome 2q37.
  • The mutation results in reduced hepatic glucuronidation (conjugation) of bilirubin.
  • Impaired hepatic glucuronidation can also alter metabolism of some drugs, and may increase the risk for or worsen hyperbilirubinemia associated with comorbid conditions, such as hemolytic disorders or neonatal jaundice.
  • Homozygous UGT1A1*28 polymorphism is the most common genotype in Gilbert syndrome.
• Prevalence varies by population, but Gilbert syndrome is reported to affect 2%-10% worldwide.
• Gilbert syndrome typically presents as mild intermittent jaundice in adolescence, or as asymptomatic hyperbilirubinemia detected on blood tests performed for other reasons.
• Bilirubin elevation often occurs with dehydration, fasting, overexertion, menstruation, or an intercurrent illness.
• Less commonly, Gilbert syndrome may present as neonatal jaundice or severe hyperbilirubinemia in patients with underlying conditions.

Evaluation

• Suspect in patients with intermittent jaundice or asymptomatic hyperbilirubinemia.
• Perform blood tests - combination of mild, predominantly unconjugated hyperbilirubinemia; absence of hemolysis; normal liver enzymes and no evidence of other causes of liver disease establishes clinical diagnosis.
  • Total bilirubin is typically ≤ 85 mcmol/L (4.09 mg/dL), and conjugated bilirubin is usually within normal range or < 20% of total.
  • Negative Coombs test, and normal complete blood count, reticulocyte count, haptoglobin, and lactate dehydrogenase all exclude hemolysis.
  • Normal liver enzyme profile helps exclude other liver disease.
• Additional testing generally is not necessary, but may be considered in some patients.
  • Consider genetic testing in patients with more severe hyperbilirubinemia, or before initiating treatment with drugs associated with genotype-specific toxicity risks (such as irinotecan).
  • Liver ultrasound may be considered to confirm absence of hepatobiliary disease.
• Provocation tests (such as by fasting, or rifampin or nicotinic acid tests) are generally no longer used for diagnosis.

Management

• Usually, no specific treatment or management is necessary.
• Advise patients to avoid medications with known or potential toxicity in Gilbert syndrome.