Core concept
- Gilbert's syndrome = reduced activity of UGT1A1 (UDP-glucuronosyltransferase) -- the enzyme that conjugates bilirubin with glucuronic acid in the liver
- Reduced conjugation capacity (~30% of normal activity, promoter polymorphism, commonly a TA repeat expansion) -> isolated mild unconjugated (indirect) hyperbilirubinaemia
- All other liver function (synthetic function, transaminases, conjugation of other substrates) is normal -- a purely bilirubin-handling defect, benign
Key detail
- Bilirubin rises specifically under conditions that increase bilirubin load or reduce hepatic uptake/conjugation demand: fasting, intercurrent illness, dehydration, physical exertion, stress
- Jaundice is mild (usually total bilirubin <3 mg/dL / <51 umol/L), fluctuating, and resolves between episodes
- Distinguish from Crigler-Najjar syndrome -- much more severe UGT1A1 deficiency (type 1 = absent activity, kernicterus risk) or near-absent (type 2, partial response to phenobarbital)
Clinical relevance
- Diagnosis is clinical/exclusionary: isolated unconjugated hyperbilirubinaemia with normal FBC (excludes haemolysis), normal LFTs otherwise, normal reticulocyte count -- genetic testing rarely needed
- No treatment required and no long-term liver consequence -- reassurance is the management
- Relevant to drug metabolism: reduced UGT1A1 activity increases risk of toxicity from drugs cleared by this pathway, notably irinotecan (SN-38 glucuronidation) -> increased neutropenia/diarrhoea risk, and can affect atazanavir handling
Correlations
- Contrast with haemolysis as a cause of unconjugated hyperbilirubinaemia -- haemolysis has anaemia, high reticulocytes, low haptoglobin, high LDH; Gilbert's has none of these
- Contrast with conjugated hyperbilirubinaemia causes (biliary obstruction, hepatocellular disease, Dubin-Johnson/Rotor syndrome -- conjugation intact, excretion defective)
- UGT1A1 polymorphism screening is sometimes used pre-emptively before irinotecan chemotherapy to predict toxicity risk
Study aid only. These notes are written with the help of AI. Not for guiding clinical decisions.