Presentation: Patient with elevated unconjugated hyperbilirubin

A 24-year-old man presented to his GP with malaise, fatigue and jaundice. He was unwell recently with a sore throat and fever, which have settled. The physical examination is unremarkable, except for mild jaundice observed in the sclera. Blood tests show alanine transaminase (ALT) of 20IU/L (normal range 0–40IU/L), alkaline phosphatase (AlkP) of 104IU/L (normal range 30–130IU/L) and total bilirubin of 40μmol/L (normal range 0–21μmol/L) which is predominantly unconjugated (conjugated 10μmol/L, unconjugated 30μmol/L). Abdominal ultrasound is unremarkable.

• Gilbert syndrome should be suspected in individuals with mild unconjugated hyperbilirubinaemia, possibly provoked by known factors (for example dehydration, fasting, intercurrent illness, menstruation or overexertion), with no apparent liver disease or haemolysis.
• A presumptive diagnosis can be made in patients with the combination of:
  • unconjugated hyperbilirubinaemia on repeated testing;
  • normal full blood count, blood film and reticulocyte count; and/or
  • normal serum aminotransferase and alkaline phosphatase levels.
• Genomic testing can confirm the diagnosis if there is diagnostic uncertainty.
• The National Genomic Test Directory eligibility criteria for genomic testing is:
  • unconjugated hyperbilirubinaemia in the absence of haemolysis, where a molecular diagnosis will contribute to management.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• To investigate Gilbert syndrome, the appropriate test is:
  • R176 Gilbert syndrome: This is a single gene test consisting of targeted variant testing of the UGT1A1 gene.
• The majority of genomic tests in adults are currently undertaken on a singleton basis, though samples may be needed from other family members in order to interpret results.
• For tests such as R176, which do not include whole genome sequencing, you can use your local Genomic Laboratory Hub test order and consent (record of discussion) forms.
• The majority of tests are DNA-based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube).
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

For clinicians

• NICE: Gilbert’s syndrome

References:

• Vítek L and Tiribelli C. ‘Gilbert’s syndrome revisited‘. Journal of Hepatology 2023: volume 79, issue 4, pages 1,049–1,055. DOI: 10.1016/j.jhep.2023.06.004

For patients

• British Liver Trust: Gilbert’s syndrome
• NHS A to Z: Gilbert’s syndrome