Approach

A presumptive diagnosis of GS can be made when the following features are present:[19]

  • Asymptomatic healthy patient with mild unconjugated hyperbilirubinaemia (<68.4 micromol/L [<4 mg/dL])

  • No evidence of haemolysis, with normal findings on full blood count, reticulocyte count, lactate dehydrogenase (LDH) level, serum haptoglobin level, Coombs' test, and blood smear

  • Normal serum transaminases and alkaline phosphatase levels

  • Exclusion of medications that cause hyperbilirubinaemia.

If diagnosis is uncertain, genetic testing for GS (UGT1A1 genotype) may be considered alongside exclusion of other rarer causes of persistent unconjugated hyperbilirubinaemia.[19]

Genetic tests

  • Polymerase chain reaction can be used to identify mutations and genetic polymorphisms (e.g., UGT1A1*28) found in the TATA promoter region of the UGT1A1 gene.[20][21]

  • Although serum bilirubin concentrations act as an indirect measure of UDPGT activity, direct assays of UDPGT enzymatic activity can be performed.[21]

Plasma unconjugated bilirubin response to fasting or administration of nicotinic acid

If confirmation of GS is needed, the following provocative tests may be employed:

Fasting:

  • GS patients who consume a diet of ≤400 kcal/day will have a 2- to 3-fold rise in plasma unconjugated bilirubin level within 48 hours of initiating the fast. The level should return to normal with the resumption of a normal diet.

  • The same effect may be seen with a normal diet that is devoid of lipids. The bilirubin level should normalise when lipids are restored to the diet. The mechanism of these processes is not entirely understood.[22]

Nicotinic acid:

  • Administration of 50 mg of nicotinic acid intravenously results in a 2- to 3-fold rise in plasma unconjugated bilirubin level within 3 hours. Normal subjects, or those with haemolysis, have more modest or no increase in bilirubin level.[8]

While these tests are rarely used in the diagnostic workup of GS, they may be of value in cases of diagnostic uncertainty, and in the further characterisation of confirmed cases.

Liver biopsy

Liver biopsy is not usually necessary. Performance of a liver biopsy is recommended only if persistent elevation of unconjugated bilirubin is otherwise unexplained, is symptomatic, is worsening over time, and/or associated with abnormal transaminases.[19]

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