Synonyms: familial non-haemolytic hyperbilirubinaemia, constitutional hepatic dysfunction

Gilbert's syndrome is usually an autosomal recessive disorder and is a common cause of unconjugated hyperbilirubinaemia. There have been some reports of heterozygous cases, mainly within Asian populations.

It was first described in 1901 by Nicolas Augustin Gilbert.¹

Epidemiology

Prevalence is estimated at 3-8%.² The worldwide prevalence of Gilbert's syndrome varies considerably depending on which diagnostic criteria are used.

Genetics

Genetic lesions of the bilirubin conjugating enzyme uridine-diphosphoglucuronate glucuronosyltransferase (UGT-1A1) gene cause both Gilbert's syndrome and the much rarer Crigler-Najjar syndrome.^3,4

• Hepatic glucuronidation (necessary for conjugating bilirubin) is reduced to around 30% of normal.
• In addition to their reduced bilirubin-UGT enzyme activity, most patients with Gilbert's syndrome may have abnormalities in the glucuronidation of aspirin or derivatives of coumarin and dopamine.⁵

Presentation

It can remain unnoticed for many years, but usually presents in adolescence with:

• Intermittent jaundice noticed after fasting, lack of sleep, vigorous exercise or during an intercurrent illness.⁶
• Exposure to certain medications may precipitate jaundice, e.g. chemotherapy. Adverse effects of anticancer agents have been observed in Gilbert's syndrome patients due to reduced drug or bilirubin glucuronidation.⁷
• Gilbert's syndrome is a determining factor for neonatal hyperbilirubinaemia ABO incompatibility.⁸

Other typical findings include:

• Jaundice
• Nausea
• Fatigue
• Shakiness
• Bowel complaints
• Vomiting
• Difficulty concentrating

Associated conditions

Haemolytic anaemias:

• Hereditary spherocytosis
• Congenital dyserythropoietic anaemia type 2

Differential diagnosis

Crigler-Najjar syndrome types I or II

Investigations

Full blood count shows normal reticulocyte count - to distinguish from haemolysis.
Gilbert's syndrome patients tend to have total serum bilirubin levels from 17-100 μmol/L.⁹

• A rise in bilirubin on fasting or after IV nicotinic acid can confirm the diagnosis.¹⁰
• Other liver function tests (including lactate dehydrogenase) and liver biopsy are normal, but the latter should rarely be required clinically.
• There is no bilirubin and subnormal amounts of urobilinogen in the urine.

Prognosis

This is excellent. No treatment is required and life expectancy is normal.

Document references

1. Gilbert A, Lereboulette P. La cholémie simple familiale. Semaine Médicale 1906 60:241-5
2. Mukherjee S; Gilbert syndrome, eMedicine, Nov 2009.
3. Bosma PJ, Chowdhury JR, Bakker C, et al; The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995 Nov 2;333(18):1171-5. [abstract]
4. Burchell B, Hume R; Molecular genetic basis of Gilbert's syndrome. J Gastroenterol Hepatol. 1999 Oct;14(10):960-6. [abstract]
5. Peters WH, te Morsche RH, Roelofs HM; Combined polymorphisms in UDP-glucuronosyltransferases 1A1 and 1A6: implications for patients with Gilbert's syndrome. J Hepatol. 2003 Jan;38(1):3-8. [abstract]
6. Ruiz-Arguelles GJ, Ruiz-Delgado GJ, David Gomez-Rangel J, et al; Gilbert's syndrome disclosed during the treatment of hematological malignancies. Hematology. 2005 Feb;10(1):59-60. [abstract]
7. Burchell B, Soars M, Monaghan G, et al; Drug-mediated toxicity caused by genetic deficiency of UDP-glucuronosyltransferases. Toxicol Lett. 2000 Mar 15;112-113:333-40. [abstract]
8. Kaplan M, Hammerman C, Renbaum P, et al; Gilbert's syndrome and hyperbilirubinaemia in ABO-incompatible neonates. Lancet. 2000 Aug 19;356(9230):652-3. [abstract]
9. OMIM; Gilbert's Syndrome. Online Mendelian Inheritance in Man.
10. Rollinghoff W, Paumgartner G, Preisig R; Nicotinic acid test in the diagnosis of Gilbert's syndrome: correlation with bilirubin clearance. Gut. 1981 Aug;22(8):663-8. [abstract]

Internet and further reading

• Smellie WS, Ryder SD; Biochemical "liver function tests". BMJ. 2006 Sep 2;333(7566):481-3.
• Action on Gilbert's Syndrome. Patient website.

Acknowledgements