Synonyms: familial non-haemolytic hyperbilirubinaemia, constitutional hepatic dysfunction, Gilbert-Meulengracht syndrome, benign constitutional unconjugated hyperbilirubinaemia.
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 and Dominique Lereboullet.
Gilbert's syndrome affects 5-10% of the Western European population. The worldwide prevalence of Gilbert's syndrome varies considerably depending on which diagnostic criteria are used. Men are more commonly affected than women.
However, many cases remain undiagnosed so true prevalence is unknown.
Patients with Gilbert's syndrome have a defect in the gene that encodes for the conjugating enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1), which results in a 60-70% reduction in the liver's ability to conjugate bilirubin. More than 100 different mutations have been identified in the UGT1A1 gene and their frequencies differ amongst different ethnic groups[2, 3].
It is a benign condition and it is not associated with liver disease.
Gilbert's syndrome is characterised by unconjugated hyperbilirubinaemia, no evidence of haemolysis, normal liver enzyme levels and no evidence of liver disease.
- Intercurrent illness.
- Physical exertion.
- Lack of sleep.
- Alcohol ingestion.
- Administration of certain drugs - eg, after chemotherapy and antiretroviral drugs.
Symptoms, including tiredness, that may occur during an episode of jaundice are caused by the precipitating factor and do not result directly from Gilbert's syndrome.
Gilbert's syndrome may present in the newborn, especially if there is concurrent haemolysis such as ABO incompatibility; it has also been associated with breast milk jaundice.
Mild hyperbilirubinaemia can be mistaken for a sign of occult, chronic, or progressive liver disease and precise diagnosis is important to avoid unnecessary invasive investigations. If there is any clinical concern then discussion with a gastroenterologist or hepatologist is advisable. Some centres offer genetic testing to confirm Gilbert's syndrome if there is any doubt.
FBC shows normal reticulocyte count - to distinguish from haemolysis. Gilbert's syndrome patients tend to have total serum bilirubin levels from 17-100 μmol/L.
- Other LFTs (including lactate dehydrogenase) and liver biopsy are normal; however, the latter should rarely be required.
- There is no bilirubin and subnormal amounts of urobilinogen in the urine.
This is excellent. No treatment is required and life expectancy is normal.
- Atazanavir and indinavir (used for the treatment of HIV infection).
- Gemfibrozil, particularly when combined with statins when there is an increased risk of toxicity including myositis.
- Irinotecan (used for the treatment of advanced bowel cancer).
- Nilotinib and imatinib (used, for example, in the treatment of chronic myeloid leukaemia (CML) and gastrointestinal stromal tumours (GISTs)).
Bilirubin is an endogenous antioxidant. Gilbert's syndrome appears to reduce the risk of various age-related diseases, particularly cancer and atherosclerosis. A population-based cohort study found that mortality rates observed for people with Gilbert's syndrome in the UK population were shown to be almost half those of people without evidence of Gilbert's syndrome. One theory that has been postulated to explain this, is that the antioxidant properties of bilirubin have an anti-thrombotic effect via reducing platelet activation. A further population study has shown a significant association between patients with UGT1A1 gene variant and higher respiratory function and lower respiratory disease, with the strongest association being found in smokers, suggesting a protective effect of bilirubin.
Further reading and references
Strassburg CP; Hyperbilirubinemia syndromes (Gilbert-Meulengracht, Crigler-Najjar, Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol. 2010 Oct24(5):555-71.
Claridge LC, Armstrong MJ, Booth C, et al; Gilbert's syndrome. BMJ. 2011 Apr 19342:d2293. doi: 10.1136/bmj.d2293.
Marques SC, Ikediobi ON; The clinical application of UGT1A1 pharmacogenetic testing: gene-environment interactions. Hum Genomics. 2010 Apr4(4):238-49.
Memon N, Weinberger BI, Hegyi T, et al; Inherited disorders of bilirubin clearance. Pediatr Res. 2016 Mar79(3):378-86. doi: 10.1038/pr.2015.247. Epub 2015 Nov 23.
Gilbert's syndrome; NICE CKS, October 2015 (UK access only)
Nag DS, Sinha N, Samaddar DP, et al; General anesthesia in a patient with Gilbert's syndrome. J Anaesthesiol Clin Pharmacol. 2011 Apr27(2):253-5. doi: 10.4103/0970-9185.81836.
Sticova E, Jirsa M; New insights in bilirubin metabolism and their clinical implications. World J Gastroenterol. 2013 Oct 1419(38):6398-6407.
Rawa K, Adamowicz-Salach A, Matysiak M, et al; Coexistence of Gilbert syndrome with hereditary haemolytic anaemias. J Clin Pathol. 2012 Jul65(7):663-5. doi: 10.1136/jclinpath-2011-200580. Epub 2012 May 3.
Ehmer U, Kalthoff S, Fakundiny B, et al; Gilbert syndrome redefined: a complex genetic haplotype influences the regulation of glucuronidation. Hepatology. 2012 Jun55(6):1912-21. doi: 10.1002/hep.25561. Epub 2012 Apr 23.
Saif MW, Smith MH, Maloney A, et al; Imatinib-induced hyperbilirubinemia with UGT1A1 (*28) promoter polymorphism: first case series in patients with gastrointestinal stromal tumor. Ann Gastroenterol. 2016 Oct-Dec29(4):551-556. Epub 2016 Jun 10.
Maruhashi T, Soga J, Fujimura N, et al; Hyperbilirubinemia, augmentation of endothelial function, and decrease in oxidative stress in Gilbert syndrome. Circulation. 2012 Jul 31126(5):598-603. doi: 10.1161/CIRCULATIONAHA.112.105775. Epub 2012 Jul 6.
Horsfall LJ, Nazareth I, Pereira SP, et al; Gilbert's syndrome and the risk of death: a population-based cohort study. J Gastroenterol Hepatol. 2013 Oct28(10):1643-7. doi: 10.1111/jgh.12279.
Kundur AR, Singh I, Bulmer AC; Bilirubin, platelet activation and heart disease: a missing link to cardiovascular protection in Gilbert's syndrome? Atherosclerosis. 2015 Mar239(1):73-84. doi: 10.1016/j.atherosclerosis.2014.12.042. Epub 2014 Dec 24.
Horsfall LJ, Hardy R, Wong A, et al; Genetic variation underlying common hereditary hyperbilirubinaemia (Gilbert's syndrome) and respiratory health in the 1946 British birth cohort. J Hepatol. 2014 Dec61(6):1344-51. doi: 10.1016/j.jhep.2014.07.028. Epub 2014 Jul 31.