Gilbert syndrome

Gilbert syndrome is a benign hepatic condition characterised by mild, intermittent unconjugated hyperbilirubinaemia in the absence of haemolysis and with otherwise normal liver function tests. Clinical onset typically occurs after puberty, with affected individuals presenting during adolescence or early adulthood with episodic mild jaundice, often detected incidentally. Episodes are triggered by physiological stressors, particularly fasting, intercurrent illness, dehydration, menstruation, and physical exertion. Serum unconjugated bilirubin levels are typically mildly elevated (>17 µmol/L), usually remaining below 85 µmol/L, and are substantially lower than those observed in more severe inherited hyperbilirubinaemias such as . Between episodes, individuals are asymptomatic, and liver structure and function are preserved. The long-term prognosis is excellent, with no progression to chronic liver disease and no requirement for specific therapy.

The prevalence of Gilbert syndrome varies between populations and is estimated at approximately 3–10% in most populations, making it one of the most common inherited disorders of bilirubin metabolism.

Gilbert syndrome is caused by germline pathogenic variants in UGT1A1 (2q37.1), which encodes hepatic UDP-glucuronosyltransferase 1A1. Reduced enzyme activity impairs glucuronidation of unconjugated bilirubin, resulting in its accumulation in peripheral blood. In populations of European descent, most affected individuals are homozygous for an additional TA dinucleotide insertion in the UGT1A1 promoter (UGT1A1*28; A(TA)₇TAA), which reduces gene expression and enzyme activity. In East Asian populations, the missense variant UGT1A1*6 (p.(Gly71Arg); c.211G>A) is a frequent cause and is associated with reduced enzyme activity.

Gilbert syndrome is inherited in an autosomal recessive manner; biallelic UGT1A1 variants are typically required for the biochemical phenotype to manifest, although heterozygous carriers may show mildly increased bilirubin levels.

The diagnosis rests on the demonstration of isolated, mild, unconjugated (indirect) hyperbilirubinaemia, typically 17-85 µmol/L, with normal aminotransferases and no laboratory or clinical evidence of haemolysis or hepatocellular disease. No formal consensus diagnostic criteria are established. In individuals with a compatible biochemical profile, molecular genetic testing of UGT1A1 confirms the diagnosis and discriminates Gilbert syndrome from other causes of unconjugated hyperbilirubinaemia.

Main differential diagnoses include:

• type II: more marked persistent unconjugated hyperbilirubinaemia presenting from early life that responds clinically to phenobarbital therapy; UGT1A1
• type I: severe unconjugated hyperbilirubinaemia from the neonatal period with high risk of kernicterus and bilirubin encephalopathy and no response to phenobarbital; UGT1A1

• Establishing the diagnosis: identification of pathogenic variants in UGT1A1 can support diagnostic confirmation and help distinguish Gilbert syndrome from other causes of unconjugated hyperbilirubinaemia.
• Clinical management: molecular genetic findings may inform clinical management, including counselling on precipitating factors and considerations for the use of drugs metabolised by UGT1A1.
• Family member testing: identification of the familial variant(s) enables testing of at-risk relatives and supports genetic counselling.

• Grant LM, Faust TW, Thoguluva Chandrasekar V, et al. Gilbert syndrome. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2024 Oct 5. Available from: https://www.ncbi.nlm.nih.gov/books/NBK470200/. PMID: .
• Vítek L, Tiribelli C. Gilbert’s syndrome revisited. J Hepatol. 2023;79(4):1049-1055. doi:10.1016/j.jhep.2023.06.004. PMID: .