Gilbert's syndrome

Definition

Gilbert's syndrome (Meulengracht's disease) is a harmless, presumably lifelong metabolic variant in which the only significant abnormality is a mild, asymptomatic rise in unconjugated (indirect) bilirubin. The liver is otherwise healthy. The syndrome belongs to the inherited unconjugated hyperbilirubinaemias, which also include the rare, more severe Crigler-Najjar syndrome.

Occurrence & epidemiology

Gilbert's syndrome affects about 3–10% of the population. It is usually discovered incidentally in young adults, either through mild jaundice or through a raised bilirubin level on routine testing.

Aetiopathogenesis

The cause is mutations in the UGT1A1 gene, which encodes the enzyme UDP-glucuronyltransferase. This enzyme conjugates bilirubin with glucuronic acid, making it water-soluble and excretable in bile. In Gilbert's syndrome, enzyme activity is reduced, but not as severely as in Crigler-Najjar syndrome type II. Depending on the mutation, inheritance is autosomal dominant or autosomal recessive.

In addition, uptake of bilirubin into the liver cell is often impaired, and red cell breakdown is slightly accelerated, without causing anemia. Fasting, infections and other stresses cause bilirubin to rise.

Clinical features

Most affected people have no symptoms. At most, there is a mild, fluctuating jaundice, mainly of the sclerae, which becomes more pronounced with fasting, infections, physical exertion or stress. Liver disease does not develop; liver histology is normal. However, the finding can be mistaken for chronic hepatitis or other liver diseases.

Diagnosis

• Bilirubin: mildly raised, usually fluctuating between 2 and 5 mg/dL, predominantly unconjugated (indirect); rises with fasting
• Other liver values normal: aminotransferases, alkaline phosphatase and GGT are unremarkable
• Urine: no bilirubin in the urine, because unconjugated bilirubin is not excreted by the kidneys
• Exclusion of hemolysis: no anemia and no increased reticulocytes
• Molecular genetics: detection of a UGT1A1 variant can confirm the diagnosis but is usually not necessary

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Further reading (open access)

1. MSD Manual Professional: Inborn Metabolic Disorders Causing Hyperbilirubinemia

Cross-references