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74: Gilbert Syndrome

Christopher DT. Corbett; Matthew J. Armstrong; Lee C. Claridge

Key Points

  • Disease syndrome:

    • Gilbert syndrome (GS) is a hereditary defect in bilirubin metabolism.

    • It has a prevalence of 3% to 7% in the United States of America, but worldwide this varies immensely with levels approaching 10% in parts of Western Europe.

    • A 60% to 70% reduction in the liver’s ability to conjugate bilirubin leads to unconjugated (indirect) hyperbilirubinemia which may intermittently manifest as clinical jaundice.

    • Jaundice due to GS does not indicate or result in liver damage.

    • GS itself has no long-term harmful effects and does not reduce life expectancy.

  • Hereditary basis:

    • GS is an autosomal recessive inherited defect in the gene that codes for the enzyme uridine diphosphonate (UDP) glucuronyltransferase.

  • Differential diagnosis:

    • Other genetic defects of bilirubin metabolism (Table 74-1)

    • Other causes of unconjugated hyperbilirubinemia such as hemolysis, drugs, and thyrotoxicosis

  • GS and Pharmacogenetics:

    • Any drug which is metabolised via glucuronidation may have altered activity in patients with GS.

    • There is associated drug toxicity in GS with the chemotherapeutic agent, irinotecan. It is associated with an increased risk of neutropenia and diarrhoea.

Table 74-1Genetic Differential Diagnosis
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Table 74-1 Genetic Differential Diagnosis
Syndrome Gene Symbol Metabolic Defect
Crigler-Najjar syndrome type I UGT1A Complete absence of bilirubin conjugation leading to severe jaundice in first few days of life.
Crigler-Najjar syndrome type II UGT1A Conjugating enzyme activity is less than 10%. It usually presents with persistent jaundice in childhood.
Dubin-Johnson Syndrome MRP2 A defect in the bile canalicular multispecific organic anion transporter results in impaired excretion of anionic conjugates from hepatocytes into bile. Consequently there is a conjugated (direct) hyperbilirubinemia and a characteristic accumulation of pigments in the liver. There is also an abnormality of porphyrin metabolism in which >80% of urinary coproporphyrin is coproporphyrin I.
Rotor syndrome Unknown gene A disorder of hepatic storage which results in conjugated hyperbilirubinemia.

Gene names: UGT1A, uridine diphosphonate glucuronyltransferase 1 family, polypeptide A cluster; MRP2, multidrug resistance protein 2.

Diagnostic Criteria and Clinical Characteristics

GS can be confidently diagnosed with a thorough clinical history, examination, and routine biochemistry (Table 74-2 below).

Table 74-2Clinical Diagnostic Criteria
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Table 74-2 Clinical Diagnostic Criteria
Diagnostic Clinical Features Explanation
Unconjugated hyperbilirubinemia Conjugated (direct) bilirubin is within the normal range and/or <20% of total bilirubin.
Normal liver enzymes and function tests Normal alanine and/or aspartate transaminases, gamma- glutamyltransferase, alkaline phosphatase, and albumin indicate that liver pathology is unlikely to be present.
Absence of other causes of unconjugated hyperbilirubinemia

  • Hemolysis

  • Thyrotoxicosis

  • Drugs (rifampicin, methyldopa, sulphasalazine, gemfibrozil)

Normal reticulocyte count, lactate dehydrogenase and blood film

Normal thyroid function tests

Some drugs inhibit the activity of UDP glucuronyltransferase and can precipitate unconjugated hyperbilirubinemia.
No symptoms or signs that are suggestive of hepatobiliary disease Absence of abdominal pain, pruritus, dark urine, and/or pale stools. There should be ...

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