What is Gilbert's syndrome?

Gilbert's Syndrome

Gilbert's syndrome is a common, benign hereditary condition affecting 5-10% of the population, characterized by mild unconjugated hyperbilirubinemia with normal liver enzymes, requiring no treatment beyond patient reassurance. 1

Definition and Pathophysiology

Gilbert's syndrome is caused by reduced activity of the enzyme UDP-glucuronosyltransferase (UGT), which is responsible for conjugating bilirubin in the liver 1. This enzymatic deficiency results in:

• Mild elevation of unconjugated bilirubin in the blood
• Normal liver function tests (ALT, AST, ALP)
• No evidence of liver disease or hemolysis

The genetic basis involves mutations affecting the UGT1A1 enzyme, with the UGT1A1*28 allele being a common variant that can reduce glucuronidation by approximately 30% 2.

Clinical Characteristics

Key features of Gilbert's syndrome include:

• Bilirubin levels:

  • Total bilirubin is typically mildly elevated, rarely exceeding 4-5 mg/dL 1
  • Unconjugated (indirect) bilirubin comprises >70-80% of the total bilirubin 1
  • Conjugated (direct) bilirubin fraction is less than 20-30% of total bilirubin 1

• Clinical presentation:

  • Usually asymptomatic
  • May present with intermittent jaundice during periods of stress, fasting, illness, or strenuous exercise 3
  • Typically becomes apparent during adolescence 3

• Laboratory findings:

  • Elevated unconjugated bilirubin
  • Normal liver enzymes (ALT, AST, ALP)
  • Normal complete blood count (no evidence of hemolysis)

Diagnosis

The diagnosis of Gilbert's syndrome involves:

1. Confirming unconjugated hyperbilirubinemia (typically <5 mg/dL)
2. Verifying normal liver enzymes
3. Ruling out other causes of hyperbilirubinemia such as hemolysis and liver disease 1

While most cases present with bilirubin levels below 5 mg/dL, rare cases with levels above 6 mg/dL have been reported, requiring additional testing to rule out other conditions 4.

Clinical Significance

Despite being traditionally viewed as a benign laboratory finding, Gilbert's syndrome has several important clinical implications:

• Drug metabolism: May affect metabolism of certain medications that require glucuronidation, particularly important with oncology drugs that have narrow therapeutic windows 2

• Potential health benefits: Growing evidence suggests that mild hyperbilirubinemia may confer protective effects against:

  • Cardiovascular diseases
  • Certain cancers
  • Neurodegenerative diseases 5

  These benefits are attributed to the antioxidant properties of bilirubin 6, 5

• Avoiding misdiagnosis: Essential to distinguish from true hepatotoxicity when evaluating drug-induced liver injury to prevent unnecessary testing 1

Management

According to the American Gastroenterological Association:

• No specific treatment is required for Gilbert's syndrome
• Patient education and reassurance are essential 1

Important Clinical Considerations

• When evaluating elevated bilirubin in a patient, always check the fraction of unconjugated vs. conjugated bilirubin
• In Gilbert's syndrome, bilirubin elevations may be more pronounced when taking certain medications that compete for glucuronidation pathways 1
• Clinical trials often make exceptions for these patients, allowing total bilirubin up to 3-5× upper limit of normal with normal direct bilirubin levels 1
• During periods of fasting, illness, or stress, bilirubin levels may increase temporarily, which is expected in Gilbert's syndrome and not cause for concern

By recognizing the characteristic pattern of isolated unconjugated hyperbilirubinemia with normal liver enzymes, clinicians can avoid unnecessary investigations and provide appropriate reassurance to patients with this common benign condition.