Gilbert Syndrome

A 20 year old male presents with yellowing of the eyes for the past few days. He has no significant past medical history and reports recent stress due to examinations. Vital signs are stable. Physical examination reveals scleral icterus. Laboratory investigations show normal CBC, normal AST, ALT, and ALP, total bilirubin of 2.4 mg/dL, and direct bilirubin of 0.2 mg/dL. There is no evidence of hemolysis. Diagnosis?

Diagnosis is Gilbert syndrome.

1. Definition

Gilbert syndrome is a benign inherited disorder of bilirubin metabolism characterized by intermittent unconjugated hyperbilirubinemia in the absence of liver disease or hemolysis, due to reduced activity of the UGT1A1 enzyme.

2. Etiology

1. UGT1A1 gene promoter polymorphism (commonly UGT1A1*28)
2. Autosomal recessive inheritance with incomplete penetrance
3. Reduced hepatic bilirubin conjugation

3. Pathophysiology

1. UGT1A1 activity reduced to about one third of normal
2. Impaired glucuronidation of unconjugated bilirubin
3. Accumulation of indirect bilirubin
4. Normal liver histology
5. Serum bilirubin typically 1 to 4 mg/dL, may increase during stress

4. Clinical Features

4.1 Core Features

1. Mild intermittent jaundice, often scleral icterus
2. Unconjugated hyperbilirubinemia
3. Otherwise asymptomatic
4. Onset in adolescence or young adulthood
5. No hepatosplenomegaly

4.2 Precipitating Factors

1. Fasting
2. Stress
3. Illness or fever
4. Dehydration
5. Vigorous exercise
6. Sleep deprivation
7. Menstruation

5. Diagnosis

5.1 Laboratory Findings

1. Elevated unconjugated bilirubin
2. Normal direct bilirubin
3. Normal AST, ALT, ALP
4. Normal CBC, LDH, and reticulocyte count

5.2 Diagnostic Criteria

1. Isolated unconjugated hyperbilirubinemia
2. Normal liver function tests
3. No evidence of hemolysis
4. Intermittent jaundice triggered by stress or fasting

6. Differential Diagnosis

1. Crigler Najjar syndrome
2. Hemolytic anemia
3. G6PD deficiency
4. Hereditary spherocytosis

7. Management

1. No treatment required
2. Patient reassurance
3. Avoid unnecessary investigations
4. Avoid precipitating factors when possible

8. Key Clinical Insight

Young patient with mild intermittent jaundice, normal liver enzymes, and isolated indirect hyperbilirubinemia, especially triggered by stress or fasting, strongly indicates Gilbert syndrome

9. Key Exam Points

1. Most common inherited cause of unconjugated hyperbilirubinemia
2. UGT1A1 deficiency
3. Bilirubin usually less than 4 mg/dL
4. Normal liver enzymes
5. No hemolysis
6. Reduced glucuronidation may increase toxicity of drugs such as irinotecan