Gilbert Syndrome

8 Interesting Facts of Gilbert Syndrome

1. Gilbert disease is a hereditary condition caused by a mild form of genetic deficiency of UDP-glucuronyl transferase 1A1 (UGT1A1), an enzyme metabolizing bilirubin through glucuronidation, resulting in impaired bilirubin metabolism and clearance
2. Characterized by intermittent, mild, asymptomatic jaundice in the absence of hemolysis or underlying liver disease
3. Laboratory tests are the primary tools for diagnosis; elevated unconjugated bilirubin level in the absence of other hepatic or hemolytic disease is usually sufficient for diagnosis 
4. This benign condition does not require treatment or long-term medical attention
5. Advise patients to avoid or reduce factors that may trigger episodes of jaundice (eg, stress, alcohol consumption, prolonged fasting)
6. Comorbidities include neonatal jaundice, hemolytic disorders, and cholelithiasis
7. Complications include severe irinotecan-induced hyperbilirubinemia and decreased clearance of drugs that undergo glucuronidation 
8. Prognosis is excellent

Pitfalls

• Patients with colon cancer and Gilbert disease experience increased toxicity and adverse effects (eg, diarrhea) when given irinotecan chemotherapy, owing to significantly lower glucuronidation rate for SN-38 (a metabolite of irinotecan) in those with Gilbert disease

• Gilbert disease is a hereditary condition caused by mild genetic deficiency of UGT1A1, which produces an enzyme that metabolizes bilirubin through glucuronidation, resulting in impaired bilirubin metabolism and clearance
• Chronic, benign, intermittent jaundice characterized by mild hyperbilirubinemia 
• Potentiates severe hyperbilirubinemia in combination with other icterogenic factors 

Clinical Presentation

History

• Most patients are asymptomatic
• Nonspecific symptoms have been occasionally reported during jaundice episodes, including:
  • Fatigue
  • Mild weakness
  • Mild upper abdominal pain
  • Pruritus

Physical examination

• Physical examination findings are typically normal
• No clinical signs of liver disease
• Intermittent, mild jaundice with a slight yellow discoloration of the sclera, skin, and mucous membranes can be noted 

Causes

• Genetic polymorphism in the promoter region (TATAA element) of UGT1A1 gene, resulting in a 60% to 70% decrease in its activity 
  • When functioning normally, UGT1A1 enzyme conjugates bilirubin to become a water-soluble molecule, thereby rendering bilirubin excretion 

Risk factors and/or associations

Age

• Typically, first noticed as intermittent mild jaundice in adolescents 

Sex

• Prevalence in males is approximately twice that of females 

Genetics

• Usually autosomal recessive genetic polymorphism in UGT1A1 causes a mild deficiency of enzyme activity
• Most common genotype of Gilbert disease is the homozygous polymorphism of a TA insertion in the (TA)₆TAA region of the UGT1A1 promoter (the 7/7 allele, also known as UGT1A1*28)
• 3 other less common heterozygous genotypes, with deletion and/or insertion of TA in (TA)₆TAA region (ie, 5/6, 5/7, and 7/8 alleles), have been associated with Gilbert disease 
• Heterozygous mutation in coding exon 1 of UGT1A1 gene (G71R) can also cause Gilbert disease
  • More prevalent in Asian populations, especially in jaundiced Japanese newborns 

Ethnicity/race

• Prevalent worldwide, occurring in all races
• Most frequent mutation (TA insertion in TATA box region) is present in up to 23% of Africans, but only 3% of Asians 
• A higher frequency of the heterozygous G71R allele that also causes Gilbert disease has been observed in Asians, especially in the Japanese population 
• Prevalence is 3% to 7% in the United States and 5% to 10% in Western European populations; 1 in 3 affected patients are unaware that they have disease 

Other risk factors/associations

• Potential triggers for jaundice in patients with Gilbert disease
  • Prolonged fasting
  • Surgery
  • Stress
  • Physical exertion
  • Alcohol consumption
  • Infections
  • Certain medications, such as UGT1A1 inhibitors (eg, gemfibrozil, atazanavir)

Diagnostic Procedures

Primary diagnostic tools

• Laboratory tests are the primary diagnostic tools
• Elevated unconjugated bilirubin level in the absence of other hepatic or hemolytic disease is usually sufficient for diagnosis
• Diagnosis is typically made without excessive and unnecessary testing 

Laboratory

• Serum bilirubin concentration, conjugated (direct) and unconjugated (indirect)
  • Elevated unconjugated bilirubin level in the absence of other hepatic or hemolytic disease is usually sufficient for diagnosis 
    • Unconjugated hyperbilirubinemia: elevated indirect bilirubin with conjugated component being within reference range and/or less than 20% of total bilirubin 
    • Serum unconjugated (indirect) bilirubin levels can be up to 5 mg/dL 
    • Serum conjugated (direct) bilirubin levels are always within reference range
• Polymerase chain reaction 
  • For diagnostic confirmation, in patients with multiple causes of hyperbilirubinemia
  • Detects UGT1A1 polymorphism to confirm the diagnosis, although it is not necessary in most cases 
• CBC with reticulocyte count and blood smear
  • As needed, to exclude hemolysis
  • Erythrocyte indices and reticulocyte count should be within reference range
• Liver function tests
  • As needed, to exclude other hepatic disease
  • AST, ALT, alkaline phosphatase, and albumin levels should be within reference range

Differential Diagnosis

Most common

• Crigler-Najjar syndrome (types 1 and 2)
  • More severe form of unconjugated hyperbilirubinemia caused by genetic defects of bilirubin metabolism
  • Involves complete absence of UGT1A1 enzymatic bilirubin glucuronidation (type 1) or mutations in UGT1A1 causing severe deficiency of the enzyme (type 2)
  • Patients with type 1 may present with kernicterus
  • Differentiated by serum unconjugated bilirubin levels that are significantly higher than those in Gilbert disease
• Other causes of hyperbilirubinemia: 
  • Overt hemolysis
    • RBCs break down and facilitate the development of extremely high serum bilirubin levels, which result in jaundice that is similar to that of Gilbert disease
    • Dizziness, headache, pallor, and cold skin can suggest hemolysis
    • CBC can detect anemia
    • Peripheral blood smear can help to diagnose underlying hematologic malignancy associated with hemolysis
    • Elevated serum lactate dehydrogenase level is sensitive for hemolysis
    • Low serum haptoglobin level suggests moderate to severe hemolysis
    • Differentiated with history, physical examination, and laboratory testing
  • Intrahepatic cholelithiasis 
    • Stones form in hepatic duct
    • Presentation includes jaundice and generalized weakness similar to that of Gilbert disease
    • Unlike Gilbert disease, nausea and vomiting may occur
    • Differentiated by ultrasonographic imaging to identify stones
  • Thyrotoxicosis 
    • Hyperthyroidism that leads to increased bilirubin, fatigue, and weakness (which can also occur in patients with Gilbert disease)
    • Unexplained weight loss and arrhythmia are distinguishing findings of thyrotoxicosis
    • Differentiated by low or undetectable levels of serum TSH

Treatment

Goals

• Prevent jaundice episodes

Treatment Options

This benign condition does not require treatment or long-term medical attention

Advise patient to avoid or reduce factors that may trigger episodes of jaundice (eg, stress, alcohol consumption, prolonged fasting)

Patients should inform medical care personnel of the condition if admitted to the hospital and when new medication is prescribed 

Comorbidities

• Neonatal jaundice
  • Gilbert disease accelerates development of neonatal jaundice during the first 2 days of life 
• Hemolytic disorders
  • Gilbert disease is a predisposing factor for hyperbilirubinemia in patients with G6PD (glucose-6-phosphate dehydrogenase) deficiency or heterozygous β-thalassemia 
• Cholelithiasis
  • Gilbert disease increases risk of cholelithiasis 
  • Patients with Gilbert disease and hereditary spherocytosis have an increased risk of pigment gallstones 

Complications

• Drug toxicity 
  • May affect glucuronidation and clearance of therapeutic drugs (eg, tolbutamide, aminopyrine, acetaminophen), potentially resulting in increased toxicity
• Severe irinotecan-induced hyperbilirubinemia
  • Increased risk of toxicity from chemotherapeutic agent irinotecan has been associated with Gilbert disease 

Prognosis

• Excellent prognosis
• Jaundice is not usually accompanied by other complications and does not reduce life expectancy

References

Hirschfield GM et al: Gilbert’s syndrome: an overview for clinical biochemists. Ann Clin Biochem. 43(Pt 5):340-3, 2006