Gilbert's Syndrome
Summary
Gilbert's Syndrome (GS) is a common, benign, hereditary condition characterized by mild, intermittent Unconjugated Hyperbilirubinemia. It affects 5-10% of the Caucasian population. It is caused by a genetic defect in the promoter region of the UGT1A1 gene, reducing the activity of the enzyme responsible for bilirubin conjugation to ~30%. It is typically asymptomatic, presenting as mild jaundice triggered by Fasting, Stress, or Illness. No treatment is required. [1,2]
Clinical Pearls
The "Fasting" Trigger: Jaundice in Gilbert's is classically precipitated by a period of caloric restriction (e.g., skipping meals for 24h) or intercurrent illness (flu). The mechanism involves depletion of UDP-glucuronic acid cofactor.
Normal Urine Color: Because the excess bilirubin is Unconjugated (water-insoluble), it cannot be filtered by the kidney. Therefore, patients have jaundice with normal urine colour. (Contrast this with Obstructive Jaundice, where conjugated bilirubin causes dark urine).
A "Beneficial" Disease?: Multiple epidemiological studies suggest patients with Gilbert's have a reduced risk of Cardiovascular Disease compared to the general population. Bilirubin is a potent antioxidant that prevents lipid peroxidation.
Demographics
- Prevalence: 3-10% of general population (extremely common).
- Gender: Diagnosed more frequently in males (likely because men have higher bilirubin levels naturally, making the rise more obvious, or diagnostic bias).
- Age: Typically diagnosed in adolescence/early adulthood (routine bloods).
The UGT1A1 Defect
- Normal: Bilirubin is a breakdown product of Heme. It is transported to the liver (Unconjugated). The enzyme UGT1A1 (Uridine Diphosphate Glucuronosyltransferase 1A1) adds glucuronic acid to it ("Conjugation"), making it water-soluble for excretion in bile.
- Gilbert's: An insertion of an extra TA dinucleotide in the TATAA box of the gene promoter (A(TA)7TAA instead of A(TA)6TAA).
- Result: Transcription is inefficient. Enzyme levels are reduced to ~30% of normal.
- Consequence: When bilirubin load increases (fasting/hemolysis) or enzyme function dips further, conjugation cannot keep up -> Mild Unconjugated Hyperbilirubinemia.
| Condition | LFTs (ALT/ALP) | Hb/Reticulocytes | Urine |
|---|---|---|---|
| Gilbert's | Normal | Normal | Normal |
| Haemolysis | Normal | Abnormal (Low Hb, High Retics) | Normal |
| Hepatitis | High ALT | Normal | Dark |
| Obstruction | High ALP | Normal | Dark |
Symptoms
Triggers for Jaundice
- Fasting / Dehydration.
- Intercurrent Illness (Febrile illness).
- Alcohol binge.
- Menstruation.
Diagnosis
- Diagnosis of Exclusion.
- Liver Function Tests: Isolated elevated Bilirubin (usually less than 60 µmol/L). All liver enzymes (ALT, AST, ALP, GGT) MUST be normal.
- Full Blood Count: Normal Hb and Reticulocyte count (excludes Haemolysis).
- Split Bilirubin: Confirm predominant fraction is Unconjugated (>85%). Rarely needed in practice if FBC/LFTs benign.
Management Algorithm
ISOLATED HIGH BILIRUBIN
↓
CHECK ALT/ALP & FBC
┌─────────┴─────────┐
ABNORMAL NORMAL
(Liver Disease (Possible Gilbert's)
or Hemolysis) ↓
REASSURE patient
(Safe, Benign)
↓
NO MONITORING NEEDED
Therapeutics
- None. No medical involvement required.
- Reassurance: Crucial. Explain it is a "genetic quirk", not a disease. It does not lead to liver failure or cirrhosis.
Pharmacogenomics (Important)
- Irinotecan (Chemotherapy): Metabolized by UGT1A1. Gilbert's patients are at high risk of severe toxicity (neutropenia/diarrhea). Dose reduction required.
- Atazanavir (HIV): Inhibits UGT1A1 further -> Deep jaundice. Cosmetic issue only.
- Gallstones: Slight increased risk of pigment stones (due to increased unconjugated bilirubin in bile).
- Diagnostic Confusion: Often misdiagnosed as hepatitis.
- Excellent. Normal life expectancy.
- Potential protective effect against atherosclerosis.
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| Jaundice | BSG | Approach to isolated hyperbilirubinemia. |
| Toxicity | FDA | Warning on Irinotecan labels for UGT1A1*28 homozygotes. |
Landmark Evidence
1. Bosma et al (NEJM 1995)
- Identified the genetic basis (TATAA box insertion) of Gilbert's Syndrome.
What is Gilbert's Syndrome?
It's not really a disease; it's a very common genetic variation (like having blue eyes). Your liver is perfectly healthy, but the "recycling plant" that clears away old red blood cell pigment (bilirubin) works a bit slower than average.
Why do I go yellow?
Normally the liver clears the pigment easily. But if you are stressed, skip meals, or get the flu, the pigment builds up slightly in the blood, tinging the whites of your eyes yellow. As soon as you recover/eat, it clears.
Can I drink alcohol?
Yes. Your liver is not damaged, so you can drink alcohol in moderation just like anyone else.
do I need treatment?
Absolutely not. It is harmless and does not affect your health or lifespan. In fact, some studies suggest having slightly higher bilirubin might protect your heart!
Primary Sources
- Bosma PJ, et al. The genetic basis of the reduced expression of bilirubin UDP-glucuronosyltransferase 1 in Gilbert's syndrome. N Engl J Med. 1995.
- Fretzayas A, et al. Gilbert syndrome. Eur J Pediatr. 2012.
- Claridge LC, et al. Gilbert's syndrome. BMJ. 2011.
Common Exam Questions
- Diagnosis: "Isolated raised bilirubin, otherwise well?"
- Answer: Gilbert's Syndrome.
- Mechanisms: "Enzyme defect?"
- Answer: UGT1A1 (Glucuronyl Transferase).
- Genetics: "Inheritance?"
- Answer: Autosomal Recessive (usually).
- Toxicity: "Chemo drug to avoid/reduce?"
- Answer: Irinotecan.
Viva Points
- Crigler-Najjar Comparison:
- Type I: Total absence of enzyme. Fatal kernicterus.
- Type II: Severe deficiency.
- Gilbert's: Mild deficiency (30% activity).
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. Clinical decisions should account for individual patient circumstances. Always consult appropriate specialists.