Bilirubin metabolism
The pathway
- Haem (80% from senescent RBC, 20% from ineffective erythropoiesis and other haemoproteins)
- -> haem oxygenase -> biliverdin -> biliverdin reductase -> unconjugated bilirubin
- Unconjugated bilirubin is lipid-soluble, albumin-bound, water-insoluble
- -> never appears in urine; can cross the blood-brain barrier -> kernicterus
- Hepatocyte uptake (OATP)
- -> UDP-glucuronosyltransferase (UGT1A1) conjugates with glucuronic acid
- -> conjugated bilirubin - water-soluble
- -> appears in urine (dark urine); cannot cross the BBB
- -> MRP2 exports into bile
- -> colonic bacteria -> urobilinogen -> stercobilin (brown stool); a fraction reabsorbed -> urine urobilinogen
The two questions that classify any jaundice
1. Unconjugated or conjugated?
2. If conjugated: hepatocellular or cholestatic? (ALT-predominant vs ALP-predominant)
- Pale stool + dark urine = conjugated + obstructed
- Dark urine alone means conjugated hyperbilirubinaemia, whatever the cause
Epidemiology
- Gilbert syndrome affects ~5-10% of the population - the commonest inherited hyperbilirubinaemia
- M > F (androgens increase bilirubin production and reduce clearance)
- Crigler-Najjar type 1 <1 per million; Dubin-Johnson and Rotor rare (Dubin-Johnson clusters in Iranian Jewish populations)
- Physiological neonatal jaundice: ~60% of term and ~80% of preterm infants
Unconjugated hyperbilirubinaemia - causes
Unconjugated hyperbilirubinaemia
A. Increased production
- Haemolysis (any cause), ineffective erythropoiesis (thalassaemia, megaloblastic anaemia), large haematoma resorption, transfusion
B. Impaired uptake
- Drugs (rifampicin, contrast), heart failure, portosystemic shunt
C. Impaired conjugation - a UGT1A1 spectrum
| Condition | UGT1A1 activity | Consequence |
|---|---|---|
| Gilbert syndrome | ~30% reduction (promoter TA repeat polymorphism) | Mild, benign, fluctuating |
| Crigler-Najjar type 2 | Partial deficiency | Moderate; responds to phenobarbitone |
| Crigler-Najjar type 1 | Near-complete absence | Severe from birth; kernicterus |
- Also: neonatal physiological jaundice, breast milk jaundice, hyperthyroidism
Conjugated hyperbilirubinaemia - causes
Conjugated hyperbilirubinaemia
A. Hepatocellular - viral, alcohol, drugs, autoimmune, ischaemic, sepsis, Wilson
B. Intrahepatic cholestasis - PBC, PSC, drugs (augmentin, flucloxacillin, anabolic steroids), TPN, pregnancy (ICP), sepsis, infiltration
C. Extrahepatic obstruction - gallstone, pancreatic head/cholangiocarcinoma, stricture, chronic pancreatitis, parasites
D. Impaired hepatocyte excretion - the benign familial ones
- Dubin-Johnson - MRP2 (ABCC2) defect. Jaundice, abdominal pain, fatigue, dark urine, worse with intercurrent illness, pregnancy or the OCP. Black-pigmented liver on biopsy. Benign, good long-term prognosis
- Rotor - OATP1B1/1B3 defect; storage rather than excretion defect. Liver is NOT pigmented; total urinary coproporphyrin markedly raised
Gilbert syndrome
- Intermittent, non-pruritic jaundice, otherwise entirely well; normal LFTs and no haemolysis
- Precipitants: fasting, intercurrent infection, dehydration, surgery, physical exertion, sleep deprivation, and drugs that inhibit glucuronyltransferase (gemfibrozil, protease inhibitors such as atazanavir and indinavir)
- Bilirubin usually <70-80 micromol/L, unconjugated, no bilirubinuria
- Diagnosis is clinical: isolated unconjugated hyperbilirubinaemia + normal FBE, reticulocytes, blood film, LDH, haptoglobin + normal LFT
- Genetic testing and provocation tests are not needed
- Clinically important because: it causes irinotecan toxicity (UGT1A1 also conjugates SN-38), and it explains atazanavir-associated jaundice
Distinguishing the benign familial syndromes
| Bilirubin | Urine bilirubin | Liver appearance | Other | |
|---|---|---|---|---|
| Gilbert | Unconjugated | Absent | Normal | Provoked by fasting |
| Crigler-Najjar 1 | Unconjugated, very high | Absent | Normal | Kernicterus |
| Crigler-Najjar 2 | Unconjugated, high | Absent | Normal | Falls with phenobarbitone |
| Dubin-Johnson | Conjugated | Present | Black pigment | Normal total coproporphyrin, raised coproporphyrin I fraction |
| Rotor | Conjugated | Present | Not pigmented | Markedly raised total urinary coproporphyrin |
Approach to any jaundiced patient
1. Split the bilirubin
2. Unconjugated -> haemolysis screen (FBE, film, reticulocytes, LDH, haptoglobin, DAT); if negative and LFTs normal -> Gilbert
3. Conjugated -> LFT pattern
- ALT-predominant -> hepatitic screen (viral, autoimmune, drugs, Wilson, ischaemia)
- ALP/GGT-predominant -> ultrasound for duct dilatation
- Dilated -> obstruction -> MRCP/EUS -> ERCP
- Not dilated -> intrahepatic cholestasis -> AMA, IgG4, MRCP, drug review, biopsy
4. Always check INR and albumin - synthetic function is what determines urgency
Management of the familial syndromes
- Gilbert syndrome: reassurance, and nothing else. Explain the precipitants so a future jaundice episode does not trigger another workup
- Flag the irinotecan interaction in oncology settings
- Crigler-Najjar type 2: phenobarbitone induces residual UGT1A1 -> bilirubin falls (a diagnostic and therapeutic test)
- Crigler-Najjar type 1:
- Lifelong intensive phototherapy from birth (converts bilirubin to water-soluble lumirubin) - up to 12 hours/day, and efficacy falls with age as skin thickens and surface-area-to-mass ratio drops
- Plasma exchange for acute crises; liver transplantation is the definitive treatment
- Does not respond to phenobarbitone - that is what separates it from type 2
- Dubin-Johnson and Rotor: no treatment needed; avoid attributing later liver disease to them
- Avoid the OCP if it provokes jaundice; jaundice worsens with intercurrent illness and pregnancy
- Neonatal jaundice: phototherapy by nomogram, exchange transfusion if severe
- *Conjugated hyperbilirubinaemia in a neonate is never physiological - urgent workup for biliary atresia* (a Kasai portoenterostomy after ~8 weeks has much poorer outcomes)
- Obstructive jaundice: relieve the obstruction (ERCP/stent/surgery); vitamin K, watch renal function and coagulopathy
Associations
- Gilbert syndrome - irinotecan toxicity (UGT1A1), atazanavir/indinavir jaundice, possibly protective against cardiovascular disease (bilirubin as an antioxidant)
- Crigler-Najjar type 1 - kernicterus, basal ganglia and brainstem nuclei injury
- Dubin-Johnson - clotting factor VII deficiency reported; worsened by pregnancy and the OCP
- Haemolysis -> pigment (calcium bilirubinate) gallstones
- Kernicterus risk factors: prematurity, sepsis, acidosis, hypoalbuminaemia, and drugs that displace bilirubin from albumin (sulfonamides, ceftriaxone)
Prognosis
- Gilbert syndrome: entirely benign, normal life expectancy, no liver disease
- Crigler-Najjar type 1: severe unconjugated hyperbilirubinaemia and pale stools from birth
- Without lifelong phototherapy or transplantation, kernicterus develops in the neonatal period
- Even treated patients remain at risk of kernicterus into young adulthood - a very different disease from Gilbert, despite sharing the enzyme
- Crigler-Najjar type 2: kernicterus uncommon; near-normal life expectancy on phenobarbitone
- Dubin-Johnson and Rotor: normal life expectancy, no progression to cirrhosis
Monitor
- Gilbert, Dubin-Johnson, Rotor - no monitoring required
- Crigler-Najjar - bilirubin levels, phototherapy hours, neurological assessment, transplant planning
- A rising bilirubin in a known Gilbert patient with abnormal transaminases is a second diagnosis, not Gilbert
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