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Mnemonics, Simplified Concepts & Thoughts

Bilirubin Metabolism and Disorders

Epomedicine, May 18, 2024May 18, 2024

Last updated on May 18, 2024

Bilirubin Metabolism

Mnemonic: ABCDE

1. Aged RBCs (80-85%)

  • Shunt bilirubin (15-20%): Bilirubin that doesn’t originate from senescent RBCs, i.e. immature or defective RBCs, non-heme compounds (hepatic cytochromes, myoglobin)
    • Dyserythropoiesis = Unconjugated hyperbilirubinemia

2. Breakdown to Biliverdin and Bilirubin (in reticuloendothelial system)

  • RBC = Heme + Globin
  • Heme = Iron + Biliverdin (green color)
    • Heme-oxygenase enzyme
  • Biliverdin = Unconjugated Bilirubin (yellow color; water insoluble; indirect bilirubin)
    • Biliverdin reductase

3. Circulation

  • Unconjugated bilirubin + Albumin
    • Low plasma albumin = Unconjugated hyperbilirubinemia
    • Drug competition for albumin = Unconjugated hyperbilirubinemia

4. Delivery to liver (Conjugation)

  • Hepatic uptake of Albumin-Bilirubin complex
    • Defect = Gilbert’s syndrome (AD; unconjugated hyperbilirubinemia)
  • Unconjugated bilirubin + Glucuronic acid = Conjugated bilirubin (water soluble; bilirubin monoglucuronide 15% + bilirubin diglucuronide 85%)
    • UDP-glucuronyl transferase encoded by UGT1A1 (defect = unconjugated hyperbilirubinemia)
      • Absence = Crigler Najjar 1 (AR)
      • Partial deficiency = Crigler Najjar 2 (AR)
      • Reduced activity = Gilbert’s syndrome (AD)
      • Slow synthesis after birth = Newborn jaundice
  • Some conjugated bilirubin excreted in urine

5. Excretion and Enterohepatic circulation

  1. Excessive conjugate bilirubin is excreted in blood and taken up by unsaturated hepatocytes
    • Defective OATPB1/B3 transporters = Rotor syndrome (AR; Conjugated hyperbilirubinemia)
  2. Into bile-canaliculus (Active transport)
    • Rate-limiting step
    • Defective MRP-2 protein = Dubin-Johnson syndrome (AR; Conjugated hyperbilirubinemia)
  3. Duodenum
  4. Terminal ileum and Colon
    • Bacterial degradation of conjugated bilirubin = Urobilinogen
      • 18% = Enterohepatic circulation (delivered back to liver)
      • 2% = Excreted in urine (Urobilin; gives characteristic color of urine)
      • 80% = Excreted in stool (Stercobilin; gives characteristic color of feces)
bilirubin synthesis and metabolism

Unconjugated Vs Conjugated Bilirubin

Unconjugated bilirubinConjugated bilirubin
Van den Bergh reactionIndirectDirect
SolubilityWater insoluble; Lipid solubleWater soluble; Lipid insoluble
Blood-brain barrierCannot passCan pass (Kernicterus)
Urinary excretionNot excretedExcreted

Stool and Urine Color in Hyperbilirubinemia

BilirubinUrineStool
Pre-hepaticUnconjugatedNormal (urobilin)Normal (stercobilin)
Post-hepaticConjugatedDark (conjugated bilirubin)Pale (less stercobilin in stool)

Inherited Disorders of Bilirubin Metabolism

inherited disorders of bilirubin metabolism
GilbertCrigler Najjar 1Crigler Najjar 2RotorDubin Johnson
HyperbilirubinemiaUnconjugatedUnconjugatedUnconjugatedConjugatedConjugated
Defect1. Hepatic uptake of unconjugated bilirubin
2. Decreased activity of UDP glucuronyl transferase
Absent UDP glucuronyl transferasePartial deficiency of UDP glucuronyl transferaseDefective hepatic uptake and storage of conjugated bilirubinDefective secretion of conjugated bilirubin into bile
Genetic defectUGT1A1UGT1A1UGT1A1OATP1B1/B3MRP-2
InheritanceADARARARAR
Liver histologyNormal or Lipofuscin pigmentNormalNormalNormalDark centrilobular pigmentation
Incidence6-12%Very rareUncommonRareUncommon
Plasma bilirubin (mg/dl)≤3 in absence of fasting or hemolysis; almost all uncojugatedUsually >20; all unconjugatedUsually <20; almost all unconjugatedUsually <7; about half conjugatedUsually <7; about half conjugated
PrognosisNormalDeath in infancy if untreatedUsually normalNormalNormal
TreatmentNot requiredLiver transplantPhenobarbitalNoneAvoid estrogens
Other features↓ bilirubin with phenobarbitalNo response to phenobarbital↓ bilirubin with phenobarbital↑↑ urinary coproporphyrin (isomer I <80%)↑ urinary coproporphyrin (isomer I >80%)

Mnemonics:

  • Dubin Johnson = Dark liver
  • Rotor = Red liver (Normal)
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PGMEE, MRCS, USMLE, MBBS, MD/MS BiochemistryGastrointestinal systemPhysiology

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Epomedicine. Bilirubin Metabolism and Disorders [Internet]. Epomedicine; 2024 May 18 [cited 2025 May 29]. Available from: https://epomedicine.com/medical-students/bilirubin-metabolism-disorders/.

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