Bilirubin Metabolism and Disorders

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)

Unconjugated Vs Conjugated Bilirubin

	Unconjugated bilirubin	Conjugated bilirubin
Van den Bergh reaction	Indirect	Direct
Solubility	Water insoluble; Lipid soluble	Water soluble; Lipid insoluble
Blood-brain barrier	Cannot pass	Can pass (Kernicterus)
Urinary excretion	Not excreted	Excreted

Stool and Urine Color in Hyperbilirubinemia

	Bilirubin	Urine	Stool
Pre-hepatic	Unconjugated	Normal (urobilin)	Normal (stercobilin)
Post-hepatic	Conjugated	Dark (conjugated bilirubin)	Pale (less stercobilin in stool)

Inherited Disorders of Bilirubin Metabolism

	Gilbert	Crigler Najjar 1	Crigler Najjar 2	Rotor	Dubin Johnson
Hyperbilirubinemia	Unconjugated	Unconjugated	Unconjugated	Conjugated	Conjugated
Defect	1. Hepatic uptake of unconjugated bilirubin 2. Decreased activity of UDP glucuronyl transferase	Absent UDP glucuronyl transferase	Partial deficiency of UDP glucuronyl transferase	Defective hepatic uptake and storage of conjugated bilirubin	Defective secretion of conjugated bilirubin into bile
Genetic defect	UGT1A1	UGT1A1	UGT1A1	OATP1B1/B3	MRP-2
Inheritance	AD	AR	AR	AR	AR
Liver histology	Normal or Lipofuscin pigment	Normal	Normal	Normal	Dark centrilobular pigmentation
Incidence	6-12%	Very rare	Uncommon	Rare	Uncommon
Plasma bilirubin (mg/dl)	≤3 in absence of fasting or hemolysis; almost all uncojugated	Usually >20; all unconjugated	Usually <20; almost all unconjugated	Usually <7; about half conjugated	Usually <7; about half conjugated
Prognosis	Normal	Death in infancy if untreated	Usually normal	Normal	Normal
Treatment	Not required	Liver transplant	Phenobarbital	None	Avoid estrogens
Other features	↓ bilirubin with phenobarbital	No 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)