Jaundice

Bilirubin Metabolism - The Foundation

• ~80% of bilirubin comes from RBC breakdown; the rest from myoglobin and cytochromes
• Heme is catabolized by heme oxygenase in macrophages (MPS) → biliverdin (green) → bilirubin (red-orange)
• This unconjugated bilirubin (UCB) is water-insoluble, so it binds albumin for transport to the liver

• UCB enters hepatocytes via facilitated diffusion, binds ligandin
• The enzyme bilirubin UDP-glucuronosyltransferase (bilirubin UGT) conjugates bilirubin with 2 glucuronic acid molecules → bilirubin diglucuronide (conjugated bilirubin, CB)
• CB is water-soluble and actively transported into bile canaliculi

• CB is secreted into bile → intestine → converted to urobilinogen by gut bacteria
• Most urobilinogen is excreted in stool as stercobilin (gives stool its brown color)
• A small fraction is reabsorbed (enterohepatic circulation), reaches the kidney, and is excreted as urobilin (gives urine its pale yellow color)

Classification of Jaundice

1. Prehepatic (Hemolytic) Jaundice

• Cause: Excessive RBC destruction overwhelms the liver's conjugation capacity
• Bilirubin type: Unconjugated hyperbilirubinemia (UCB elevated)
• Mechanism: Hemolysis produces bilirubin faster than it can be conjugated
• Examples: Sickle cell anemia, G6PD deficiency, pyruvate kinase deficiency, immune hemolysis (Coombs+), microangiopathic hemolytic anemia, mechanical hemolysis (prosthetic heart valves)
• Urine findings: Urobilinogen increased; NO bilirubin in urine (UCB is not filtered by kidneys)
• Stool: Normal color (stercobilin normal or increased)

2. Hepatocellular (Intrahepatic) Jaundice

• Cause: Liver cell damage impairs both conjugation and excretion
• Bilirubin type: Mixed (both UCB and CB elevated)
• Examples: Viral hepatitis, cirrhosis, alcoholic liver disease, ischemic hepatitis, drug toxicity
• Inherited enzyme disorders:
  • Gilbert's syndrome - diminished bilirubin UGT activity; affects 4-7% of the population; benign, causes mild transient UCB elevation during fasting/stress/illness
  • Crigler-Najjar syndrome (I & II) - more severe deficiency of bilirubin UGT; neonates at risk of kernicterus
  • Dubin-Johnson syndrome - defect in CB transport out of hepatocyte; CB accumulates in blood
  • Rotor's syndrome - similar to Dubin-Johnson, disrupts CB secretion
• Urine: Dark (urobilinogen increased - less reabsorbed by damaged liver, more reaches urine; plus urinary bilirubin present)
• Stool: Pale/clay-colored (less stercobilin)

3. Posthepatic (Obstructive/Cholestatic) Jaundice

• Cause: Blockage of the common bile duct preventing CB from reaching the intestine
• Bilirubin type: Conjugated hyperbilirubinemia (CB elevated)
• Examples:
  • Intraluminal: choledocholithiasis (gallstones), biliary sludge
  • Mural: cholangiocarcinoma, biliary strictures (post-operative, PSC)
  • Extramural: pancreatic head cancer, periampullary tumors, lymph node compression
• Urine: Dark (CB filtered by kidneys - "bilirubinuria"); urinary urobilinogen ABSENT
• Stool: Pale, clay-colored (no bile reaching intestine)
• Symptoms: Pruritus (bile salt deposition in skin), right upper quadrant pain, nausea

Comparison Table

Special Topic: Neonatal Jaundice

• Occurs in ~60% of full-term and ~80% of preterm neonates in the first postnatal week
• Cause: Low bilirubin UGT activity at birth (reaches adult levels at ~4 weeks) → physiologic UCB accumulation
• Danger: UCB >20-25 mg/dL can cross the blood-brain barrier → deposits in basal ganglia → kernicterus (bilirubin encephalopathy)
• Treatment: Phototherapy with blue fluorescent light converts bilirubin to water-soluble photoisomers that can be excreted without conjugation
• Pathologic causes include: ABO/Rh incompatibility, G6PD deficiency, biliary atresia, Crigler-Najjar

Lab Investigations

Key Causes by Clinical Context

• Lippincott Illustrated Reviews: Biochemistry, 8th ed, Chapter 21 (Bilirubin metabolism & jaundice classification)
• Schwartz's Principles of Surgery, 11th ed (Prehepatic/intrahepatic/posthepatic classification, workup)
• Sleisenger and Fordtran's GI and Liver Disease (Pruritus management, palliative context)