Jaundice (Icterus)

Definition

Bilirubin Metabolism (Normal Physiology)

1. Formation: ~85% of bilirubin comes from breakdown of senescent RBCs (lifespan ~120 days) by the mononuclear phagocyte system. Heme oxygenase opens the porphyrin ring, converting heme → biliverdin (green) → bilirubin (red-orange).
2. Transport to liver: Bilirubin is water-insoluble (unconjugated bilirubin, UCB), so it is transported in plasma bound to albumin. It enters hepatocytes via facilitated diffusion and binds to ligandin.
3. Conjugation: In hepatocytes, bilirubin UDP-glucuronosyltransferase (UGT) adds 2 glucuronic acid molecules to form bilirubin diglucuronide (conjugated bilirubin, CB) - making it water-soluble.

1. Secretion into bile: CB is actively transported into bile canaliculi (rate-limiting step; impaired in liver disease).
2. Intestinal metabolism: Gut bacteria reduce CB → urobilinogen (colorless) → stercobilin (brown, gives feces its color). Some urobilinogen is reabsorbed, recycled enterohepatic, and a fraction excreted by kidneys as urobilin (yellow urine color).

• Lippincott Illustrated Reviews: Biochemistry, 8th ed, pp. 794-798

Classification of Jaundice

1. Prehepatic (Hemolytic) Jaundice

• Mechanism: Excessive RBC breakdown overwhelms the liver's conjugation capacity (normal liver can conjugate >3,000 mg/day vs. normal production of ~300 mg/day).
• Bilirubin type: Predominantly unconjugated (indirect) hyperbilirubinemia
• Urine: Urobilinogen elevated; no bilirubin in urine (UCB not filtered by kidney)
• Stool: Dark (increased stercobilin)
• Causes:
  • Hereditary hemolytic anemias (sickle cell, thalassemia, hereditary spherocytosis, G6PD deficiency)
  • Acquired hemolytic anemias: immune-mediated (autoimmune, drug-induced, positive Coombs test) and non-immune (mechanical valve hemolysis, microangiopathy, infections, toxins)
  • Reduced albumin (malnutrition, burns) - impairs UCB transport
• Schwartz's Principles of Surgery, 11th ed, p. 1381

2. Intrahepatic (Hepatocellular) Jaundice

• Mechanism: Damage to hepatocytes impairs both conjugation and excretion of bilirubin. Intrahepatic cholestasis causes regurgitation of CB back into blood.
• Bilirubin type: Both unconjugated and conjugated elevated
• Urine: Dark (bilirubinuria present); increased urobilinogen
• Stool: Pale/clay-colored (decreased stercobilin)
• LFTs: Elevated ALT and AST
• Causes:
  • Hepatitis (viral, alcoholic, autoimmune)
  • Cirrhosis
  • Ischemic hepatitis
  • Inherited disorders:
    • Gilbert's syndrome: Reduced UGT activity → mild unconjugated hyperbilirubinemia triggered by fasting/illness; benign, affects 4-7% of population
    • Crigler-Najjar syndrome: Rare, severe UGT deficiency in neonates; risk of kernicterus/bilirubin encephalopathy
    • Dubin-Johnson syndrome: Defect in canalicular transport protein (MRP2) → conjugated hyperbilirubinemia; generally benign
    • Rotor's syndrome: Similar to Dubin-Johnson but without liver pigmentation
• Schwartz's Principles of Surgery, 11th ed, p. 1381

3. Posthepatic (Obstructive/Cholestatic) Jaundice

• Mechanism: Obstruction of bile flow prevents CB from reaching the duodenum; CB regurgitates into blood.
• Bilirubin type: Predominantly conjugated (direct) hyperbilirubinemia
• Urine: Dark (bilirubinuria - CB is water-soluble and renally filtered); no urobilinogen (bile not reaching gut)
• Stool: Pale/clay-colored (absence of stercobilin)
• Symptoms: RUQ/epigastric pain, nausea, pruritus (bile salt deposition)
• Causes:
  • Intrinsic: Cholelithiasis, choledocholithiasis, cholangiocarcinoma, biliary strictures (benign or malignant), primary sclerosing cholangitis, cholangitis, papilla of Vater disorders
  • Extrinsic: Pancreatic cancer (classic painless obstructive jaundice + Courvoisier's sign), pancreatitis, pancreatic pseudocyst
  • Iatrogenic: Surgical clip misplacement, retained stones, bile duct injury
• Schwartz's Principles of Surgery, 11th ed, p. 1381-1382

Comparative Summary Table

Neonatal Jaundice

• Accelerated physiological hemolysis (fetal Hb replacement)
• Immature hepatic UGT enzyme expression (delayed postnatal induction)

Clinical Approach to a Jaundiced Patient

1. History: Duration, associated pain (colicky = stones; painless = malignancy), fever (cholangitis), drug/alcohol use, travel, family history
2. Physical exam: Hepatomegaly, splenomegaly, stigmata of chronic liver disease, Courvoisier's sign (palpable gallbladder in painless jaundice = suggests malignant obstruction)
3. Labs:
   • Fractionated bilirubin (direct vs. indirect)
   • LFTs: ALT, AST (hepatocellular pattern) vs. ALP, GGT (cholestatic pattern)
   • CBC (hemolysis: anemia, reticulocytosis, elevated LDH, low haptoglobin)
   • Peripheral smear
   • Coagulation (PT/INR - synthetic function)
4. Imaging: Ultrasound abdomen (first-line to detect biliary dilation, stones, liver lesions); CT or MRCP for further characterization; ERCP for therapeutic intervention
   • Important: ERCP should not be the primary investigation if hilar cholangiocarcinoma is suspected - axial imaging first. - Maingot's Abdominal Operations

Pruritus in Jaundice

• Topical: Astringents, moisturizers, steroid creams
• Antihistamines (H1 and H2), phenothiazines, bile acid resins (cholestyramine)
• Opioid antagonists (note: reverses analgesia in patients on opioids)
• Rifampicin, gabapentin (anecdotal evidence)
• Sleisenger & Fordtran's Gastrointestinal and Liver Disease