Pathophysiology of jaundice, defects of bilirubin and bile formation. Cholelithiasis

1. Jaundice — Definition

• Yellow discoloration of skin/mucosa from hyperbilirubinemia (serum bilirubin > 2.0 mg/dL).
• Bile is the primary route for elimination of bilirubin, excess cholesterol, lipophilic xenobiotics; also emulsifies dietary fat.

2. Bilirubin Metabolism

Outside the liver

• Heme → (heme oxygenase) → biliverdin → (biliverdin reductase) → unconjugated bilirubin.
• Taken up by RES macrophages; released into blood bound to albumin → liver.

In the hepatocyte

1. Sinusoidal uptake → delivery to ER.
2. Conjugation with glucuronic acid (UDP-glucuronyl transferase) → conjugated bilirubin (water-soluble, non-toxic).
3. Canalicular excretion into bile.

In the gut

• Bacterial deconjugation → colorless urobilinogen → excreted in feces; small fraction reabsorbed and re-excreted (enterohepatic circulation).

3. Types of Jaundice

A) Pre-hepatic (unconjugated)

• Hemolytic anemia → ↑ heme breakdown → hepatic conjugating capacity overwhelmed.
• Neonatal jaundice:
  • Rh incompatibility (Rh⁻ mother / Rh⁺ fetus) → hemolytic disease of newborn.
  • Physiological jaundice: immature hepatic conjugation system.
  • Dangerous → kernicterus (irreversible brain damage).

B) Hepatic

• Liver parenchymal disease: hepatitis, cirrhosis.
• Crigler-Najjar syndrome — unconjugated hyperbilirubinemia:
  • Type 1: complete lack of UDP-glucuronyl transferase → fatal early.
  • Type 2: reduced activity — milder.
• Gilbert syndrome: mild fluctuating unconjugated hyperbilirubinemia (↓ transferase activity); benign, triggered by stress/fasting.
• Dubin-Johnson syndrome: AR defect in canalicular transporter of conjugated bilirubin → conjugated hyperbilirubinemia (black liver).

C) Post-hepatic (conjugated)

• Obstruction: gallstones, tumors of biliary tree / head of pancreas.

4. Cholelithiasis (Gallstones)

A) Cholesterol stones

• Crystalline cholesterol monohydrate; found only in the gallbladder.
• Four simultaneous conditions for formation:
  1. Cholesterol supersaturation of bile
  2. Nucleation into monohydrate crystals
  3. Gallbladder hypomotility / stasis
  4. Mucus hypersecretion trapping crystals
• Risk factors:
  • Female sex hormones (estrogen) → ↑ hepatic cholesterol secretion
  • Obesity, rapid weight loss, hypocholesteremic drugs
  • Hyperlipidemia
• Gross: pure = pale yellow; mixed (Ca-carb/phosphate/bilirubin) = gray-white-black; ovoid, firm.
• ~80 % radiolucent (X-ray transparent); 20 % radiopaque (Ca content).

B) Pigment stones

• Insoluble calcium bilirubinate salts; favored by unconjugated bilirubin.
• Risk factors:
  • Chronic hemolytic syndromes
  • Biliary infection
  • GI disorders: Crohn, CF + pancreatic insufficiency, ileal resection/bypass

Pigment subtype	Black	Brown
Setting	Sterile gallbladder bile	Infected ducts
Size / number	Small, many	Large, few
Consistency	Crumble easily	Soft, grease-like (fatty acids)
Radiology	Often radiopaque	Radiolucent

General risk factors (the classic 5 F’s)

• Female (2× in white women), Fat, Forty+, Fertile, Fair; also: ethnicity/geography (western industrialized), genetics, ↓ gallbladder motility (pregnancy, rapid weight loss, spinal cord injury).

Clinical features

• 70–80 % asymptomatic for life.
• Symptomatic: biliary colic, cholecystitis, empyema, perforation / fistula, obstructive cholestasis or pancreatitis, gallstone ileus (large stone → intestinal obstruction).

💡 High-yield: Jaundice = bilirubin > 2 mg/dL. Pre-hepatic / hepatic-conjugating defect = unconjugated (hemolysis, neonatal, Gilbert, Crigler-Najjar). Hepatic-excretion / post-hepatic = conjugated (Dubin-Johnson black liver, stones, tumor). Gallstones: cholesterol (estrogen, gallbladder only, 80 % radiolucent, 5 F’s) vs pigment (hemolysis/infection, Ca-bilirubinate; black = sterile, brown = infected).