Pathophysiology of Jaundice
Jaundice results from the accumulation of bilirubin in body tissues due to disorders in bilirubin metabolism, hepatocellular dysfunction, or biliary obstruction, becoming clinically apparent when serum bilirubin levels exceed 2.5-3 mg/dL. 1
Bilirubin Metabolism
- Production: Bilirubin is a byproduct of heme metabolism, primarily from the breakdown of aged red blood cells
- Transport: Unconjugated (indirect) bilirubin is bound to albumin and transported to the liver
- Conjugation: In the liver, bilirubin is conjugated with glucuronic acid by UDP-glucuronosyltransferase to form water-soluble conjugated (direct) bilirubin
- Excretion: Conjugated bilirubin is excreted into bile and eventually into the intestine, where it is converted to urobilinogen and stercobilin
Classification of Jaundice
Jaundice can be classified based on the site of disruption in the bilirubin pathway:
1. Prehepatic (Hemolytic) Jaundice
- Mechanism: Increased bilirubin production due to accelerated red blood cell destruction
- Laboratory findings: Predominantly unconjugated hyperbilirubinemia
- Causes:
- Hemolytic anemias
- Hematoma resorption
- Ineffective erythropoiesis
2. Hepatic (Hepatocellular) Jaundice
- Mechanism: Impaired uptake, conjugation, or excretion of bilirubin by damaged hepatocytes
- Laboratory findings: Mixed conjugated and unconjugated hyperbilirubinemia
- Causes:
- Viral hepatitis
- Alcoholic liver disease
- Drug-induced liver injury
- Cirrhosis
- Genetic disorders (Gilbert's syndrome, Crigler-Najjar syndrome)
3. Posthepatic (Obstructive) Jaundice
- Mechanism: Obstruction to bile flow in the biliary tract
- Laboratory findings: Predominantly conjugated hyperbilirubinemia
- Causes:
- Choledocholithiasis (gallstones)
- Biliary strictures
- Pancreatic cancer
- Cholangiocarcinoma
- Pancreatitis
Clinical Manifestations
- Yellowing of skin and sclera: Occurs when bilirubin accumulates in tissues
- Dark urine: Due to conjugated bilirubin excretion in urine
- Clay-colored stools: Due to absence of bile pigments in stool
- Pruritus: More common in obstructive jaundice due to accumulation of bile salts
Associated Findings
- Hepatomegaly: Common in hepatocellular causes
- Cholangitis: Characterized by fever, right upper quadrant pain, and jaundice (Charcot's triad)
- Fulminant hepatic failure: Severe form with rapid deterioration of liver function and encephalopathy 2
Diagnostic Approach
Laboratory tests:
- Fractionated bilirubin (total, direct, indirect)
- Liver enzymes (AST, ALT, ALP, GGT)
- Complete blood count
- Prothrombin time and INR (for liver synthetic function) 3
Imaging:
- Ultrasound: First-line imaging for suspected obstructive jaundice
- CT or MRI: When ultrasound is inconclusive or for further characterization
- MRCP: For detailed evaluation of biliary tract 2
Special Considerations
- Age-related differences: In children younger than 6 years, hepatitis A infections are often asymptomatic, while more than two-thirds of older children and adults develop jaundice 2
- Pregnancy: Not a risk factor for more severe hepatitis A infections, though rare cases of transmission to the fetus have been reported 2
- Risk factors for fulminant disease: Age over 50 years and underlying chronic liver disease increase the risk of severe complications 2
Common Pitfalls
- Overlooking drug-induced jaundice: Many medications can cause liver injury and jaundice
- Missing hemolytic causes: Focusing only on hepatobiliary causes may lead to missed diagnosis of hemolytic jaundice
- Delayed diagnosis of malignancy: Studies from Europe have shown malignancy as the most common etiology of severe jaundice 2
- Relying solely on physical examination: Clinical assessment alone is insufficient; laboratory testing and imaging are essential for accurate diagnosis
Understanding the pathophysiology of jaundice is crucial for appropriate diagnostic workup and management of patients presenting with this clinical manifestation.