What are the causes of jaundice?

Causes of Jaundice

Jaundice is primarily caused by four major categories of disorders: hepatitis, alcoholic liver disease, blockage of the common bile duct by gallstones or tumors, and toxic reactions to drugs or medicinal herbs. 1

Classification of Jaundice by Mechanism

Jaundice can be systematically categorized based on the underlying pathophysiology:

1. Prehepatic/Hemolytic (Unconjugated Hyperbilirubinemia)

• Hemolysis (red blood cell destruction)
• Hematoma resorption
• Gilbert syndrome (impaired bilirubin conjugation)
• Crigler-Najjar syndrome

2. Hepatic/Hepatocellular (Mixed or Predominantly Conjugated)

• Viral hepatitis - most common cause in many regions 1
• Alcoholic liver disease - second most common cause in the US 1
• Drug-induced liver injury
• Autoimmune hepatitis
• Cirrhosis
• Sepsis - most common cause of new-onset jaundice in one US study (22%) 1

3. Post-hepatic/Obstructive (Conjugated Hyperbilirubinemia)

• Common bile duct obstruction by gallstones - 13-14% of cases 1
• Malignancy (pancreatic, biliary, metastatic) - leading cause of severe jaundice in European studies 1
• Biliary strictures
• Cholangitis
• Pancreatitis

Laboratory Differentiation

The type of hyperbilirubinemia can be determined by measuring fractionated bilirubin:

• Predominantly unconjugated: <20-30% conjugated bilirubin 2
• Predominantly conjugated: >35% conjugated bilirubin 2

Regional and Demographic Variations

The prevalence of different causes varies significantly by:

• Geographic location
• Hospital setting (tertiary vs. community)
• Inpatient vs. outpatient
• Severity of jaundice
• Demographics 1

For example:

• In the US: sepsis (22%), decompensated chronic liver disease (20.5%), alcoholic hepatitis (16%), and gallstone disease (14%) are most common 1
• In Europe: malignancy is the most common cause of severe jaundice 1
• In Vietnam: cirrhosis is reported as the most common cause 1

Common Pitfalls in Diagnosis

• Overlooking malignancy as a cause of isolated elevated alkaline phosphatase 2
• Assuming normal aminotransferases rule out significant liver disease 2
• Misinterpreting medication-induced bilirubin elevations that may be transient 2
• Failing to recognize the "Hy's law pattern" (ALT >3× ULN and bilirubin >2× ULN without cholestasis) which suggests high risk of severe drug-induced liver injury 2

Diagnostic Algorithm

1. Initial laboratory evaluation:

   • Fractionated bilirubin (total, direct/conjugated, indirect/unconjugated)
   • Complete blood count with peripheral smear
   • Liver function tests (ALT, AST, alkaline phosphatase, γ-glutamyltransferase)
   • Albumin, total protein, prothrombin time/INR 2

2. First-line imaging:

   • Abdominal ultrasound for suspected biliary obstruction (sensitivity 32-100%, specificity 71-97%) 2
   • If ultrasound negative but clinical suspicion persists, proceed to MRI with MRCP 2
   • CT abdomen with contrast for suspected pancreatic or biliary malignancy 2

3. Further evaluation based on initial results:

   • For predominantly unconjugated hyperbilirubinemia: evaluate for hemolysis or genetic disorders
   • For predominantly conjugated hyperbilirubinemia: evaluate for hepatocellular or obstructive causes
   • If imaging suggests obstruction: consider ERCP or endoscopic ultrasound
   • If diagnosis remains unclear: consider liver biopsy 1

Understanding the pattern of jaundice and following a systematic approach to diagnosis is essential for identifying the underlying cause and initiating appropriate treatment to improve patient outcomes.