What causes jaundice (yellowing of the eyes) in adults and newborns?

What Causes Jaundice (Yellowing of the Eyes)

Jaundice occurs when bilirubin accumulates in body tissues due to bilirubin overproduction, impaired liver conjugation, biliary obstruction, or hepatic inflammation, becoming visible in the eyes first when serum bilirubin exceeds 2.5-3 mg/dL. 1, 2

Fundamental Mechanism

Jaundice results from systemic hyperbilirubinemia affecting the entire body, with the sclera (whites of the eyes) showing yellowing first due to elastin's high affinity for bilirubin. 2 The underlying pathophysiology involves disruption at any point in bilirubin metabolism—from production through excretion. 1, 3

Most Common Causes in Adults

In the United States

The four most common etiologies are: 1

• Hepatitis (viral, autoimmune, or alcoholic)
• Alcoholic liver disease (accounts for 16% of cases, often presenting as first sign of decompensation) 1, 4
• Common bile duct obstruction from gallstones (14% of cases) or tumor (6.2% of cases) 1, 4
• Drug-induced liver injury or toxic reactions to medications/herbal supplements 1, 4

Additional Major Causes

• Sepsis/shock: 22-27% of severe jaundice cases, creating dual mechanisms through hemolysis and hepatic dysfunction 1, 4
• Decompensation of pre-existing cirrhosis: 20.5% of new-onset jaundice 1, 4
• Hemolysis: 2.5% of cases, causing unconjugated hyperbilirubinemia 1
• Gilbert syndrome: 5.6% of cases, representing inherited bilirubin metabolism deficiency 1, 4

Important caveat: The dominant cause varies significantly by geography—European studies show malignancy as the most common cause of severe jaundice, while Vietnamese data cite cirrhosis as most common. 1

Causes in Newborns

Unconjugated Hyperbilirubinemia (Most Common)

• Physiological jaundice: Results from red blood cell breakdown combined with immature liver conjugation capacity, responds to phototherapy 5
• Hemolysis: From blood group incompatibilities or other hemolytic disorders 5
• Inadequate feeding: Leads to increased enterohepatic circulation of bilirubin 5

Conjugated Hyperbilirubinemia (Requires Urgent Evaluation)

• Biliary atresia: Must be identified early; any infant with persistent jaundice requires conjugated bilirubin measurement 5
• Neonatal hepatitis 5
• Parenteral nutrition-associated cholestasis: Particularly in preterm infants on long-term IV nutrition 5

Critical warning: Rapidly rising unconjugated bilirubin in newborns risks kernicterus (neurotoxicity) and requires urgent phototherapy or exchange transfusion. 5

Mechanistic Categories

Prehepatic (Unconjugated Hyperbilirubinemia)

• Hemolysis from any cause 6
• Hematoma resorption 6
• Inherited disorders (Gilbert syndrome, Crigler-Najjar syndrome) 4

Intrahepatic (Can Be Either Type)

• Viral hepatitis (hepatitis A, B, C, E) 1, 6
• Alcoholic hepatitis (requires >50 g/day alcohol for minimum 6 months) 4
• Drug-induced liver injury 1, 6
• Autoimmune hepatitis 1, 6
• Cirrhosis with decompensation 1, 4

Posthepatic (Conjugated Hyperbilirubinemia)

• Choledocholithiasis (gallstones in common bile duct; small stones <5 mm carry 4-fold increased migration risk) 4
• Malignancy (pancreatic cancer, cholangiocarcinoma, ampullary tumors) 1, 4
• Cholangitis (presents with right upper quadrant pain, fever, jaundice) 1
• Pancreatitis 1
• Biliary strictures 7

High-Risk Populations

Genetic and demographic factors: 4

• PNPLA3 G allele carriers (increased alcoholic hepatitis susceptibility)
• Female gender (independent risk factor for alcoholic hepatitis)
• Elevated BMI (risk for both alcoholic and nonalcoholic steatohepatitis)

Clinical risk factors: 4

• Pre-existing chronic liver disease (20.5% of new jaundice)
• Heavy alcohol consumption
• Medication/herbal supplement use
• Gallstone disease
• Malnutrition (impairs recovery in alcoholic hepatitis)

Diagnostic Approach

Initial laboratory evaluation distinguishes unconjugated from conjugated hyperbilirubinemia: 7

• Elevated unconjugated bilirubin: Suggests hemolysis, Gilbert syndrome, or Crigler-Najjar syndrome
• Elevated conjugated bilirubin with alkaline phosphatase/GGT elevation: Indicates cholestasis requiring imaging
• Elevated transaminases: Suggests hepatocellular injury

Abdominal ultrasound is the initial imaging test of choice, with 65-95% sensitivity for cirrhosis and 32-100% sensitivity for biliary obstruction. 4