What causes yellow eyes (jaundice)?

Causes of Yellow Eyes (Jaundice)

Jaundice results from the accumulation of bilirubin in body tissues and can be caused by a variety of disorders including bilirubin overproduction, impaired bilirubin conjugation, biliary obstruction, and hepatic inflammation. 1 Understanding the underlying mechanisms is crucial for proper diagnosis and treatment.

Major Categories of Causes

1. Prehepatic Causes (Unconjugated Hyperbilirubinemia)

• Hemolysis - Excessive breakdown of red blood cells leading to increased bilirubin production 2
• Hematoma resorption - When large amounts of blood are reabsorbed 2
• Gilbert syndrome - A common genetic condition causing mild unconjugated hyperbilirubinemia 1

2. Hepatic Causes (Mixed or Conjugated Hyperbilirubinemia)

• Hepatitis - Viral, alcoholic, or autoimmune 1
• Alcoholic liver disease - Most common cause of liver damage in the United States 3
• Drug-induced liver injury - Medications, dietary supplements, and herbal remedies 3, 4
• Sepsis/shock - Can cause jaundice through multiple mechanisms 1
• Cirrhosis - End-stage liver disease from various etiologies 1
• Non-alcoholic fatty liver disease (NAFLD) - Most common liver disease in developed countries 3

3. Posthepatic Causes (Conjugated Hyperbilirubinemia)

• Biliary obstruction - Most commonly from:
  • Gallstones - Most common benign posthepatic cause 2
  • Tumors - Pancreatic cancer, cholangiocarcinoma, ampullary tumors 1
  • Strictures - From prior surgery, inflammation, or malignancy 4
• Biliary tract infection - Cholangitis, cholecystitis 2
• Pancreatitis - Can cause biliary compression 2

Epidemiology of Jaundice Causes

In the United States, the most common causes of jaundice fall into four categories:

1. Hepatitis
2. Alcoholic liver disease
3. Blockage of the common bile duct by gallstones or tumors
4. Toxic reactions to drugs or herbal supplements 1

A U.S. study found sepsis to be the most common cause of new-onset jaundice (22%), followed by decompensation of pre-existing liver disease (20.5%), alcoholic hepatitis (16%), gallstone disease (14%), Gilbert syndrome (5.6%), malignancy (6.2%), and hemolysis (2.5%). 1

Diagnostic Approach

Laboratory evaluation should include:

• Fractionated bilirubin (total, direct/conjugated, indirect/unconjugated)
• Complete blood count
• Liver enzymes (AST, ALT, alkaline phosphatase, GGT)
• Tests of liver synthetic function (albumin, prothrombin time) 4

Imaging typically begins with abdominal ultrasound, which can detect:

• Cirrhosis with 65-95% sensitivity 1
• Biliary obstruction with variable sensitivity (32-100%) 1

Special Considerations

• AST:ALT ratio > 2 suggests alcoholic liver disease, compared to < 1 in NAFLD 3
• Malaria can cause jaundice through hemolysis, disseminated intravascular coagulation, or rarely "malarial hepatitis" 5
• Clinical signs of jaundice typically appear when serum bilirubin exceeds 2.5-3 mg/dL 6

Common Pitfalls

1. Overlooking drug-induced causes - Always obtain a thorough medication history, including over-the-counter and herbal supplements
2. Misdiagnosing malignancy - Painless jaundice in older adults should raise suspicion for pancreaticobiliary malignancy
3. Failing to recognize alcoholic hepatitis - Often presents with AST:ALT ratio >2 and may require specific management
4. Confusing viral hepatitis with other causes - Serologic testing is essential for proper diagnosis
5. Underestimating sepsis-induced jaundice - Particularly in critically ill patients

Understanding the broad differential diagnosis and systematic approach to jaundice is essential for timely diagnosis and appropriate management of potentially life-threatening conditions.