Common Causes of Yellowing of the Sclera
The yellowing of the sclera (scleral icterus) is primarily caused by hyperbilirubinemia, which can result from prehepatic, hepatic, or posthepatic disorders affecting bilirubin metabolism and excretion.
Classification of Causes
1. Prehepatic Causes (Unconjugated Hyperbilirubinemia)
- Hemolytic disorders
- Hemolytic anemias
- Sickle cell disease
- Thalassemias
- Autoimmune hemolytic anemia
- G6PD deficiency
- Hematoma resorption (large internal bleeding)
- Ineffective erythropoiesis
2. Hepatic Causes
- Hepatocellular damage
- Viral hepatitis (A, B, C, D, E)
- Alcoholic hepatitis
- Drug-induced liver injury
- Autoimmune hepatitis
- Impaired bilirubin conjugation
- Gilbert syndrome
- Crigler-Najjar syndrome
- Impaired bilirubin excretion
- Dubin-Johnson syndrome
- Rotor syndrome
3. Posthepatic Causes (Conjugated Hyperbilirubinemia)
- Biliary obstruction
- Choledocholithiasis (gallstones)
- Pancreatic cancer
- Cholangiocarcinoma (bile duct cancer)
- Ampullary carcinoma
- Metastatic lymphadenopathy
- Primary sclerosing cholangitis
- Biliary strictures
- Pancreatic disorders
- Pancreatitis (acute and chronic)
- Pancreatic pseudocyst compressing bile ducts 1
Clinical Evaluation
Key Diagnostic Tests
Initial laboratory tests:
- Fractionated bilirubin (conjugated vs. unconjugated)
- Complete blood count
- Liver function tests (ALT, AST, alkaline phosphatase, γ-glutamyltransferase)
- Prothrombin time/INR
- Albumin and protein 2
Imaging:
Distinguishing Features
Unconjugated Hyperbilirubinemia
- Elevated indirect bilirubin
- Normal or minimally elevated liver enzymes
- Negative urine bilirubin test (unconjugated bilirubin is not water-soluble)
- Often associated with hemolysis markers (elevated LDH, decreased haptoglobin)
Conjugated Hyperbilirubinemia
- Elevated direct bilirubin
- Positive urine bilirubin test
- Often accompanied by elevated alkaline phosphatase and GGT
- May present with dark urine and clay-colored stools in obstructive cases 4
Management Considerations
Obstructive Jaundice
- Requires prompt evaluation for potential biliary decompression
- ERCP (endoscopic retrograde cholangiopancreatography) is the preferred first-line approach for biliary drainage in distal obstruction
- Percutaneous transhepatic biliary drainage (PTBD) is typically reserved for patients who have failed ERCP or have difficult anatomy 1
Malignant Biliary Obstruction
- Decompression of obstructive biliary system is preferred over medical management even in palliative settings
- Improves overall quality of life in patients with malignant obstruction 1
Hepatitis-Related Jaundice
- Management depends on the specific cause (viral, alcoholic, autoimmune)
- May require specific antiviral therapy, immunosuppression, or supportive care
Special Considerations
Jaundice Without Pain
- Painless jaundice is a concerning sign that may indicate malignancy (pancreatic cancer, cholangiocarcinoma)
- Requires thorough investigation to differentiate between benign and malignant causes 5
Jaundice in Pancreatitis
- Can occur due to pancreatic edema, fibrosis, or pseudocyst compressing the common bile duct
- May require biliary decompression if persistent 5
Blue Sclera vs. Yellow Sclera
- Blue sclera is associated with conditions like osteogenesis imperfecta or iron deficiency anemia
- Yellow sclera (scleral icterus) indicates hyperbilirubinemia 1
Clinical Pearls
- Scleral icterus becomes clinically apparent when serum bilirubin exceeds 2.5-3 mg/dL 3
- The pattern of liver enzyme elevation can help differentiate between hepatocellular and cholestatic processes
- In patients with obstructive jaundice, injection of contrast under pressure should be avoided during procedures as it may lead to cholangio-venous reflux and exacerbate septicemia 1
- Yellowing of the sclera is typically one of the earliest and most sensitive physical findings of hyperbilirubinemia, often preceding skin jaundice