What is the differential diagnosis for hyperbilirubinemia in a patient?

Differential Diagnosis of Elevated Bilirubin

The differential diagnosis for hyperbilirubinemia is fundamentally determined by whether the elevation is unconjugated or conjugated, which must be established first by fractionating the total bilirubin. 1

Initial Categorization by Bilirubin Type

Unconjugated (Indirect) Hyperbilirubinemia

When conjugated bilirubin is <20-30% of total bilirubin, consider the following etiologies 1:

Impaired Conjugation:

• Gilbert's syndrome - the most common cause of isolated mild unconjugated hyperbilirubinemia in asymptomatic adults, with total bilirubin rarely exceeding 4-5 mg/dL 1, 2
• Crigler-Najjar syndrome 3, 4
• Medication-induced impaired conjugation 1

Increased Bilirubin Production:

• Hemolytic disorders (evaluate with peripheral smear, reticulocyte count, haptoglobin, and LDH) 1, 4
• G6PD deficiency (particularly important in African American patients where prevalence is 11-13%, and those of Mediterranean or Asian descent) 1
• Hematoma resorption 5

Conjugated (Direct) Hyperbilirubinemia

When direct bilirubin is >35% of total bilirubin, suspect hepatocellular injury or cholestatic disease 1:

Hepatocellular Disorders:

• Viral hepatitis (hepatitis A, B, C, E) 3, 4
• Alcoholic hepatitis 3, 4
• Non-alcoholic fatty liver disease 2
• Drug-induced liver injury 3, 1
• Autoimmune hepatitis 3, 4
• Cirrhosis 3

Cholestatic/Obstructive Disorders:

• Choledocholithiasis (gallstones in common bile duct) - the most common benign posthepatic cause 3, 5
• Biliary tract infection/cholangitis 5
• Primary sclerosing cholangitis 1
• Primary biliary cirrhosis 1
• Pancreatic malignancy 3, 5
• Cholangiocarcinoma 5
• Pancreatitis 5

Inherited Conjugated Hyperbilirubinemia:

• Dubin-Johnson syndrome 2
• Rotor syndrome 2

Critical Diagnostic Pitfalls

Direct bilirubin is not synonymous with conjugated bilirubin - it includes both conjugated bilirubin and delta bilirubin, which has a 21-day half-life and can cause persistent hyperbilirubinemia even after the underlying cause resolves 1. This explains why hyperbilirubinemia may persist longer than expected in recovering patients.

In cholestatic disease, check vitamin K status before interpreting elevated INR - fat-soluble vitamin deficiencies are common in cholestasis and can cause elevated INR that mimics synthetic liver dysfunction rather than true hepatic impairment 1.

Never rely on visual estimation of jaundice, especially in darkly pigmented patients - always obtain objective bilirubin measurements 1.

Special Population Considerations

Neonates and Infants:

• Conjugated bilirubin >25 μmol/L requires immediate referral to pediatrics for urgent assessment of possible liver disease 3, 1
• Total bilirubin ≥25 mg/dL or ≥20 mg/dL in a sick infant is a medical emergency requiring immediate hospital admission, type and crossmatch, and consideration for exchange transfusion 1
• Jaundice in the first 24 hours of life requires immediate measurement of total and direct/conjugated bilirubin 1

Critically Ill Patients:

• In severe sepsis and septic shock, elevated bilirubin independently predicts mortality, with adjusted odds of death 3.85 times higher for bilirubin 1.1-2 mg/dL and 9.85 times higher for bilirubin >2 mg/dL compared to normal levels 6

Algorithmic Approach to Workup

Step 1: Fractionate the bilirubin to determine unconjugated vs. conjugated 1, 4

Step 2: If unconjugated predominates:

• Obtain CBC with differential, peripheral smear, reticulocyte count, haptoglobin, and LDH to evaluate for hemolysis 1
• Test for G6PD deficiency in appropriate ethnic populations 1
• Review medications for drugs causing impaired conjugation 1
• If hemolysis is excluded and bilirubin is mildly elevated, diagnose Gilbert's syndrome and reassure the patient - no treatment is needed 3, 1

Step 3: If conjugated predominates:

• Check ALT, AST, alkaline phosphatase, GGT, albumin, and PT/INR 3, 1
• If alkaline phosphatase is elevated, confirm hepatic origin with GGT 3, 1
• Obtain abdominal ultrasound as first-line imaging to exclude biliary obstruction (specificity 71-97% for excluding mechanical obstruction, sensitivity 65-95% for detecting cirrhosis) 3, 1
• The most accurate ultrasound finding for cirrhosis is a nodular liver surface, particularly on the undersurface (86% sensitivity) 3
• If ultrasound is negative but clinical suspicion remains high for primary sclerosing cholangitis or primary biliary cirrhosis, obtain MRI with MRCP before proceeding to liver biopsy 1

Step 4: Additional testing based on imaging results:

• If obstruction is present, consider ERCP for stone removal (successful in 80-95% of cases) or stent placement (successful in >90% of distal CBD strictures) 3
• If no obstruction but hepatocellular pattern, obtain viral hepatitis serologies and autoimmune antibody assays 4
• Consider liver biopsy for persistent unexplained conjugated hyperbilirubinemia ≥6 months 1