What are the differentials for a patient presenting with elevated transaminases (liver enzymes)?

Differential Diagnosis of Elevated Transaminases

Primary Differential Diagnoses

The most common causes of elevated transaminases are nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease, which together account for the majority of cases in primary care. 1, 2

Most Common Causes (Prevalence-Based Approach)

• Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of the population and is the leading cause of elevated transaminases, typically presenting with AST:ALT ratio <1 and mild to moderate elevations 3, 4, 1, 2
• Alcoholic liver disease characteristically shows AST:ALT ratio >2 (particularly >3 for high specificity), with AST typically 2-6 times upper limit of normal 3, 4
• Medication-induced liver injury causes 8-11% of cases with mildly elevated liver enzymes, including prescription drugs, over-the-counter medications, and herbal supplements 3, 4, 1
• Viral hepatitis (hepatitis B, C, and E) commonly presents with fluctuating transaminase elevations, with acute hepatitis typically showing ALT >400 IU/L 3, 4, 5, 1

Uncommon but Important Causes

• Hereditary hemochromatosis should be screened with serum iron, ferritin, and total iron-binding capacity 4, 1, 2
• Autoimmune hepatitis typically presents with higher ALT elevations, elevated immunoglobulins, and positive autoantibodies (ANA, anti-smooth muscle antibody) 3, 4, 1
• Wilson disease must be considered in patients <40 years old, especially those presenting with apparent autoimmune hepatitis that responds poorly to corticosteroids 3

Rare but Critical Causes

• Alpha-1 antitrypsin deficiency requires measurement of alpha-1 antitrypsin levels 4, 1, 2
• Wilson disease in acute liver failure presents with Coombs-negative hemolytic anemia, modest transaminase elevations (typically <2000 IU/L), markedly low alkaline phosphatase (typically <40 IU/L), and alkaline phosphatase to bilirubin ratio <2 3

Extrahepatic Causes

• Thyroid disorders can cause transaminase elevations and should be screened with thyroid function tests 4, 1, 2
• Celiac disease may present with elevated transaminases and warrants screening if clinically indicated 4, 1, 2
• Muscle disorders elevate AST more than ALT; creatine kinase should be measured to exclude muscle injury, particularly after intensive exercise 4, 1, 2
• Hemolysis can elevate AST due to its presence in red blood cells 4, 1

Pattern Recognition for Diagnosis

Hepatocellular Pattern (Predominant ALT/AST Elevation)

• AST:ALT ratio <1 suggests NAFLD, viral hepatitis, or medication-induced injury 4, 6
• AST:ALT ratio ≥2 is highly suggestive of alcoholic liver disease, with ratios >3 being particularly specific 4, 6
• Modest elevations (<2000 IU/L) with low alkaline phosphatase should raise suspicion for Wilson disease, especially with hemolytic anemia 3

Cholestatic Pattern (Predominant Alkaline Phosphatase/GGT Elevation)

• Elevated alkaline phosphatase and GGT suggest biliary obstruction or cholestatic disease 4, 6
• GGT confirms hepatic origin of alkaline phosphatase elevation, as alkaline phosphatase can be elevated in bone disease 4, 6

Critical Diagnostic Pitfalls

• Normal ALT does not exclude significant liver disease—up to 50% of patients with NAFLD and 10% with advanced fibrosis may have normal ALT using conventional thresholds 3, 4
• Sex-specific reference ranges matter—normal ALT is 29-33 IU/L for males and 19-25 IU/L for females, significantly lower than commercial laboratory cutoffs 4
• Hepatitis E is frequently overlooked—screening for hepatitis E should be included in patients with markedly elevated transaminases and suspected drug-induced liver injury 5
• Drug-induced liver injury from minocycline and nitrofurantoin can occur after months or years of use, not just acute exposure 3
• Wilson disease mimics autoimmune hepatitis—all children with apparent autoimmune hepatitis and adults responding poorly to corticosteroids must be evaluated for Wilson disease 3