What is the differential diagnosis and management of elevated Alanine Transaminase (ALT) and Aspartate Transaminase (AST) levels?

Differential Diagnosis of Elevated ALT and AST

Primary Hepatic Causes

The most common causes of elevated transaminases in primary care are nonalcoholic fatty liver disease (NAFLD), chronic viral hepatitis, alcohol-related liver disease, and drug-induced liver injury. 1, 2

Hepatocellular Injury Pattern (ALT/AST Predominant)

• NAFLD/NASH is the most common cause in patients with metabolic risk factors (obesity, diabetes, hypertension), typically presenting with AST:ALT ratio <1 and mild to moderate elevations 1, 3
• Chronic viral hepatitis (B, C) should be considered, especially with ALT >2× ULN, though enzyme elevation may not correlate with degree of liver damage 1, 2
• Alcoholic liver disease characteristically shows AST:ALT ratio >2, though this is an exception to the usual pattern 1, 3
• Autoimmune hepatitis typically presents with higher ALT elevations and elevated autoantibodies 1
• Drug-induced liver injury from prescription medications, over-the-counter drugs, or herbal supplements can present with various patterns and normal synthetic function 1
• Hereditary hemochromatosis should be screened in the initial evaluation 4
• Wilson's disease and alpha-1 antitrypsin deficiency should be considered in younger patients 4

Cholestatic Pattern (Alkaline Phosphatase Predominant with Elevated Transaminases)

• Primary biliary cholangitis and primary sclerosing cholangitis should be tested when alkaline phosphatase is disproportionately elevated 4
• Biliary obstruction from stones, strictures, or malignancy 1

Non-Hepatic Causes

AST is less specific for liver injury and can be elevated in cardiac, skeletal muscle, kidney, and red blood cell disorders, making ALT the preferred marker for hepatocellular injury. 1, 5

• Acute myocardial infarction can cause transient AST elevation disproportionate to ALT 2, 5
• Skeletal muscle disorders including polymyositis, muscular dystrophy, and acute muscle injury from vigorous exercise elevate AST more than ALT 1, 2
• Hypothyroidism can cause mild transaminase elevations 1, 2
• Hemolysis affects AST due to its presence in erythrocytes 5

Cancer-Related Causes

In patients with malignancy, alternative causes include:

• Primary liver tumors or hepatic metastases 6
• Intra- or extra-hepatic biliary obstruction 6
• Systemic infection or sepsis 6
• Congestive heart failure 6

Clinical Context for Mild Elevations

Mild asymptomatic increases in ALT or AST (>1× to <3× ULN) without elevated bilirubin are often nonspecific and may be related to NAFLD, dietary changes, or vigorous exercise. 6 These mild elevations may be transient and spontaneously revert to baseline even when therapy is continued, a phenomenon called "adaptation" 6

Important Diagnostic Considerations

• ALT is more liver-specific than AST because it has minimal presence in skeletal muscle and kidney, making it the preferred marker for hepatocellular injury 1, 4
• Normal ALT ranges differ by sex: 29-33 IU/L for males and 19-25 IU/L for females 1, 4
• AST:ALT ratio <1 suggests NAFLD, viral hepatitis, or drug-induced injury 1, 3
• AST:ALT ratio >1 in nonalcoholic liver disease should raise suspicion for cirrhosis 3
• Creatine kinase should be measured to rule out muscle disorders as a cause of AST elevation 1

Common Pitfalls to Avoid

• Do not ignore mild persistent elevations—even mild elevations persisting beyond 6 months warrant thorough evaluation 7
• Do not attribute all elevations to fatty liver without excluding other causes, even when NAFLD is suspected 7
• Do not use the term "hepatitis" without histological confirmation; use "liver injury" instead 6
• ALT elevations ≥5× ULN are rare in NAFLD/NASH alone and should prompt evaluation for other causes including viral hepatitis, autoimmune hepatitis, ischemic hepatitis, and acute biliary obstruction 1