Causes of Elevated AST and ALT
Primary Hepatocellular Causes
Elevated AST and ALT primarily indicate hepatocellular injury, with ALT being more liver-specific than AST, which can also originate from cardiac muscle, skeletal muscle, kidney, and red blood cells 1, 2.
Most Common Causes in Asymptomatic Patients
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of mild hypertransaminasemia worldwide, particularly in patients with metabolic syndrome components including obesity, diabetes, and hypertension 1, 3.
Alcoholic liver disease is a frequent cause, with the AST/ALT ratio typically >2.0 in alcoholic liver disease versus <1.0 in most other chronic liver conditions 4, 5.
Chronic viral hepatitis (hepatitis B and C) commonly presents with elevated transaminases, with ALT typically exceeding AST (AST/ALT ratio <1.0) 4, 3.
Medication-induced liver injury from prescription medications, over-the-counter drugs, or herbal supplements is a common cause that requires comprehensive medication review 1, 3.
Less Common Hepatic Causes
Autoimmune hepatitis typically presents with higher ALT elevations and elevated autoantibodies 1.
Hemochromatosis, α1-antitrypsin deficiency, and Wilson's disease are less common genetic causes that should be considered in persistent unexplained elevations 3.
Acute hepatitis A presents with marked transaminase elevations 6.
Pattern Recognition for Differential Diagnosis
AST/ALT Ratio Interpretation
AST/ALT ratio <1.0 suggests nonalcoholic fatty liver disease, viral hepatitis, or medication-induced injury 1, 5.
AST/ALT ratio ≥2.0 is highly suggestive of alcoholic liver disease 4, 5.
AST/ALT ratio >1.0 in nonalcoholic disease should raise suspicion for cirrhosis, as this ratio often rises above 1.0 when cirrhosis first becomes manifest 5.
Severity-Based Patterns
Mild elevations (<5× ULN) are most commonly due to NAFLD, chronic viral hepatitis, or medication effects 1, 3.
Moderate to severe elevations (≥5× ULN) warrant urgent evaluation for acute viral hepatitis, autoimmune hepatitis, ischemic hepatitis, or acute biliary obstruction 1.
**ALT/LDH ratio <1.5** suggests ischemic hepatitis or acetaminophen toxicity rather than viral hepatitis (which typically has ALT/LDH ratio >4.0) 6.
Extrahepatic Causes
Muscle-Related Causes
Skeletal muscle injury from vigorous exercise or myopathic conditions can elevate AST more than ALT 7, 1.
Creatine kinase should be measured to rule out muscle disorders when AST is disproportionately elevated compared to ALT 7, 1.
Other Systemic Causes
Cardiac injury including myocardial infarction can cause transaminase elevations, particularly AST 2.
Thyroid disorders should be ruled out with thyroid function tests in unexplained transaminase elevations 1.
Celiac disease should be considered in the differential diagnosis of mild hypertransaminasemia 3.
Specific Clinical Contexts
Hepatitis B-Related Patterns
Reactivation of hepatitis B presents with elevated, often fluctuating transaminase levels and HBV DNA >2000 IU/mL 7.
ALT levels in chronic hepatitis B may be affected by body mass index, gender, abnormal lipid and carbohydrate metabolism, fatty liver, and uremia 7.
Lower ALT thresholds (30 IU/mL for men, 19 IU/mL for women) should be considered as upper limits of normal, as HBV-infected individuals with ALT 20-30 IU/mL have increased mortality risk from liver complications 7.
Immune Checkpoint Inhibitor Context
Immune-mediated liver injury (ILICI) typically presents as asymptomatic ALT and AST elevation with normal or moderately elevated alkaline phosphatase 7.
Disproportionate AST elevation with less pronounced ALT increase should prompt evaluation for alternative causes including muscle injury and alcohol-related disease 7.
Mild elevations (>1× to <3× ULN) may be nonspecific and related to NAFLD, dietary changes, or vigorous exercise rather than true drug-induced injury 7.
Critical Pitfalls to Avoid
Do not rely solely on commercial laboratory reference ranges for ALT, as optimal ULN values are significantly lower (30 IU/mL for men, 19 IU/mL for women) than traditionally used cutoffs 7, 1.
Do not assume normal synthetic function excludes significant disease, as ALT elevation can occur with preserved albumin, bilirubin, and coagulation parameters in early hepatocellular injury 1.
Do not attribute severe ALT elevations (≥5× ULN) to NAFLD alone, as this level of elevation is rare in NAFLD and warrants evaluation for other causes 1.
Do not overlook alcohol consumption, as even moderate amounts can significantly impact transaminase levels and impede recovery 1.