Causes of Elevated ALT and AST
Most Common Causes
Nonalcoholic fatty liver disease (NAFLD) is the leading cause of elevated transaminases in developed countries, affecting 20-30% of the general population and up to 70% in obese individuals, typically presenting with an AST:ALT ratio <1. 1, 2
Alcoholic liver disease is characterized by an AST:ALT ratio >2:1, which is highly suggestive of this diagnosis, with 70% of alcoholic hepatitis patients demonstrating this pattern 1, 2, 3
Medication-induced liver injury accounts for 8-11% of cases with mildly elevated liver enzymes and can be caused by prescription medications, over-the-counter drugs, or herbal supplements 1, 4
Viral hepatitis (acute or chronic hepatitis B, C, and E) commonly presents with fluctuating transaminase elevations, particularly during reactivation phases, with viral hepatitis showing the highest ALT/LD ratio (mean 4.65) 1, 3, 4
Less Common Hepatic Causes
Hereditary hemochromatosis should be evaluated with serum iron, ferritin, and total iron-binding capacity as part of the initial workup 1, 4
Autoimmune hepatitis can present with AST levels in the thousands in approximately 40% of cases and requires immediate corticosteroid therapy when identified 3
Alpha-1 antitrypsin deficiency and Wilson disease are rare causes that should be considered if initial testing is unremarkable and transaminases remain elevated for ≥6 months 1, 4
Non-Hepatic Causes
AST is significantly less liver-specific than ALT because it is present in cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells, making it essential to determine whether the elevation originates from hepatic or non-hepatic sources. 1, 5
Muscle injury or rhabdomyolysis can cause elevated transaminases, confirmed by markedly elevated creatine kinase (CK) levels 1, 2
Intensive exercise, particularly weight lifting, can lead to acute elevations in liver enzymes due to muscle injury that can be mistaken for liver disease 1, 2
Cardiac injury from myocardial infarction can cause transient AST elevation due to cardiac muscle damage 5
Thyroid disorders should be ruled out with thyroid function tests as they can cause transaminase elevations 1
Celiac disease and hemolysis are extrahepatic conditions associated with mildly elevated transaminase levels 4, 6
Important Clinical Context
Mild asymptomatic increases in serum ALT or AST (>1x to <3x ULN) in the absence of elevated bilirubin are often not specific and may be related to NAFLD, dietary changes, or vigorous exercise 7
In cancer patients, alternative causes of ALT and AST elevations include primary liver tumors, hepatic metastasis, biliary obstruction, systemic infection, sepsis, congestive heart failure, and concomitant medications 7
Normal ALT ranges differ by sex: 29-33 IU/L for males and 19-25 IU/L for females, significantly lower than commercial laboratory cutoffs 1
Severity Classification
- Mild elevation: <5× upper limit of normal (ULN) 1, 2
- Moderate elevation: 5-10× ULN 1, 2
- Severe elevation: >10× ULN 1, 2
Key Diagnostic Patterns
AST:ALT ratio <1 suggests NAFLD, viral hepatitis, or medication-induced liver injury 1, 3
AST:ALT ratio ≥2 is highly suggestive of alcoholic liver disease, with ratios >3 being particularly specific 1, 3
ALT elevation of ≥5× ULN is rare in NAFLD and usually should not be attributed to fatty liver disease alone, requiring investigation for viral hepatitis, autoimmune hepatitis, or drug-induced liver injury 1, 2
Transaminases >1000 IU/L should never be attributed to NAFLD and typically indicate acute viral hepatitis, ischemic hepatitis, drug-induced liver injury, or autoimmune hepatitis 3