What are the causes of elevated Alanine Transaminase (ALT) and Aspartate Transaminase (AST) levels?

Causes of Elevated ALT and AST

Hepatic Causes

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of elevated liver enzymes in developed countries, affecting 20-30% of the general population and up to 70% in obese individuals, characteristically presenting with an AST:ALT ratio <1. 1, 2, 3

Common Hepatic Etiologies

• Alcoholic liver disease shows a distinctive AST:ALT ratio >2:1, which is highly suggestive of this condition, with ratios >3 being even more specific for alcohol-related injury 1, 3

• Viral hepatitis (both acute and chronic forms including hepatitis B and C) causes AST/ALT elevation, with chronic forms showing fluctuating enzyme levels particularly during reactivation phases 4, 1, 2

• Drug-induced liver injury and toxic hepatitis, particularly acetaminophen overdose, can produce severe elevations through direct hepatotoxicity 1

• Ischemic hepatitis produces the most dramatic AST elevations (often reaching thousands of units per liter), occurring after hypotensive episodes or cardiac arrest 1

• Acute Budd-Chiari syndrome causes severe elevations through acute hepatic venous outflow obstruction leading to hepatocyte necrosis 1

Less Common Hepatic Causes

• Metabolic storage diseases including glycogen storage diseases (types I, IX, XI), hereditary hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson's disease 1, 2

• Autoimmune hepatitis can present with elevated transaminases and should be considered in the differential diagnosis 5

• Primary sclerosing cholangitis typically presents with a cholestatic pattern (elevated alkaline phosphatase and γ-glutamyl transpeptidase) but AST and ALT are often mildly raised; a raised AST>ALT may be an indicator of cirrhosis and poor prognosis 4

Non-Hepatic Causes

Muscle injury or rhabdomyolysis can significantly elevate AST and ALT, confirmed by checking creatine kinase (CK) levels, which will be markedly elevated. 1, 2, 3, 6

• Intensive exercise, particularly weight lifting, can lead to acute AST/ALT elevations due to muscle damage that may be mistaken for liver injury 1, 2, 3

• Myocardial infarction and other cardiac injuries can cause AST elevation, as AST is present in cardiac muscle 1, 3, 7

• Hemolysis can elevate AST since the enzyme is present in erythrocytes 1, 3

• Seizures can cause muscle necrosis leading to elevated transaminases 6

• Polymyositis and other skeletal muscle diseases can elevate both AST and ALT 6

• Celiac disease and thyroid disorders should be considered in the differential diagnosis of mild hypertransaminasemia 5

Diagnostic Approach Algorithm

Step 1: Classify Severity

The American College of Gastroenterology recommends classifying elevation severity as mild (<5× upper limit of normal), moderate (5-10× ULN), or severe (>10× ULN). 1, 2, 3

Step 2: Calculate AST:ALT Ratio

• AST:ALT ratio >2:1 suggests alcoholic liver disease 1, 3, 8
• AST:ALT ratio <1 suggests NAFLD 1, 3
• AST:ALT ratio ≥1 in nonalcoholic liver disease is highly suggestive of cirrhosis 9, 8
• AST:ALT ratio >3 in acute muscle injury (due to faster decline in AST half-life) 6

Step 3: Exclude Non-Hepatic Sources

• Check creatine kinase (CK) to confirm or exclude muscle injury (markedly elevated in rhabdomyolysis) 1, 2, 3, 6
• Obtain detailed exercise history, specifically asking about recent intensive weight training or unusual physical exertion 1, 2
• Assess for cardiac injury with troponins if clinical suspicion exists 1
• Check for hemolysis with complete blood count, haptoglobin, and LDH 1

Step 4: Evaluate Hepatic Pattern

• Check alkaline phosphatase and bilirubin to determine if the pattern is hepatocellular versus cholestatic 1, 2
• Screen for viral hepatitis with HAV-IgM, HBsAg, HBcIgM, and HCV antibody 3
• Obtain detailed alcohol consumption history (quantity, frequency, duration) 1, 3
• Review all medications and supplements for potential hepatotoxicity 1, 2
• Assess metabolic risk factors including body mass index, presence of diabetes, dyslipidemia 4

Step 5: First-Line Imaging

The American Association for the Study of Liver Diseases recommends ultrasound as the first-line investigation for mild asymptomatic increases, particularly to assess for NAFLD, hepatomegaly, or biliary obstruction. 1, 2, 3

Step 6: Consider Special Circumstances

• For isolated chronic AST elevation, consider metabolic disorders including glycogen storage diseases, particularly if hepatomegaly with fasting hypoglycemia is present 1
• For severe elevations (>10× ULN), consider ischemic hepatitis, acute viral hepatitis, drug-induced liver injury, or Budd-Chiari syndrome 1
• For persistent unexplained ALT elevation >6 months, the European Association for the Study of the Liver recommends liver biopsy 2
• In patients >35-40 years with HBV DNA ≥2000 IU/mL and normal ALT, consider liver biopsy or transient elastography as they are less likely to be in immune tolerance phase 4

Important Clinical Pitfalls

• ALT levels do not strictly correlate with the extent of liver cell necrosis, and ALT alone does not identify patients with necroinflammatory activity or fibrosis with optimal reliability 4

• ALT activity may be affected by body mass index, gender, abnormal lipid and carbohydrate metabolism, fatty liver, and uremia 4

• The upper limit of normal for ALT should be 30 IU/mL for men and 19 IU/mL for women (significantly lower than values used by commercial laboratories), and HBV-infected individuals with ALT values <40-45 IU/mL are still at risk for significant liver disease 4

• AST can remain elevated in patients whose ALT has normalized, suggesting that measuring AST may be useful when ALT is consistently normal 9

• In acute muscle injury, both AST and ALT are elevated with AST/ALT ratio >3, but this ratio approaches 1 after a few days because of faster decline in AST 6

• ALT elevation of ≥5× ULN is rare in NAFLD/NASH and usually should not be attributed to these conditions 2