What are the causes of elevated Aspartate Aminotransferase (AST) or Serum Glutamic-Oxaloacetic Transaminase (SGOT) levels?

Causes of Elevated SGOT (AST)

Elevated AST has both hepatic and non-hepatic causes, with nonalcoholic fatty liver disease being the most common hepatic cause in developed countries, but muscle injury, cardiac damage, and hemolysis must always be excluded before attributing elevation to liver disease alone. 1

Hepatic Causes

Most Common

• Nonalcoholic fatty liver disease (NAFLD) is the leading cause of elevated liver enzymes, affecting 20-30% of the general population and up to 70% in obese individuals, characteristically presenting with an AST:ALT ratio <1 1, 2
• 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, 2, 3
• Viral hepatitis (both acute and chronic forms) causes AST/ALT elevation, with chronic forms showing fluctuating enzyme levels particularly during reactivation phases 1, 2

Less Common Hepatic Causes

• Drug-induced liver injury and toxic hepatitis, particularly acetaminophen overdose, can produce severe elevations through direct hepatotoxicity 4
• Ischemic hepatitis produces the most dramatic AST elevations (often reaching thousands of units per liter), occurring after hypotensive episodes or cardiac arrest 4
• Acute Budd-Chiari syndrome causes severe elevations through acute hepatic venous outflow obstruction leading to hepatocyte necrosis 4
• Metabolic storage diseases including glycogen storage diseases (types I, IX, XI), hereditary hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson's disease 5, 2

Non-Hepatic Causes

Muscle-Related

• Rhabdomyolysis and muscle injury can significantly elevate AST, confirmed by checking creatine kinase (CK) levels, which will be markedly elevated 1, 2
• Intensive exercise, particularly weight lifting, can lead to acute AST elevations due to muscle damage that may be mistaken for liver injury 1, 2
• Inflammatory myopathies (dermatomyositis/polymyositis) can cause concomitant elevation of both AST and ALT during disease flares, even when isolated from liver disease 6

Cardiac and Hematologic

• Myocardial infarction and other cardiac injuries can cause AST elevation, as AST is present in cardiac muscle 1, 7
• Hemolysis can elevate AST since the enzyme is present in erythrocytes 1, 7

Rare Benign Cause

• Macro-AST is a benign condition where AST binds to immunoglobulins, creating a high-molecular-weight complex that persists in circulation, causing isolated chronic AST elevation without actual tissue damage 8

Diagnostic Approach Algorithm

Step 1: Classify Severity

• Mild elevation: <5× upper limit of normal (ULN) 1, 4
• Moderate elevation: 5-10× ULN 1, 4
• Severe elevation: >10× ULN 1, 4

Step 2: Calculate AST:ALT Ratio

• Ratio >2:1 suggests alcoholic liver disease 1, 2, 3
• Ratio <1 suggests NAFLD 1, 2
• Ratio >3 is highly specific for alcoholic liver disease 4, 3

Step 3: Exclude Non-Hepatic Sources

• Check creatine kinase (CK) to confirm or exclude muscle injury as the source 1, 2
• Obtain detailed exercise history, particularly recent weight training or intense physical activity 1, 2
• Assess for cardiac injury with troponins if clinically indicated, especially in patients with chest pain or recent hypotensive episodes 4, 7
• Check for hemolysis with complete blood count, haptoglobin, and LDH if anemia is present 1

Step 4: Evaluate Hepatic Pattern

• Check alkaline phosphatase and bilirubin to determine if the pattern is hepatocellular versus cholestatic 1
• Screen for viral hepatitis with HAV-IgM, HBsAg, HBcIgM, and HCV antibody 1
• Obtain alcohol consumption history with specific quantification of daily/weekly intake 1, 2
• Review all medications and supplements for potential hepatotoxicity 2

Step 5: First-Line Imaging

• Ultrasound is the first-line investigation for mild asymptomatic increases, particularly to assess for NAFLD, hepatomegaly, or biliary obstruction 1, 2

Step 6: Consider Special Circumstances

• For isolated chronic AST elevation with negative workup, perform polyethylene glycol (PEG) precipitation test to diagnose macro-AST 8
• For severe elevations (>10× ULN), immediately assess for ischemic hepatitis, acute viral hepatitis, acetaminophen overdose, or acute Budd-Chiari syndrome 4
• In patients with hepatomegaly and fasting hypoglycemia, consider glycogen storage diseases and other metabolic disorders 5

Critical Pitfalls to Avoid

• Do not assume AST elevation is always hepatic: AST is present in cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells, making it a non-specific marker 1, 4
• Do not attribute severe elevations (>10× ULN) to alcoholic liver disease: While alcoholic hepatitis has an AST:ALT ratio >2, it typically produces only mild-to-moderate elevations, NOT severe elevations 4
• Do not overlook recent exercise: Vigorous exercise can cause mild-to-moderate AST elevation that resolves with rest, and checking CK confirms muscle origin 1, 2
• Do not perform liver biopsy prematurely: When glycogen storage disease is suspected based on hepatomegaly and metabolic abnormalities, gene sequencing panels are now available and preferred over biopsy 5