What causes elevated Aspartate Aminotransferase (AST) levels?

Causes of Elevated Aspartate Aminotransferase (AST) Levels

The most common causes of elevated AST levels are nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease, medications, viral hepatitis, and non-hepatic sources including cardiac and skeletal muscle injury. 1, 2

Hepatic Causes

Common Causes

• Nonalcoholic Fatty Liver Disease (NAFLD)

  • Most prevalent cause in developed countries (20-30% general population, 70% in obesity, 90% in diabetes) 1
  • AST:ALT ratio typically <1 1
  • Associated with metabolic syndrome and insulin resistance

• Alcoholic Liver Disease

  • Distinguished by AST:ALT ratio >2 1
  • Present in approximately 75% of habitual drinkers 1

• Viral Hepatitis

  • Hepatitis B and C infections 2
  • Elevation may not correlate with degree of liver damage 3

• Drug-Induced Liver Injury

  • Medications including experimental drugs (remdesivir, chloroquine, hydroxychloroquine) 4
  • Antibiotics and antifungal agents 4
  • Statins 1

Less Common Causes

• Autoimmune Hepatitis 2
• Hereditary Hemochromatosis 2
• Alpha1-Antitrypsin Deficiency 2
• Wilson Disease 2
• Immune-Mediated Liver Injury (e.g., from immune checkpoint inhibitors) 4

Non-Hepatic Causes

• Muscle Disorders

  • Polymyositis 3, 5
  • Acute muscle injury/extreme exercise 3, 5
  • In acute muscle injury, AST:ALT ratio >3 initially, approaching 1 after a few days 5

• Cardiac Conditions

  • Myocardial infarction 3, 5
  • Congestive heart failure 4

• Other Conditions

  • Hypothyroidism 3
  • Celiac disease 2
  • Hemolysis 2
  • Macro-AST (benign condition where AST binds to immunoglobulins) 6

• Physiological Factors

  • Intensive exercise 1
  • Rapid weight loss 1

Evaluation Algorithm for Elevated AST

1. Initial Assessment

   • Calculate AST:ALT ratio

     • 2 suggests alcoholic liver disease

     • <1 suggests NAFLD

     • 3 acutely suggests muscle injury 1, 5

   • Calculate R value = (ALT/ULN)/(FA/ULN)
     • R ≥5 indicates hepatocellular pattern
     • R <2 indicates cholestatic pattern 1

2. First-Line Testing

   • Complete metabolic panel
   • Complete blood count with platelets
   • Serum albumin
   • Assessment for metabolic syndrome (waist circumference, blood pressure, fasting lipids, glucose/A1C)
   • Hepatitis B surface antigen and hepatitis C antibody
   • Iron studies (serum iron, total iron-binding capacity, ferritin)
   • Creatine kinase (to rule out muscle injury)
   • Alcohol use assessment 1, 2

3. Risk Stratification

   • Calculate FIB-4 or NAFLD Fibrosis Score to determine liver fibrosis risk 1
   • If intermediate/high risk, proceed to second-line testing (elastography)

4. Second-Line Testing (if initial evaluation inconclusive)

   • Hepatobiliary imaging (ultrasonography)
   • Tests for autoimmune hepatitis (ANA, ASMA)
   • Tests for viral infections (EBV, CMV, HSV)
   • Thyroid function tests
   • Alpha1-antitrypsin levels
   • Ceruloplasmin (Wilson disease)
   • Polyethylene glycol (PEG) precipitation test for macro-AST 4, 1, 6

Important Clinical Considerations

• AST is present in liver, cardiac and skeletal muscle, and erythrocytes, making it less specific for liver damage than ALT 7
• Normal AST levels do not exclude significant liver disease, including chronic hepatitis and cirrhosis 1
• LFT abnormalities are more common in severe COVID-19 than in mild cases 4
• Liver enzyme monitoring should occur approximately every 3 months during treatment of elevated levels 1
• More frequent monitoring (every 1-2 months) is recommended if liver enzymes are >2 times ULN 1

Referral to Hepatology

Consider referral for:

• Persistent elevation >6 months despite interventions
• Suspected autoimmune hepatitis
• Conflicting clinical, laboratory, and imaging findings
• Development of jaundice, ALT elevation >5× ULN
• Elevated bilirubin with elevated transaminases
• Signs of hepatic decompensation 1