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

Causes of Elevated ALT and AST

Elevated ALT and AST levels are most commonly caused by nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease, viral hepatitis, drug-induced liver injury, and autoimmune hepatitis, with NAFLD being the predominant cause in developed countries affecting 20-30% of the general population and up to 90% in patients with diabetes. 1

Common Causes of Elevated Liver Enzymes

Hepatic Causes

• Nonalcoholic Fatty Liver Disease (NAFLD)

  • Most common cause in developed countries (20-30% prevalence)
  • Higher prevalence in obesity (70%) and diabetes (90%) 1
  • Usually mild elevations (<5× ULN)
  • AST/ALT ratio typically <1

• Alcoholic Liver Disease

  • AST/ALT ratio ≥2 is highly suggestive 1, 2
  • May have associated GGT elevation

• Viral Hepatitis

  • Hepatitis A, B, C, D, E
  • AST/ALT ratio typically <1 in chronic viral hepatitis without cirrhosis 2
  • AST/ALT ratio often rises to >1 when cirrhosis develops 2

• Drug-Induced Liver Injury

  • Common medications: acetaminophen, antibiotics, statins, NSAIDs
  • Immune checkpoint inhibitors can cause immune-mediated liver injury 3
  • Acetaminophen toxicity has ALT/LD ratio of approximately 1.46 4

• Autoimmune Hepatitis

  • May require liver biopsy for diagnosis 1
  • Often responds to corticosteroid therapy

• Cirrhosis (any etiology)

  • AST/ALT ratio often >1 regardless of underlying cause 2
  • Important prognostic indicator

Non-Hepatic Causes

• Muscle Disorders/Injury

  • Polymyositis, rhabdomyolysis, intense exercise 1, 5
  • AST is present in skeletal muscle, causing disproportionate AST elevation 6
  • Check creatine kinase (CK) levels

• Cardiac Conditions

  • Myocardial infarction, heart failure 1, 6
  • Ischemic hepatitis shows markedly elevated LDH with ALT/LD ratio of approximately 0.87 4

• Other Causes

  • Thyroid disorders (hypothyroidism) 5
  • Hemolysis (affects AST)
  • Malignancy with liver metastases 3
  • Biliary obstruction
  • Systemic infections/sepsis 3

Diagnostic Approach

Initial Assessment

• Laboratory Testing

  • Complete liver panel (ALT, AST, ALP, GGT, bilirubin, albumin)
  • Calculate AST/ALT ratio:
    • ≥2: Suggests alcoholic liver disease

    • 1: Consider cirrhosis even in non-alcoholic disease 2

    • <1: Typical of viral hepatitis without cirrhosis, NAFLD

• Viral Hepatitis Screening

  • Anti-HAV IgM
  • HBsAg, Anti-HBc (IgG, IgM), HBV DNA
  • Anti-HCV, HCV RNA
  • Anti-HEV (IgG, IgM), HEV RNA 3

• Autoimmune Markers

  • ANA, ASMA, Anti-LKM-1
  • Quantitative immunoglobulins (IgG, IgM, IgA) 3

• Additional Tests

  • Serum CK (to rule out muscle injury)
  • Alcohol markers (EtOH level, phosphatidylethanol)
  • Acetaminophen level if overdose suspected 3

Imaging

• Abdominal ultrasound as first-line imaging to:
  • Assess liver structure
  • Rule out biliary obstruction
  • Evaluate for steatosis, masses, or metastases 1

Non-Invasive Fibrosis Assessment

• FIB-4 score as first step
• Liver elastography if fibrosis is suspected 1

Management Considerations

Classification of Elevation Severity

• Mild: <5× ULN
• Moderate: 5-10× ULN
• Severe: >10× ULN 1

Monitoring and Referral

• For persistent elevations (>6 months) despite interventions
• For suspected autoimmune hepatitis
• For ALT elevation >5× ULN
• For signs of hepatic decompensation 1

Special Situations

• Acetaminophen Toxicity

  • AST/ALT ratio ≤0.4 is 99% sensitive for identifying resolving transaminases 7
  • Consider N-acetylcysteine therapy for suspected cases 1

• Immune Checkpoint Inhibitor-Related Elevations

  • For grade ≥2 elevation: hold immunotherapy
  • Consider steroids (0.5-1 mg/kg/day prednisone) if no improvement after 3-5 days 1

Remember that the degree of enzyme elevation may not correlate well with the severity of liver damage, particularly in chronic viral hepatitis 5. A thorough evaluation is necessary even for asymptomatic patients with elevated liver enzymes.