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

Causes of Elevated AST and ALT Levels

The most common causes of elevated AST and ALT levels include nonalcoholic fatty liver disease (NAFLD), alcoholic liver disease, viral hepatitis, drug-induced liver injury, autoimmune hepatitis, and non-hepatic conditions such as muscle injury. 1

Common Hepatic Causes

Nonalcoholic Fatty Liver Disease (NAFLD)

• Most common cause of isolated ALT elevation in developed countries, with prevalence of 20-30% in general population, increasing to 70% in obesity 1
• Typically presents with AST:ALT ratio <1 1
• Represents a spectrum from simple steatosis (70-75% of cases) to nonalcoholic steatohepatitis (NASH) with inflammation (25-30% of cases) 1

Alcoholic Liver Disease

• Characterized by AST:ALT ratio >2:1, highly suggestive of alcoholic liver disease 2, 1
• The ratio may be <1 when several days have elapsed since alcohol exposure 3

Viral Hepatitis

• Both acute and chronic viral hepatitis (B and C) can cause ALT/AST elevation 1
• In acute viral hepatitis, ALT is usually higher than AST (AST:ALT ratio <1) 3, 4
• AST greater than ALT in acute viral hepatitis can indicate fulminant disease 3
• In chronic viral hepatitis, ALT elevation may fluctuate, particularly during reactivation phases 1

Drug-Induced Liver Injury (DILI)

• Many medications can cause ALT/AST elevation, including:
  • Statins, antibiotics, antiepileptics, and herbal supplements 1
  • Immune checkpoint inhibitors (causing immune-mediated liver injury) 5, 1
  • COVID-19 treatments (favipiravir, lopinavir-ritonavir, remdesivir) 5
  • Acetaminophen toxicity (typically with ALT/LD ratio of 1.46) 6

Autoimmune Hepatitis

• Presents with elevated serum AST/ALT levels and increased IgG concentration 5
• Characterized by interface hepatitis on liver biopsy 5
• May be associated with specific autoantibodies:
  • Type 1: Antinuclear antibodies (ANA) and/or smooth muscle antibodies (SMA) 5
  • Type 2: Antibodies to liver kidney microsome (anti-LKM1) 5

Less Common Hepatic Causes

• Hereditary hemochromatosis 1
• Alpha-1 antitrypsin deficiency 1
• Wilson's disease (especially in younger patients) 1
• Ischemic hepatitis (characterized by ALT/LD ratio of 0.87) 6

Non-Hepatic Causes

• Muscle injury/rhabdomyolysis (can be confirmed with elevated creatine kinase) 5, 1
• Intensive exercise, particularly weight lifting 1
• Myocardial infarction (AST elevation more prominent) 7, 8
• Polymyositis 8
• Hypothyroidism 8

Severity Classification of ALT/AST Elevation

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

Diagnostic Approach

• For mild asymptomatic increases (<3× ULN) without elevated bilirubin, consider NAFLD, dietary changes, or exercise 1
• Ultrasound is useful as first-line investigation for mild ALT elevation (84.8% sensitivity for moderate to severe hepatic fat) 1
• For isolated ALT elevation, check creatine kinase to rule out muscle-related causes 1
• In suspected DILI, assess pattern of injury:
  • Hepatocellular: ALT ≥5× ULN 2
  • Cholestatic: ALP ≥2× ULN 2
  • Mixed: ALT ≥3× ULN with simultaneous total bilirubin >2× ULN 2
• For persistent unexplained ALT elevation, liver biopsy may be necessary 1

Clinical Pitfalls

• AST/ALT ratio may be less helpful in differentiating alcoholic from non-alcoholic liver disease in the presence of cirrhosis 4
• ALT activity may be affected by factors such as BMI, gender, lipid metabolism, and uremia 1
• Mild drug-induced elevations may spontaneously revert to baseline even when therapy is continued (adaptation) 1
• Overinterpreting isolated low AST/ALT values without clinical context 2