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

Causes of Elevated AST and ALT

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in developed countries, affecting 20-30% of the general population and up to 70% in obesity, typically presenting with an AST:ALT ratio <1. 1

Most Common Hepatic Causes

Nonalcoholic Fatty Liver Disease (NAFLD)

• NAFLD is the leading cause of isolated ALT elevation, with prevalence increasing to 90% in patients with diabetes mellitus 2
• Typically presents with AST:ALT ratio <1, distinguishing it from alcoholic liver disease 1, 2
• Represents a spectrum from simple steatosis (70-75% of cases) to nonalcoholic steatohepatitis (NASH) with inflammation (25-30% of cases) 2
• ALT elevation of ≥5× ULN is rare in NAFLD/NASH and should prompt investigation for other causes 1

Alcoholic Liver Disease

• Characterized by AST:ALT ratio >2:1, which is highly suggestive of this diagnosis 1, 2
• This ratio pattern is a key distinguishing feature from NAFLD 3

Viral Hepatitis

• Both acute and chronic viral hepatitis (hepatitis A, B, and C) cause ALT/AST elevation 1, 2
• Chronic hepatitis B shows fluctuating ALT elevation, particularly during reactivation phases 1, 2
• Screening for viral hepatitis is essential in unexplained ALT elevation 2

Drug-Induced Liver Injury (DILI)

• Common cause of isolated ALT elevation 2
• Many medications implicated including statins, antibiotics, antiepileptics, and herbal supplements 2
• Immune checkpoint inhibitors can cause immune-mediated liver injury with isolated ALT elevation 2
• Assess the pattern of injury: hepatocellular, cholestatic, or mixed 1

Less Common Hepatic Causes

• Autoimmune hepatitis can present with isolated ALT elevation 2
• Hereditary hemochromatosis 1, 2
• Alpha-1 antitrypsin deficiency 1, 2
• Wilson's disease, particularly in younger patients with unexplained ALT elevation 1, 2

Non-Hepatic Causes

Muscle Injury

• Intensive exercise, particularly weight lifting, can cause acute elevations in liver enzymes due to muscle injury that can be mistaken for acute DILI 1
• While ALT is more liver-specific, it is still present in skeletal muscle and can be elevated with significant muscle damage 1
• Testing for creatine phosphokinase (CK), aldolase, or other muscle-related enzymes confirms the non-hepatic origin 1, 2
• CK is markedly elevated in exercise-induced muscle damage and serves as the primary marker to differentiate muscle injury from liver injury 1

Other Non-Hepatic Causes

• Rhabdomyolysis 1
• Statin-related muscle injury 2
• Acute myocardial infarction 4
• Polymyositis 4
• Hypothyroidism 4

Severity Classification

The American Association for the Study of Liver Diseases classifies ALT/AST elevation as:

• Mild: <5× upper limit of normal (ULN) 1, 2
• Moderate: 5-10× ULN 1, 2
• Severe: >10× ULN 1, 2

Diagnostic Algorithm Based on Severity and Pattern

For Mild Asymptomatic Increases (<3× ULN)

• Consider NAFLD, dietary changes, or vigorous exercise 1, 2
• Check CK levels to rule out muscle-related causes 1, 2
• Ultrasound as first-line investigation (84.8% sensitivity and 93.6% specificity for moderate to severe hepatic fat deposition) 2
• Assess for metabolic syndrome components (obesity, diabetes) 2

For Moderate to Severe Elevations (≥5× ULN)

• For ALT/AST ≥1000 IU/L, the differential includes ischemic hepatitis, acute viral hepatitis, and acetaminophen toxicity 5
• Check ALT/LD ratio: An ALT/LD ratio of 1.5 differentiates acute viral hepatitis (ratio typically 4.65) from ischemic hepatitis (ratio 0.87) and acetaminophen injury (ratio 1.46) with 94% sensitivity and 84% specificity 6
• Screen for viral hepatitis (hepatitis A, B, C) 2
• Obtain detailed medication and supplement history 2
• Assess for autoimmune markers if other causes excluded 2

Pattern Recognition

• AST:ALT ratio >2:1: Think alcoholic liver disease 1, 2, 3
• AST:ALT ratio <1: Think NAFLD 1, 2
• Elevated CK with elevated ALT/AST: Think muscle injury, not liver disease 1, 2

Critical Pitfalls to Avoid

• Do not rely on traditional laboratory reference ranges: Normal ALT should be considered as 30 IU/mL for men and 19 IU/mL for women 2
• Do not assume strict correlation between ALT elevation and liver cell necrosis severity 2
• Do not overlook exercise history: Mild asymptomatic increases in ALT/AST without elevated bilirubin may be related to vigorous exercise 1, 2
• Do not miss adaptation phenomenon: Mild drug-induced ALT elevations may be transient and spontaneously revert to baseline even when therapy is continued 2
• Do not forget non-hepatic causes: Always check CK when evaluating elevated liver enzymes, especially in athletes or those with muscle symptoms 1, 2

When to Pursue Further Investigation

• Liver biopsy is recommended for persistent unexplained ALT elevation after initial workup 1, 2
• Consider biopsy to differentiate autoimmune hepatitis from NASH when antibodies are positive at low titers 2