What causes isolated elevation of Alanine Transaminase (ALT)?

Causes of Isolated Elevation of ALT

The most common causes of isolated ALT elevation are nonalcoholic fatty liver disease (NAFLD) and alcohol-induced liver disease, while less common causes include drug-induced liver injury, viral hepatitis, and hereditary conditions such as hemochromatosis. 1

Primary Causes of Isolated ALT Elevation

Common Causes

• Nonalcoholic fatty liver disease (NAFLD)

  • Most common liver disease in developed countries (20-30% prevalence)
  • Prevalence increases to 70% in obesity and 90% in diabetes 1
  • AST:ALT ratio typically <1 in metabolic-related fatty liver

• Alcohol-induced liver disease

  • AST:ALT ratio generally >2 (distinguishing feature from NAFLD) 1
  • Excessive alcohol consumption is the primary cause

Uncommon Causes

• Drug-induced liver injury

  • Prescription medications
  • Over-the-counter drugs
  • Herbal supplements and dietary supplements 1

• Viral hepatitis

  • Hepatitis B and C infections 1
  • Other viral hepatitis (A, D, E)

• Hereditary hemochromatosis 1

Rare Causes

• Alpha1-antitrypsin deficiency
• Autoimmune hepatitis
• Wilson disease 1

Severity Classification of ALT Elevation

ALT elevation can be classified based on severity 1:

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

Non-Hepatic Causes of ALT Elevation

While ALT is more liver-specific than AST, some non-hepatic conditions can cause ALT elevation:

• Intensive exercise/muscle injury

  • Weight lifting and other strenuous activities can cause transient ALT elevation 1
  • Can be differentiated by testing creatine phosphokinase (CK) levels

• Statin-related muscle injury

  • Can cause elevated ALT due to muscle effects rather than direct liver injury 1

Clinical Pearls and Pitfalls

Important Diagnostic Considerations

• ALT is more specific for liver injury than AST, which can also be elevated in cardiac and skeletal muscle disorders 2
• Normal ALT levels are 29-33 IU/L in men and 19-25 IU/L in women 1
• ALT elevation ≥5× ULN is rare in NAFLD/NASH and should prompt investigation for other causes 1

Risk Factors for Abnormal ALT

• Female sex, Latinx ethnicity, Asian/Pacific Islander race, and overweight/obesity are associated with greater odds of abnormal ALT in the absence of known chronic liver disease 3
• HIV infection with high viral load is associated with chronic ALT elevation even without hepatitis co-infection 4

Diagnostic Approach

• For mild ALT elevation (<3× ULN), monitor and evaluate for metabolic risk factors
• For moderate to severe elevation (>5× ULN), comprehensive workup for viral hepatitis, autoimmune conditions, and drug-induced liver injury is warranted 1
• Ultrasound is recommended as first-line investigation for mild increases in liver enzymes, especially when NAFLD is suspected 1

Special Considerations

• Isolated ALT elevation in the context of immune checkpoint inhibitor therapy may represent immune-mediated liver injury and requires specific management 1
• In patients with NASH, ALT elevation ≥5× ULN should not be attributed to NASH alone and warrants further investigation 1
• ALT is not a test of liver function but rather a marker of hepatocellular injury 5
• Elevated autoantibodies (ANA, ASMA) are common in NASH patients and may confound diagnosis of autoimmune hepatitis 1

By systematically evaluating these potential causes and considering patient-specific risk factors, the underlying etiology of isolated ALT elevation can be identified and appropriate management initiated.