What causes elevated Alanine Transaminase (ALT) levels?

Causes of Elevated ALT Levels

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated ALT in developed countries, affecting 20-30% of the general population and up to 90% of patients with diabetes, while alcohol-induced liver disease, viral hepatitis, and drug-induced liver injury represent other major etiologies. 1

Primary Hepatic Causes

Nonalcoholic Fatty Liver Disease (NAFLD)

• NAFLD is the leading cause of isolated ALT elevation, with prevalence increasing to 70% in obese patients 1
• Typically presents with an AST:ALT ratio <1, distinguishing it from alcoholic liver disease 1
• Encompasses a spectrum from simple steatosis (70-75% of cases) to nonalcoholic steatohepatitis with inflammation (25-30%) 1
• Associated with metabolic syndrome components including obesity, diabetes, and hypertension 2

Alcoholic Liver Disease

• Characteristically shows AST:ALT ratio >2, with ratios >3 being highly suggestive of alcohol-related injury 3
• AST typically elevated 2-6 times upper limit of normal in severe alcoholic hepatitis 3
• Even modest alcohol intake increases liver-related mortality in patients with elevated ALT levels, necessitating complete abstinence 4
• Levels of AST >500 IU/L or ALT >200 IU/L are uncommon in alcoholic hepatitis alone and should prompt evaluation for alternative diagnoses 3

Viral Hepatitis

• Both acute and chronic hepatitis B and C cause isolated ALT elevation 1
• ALT levels may fluctuate in chronic hepatitis B, particularly during immune clearance or reactivation phases 3, 1
• Screening with HBsAg, HBcIgM, and HCV antibody is essential in unexplained ALT elevation 2

Drug-Induced Liver Injury (DILI)

• Common culprits include statins, antibiotics, antiepileptics, and herbal supplements 1
• Immune checkpoint inhibitors can cause immune-mediated liver injury with isolated ALT elevation 1
• Mild drug-induced elevations may be transient and spontaneously resolve even with continued therapy (adaptation) 1

Less Common Hepatic Causes

Autoimmune Hepatitis

• Can present with isolated ALT elevation 1
• Important caveat: Low-titer ANA and anti-smooth muscle antibodies may be positive in NASH patients, complicating differentiation from autoimmune hepatitis 1

Hereditary Conditions

• Hereditary hemochromatosis presents with isolated ALT elevation 1
• Alpha-1 antitrypsin deficiency is a rare cause 1
• Wilson disease should be considered particularly in younger patients with unexplained elevation 1

Non-Hepatic Causes

Muscle-Related Causes

• Intensive exercise, particularly weight lifting, elevates ALT due to muscle injury 1
• Polymyositis and acute muscle injury can raise both ALT and AST 5
• AST is less specific for liver injury as it is present in cardiac muscle, skeletal muscle, kidney, and red blood cells 2
• Testing creatine kinase, aldolase, or other muscle enzymes confirms non-hepatic origin 1

Cardiac Causes

• Acute myocardial infarction can cause transaminase elevation 5
• Cardiac muscle injury preferentially elevates AST over ALT 6

Other Systemic Causes

• Hypothyroidism can cause elevated transaminases 5
• Thyroid function tests should be performed to rule out thyroid disorders 2

Factors Affecting ALT Levels

Physiologic and Metabolic Factors

• Body mass index significantly impacts ALT levels, with obese subjects (BMI ≥31 kg/m²) showing eight times higher prevalence of elevated ALT compared to normal weight individuals 7
• Gender affects normal ranges: 29-33 IU/L for males and 19-25 IU/L for females 2, 1
• Abnormal lipid and carbohydrate metabolism, fatty liver, and uremia can affect ALT activity 3, 1

Lifestyle Factors

• Decreasing physical activity levels correlate with increased mean ALT levels 7
• Alcohol consumption shows positive correlation with all three liver enzymes (ALT, AST, GGT) 7

Clinical Interpretation Pitfalls

Important Caveats

• ALT alone does not identify patients with necroinflammatory activity or fibrosis with optimal reliability, as there is lack of strict correlation between extent of liver cell necrosis and degree of ALT increase 3, 1
• Commercial laboratories often use upper limit of normal values significantly higher than recommended thresholds of 30 IU/mL for men and 19 IU/mL for women 3, 1
• HBV-infected individuals with ALT <40-45 IU/mL remain at risk for significant liver disease 3
• Even ALT levels between 20-30 IU/mL increase risk of mortality from liver complications 3

Pattern Recognition

• In approximately two-thirds of blood donors with initially elevated ALT, elevations are intermittent or persistent on follow-up 8
• About 20% of cases have no apparent cause other than possible non-A, non-B hepatitis 8
• Mild asymptomatic increases (<3× ULN) without elevated bilirubin are often non-specific and may relate to NAFLD, dietary changes, or vigorous exercise 1