What are the causes of significant elevation of Alanine Transaminase (ALT) and Aspartate Transaminase (AST)?

Causes of Significant ALT and AST Elevation

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated ALT and AST in developed countries, followed by alcohol-induced liver disease, viral hepatitis, and drug-induced liver injury, though the specific pattern of elevation and AST:ALT ratio helps differentiate these etiologies. 1, 2

Severity Classification

Before discussing causes, significant elevation should be defined as:

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

Note that normal ALT ranges are sex-specific: 29-33 IU/L for men and 19-25 IU/L for women, significantly lower than traditional laboratory cutoffs. 1, 3

Most Common Hepatic Causes

Nonalcoholic Fatty Liver Disease (NAFLD)

• Prevalence of 20-30% in general population, increasing to 70% in obesity and 90% in diabetes mellitus 2
• Characteristically presents with AST:ALT ratio <1 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 ≥5× ULN is rare in NAFLD/NASH and should prompt investigation for alternative diagnoses 1, 3

Alcoholic Liver Disease

• Characterized by AST:ALT ratio >2:1, which is highly suggestive of this condition 1, 4
• AST elevation typically 2-6 times ULN with AST/ALT ratio >2 in 70% of patients 3
• Ratios >3 are particularly specific for alcoholic liver disease 3

Viral Hepatitis

• Both acute and chronic viral hepatitis (B and C) cause ALT/AST elevation 1, 2
• Chronic viral hepatitis shows fluctuating ALT elevation, particularly during reactivation phases 1, 2
• Acute viral hepatitis typically shows higher elevations (>400 IU/mL) 3
• In chronic hepatitis B, spontaneous HBeAg loss can cause transient ALT elevations 3

Drug-Induced Liver Injury (DILI)

• Causes 8-11% of cases with elevated liver enzymes 3, 2
• Common culprits include statins, antibiotics, antiepileptics, and herbal supplements 2
• Immune checkpoint inhibitors can cause immune-mediated liver injury (ILICI) 5, 2
• Cholestatic drug-induced injury comprises up to 61% of cases in patients ≥60 years 3

Less Common Hepatic Causes

Autoimmune Hepatitis

• Can present with isolated ALT elevation 2
• Typically shows higher elevations and elevated autoantibodies 3
• Anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies (ASMA) may be positive in NASH patients with low titers, making differentiation challenging 2

Hereditary Metabolic Disorders

• Hereditary hemochromatosis, alpha-1 antitrypsin deficiency, and Wilson disease are less common causes 1, 2
• Wilson disease should be considered particularly in younger patients with unexplained elevation 2

Ischemic Hepatitis

• For a given ALT and AST level, lactate dehydrogenase (LD) is markedly higher in ischemic hepatitis than viral hepatitis 6
• Mean ALT/LD ratio for ischemic hepatitis is 0.87 compared to 4.65 for viral hepatitis 6
• An ALT/LD ratio of 1.5 differentiates acute viral hepatitis from ischemic hepatitis with 94% sensitivity and 84% specificity 6

Non-Hepatic Causes

Muscle Injury

• Intensive exercise, particularly weight lifting, can cause acute elevations in liver enzymes due to muscle injury 1, 2
• Rhabdomyolysis can cause elevated liver enzymes, confirmed with elevated creatine kinase 1
• Testing for creatine phosphokinase (CK), aldolase, or other muscle-related enzymes confirms non-hepatic origin 1, 2
• While ALT is more liver-specific, it is still present in skeletal muscle and can be elevated with significant muscle damage 1

Cardiac Causes

• Acute myocardial infarction can cause AST elevation 7
• Congestive heart failure may cause transaminase elevation 5

Other Non-Hepatic Causes

• Polymyositis, hypothyroidism, and hemolysis can elevate transaminases 7
• AST is present in cardiac muscle, skeletal muscle, kidneys, brain, and red blood cells, making it less specific than ALT 3, 8

Important Clinical Patterns

AST:ALT Ratio as a Diagnostic Tool

• AST:ALT ratio <1.0 suggests chronic viral hepatitis, NAFLD, or drug-induced liver injury 1, 4, 9
• AST:ALT ratio ≥1.0 in nonalcoholic liver disease suggests presence of cirrhosis 4, 9
• The ratio often rises to >1.0 when cirrhosis first becomes manifest 4
• Among patients with chronic hepatitis B, mean AST/ALT ratio was 0.59 without cirrhosis and 1.02 with cirrhosis 4

Context-Specific Considerations

• Patients with malignancy often have alternative causes including primary liver tumors, hepatic metastasis, biliary obstruction, systemic infection, sepsis, and concomitant medications 5
• Mild asymptomatic increases (<3× ULN) without elevated bilirubin may be related to NAFLD, dietary changes, or vigorous exercise 5, 1, 2
• Mild elevations may be transient and spontaneously revert to baseline even when therapy is continued (adaptation) 5, 2

Critical Pitfall to Avoid

Do not assume that mild ALT/AST elevation is benign without proper evaluation, as the degree of enzyme elevation does not always correlate with the extent of liver damage. 2, 7 In chronic viral hepatitis, elevation may not correlate well with degree of liver damage, and up to 10% of patients with advanced fibrosis may have normal ALT using conventional thresholds. 3, 7