What are the causes of elevated liver enzymes, such as alanine transaminase (ALT) and aspartate transaminase (AST)?

Causes of Elevated Liver Enzymes

The most common causes of elevated liver enzymes are nonalcoholic fatty liver disease (NAFLD), alcohol-induced liver disease, drug-induced liver injury, viral hepatitis (B and C), and hemochromatosis, with NAFLD affecting up to 30% of the general population. 1, 2, 3

Classification of Liver Enzyme Patterns

Liver enzyme elevations can be categorized into three distinct patterns, each suggesting different underlying pathologies:

1. Hepatocellular Pattern (Predominant Transaminase Elevation)

• Common causes:

  • Nonalcoholic fatty liver disease (NAFLD) - most common in first world countries (20-30% prevalence, up to 70% in obesity, 90% in diabetes) 1
  • Alcoholic liver disease 1, 4
  • Viral hepatitis (B and C) 1, 3
  • Drug-induced liver injury 1, 2
  • Hemochromatosis 2, 3
  • Autoimmune hepatitis 1, 3
  • Alpha-1-antitrypsin deficiency 1, 3
  • Wilson disease 1, 2

• Diagnostic clues:

  • AST:ALT ratio >2 suggests alcoholic liver disease 1, 4
  • AST:ALT ratio <1 suggests metabolic-related fatty liver 1

2. Cholestatic Pattern (Predominant ALP and GGT Elevation)

• Common causes:

  • Biliary obstruction (gallstones, tumors) 1, 4
  • Primary or secondary sclerosing cholangitis 4
  • Drug-induced cholestasis 4
  • Genetic disorders of canalicular membrane transporters 4

• Diagnostic approach:

  • Ultrasound is essential to differentiate intrahepatic from extrahepatic cholestasis 4

3. Isolated GGT Elevation

• Common causes:
  • Alcoholic liver disease 4
  • Nonalcoholic fatty liver disease 4
  • Infiltrative liver diseases 4
  • Medication/drug effect (enzyme induction) 4, 5

Non-Hepatic Causes of Elevated Liver Enzymes

• Muscle disorders:

  • Intense exercise or muscle injury can cause transient ALT/AST elevation 2, 4
  • Consider checking creatine kinase if suspected 2

• Other systemic conditions:

  • Thyroid disorders 3
  • Celiac disease 3
  • Hemolysis 3
  • Macro-AST (benign condition causing isolated AST elevation) 6

Severity Classification

Liver enzyme elevations are typically classified as:

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

Diagnostic Approach

Initial Evaluation for Mild Elevations (Most Common Scenario)

1. First-line testing:

   • Fasting lipid profile and glucose (for NAFLD/metabolic syndrome) 2, 3
   • Serum iron, ferritin, total iron-binding capacity (for hemochromatosis) 2, 3
   • Hepatitis B surface antigen and hepatitis C virus antibody 2, 3
   • Ultrasound of abdomen 1, 2
   • Review of medications, supplements, and alcohol consumption 2

2. If initial tests are normal:

   • Monitor liver enzymes every 2-4 weeks until normalization 2
   • Consider lifestyle modifications (weight loss, Mediterranean diet, exercise) 2
   • Discontinue suspected hepatotoxic medications if appropriate 2

3. For persistent elevations (>6 months):

   • Additional testing:
     • Alpha-1-antitrypsin level 2, 3
     • Ceruloplasmin (for Wilson disease, especially in younger patients) 2, 3
     • Autoimmune markers (ANA, ASMA, ANCA) 2, 3
     • Serum protein electrophoresis 3
     • Consider PEG precipitation test if isolated AST elevation 6

Important Clinical Considerations

• Mild asymptomatic increases in ALT/AST (<3× ULN) without elevated bilirubin are often not specific and may be related to NAFLD, dietary changes, or exercise 1
• Prognosis is better for patients with elevated ALT but normal bilirubin compared to those with elevated bilirubin 2
• Transient elevations may spontaneously normalize in up to 30% of cases during follow-up 4
• Referral to hepatology is recommended if:
  • ALT/AST >5× ULN
  • Elevated bilirubin with elevated transaminases
  • Persistent elevations despite interventions for 6 months 2

Medication Considerations

• Common medications that can cause liver injury include statins, methotrexate, and antibiotics 2
• Herbal supplements can also cause significant liver injury 2
• Consider discontinuing suspected hepatotoxic medications and monitoring liver enzymes until normalization 2
• Avoid rechallenging with suspected medications if ALT was >5× ULN or if jaundice occurred 2

By understanding these patterns and following a systematic approach to evaluation, the underlying cause of elevated liver enzymes can be identified and appropriate management initiated.