What is the work-up for mildly elevated liver enzymes, specifically elevated Alanine Transaminase (ALT) and Aspartate Transaminase (AST)?

From the Guidelines

The initial work-up for mildly elevated liver enzymes, specifically elevated Alanine Transaminase (ALT) and Aspartate Transaminase (AST), should include a thorough history, physical examination, and targeted laboratory testing, as outlined in the most recent guidelines from 2023 1. The work-up should begin with a comprehensive metabolic panel to confirm the elevation and assess liver function, complete blood count to evaluate for infection or inflammation, and coagulation studies.

• Specific testing should include:
  • Hepatitis serologies (A, B, and C) to evaluate for viral hepatitis
  • Iron studies to assess for hemochromatosis
  • Ceruloplasmin to evaluate for Wilson's disease
  • Antimitochondrial antibodies for primary biliary cholangitis
  • Anti-smooth muscle antibodies for autoimmune hepatitis
  • Immunoglobulin levels to assess for immune-mediated liver disease
• An ultrasound of the liver is recommended as the first imaging study to evaluate for structural abnormalities, fatty infiltration, or biliary obstruction, as suggested by the American College of Radiology 1.
• Medication review is essential, as many drugs can cause liver enzyme elevation, including acetaminophen, statins, antibiotics, and herbal supplements.
• Lifestyle factors, such as alcohol consumption, should be assessed, and patients should be counseled on limiting alcohol intake.
• If the etiology remains unclear after initial testing, consider referral to a gastroenterologist or hepatologist for further evaluation, which might include additional specialized testing or liver biopsy, as recommended by the American College of Radiology 1 and the American Diabetes Association 1. The urgency of the work-up depends on the degree of elevation, with AST/ALT less than 2-3 times the upper limit of normal often allowing for outpatient evaluation, while higher elevations may require more urgent assessment, as suggested by the guidelines from 2023 1.

From the Research

Initial Evaluation

The initial evaluation for mildly elevated liver enzymes, specifically elevated Alanine Transaminase (ALT) and Aspartate Transaminase (AST), should include a thorough history and physical examination to identify potential causes 2, 3, 4, 5.

• A fasting lipid profile
• Measurement of glucose, serum iron, and ferritin
• Total iron-binding capacity
• Hepatitis B surface antigen and hepatitis C virus antibody testing should be performed 2, 3, 5

Common Causes

The most common causes of mildly elevated liver transaminase levels are:

• Nonalcoholic fatty liver disease (NAFLD) 2, 3, 5, 6
• Alcoholic liver disease 2, 3, 5
• Medication-associated liver injury 2, 3, 5
• Viral hepatitis (hepatitis B and C) 2, 3, 4, 5, 6

Less Common Causes

Less common causes of elevated liver transaminase levels include:

• α(1)-antitrypsin deficiency 2, 3, 4, 5
• Autoimmune hepatitis 2, 3, 4, 5
• Wilson disease 2, 3, 4, 5
• Hemochromatosis 2, 3, 5
• Extrahepatic conditions (e.g., thyroid disorders, celiac disease, hemolysis, muscle disorders) 2, 3, 4, 5, 6

Further Testing

If initial test results are normal, a trial of lifestyle modification with observation or further testing for less common causes is appropriate 2, 3, 5.

• Additional testing may include ultrasonography
• Measurement of α(1)-antitrypsin and ceruloplasmin
• Serum protein electrophoresis
• Antinuclear antibody, smooth muscle antibody, and liver/kidney microsomal antibody type 1 testing 2
• The nonalcoholic fatty liver disease fibrosis score and the alcoholic liver disease/nonalcoholic fatty liver disease index can be helpful in the evaluation of mildly elevated transaminase levels 3
• The FIB-4 Index Score or NAFLD Fibrosis Score can be used to predict which patients are at risk for fibrosis and may benefit from further testing or referral to a hepatologist 5

Referral and Follow-up

Referral for further evaluation and possible liver biopsy is recommended if transaminase levels remain elevated for six months or more 2. All patients with elevated transaminases should be counseled about moderation or cessation of alcohol use, weight loss, and avoidance of hepatotoxic drugs 5.