What is the appropriate workup for a patient with elevated transaminases (liver enzymes)?

Workup for Elevated Transaminases

Begin with a comprehensive metabolic panel (AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, INR) to characterize the injury pattern and assess synthetic function, followed by immediate viral hepatitis screening (hepatitis B surface antigen, hepatitis C antibody), iron studies (fasting transferrin saturation and ferritin), and a detailed medication/supplement review. 1, 2, 3

Initial Laboratory Testing

The first-line workup should include:

• Complete metabolic panel with AST, ALT, alkaline phosphatase, GGT, bilirubin (total and direct), albumin, and INR to assess liver function and injury pattern 1
• Viral hepatitis screening: Hepatitis B surface antigen, hepatitis C antibody, and hepatitis A IgM if acute presentation 1, 2, 4
• Iron studies: Fasting transferrin saturation and ferritin to evaluate for hereditary hemochromatosis 1, 4
• Fasting lipid profile and glucose/HbA1c to assess for metabolic syndrome and NAFLD risk 1, 3
• Complete blood count with platelets 3

The AST:ALT ratio provides diagnostic clues: AST:ALT <1 suggests NAFLD, while AST:ALT >1 may indicate advanced fibrosis or alcoholic liver disease 1

Medication and Exposure History

Conduct a comprehensive medicines use review, as discrepancies between patient-reported and documented medications exist in >50% of patients with liver disease 1. Specifically inquire about:

• Hepatotoxic medications: methotrexate, NSAIDs, statins, anticonvulsants, antiarrhythmics, tamoxifen, nitrofurantoin, minocycline, infliximab 1
• Herbal and dietary supplements 1
• Quantified alcohol consumption 1, 3
• Duration of exposure and cumulative doses, particularly for methotrexate 1

Imaging

Obtain liver ultrasound to assess for steatosis, hepatomegaly, cirrhosis features, biliary obstruction, or masses 1. However, recognize that normal ultrasound does not exclude NAFLD, as ultrasound misses mild steatosis when <20-30% of hepatocytes are affected 1.

Second-Tier Testing (If Initial Workup Negative)

If transaminases remain elevated after initial testing, proceed with:

• Autoimmune markers: Anti-smooth muscle antibody (ASMA), anti-nuclear antibody (ANA), and anti-liver-kidney microsomal antibody (anti-LKM1) for autoimmune hepatitis 1, 4
• Alpha-1 antitrypsin phenotyping (not just serum levels) for AAT deficiency 1, 4
• Ceruloplasmin for Wilson disease screening in patients <40 years old; if low-normal, obtain 24-hour urine copper collection 1, 4
• Celiac screening (tissue transglutaminase antibody), as 75-100% of celiac patients with transaminitis normalize on gluten-free diet 1

Severity-Based Management

Grade 1 (AST/ALT >ULN to 3× ULN): Close monitoring with labs 1-2 times weekly without specific treatment 1

Grade 2 (AST/ALT >3× to 5× ULN): Discontinue potential hepatotoxic medications if medically feasible, increase monitoring to every 3 days, consider prednisone 0.5-1 mg/kg/day if no improvement after 3-5 days 1

Grade 3 (AST/ALT >5× to 20× ULN): Urgent hepatology consultation, discontinue hepatotoxic medications, start methylprednisolone 1-2 mg/kg/day, consider liver biopsy if steroid-refractory 1

Grade 4 (AST/ALT >20× ULN): Immediate hospitalization at a liver center, permanently discontinue causative agents, administer methylprednisolone 2 mg/kg/day with planned 4-6 week taper 1

Special Populations and Contexts

For patients with type 2 diabetes: Screen for nonalcoholic fatty liver disease by measuring AST and ALT at diagnosis and annually thereafter, with referral to gastroenterology for persistently elevated or worsening transaminases 5

For HIV-infected patients: Evaluate for hepatitis B and C coinfection, antiretroviral therapy hepatotoxicity, and metabolic comorbidities leading to NAFLD 6

Fibrosis Assessment

For suspected NAFLD, use FIB-4 Index Score or NAFLD Fibrosis Score to identify patients at risk for advanced fibrosis who may benefit from hepatology referral 1, 3. Perform sequential fibrosis testing using FIB-4 initially, followed by specialist tests 1.

Critical Red Flags Requiring Urgent Evaluation

Any elevation with bilirubin ≥2× ULN or INR >1.5 suggests potential acute liver injury requiring immediate evaluation 1. Liver-related symptoms (severe fatigue, nausea, vomiting, right upper quadrant pain) with Grade 2 or higher elevation require urgent assessment 1.

Follow-Up Timing

Repeat liver enzymes in 2-4 weeks to assess for spontaneous resolution or progression 1, 3. If transaminases remain elevated >3-6 months despite negative workup, consider liver biopsy 1, 4. Reassess at 12 weeks to confirm sustained resolution 1.

Common Pitfalls to Avoid

• Do not rely solely on normal immunoglobulins to exclude autoimmune hepatitis; autoantibodies are more sensitive and specific 1
• Do not dismiss low-normal ceruloplasmin; this warrants 24-hour urine copper collection 1
• Do not delay viral hepatitis screening even in obese patients with presumed NAFLD 1
• Do not assume normal ALT excludes NASH; approximately 50% of patients with chronic liver disease can have normal transaminases 7