What is the next step in managing a patient with transaminitis (elevated liver enzymes), no history of ethanol (ETOH) use, and no steatosis (fatty liver) found on ultrasound (US), with normal immunoglobulin levels and ceruloplasmin?

Workup for Transaminitis with Normal Initial Testing

The next step is to check anti-smooth muscle antibody (ASMA), anti-nuclear antibody (ANA), and anti-liver-kidney microsomal antibody (anti-LKM1) to evaluate for autoimmune hepatitis, followed by alpha-1 antitrypsin phenotyping and ferritin/transferrin saturation to complete the standard workup for unexplained transaminitis. 1

Complete the Autoimmune Hepatitis Workup

Your patient has normal IgG (998 mg/dL), IgA, and IgM levels, which makes autoimmune hepatitis (AIH) less likely but does not exclude it. Approximately 30% of AIH cases can present without hypergammaglobulinemia, particularly in acute presentations. 2

• Check anti-smooth muscle antibody (ASMA), anti-nuclear antibody (ANA), and anti-liver-kidney microsomal antibody (anti-LKM1) as these are the primary autoantibodies for diagnosing Type 1 and Type 2 AIH 1
• AIH affects women 3-4 times more than men and can present with persistently elevated transaminases even without elevated immunoglobulins 2
• If autoantibodies are positive with transaminitis, liver biopsy becomes essential to confirm interface hepatitis and guide treatment decisions 1

Complete Metabolic Liver Disease Screening

Since ceruloplasmin is low-normal at 19 mg/dL (normal range typically 20-60 mg/dL), Wilson disease requires further evaluation:

• Obtain 24-hour urine copper collection - this is critical as ceruloplasmin in the low-normal range warrants exclusion of Wilson disease 1
• Check serum copper levels to calculate free copper if Wilson disease remains a consideration 1
• Wilson disease can present with isolated transaminitis and must be excluded in patients under 40 years old with unexplained liver enzyme elevation 1

Alpha-1 Antitrypsin Deficiency Evaluation

• Order alpha-1 antitrypsin (AAT) phenotyping, not just serum levels, as this is the definitive test for AAT deficiency 1
• AAT deficiency should be considered in all patients with unexplained transaminitis, as it can present with chronic hepatitis, cirrhosis, or asymptomatic enzyme elevation 1
• The PI*ZZ phenotype accounts for most clinically significant liver disease from AAT deficiency 1

Iron Studies

• Measure fasting transferrin saturation and ferritin to evaluate for hereditary hemochromatosis 1, 2
• Transferrin saturation >45% warrants HFE gene mutation testing 2
• Iron overload can cause persistent transaminitis even without other clinical manifestations 1

Additional Metabolic Assessment

Since ultrasound showed no steatosis, NAFLD is less likely, but metabolic syndrome components still require evaluation:

• Obtain fasting glucose, HbA1c, and lipid panel if not already done, as insulin resistance can cause transaminitis even without visible steatosis on ultrasound 1
• Ultrasound has limited sensitivity for detecting steatosis when <20-30% of hepatocytes are affected 1
• Check thyroid function tests (TSH, free T4) as hypothyroidism can cause mild transaminitis 2

Medication and Supplement Review

• Conduct a comprehensive medicines use review, as discrepancies between patient-reported and documented medications exist in >50% of patients with liver disease 2
• Specifically inquire about:
  • Over-the-counter NSAIDs, acetaminophen use 2
  • Herbal supplements and dietary supplements 1, 2
  • Recent antibiotic courses (particularly fluoroquinolones) 3
  • Statins, anticonvulsants, antiarrhythmics 2

Celiac Disease Screening

• Check tissue transglutaminase IgA antibody and total IgA to screen for celiac disease 2
• Celiac disease causes transaminase elevations that normalize with a gluten-free diet in 75-100% of cases 2
• This is particularly important if the patient has any gastrointestinal symptoms or unexplained iron deficiency 2

Timing of Repeat Testing

• Repeat liver enzymes in 2-4 weeks to assess for spontaneous resolution or progression 2
• If transaminases remain elevated >3 months despite negative workup, liver biopsy should be considered to evaluate for cryptogenic hepatitis or early cirrhosis 1

Common Pitfalls to Avoid

• Do not rely solely on normal immunoglobulins to exclude autoimmune hepatitis - autoantibodies are more sensitive and specific 1, 2
• Do not dismiss low-normal ceruloplasmin (19 mg/dL) - this warrants 24-hour urine copper collection to exclude Wilson disease 1
• Do not assume normal ultrasound excludes NAFLD - ultrasound misses mild steatosis and cannot assess for NASH or fibrosis 1
• Do not forget muscle sources of AST elevation - check creatine kinase if AST is disproportionately elevated compared to ALT 2