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

Workup for Transaminitis

Begin with a comprehensive metabolic panel (AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, INR) to characterize the pattern of liver injury and assess synthetic function, followed by a systematic evaluation based on severity and pretest probability of underlying etiologies. 1

Initial Laboratory Evaluation

First-Line Testing

• Obtain a complete metabolic panel including AST, ALT, alkaline phosphatase, GGT, bilirubin (total and direct), albumin, and INR to determine injury pattern (hepatocellular vs cholestatic) and assess liver synthetic function 1
• Check viral hepatitis serologies: hepatitis B surface antigen and hepatitis C antibody testing are essential first-line tests 1, 2
• Order fasting lipid profile, glucose, and HbA1c to assess for metabolic syndrome components, as NAFLD is the most common cause of mild transaminitis in developed countries 1, 2
• Measure iron studies: fasting transferrin saturation and ferritin to evaluate for hereditary hemochromatosis 1, 2
• Obtain liver ultrasound to assess for steatosis, hepatomegaly, cirrhosis features, biliary obstruction, or masses, though normal ultrasound does not exclude NAFLD 1

Critical Pattern Recognition

• **AST:ALT ratio <1 suggests NAFLD**, while AST:ALT >1 may indicate advanced fibrosis or alcoholic liver disease, though this ratio can reverse in later stages of NAFLD 3, 1
• Presence of bilirubin ≥2× ULN or INR >1.5 with any transaminase elevation suggests potential acute liver injury requiring immediate evaluation 1
• ALT is more specific for liver injury than AST and serves as a better predictor of liver-related and all-cause mortality 4

Medication and Exposure History

Hepatotoxic Agent Review

• Conduct a comprehensive medicines use review, as discrepancies between patient-reported and documented medications exist in >50% of patients with liver disease, particularly those taking more than five medications 1
• Specifically inquire about: methotrexate (document cumulative dose and duration), NSAIDs, statins, anticonvulsants, antiarrhythmics, tamoxifen, nitrofurantoin, minocycline, infliximab, and glucocorticoids 1
• Ask about herbal and dietary supplements, as these are frequently overlooked causes of drug-induced liver injury 1
• Quantify alcohol consumption precisely, as alcoholic liver disease typically presents with AST > ALT (often AST:ALT ratio >2) 1, 5

Second-Line Testing (If Initial Workup Negative)

Autoimmune and Metabolic Screening

• Check autoantibodies: anti-smooth muscle antibody (ASMA), anti-nuclear antibody (ANA), and anti-liver-kidney microsomal antibody (anti-LKM1) to evaluate for autoimmune hepatitis 1, 2
• Order alpha-1 antitrypsin phenotyping (not just serum levels), as AAT deficiency can present with asymptomatic enzyme elevation and must be excluded in all patients with unexplained transaminitis 1, 2
• Measure ceruloplasmin in patients under 40 years old to screen for Wilson disease; if low-normal, obtain 24-hour urine copper collection and calculate free copper 1, 2
• Consider celiac serologies (tissue transglutaminase antibody), as celiac disease causes transaminase elevations that normalize with gluten-free diet in 75-100% of cases 1

Non-Hepatic Causes

• Evaluate thyroid function (TSH, free T4), as thyroid disorders can cause elevated transaminases 2
• Consider muscle disorders if AST is disproportionately elevated compared to ALT, including myopathies, rhabdomyolysis, or recent vigorous exercise 1
• Assess for cardiac conditions such as congestive heart failure causing hepatic congestion 1

Severity-Based Management Algorithm

Grade 1 (AST/ALT >ULN to 3× ULN)

• Monitor liver function tests 1-2 times weekly without specific treatment 1
• Repeat testing in 2-4 weeks to assess for spontaneous resolution, as mild elevations may be transient and related to dietary changes or exercise 1, 2

Grade 2 (AST/ALT >3× to 5× ULN)

• Discontinue potentially hepatotoxic medications if medically feasible, as this leads to enzyme normalization in 83% of cases 1
• Increase monitoring frequency to every 3 days 1
• Consider prednisone 0.5-1 mg/kg/day if no improvement after 3-5 days 1

Grade 3 (AST/ALT >5× to 20× ULN)

• Obtain urgent hepatology consultation 1
• Discontinue all hepatotoxic medications immediately 1
• Start methylprednisolone 1-2 mg/kg/day or equivalent 1
• Consider liver biopsy if steroid-refractory or diagnostic uncertainty persists 1

Grade 4 (AST/ALT >20× ULN)

• Hospitalize immediately, preferably at a liver center 1
• Permanently discontinue causative agents 1
• Administer methylprednisolone 2 mg/kg/day with planned 4-6 week taper 1
• Add second-line immunosuppression if transaminases don't decrease by 50% within 3 days 1

Special Considerations and Pitfalls

Critical Caveats

• Normal ALT does not exclude NASH, as up to 50% of patients with NAFLD have normal liver chemistries 3, 1
• Normal ultrasound does not exclude NAFLD, as ultrasound misses mild steatosis (<20-30% hepatocyte involvement) and cannot assess for NASH or fibrosis 3, 1
• Do not rely solely on normal immunoglobulins to exclude autoimmune hepatitis, as autoantibodies are more sensitive and specific 1
• Do not dismiss low-normal ceruloplasmin, as this warrants 24-hour urine copper collection to exclude Wilson disease 1
• Do not delay viral hepatitis screening, even in obese patients with presumed NAFLD 1

Timing for Specialist Referral

• Refer for hepatology consultation and possible liver biopsy if transaminase levels remain elevated for 6 months or more despite negative workup 1, 2
• If autoantibodies are positive with transaminitis, liver biopsy becomes essential to confirm interface hepatitis and guide treatment decisions 1
• Consider non-invasive fibrosis assessment using FIB-4 initially, followed by specialist tests to identify patients with advanced fibrosis who have greatest risk of hepatic morbidity 1