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

Basic Workup for Transaminitis

Begin with a comprehensive metabolic panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and INR to characterize the injury pattern and assess synthetic function. 1, 2

Initial Laboratory Testing

Core Liver Panel

• Obtain AST, ALT, alkaline phosphatase, GGT, bilirubin (total and direct), albumin, and prothrombin time/INR to distinguish hepatocellular from cholestatic injury and evaluate liver synthetic function 3, 1, 2
• Measure complete blood count with platelets, as thrombocytopenia may indicate portal hypertension or advanced liver disease 3

Viral Hepatitis Screening

• Test hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) IgG, and hepatitis C antibody in all patients with elevated transaminases 3, 1, 2
• If HBsAg is positive, check HBeAg, HBeAb, and quantitative HBV DNA and refer to hepatology 3
• If hepatitis C antibody is positive, check quantitative HCV RNA and genotype and refer to hepatology 3
• An isolated HBcAb IgG may still represent chronic HBV and should prompt testing for quantitative HBV DNA 3

Metabolic and Iron Studies

• Obtain fasting glucose or HbA1c and fasting lipid profile to assess for metabolic syndrome and NAFLD risk 1, 2, 4
• Measure fasting transferrin saturation and ferritin to evaluate for hereditary hemochromatosis 1, 2

Autoimmune Markers

• Check anti-smooth muscle antibody (ASMA), anti-nuclear antibody (ANA), and anti-liver-kidney microsomal antibody (anti-LKM1) to evaluate for autoimmune hepatitis 1, 2
• Measure immunoglobulin G (IgG) levels, as elevated IgG supports autoimmune hepatitis diagnosis 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, 2
• Specifically inquire about hepatotoxic medications including methotrexate, NSAIDs, statins, anticonvulsants, antiarrhythmics, tamoxifen, nitrofurantoin, minocycline, and infliximab 1, 2
• Review all herbal supplements and dietary supplements, as these are frequently overlooked causes of liver injury 1, 2
• Quantify alcohol consumption in standard drinks per week 1, 2, 4

Imaging

• Obtain abdominal ultrasound to assess for steatosis, hepatomegaly, cirrhosis features, biliary obstruction, or masses 1, 2, 4
• Ultrasound has 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis 2, 4

Additional Testing Based on Clinical Context

If Initial Workup is Negative

• Order alpha-1 antitrypsin phenotyping (not just serum levels) to evaluate for alpha-1 antitrypsin deficiency 1
• Check ceruloplasmin in patients under 40 years old to exclude Wilson disease 1
• If ceruloplasmin is low-normal, obtain 24-hour urine copper collection 1
• Consider thyroid function tests and creatine kinase to rule out non-hepatic causes of transaminase elevation 4

Risk Stratification for Fibrosis

• Calculate FIB-4 score using age, ALT, AST, and platelet count 1, 2
• A FIB-4 score >2.67 indicates high risk for advanced fibrosis and warrants hepatology referral 1, 2
• A FIB-4 score <1.3 (<2.0 if age >65) indicates low risk with negative predictive value ≥90% 2

Severity-Based Management

Grade 1 (AST/ALT >ULN to 3× ULN)

• Monitor liver enzymes every 1-2 weeks without specific treatment 3, 1
• Continue ICI therapy if applicable 3

Grade 2 (AST/ALT >3× to 5× ULN)

• Discontinue potential hepatotoxic medications if medically feasible 3, 1
• Increase monitoring frequency to every 3 days 3, 1
• Consider prednisone 0.5-1 mg/kg/day if no improvement after 3-5 days 3, 1

Grade 3 (AST/ALT >5× to 20× ULN)

• Obtain urgent hepatology consultation 1
• Discontinue hepatotoxic medications 1
• Start methylprednisolone 1-2 mg/kg/day 1
• Consider liver biopsy if steroid-refractory or diagnostic uncertainty 3, 1

Grade 4 (AST/ALT >20× ULN)

• Immediate hospitalization at a liver center is required 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 3, 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, 2
• Liver-related symptoms (severe fatigue, nausea, vomiting, right upper quadrant pain) with Grade 2 or higher elevation require urgent assessment 1, 2

Follow-Up Timing

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

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; this warrants 24-hour urine copper collection to exclude Wilson disease 1, 2
• Do not assume normal ultrasound excludes NAFLD, as ultrasound misses mild steatosis (<20-30% hepatocyte involvement) 3, 1
• Do not delay viral hepatitis screening even in obese patients with presumed NAFLD 1, 2
• Normal ALT does not exclude NASH or significant liver disease; approximately 50% of HCV-infected patients have normal transaminases 3, 2
• AST is less specific for liver injury and can be elevated in cardiac, skeletal muscle, kidney, and red blood cell disorders 4