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

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, followed immediately by viral hepatitis screening (HBsAg, HBcAb IgG, HCV antibody), iron studies (fasting transferrin saturation and ferritin), and a detailed medication/supplement review. 1, 2

Initial Laboratory Evaluation

First-tier testing should include:

• Complete metabolic panel: AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, INR to distinguish hepatocellular from cholestatic injury and assess synthetic function 1, 2
• Complete blood count with platelets: Thrombocytopenia may indicate portal hypertension or advanced liver disease 2
• Viral hepatitis screening: Hepatitis B surface antigen, hepatitis B core antibody IgG, hepatitis C antibody in all patients (add hepatitis A IgM if acute presentation) 1, 2, 3
• Iron studies: Fasting transferrin saturation and ferritin to evaluate for hereditary hemochromatosis 1, 2
• Metabolic assessment: Fasting lipid profile, glucose/HbA1c to evaluate for metabolic syndrome and NAFLD risk 1, 2
• Liver ultrasound: To assess for steatosis, hepatomegaly, cirrhosis features, biliary obstruction, or masses 1, 2

Critical 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:

• Hepatotoxic medications: Methotrexate (document cumulative dose), NSAIDs, statins, anticonvulsants, antiarrhythmics, tamoxifen, nitrofurantoin, minocycline, infliximab, labetalol 1, 2, 4
• Herbal and dietary supplements: Specifically inquire about these, as patients often don't report them 1, 2
• Quantified alcohol consumption: Document specific amounts and patterns 1, 2
• Dietary habits: Overall caloric intake and specific patterns 1

Pattern Recognition and Interpretation

The pattern of elevation guides further workup 1, 2:

• AST:ALT ratio <1: Suggests NAFLD 1
• AST:ALT ratio >1: May indicate advanced fibrosis or alcoholic liver disease 1
• Elevated alkaline phosphatase: Consider cholestatic causes, overlap syndromes (AIH/PBC, AIH/PSC), or biliary obstruction 5

Second-Tier Testing (If Initial Workup Negative)

Autoimmune evaluation:

• Anti-smooth muscle antibody (ASMA), anti-nuclear antibody (ANA), anti-liver-kidney microsomal antibody (anti-LKM1) for autoimmune hepatitis 1, 2
• If autoantibodies positive, liver biopsy becomes essential to confirm interface hepatitis and guide treatment 1

Metabolic liver disease screening:

• Alpha-1 antitrypsin phenotyping (not just serum levels) - definitive test for AAT deficiency 5, 1
• Ceruloplasmin: If low-normal, obtain 24-hour urine copper collection to exclude Wilson disease (must be excluded in patients <40 years old) 1, 2
• Serum copper levels: To calculate free copper if Wilson disease remains a consideration 1

Severity-Based Management Algorithm

Grade 1 (AST/ALT >ULN to 3× ULN):

• Monitor liver enzymes every 1-2 weeks without specific treatment 1, 2
• Repeat in 2-4 weeks to assess for spontaneous resolution 1, 2

Grade 2 (AST/ALT >3× to 5× ULN):

• Discontinue potential hepatotoxic medications if medically feasible 1, 2
• Increase monitoring to every 3 days 1, 2
• 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 1, 2
• Discontinue hepatotoxic medications 1, 2
• Start methylprednisolone 1-2 mg/kg/day 1, 2
• Consider liver biopsy if steroid-refractory or diagnostic uncertainty 1, 2

Grade 4 (AST/ALT >20× ULN):

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

Critical Red Flags Requiring Urgent Evaluation

Any of the following mandate immediate assessment 1, 2:

• Bilirubin ≥2× ULN or INR >1.5 with any transaminase elevation - suggests potential acute liver injury 1, 2
• Liver-related symptoms (severe fatigue, nausea, vomiting, right upper quadrant pain) with Grade 2 or higher elevation 1, 2
• Decompensation signs: Ascites, hepatic encephalopathy, hepatorenal syndrome, variceal bleeding 5

Special Considerations for Overlap Syndromes

Consider overlap syndromes when 5:

• Serum alkaline phosphatase is more than mildly elevated and does not normalize rapidly with immunosuppressive treatment 5
• Liver biopsy should be considered in patients with PBC when serum transaminases persistently exceed 100 U/L 5
• MRCP should be considered in patients with AIH who have raised serum alkaline phosphatase that doesn't settle rapidly with treatment, or who have inflammatory bowel disease 5

Follow-Up Timing and Liver Biopsy Indications

Repeat liver enzymes in 2-4 weeks to assess for spontaneous resolution or progression 1, 2:

• If transaminases remain elevated >3-6 months despite negative workup, consider liver biopsy 1, 2
• Reassess at 12 weeks to confirm sustained resolution 2
• Liver biopsy is essential when autoantibodies are positive to confirm interface hepatitis 1
• Consider biopsy when careful non-invasive evaluation remains inconclusive 5

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 - ultrasound misses mild steatosis (<20-30% hepatocyte involvement) and cannot assess for NASH or fibrosis 1, 2
• Do not delay viral hepatitis screening even in obese patients with presumed NAFLD 1, 2, 3
• Do not assume normal ALT excludes NASH - approximately 50% of patients with chronic liver disease can have normal transaminases 1, 2
• Do not wait 3 months to recheck if viral hepatitis screening is not performed initially - this misses many chronic hepatitis patients and is not cost-effective 3

Special Population Considerations

For patients with abnormal baseline transaminases: Use multiples of individual baseline rather than absolute ULN values, and adjust action thresholds accordingly 1

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

For patients on methotrexate: Document duration of exposure and cumulative dose, as this promotes persistent transaminitis and increased risk of advanced fibrosis/cirrhosis in overweight or diabetic patients 1