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

Initial Workup for Transaminitis

The initial workup for transaminitis should include a comprehensive metabolic panel (AST, ALT, alkaline phosphatase, GGT, bilirubin, albumin), viral hepatitis serologies (HBsAg, HCV antibody), fasting lipid profile and glucose, iron studies (ferritin and transferrin saturation), autoimmune markers (ANA, ASMA, anti-LKM1), alpha-1 antitrypsin phenotyping, ceruloplasmin, and a detailed medication/supplement review. 1

Pattern Recognition and Grading

Before initiating workup, classify the severity and pattern of elevation:

• Grade 1: AST/ALT >ULN to 3× ULN 1
• Grade 2: AST/ALT >3 to 5× ULN 1
• Grade 3: AST/ALT >5 to 20× ULN 1
• Grade 4: AST/ALT >20× ULN 1

The pattern matters: AST:ALT ratio <1 suggests NAFLD, while AST:ALT >1 may indicate advanced fibrosis or alcoholic liver disease (though this ratio does not exclude NAFLD). 2

First-Line Laboratory Evaluation

Immediate Testing Panel

• Complete metabolic panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and INR to characterize injury pattern and assess synthetic function 2, 1
• Viral hepatitis screening: Hepatitis B surface antigen and hepatitis C antibody are essential first-line tests 1, 3
• Fasting glucose, HbA1c, and lipid panel to assess for metabolic syndrome and NAFLD risk factors 1
• Complete blood count to evaluate for thrombocytopenia (suggesting portal hypertension) or anemia 2
• Iron studies: Fasting transferrin saturation and ferritin to screen for hereditary hemochromatosis 1

Autoimmune and Metabolic Screening

• Autoimmune markers: Anti-smooth muscle antibody (ASMA), anti-nuclear antibody (ANA), and anti-liver-kidney microsomal antibody (anti-LKM1) to evaluate for autoimmune hepatitis 1
• Alpha-1 antitrypsin phenotyping (not just serum levels) as the definitive test for AAT deficiency, which can present with isolated transaminitis 1
• Ceruloplasmin to screen for Wilson disease, particularly in patients under 40 years old; if low-normal, obtain 24-hour urine copper collection 1
• Immunoglobulin G levels if autoimmune hepatitis is suspected 1

Critical History Components

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. 1 Specifically inquire about:

• Hepatotoxic medications: Methotrexate, NSAIDs, statins, anticonvulsants, antiarrhythmics, tamoxifen, nitrofurantoin, minocycline, infliximab 1
• Herbal and dietary supplements, which are frequently overlooked but commonly hepatotoxic 1
• Duration of exposure and cumulative dose for medications like methotrexate, which promotes persistent transaminitis and increased fibrosis risk in overweight or diabetic patients 1

Risk Factor Assessment

• Alcohol consumption: Detailed quantification of daily/weekly intake 2
• Metabolic syndrome components: Obesity (BMI, waist circumference), diabetes, hypertension, hyperlipidemia 2, 1
• Dietary habits: Overall caloric intake and specific dietary patterns 1
• Recent viral illness or exposures 1

Imaging Evaluation

• Liver ultrasound to assess for steatosis, hepatomegaly, cirrhosis features, biliary obstruction, or masses 2

Critical caveat: Ultrasound has limited sensitivity for detecting steatosis when <20-30% of hepatocytes are affected, and normal ultrasound does not exclude NAFLD or assess for NASH or fibrosis. 1

Common Etiologies by Prevalence

Most Common Causes

• NAFLD is the most common cause of mild transaminitis in developed countries, strongly associated with metabolic syndrome 2, 1
• Drug-induced liver injury (DILI) from common medications 1
• Chronic hepatitis C was found in 15.3% of asymptomatic patients with mild transaminitis in one study 4
• Alcoholic liver disease 4

Less Common but Important Causes

• Autoimmune hepatitis: Presents with persistently elevated transaminases, hyperglobulinemia, and positive autoantibodies; affects women 3-4 times more than men 1
• Celiac disease: Associated with transaminase elevations that improve or normalize with gluten-free diet in 75-100% of cases 1
• Hereditary hemochromatosis 1
• Alpha-1 antitrypsin deficiency 1
• Wilson disease (must be excluded in patients under 40) 1

Unusual Presentations to Consider

• Choledocholithiasis can cause markedly elevated transaminases (hepatocellular pattern) despite being primarily biliary disease, especially with severe abdominal pain 5
• Chronic cholecystitis rarely presents with acute severe transaminitis 6
• Muscle disorders (myopathies, rhabdomyolysis, vigorous exercise) can elevate AST more than ALT 1
• Cardiac conditions such as congestive heart failure causing hepatic congestion 1

Follow-Up Strategy

• Repeat liver enzymes in 2-4 weeks to assess for spontaneous resolution or progression 1
• If transaminases remain elevated >3 months despite negative workup, consider liver biopsy 1
• For mild elevations without clear etiology, non-invasive fibrosis assessment using FIB-4 initially, followed by specialist tests if indicated 1

Critical 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 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 delay viral hepatitis screening even in obese patients with presumed NAFLD; the obesity epidemic has led to missed hepatitis diagnoses 3
• Do not assume normal ALT excludes NASH; approximately 50% of patients with NAFLD have normal liver chemistries 2
• Statin-induced transaminitis >3× ULN is infrequent, often resolves with dose reduction, and statins are not contraindicated in chronic stable liver disease like NAFLD 1

When to Escalate Care

• Grade 3 or higher transaminitis: Urgent hepatology consultation required 1
• Any elevation with bilirubin ≥2× ULN or INR >1.5: Suggests potential acute liver injury requiring immediate evaluation 2
• Presence of liver-related symptoms (severe fatigue, nausea, vomiting, right upper quadrant pain) with Grade 2 or higher elevation 2