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

Initial Workup for Transaminitis

Begin with a comprehensive metabolic panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR to characterize the injury pattern (hepatocellular vs. cholestatic) and assess synthetic liver function. 1

Immediate Laboratory Testing

First-Line Blood Tests

• Complete metabolic panel with AST, ALT, alkaline phosphatase, GGT, bilirubin (total and direct), albumin, and PT/INR to distinguish hepatocellular from cholestatic injury 1
• Complete blood count with platelets, as thrombocytopenia may indicate portal hypertension or advanced liver disease 1
• Viral hepatitis serologies: hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc IgG), and hepatitis C antibody in all patients 1, 2
• Fasting glucose or HbA1c and fasting lipid panel to assess for metabolic syndrome and NAFLD risk factors 1, 2

Pattern Recognition Matters

• AST:ALT ratio <1 suggests NAFLD, viral hepatitis, or medication-induced injury 1
• AST:ALT ratio >2 is highly suggestive of alcoholic liver disease, with ratios >3 being particularly specific 1
• ALT is more liver-specific than AST, which can be elevated from cardiac muscle, skeletal muscle, kidney, or red blood cells 1

Severity Grading and Urgency

Transaminitis Classification

• Grade 1: AST/ALT >ULN to 3× ULN - monitor every 1-2 weeks 1
• Grade 2: AST/ALT >3× to 5× ULN - discontinue hepatotoxic medications, monitor every 3 days 1
• Grade 3: AST/ALT >5× to 20× ULN - urgent hepatology consultation, consider liver biopsy 1
• Grade 4: AST/ALT >20× ULN - immediate hospitalization, preferably at liver center 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
• Liver-related symptoms (severe fatigue, nausea, vomiting, right upper quadrant pain) with Grade 2 or higher elevation require urgent evaluation 1

Comprehensive Etiologic Workup

Second-Line Testing (If Initial Tests Normal)

• Iron studies: fasting transferrin saturation and ferritin to evaluate for hereditary hemochromatosis 1, 2
• Autoimmune markers: anti-smooth muscle antibody (ASMA), anti-nuclear antibody (ANA), and anti-liver-kidney microsomal antibody (anti-LKM1) for autoimmune hepatitis 3, 1
• Alpha-1 antitrypsin phenotyping (not just serum levels) - definitive test for AAT deficiency 1
• Ceruloplasmin level to exclude Wilson disease, especially in patients <40 years old 1
• Thyroid function tests to rule out thyroid disorders as a cause 4
• Creatine kinase to exclude muscle disorders as a source of AST elevation 1, 4

Critical Medication and Exposure History

• Comprehensive medication review including prescription drugs, over-the-counter products, herbal supplements, and dietary supplements - discrepancies exist in >50% of patients with liver disease 1
• Check medications against LiverTox® database for hepatotoxic potential 1
• Quantify alcohol consumption: ≥14-21 drinks/week in men or ≥7-14 drinks/week in women suggests alcoholic liver disease 1
• Document metabolic syndrome components: obesity, diabetes, hypertension, hyperlipidemia 1, 2

Imaging Evaluation

First-Line Imaging

• Abdominal ultrasound is the recommended first-line imaging with 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis 1, 4
• Ultrasound identifies hepatic steatosis, biliary obstruction, focal liver lesions, portal hypertension features, and structural abnormalities 1

Important Imaging Caveats

• Normal ultrasound does not exclude NAFLD - ultrasound misses mild steatosis (<20-30% hepatocyte involvement) 1
• Normal ultrasound does not exclude NASH or significant fibrosis 1

Risk Stratification for Advanced Fibrosis

FIB-4 Score Calculation

• Calculate FIB-4 score using age, ALT, AST, and platelet count as primary screening tool 1
• FIB-4 <1.3 (<2.0 if age >65): low risk for advanced fibrosis with negative predictive value ≥90% 1
• FIB-4 >2.67: high risk for advanced fibrosis requiring hepatology referral 1

Monitoring and Follow-Up Strategy

Repeat Testing Timeline

• For mild elevations (<2× ULN): repeat liver enzymes in 2-4 weeks to establish trend 1, 4, 2
• If transaminases remain elevated >3-6 months despite negative workup, consider liver biopsy 1
• If ALT increases to >5× ULN (>235 IU/L for males, >125 IU/L for females) or bilirubin >2× ULN, urgent hepatology referral 1

Common Pitfalls to Avoid

Critical Diagnostic Errors

• 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 1
• Normal ALT does not exclude NASH - approximately 50% of HCV-infected patients have normal transaminases 1

Sex-Specific Considerations

• Normal ALT ranges differ by sex: 29-33 IU/L for males and 19-25 IU/L for females - significantly lower than commercial laboratory cutoffs 1, 4

Most Common Etiologies by Prevalence

Leading Causes in Developed Countries

• Nonalcoholic fatty liver disease (NAFLD) is the most common cause, affecting up to 30% of the population 1, 2
• Medication-induced liver injury causes 8-11% of cases with mildly elevated liver enzymes 1, 2
• Chronic viral hepatitis (hepatitis B and C) commonly presents with fluctuating transaminase elevations 1, 2
• Alcoholic liver disease typically shows AST:ALT ratio >2 1
• Autoimmune hepatitis presents with persistently elevated transaminases, hyperglobulinemia, and positive autoantibodies 1