What is the recommended work‑up and management for a patient with transaminitis (elevated alanine aminotransferase and aspartate aminotransferase)?

Workup and Management of Transaminitis

For a patient with elevated ALT and AST, begin with a comprehensive liver panel and targeted history to identify the underlying cause, with the urgency and depth of evaluation determined by the degree of elevation and presence of symptoms.

Initial Risk Stratification by Severity

The pace of your workup depends critically on the degree of transaminase elevation 1, 2:

• Mild elevation (<3× ULN): Systematic outpatient evaluation over 2-4 weeks 1, 3
• Moderate elevation (3-5× ULN): Prompt evaluation within 2-5 days 1, 2
• Severe elevation (>5× ULN): Urgent evaluation within 48-72 hours for acute hepatitis, drug-induced liver injury, or ischemic hepatitis 1, 2

Critical threshold: ALT ≥3× ULN with total bilirubin ≥2× ULN or INR >1.5 requires immediate evaluation due to risk of acute liver failure 1.

Essential First-Line Laboratory Testing

Order the following immediately to establish the pattern and severity 1, 3, 2:

• Complete liver panel: ALT, AST, alkaline phosphatase, GGT, total and direct bilirubin, albumin, PT/INR 1, 3
• Viral hepatitis serologies: HBsAg, anti-HBc IgM, anti-HCV antibody 1, 3, 2
• Metabolic screening: Fasting glucose or HbA1c, fasting lipid panel 3, 2
• Complete blood count with platelets to assess for thrombocytopenia suggesting portal hypertension 3

Critical History Elements

Medication Review

Perform a comprehensive medication review checking all agents against the LiverTox® database 3, 2:

• Prescription medications
• Over-the-counter products
• Herbal supplements
• Dietary supplements

Medication-induced liver injury causes 8-11% of cases with elevated transaminases 3.

Alcohol Quantification

Precisely quantify alcohol consumption 3, 2:

• Men: >21 standard drinks/week over 2 years is excessive 2
• Women: >14 standard drinks/week over 2 years is excessive 2

Metabolic Risk Factors

Assess for components of metabolic syndrome 1, 3:

• Obesity (measure waist circumference)
• Type 2 diabetes
• Hypertension
• Dyslipidemia

NAFLD is the most common cause of persistently elevated ALT in patients with metabolic risk factors 3.

Pattern Recognition for Differential Diagnosis

AST/ALT Ratio Interpretation

The ratio provides critical diagnostic clues 3, 2:

• AST/ALT <1: Suggests NAFLD, viral hepatitis, or medication-induced injury 3, 2
• AST/ALT ≥2: Highly suggestive of alcoholic liver disease (70% of alcoholic hepatitis cases) 3, 2
• AST/ALT >3: Particularly specific for alcoholic liver disease 3

R-Value Calculation

Calculate R-value to classify injury pattern 3:

• R = (ALT ÷ ULN ALT) / (ALP ÷ ULN ALP)
• R ≥5: Hepatocellular injury
• R ≤2: Cholestatic injury
• 2 < R < 5: Mixed injury

First-Line Imaging

Order abdominal ultrasound as the initial imaging modality 1, 3, 2:

• Sensitivity: 84.8% and specificity: 93.6% for moderate-to-severe hepatic steatosis 1, 3
• Identifies biliary obstruction, focal liver lesions, and portal hypertension features 1, 3

Risk Stratification for Advanced Fibrosis

Calculate the FIB-4 score using age, ALT, AST, and platelet count 1, 3:

• <1.3 (<2.0 if age >65): Low risk for advanced fibrosis (NPV ≥90%) 1, 3
• >2.67: High risk for advanced fibrosis—requires hepatology referral 1, 3

Second-Tier Testing (If Initial Workup Unrevealing)

Proceed with additional testing for less common causes 3, 2:

• Iron studies: Ferritin, transferrin saturation (hemochromatosis screening) 3, 2
• Autoimmune markers: ANA, anti-smooth muscle antibody, immunoglobulin G levels 3, 2
• Alpha-1 antitrypsin level 3
• Ceruloplasmin (Wilson disease—especially if age <40) 3, 2
• Thyroid function tests 1
• Creatine kinase to exclude muscle injury as source of AST elevation 1, 3

Monitoring Algorithm

For Mild Elevations (<3× ULN)

• Repeat liver enzymes in 2-4 weeks to establish trend 1, 3
• If normalizing: Continue monitoring every 4-8 weeks until stable 1, 3
• If persistent ≥6 months: Intensify workup and consider hepatology referral 1, 3

For Moderate Elevations (3-5× ULN)

• Repeat testing within 2-5 days 1, 2
• Escalate evaluation for alternative etiologies 1, 2

For Severe Elevations (>5× ULN)

• Immediate comprehensive evaluation 1, 2
• Consider hepatology referral 1, 3

Hepatology Referral Criteria

Refer to hepatology when 1, 3:

• ALT >5× ULN (>235 IU/L for males, >125 IU/L for females)
• Transaminases remain elevated ≥6 months without identified cause
• Evidence of synthetic dysfunction (low albumin, elevated INR)
• FIB-4 score >2.67
• Total bilirubin ≥2× ULN with elevated transaminases

Management by Specific Etiology

NAFLD (Most Common Cause)

Lifestyle modifications are the cornerstone 3:

• Target 7-10% weight loss through caloric restriction 3
• Low-carbohydrate, low-fructose diet 3
• 150-300 minutes of moderate-intensity aerobic exercise weekly 3
• Manage metabolic comorbidities: statins for dyslipidemia, GLP-1 agonists or SGLT2 inhibitors for diabetes 3

Pharmacotherapy (for biopsy-proven NASH) 3:

• Vitamin E 800 IU daily improves liver histology in 43% vs 19% placebo 3
• Pioglitazone for patients with type 2 diabetes 3

Medication-Induced Liver Injury

• Discontinue suspected hepatotoxic medication when possible 3, 2
• Monitor ALT every 3-7 days until declining 3
• Expect normalization within 2-8 weeks after drug discontinuation 3

Alcoholic Liver Disease

• Complete alcohol abstinence is essential 3
• Even moderate consumption impedes recovery 3
• If AST >5× ULN with suspected alcoholic hepatitis: Consider corticosteroid therapy 3

Statin-Associated Elevations

• If ALT <3× ULN: Continue statin, recheck in 4-6 weeks 4, 3
• If ALT ≥3× ULN: Consider dose reduction or temporary discontinuation 4, 3
• Cardiovascular benefits typically outweigh risks of mild elevations 4

Common Pitfalls to Avoid

• Don't assume mild elevations are benign: Up to 10% of patients with advanced fibrosis may have normal or near-normal ALT 3
• Don't overlook non-hepatic causes: Intensive exercise, muscle injury, cardiac injury, and thyroid disorders can elevate transaminases, particularly AST 3, 5, 6
• Don't ignore thrombocytopenia: Platelet count <150 × 10⁹/L suggests possible portal hypertension from chronic liver disease 3
• Don't attribute ALT ≥5× ULN to NAFLD alone: This degree of elevation is rare in NAFLD and warrants investigation for viral hepatitis, autoimmune hepatitis, or drug-induced injury 3
• Don't forget sex-specific reference ranges: Normal ALT is 29-33 IU/L for males and 19-25 IU/L for females—significantly lower than many commercial laboratory cutoffs 1, 3, 7

Special Considerations

Immune Checkpoint Inhibitor Therapy

For patients on ICIs, the term "transaminitis" is imprecise 4. Mild asymptomatic increases (>1× to <3× ULN) without elevated bilirubin are often non-specific and may not represent clinically significant immune-mediated liver injury 4. True immune-mediated liver injury typically requires ALT/AST ≥3× ULN 4.

Post-Operative Setting

After cholecystectomy, mild ALT elevation (2-3× ULN) does not require urgent workup but should be monitored 3. Evaluate for postoperative biliary complications if elevation persists, though bile duct injury typically presents with a cholestatic pattern 3.