What is the best course of action for a 50-year-old non-drinker with increasing liver function test (LFT) values, specifically elevated Alanine Transaminase (ALT), Aspartate Transaminase (AST), and Gamma-Glutamyl Transferase (GGT)?

Evaluation and Management of Increasing Liver Function Values in a 50-Year-Old Non-Drinker

Begin with a comprehensive metabolic and viral hepatitis workup, followed by abdominal ultrasound, as nonalcoholic fatty liver disease (NAFLD) is the most common cause of elevated liver enzymes in non-drinkers with metabolic risk factors. 1, 2

Initial Diagnostic Workup

Essential Laboratory Testing (Complete Within 2-4 Weeks)

• Complete liver panel including AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, and prothrombin time/INR to assess synthetic function and distinguish hepatocellular from cholestatic patterns 2, 3
• Viral hepatitis serologies including hepatitis B surface antigen (HBsAg), hepatitis B core antibody (anti-HBc IgM), and hepatitis C antibody with reflex RNA testing if positive 2, 3
• Metabolic parameters including fasting glucose or HbA1c, fasting lipid panel, and assessment for metabolic syndrome components (waist circumference, blood pressure) 2, 3, 4
• Iron studies (ferritin and transferrin saturation) to screen for hemochromatosis 1, 4
• Creatine kinase (CK) to exclude muscle injury as a source of AST elevation 2, 3

Pattern Recognition Based on Enzyme Elevation

The pattern of enzyme elevation guides your diagnostic approach:

• AST:ALT ratio <1 strongly suggests NAFLD, viral hepatitis, or medication-induced liver injury rather than alcoholic liver disease 2, 3
• AST:ALT ratio >2 is highly suggestive of alcoholic liver disease, though you've excluded significant alcohol use 2
• Elevated GGT with mildly elevated transaminases suggests cholestatic pattern warranting imaging evaluation for biliary obstruction 2

First-Line Imaging

Order abdominal ultrasound immediately as it is the recommended first-line imaging modality with 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis 1, 2, 3. Ultrasound can identify:

• Hepatic steatosis (fatty liver)
• Biliary obstruction or dilation
• Focal liver lesions
• Portal hypertension features
• Structural abnormalities 2, 3

Risk Stratification for Advanced Fibrosis

Calculate the FIB-4 score using age, ALT, AST, and platelet count to determine risk of advanced fibrosis 1, 2, 3:

• FIB-4 <1.3 (or <2.0 if age >65): Low risk for advanced fibrosis with negative predictive value ≥90% 2
• FIB-4 >2.67: High risk for advanced fibrosis requiring immediate hepatology referral 2, 3

If FIB-4 suggests intermediate or high risk, consider transient elastography (FibroScan) with values >12.0 kPa indicating high risk of advanced fibrosis 2

Extended Testing If Initial Workup Is Unrevealing

If common causes are excluded, proceed with:

• Autoimmune markers: Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and immunoglobulin G levels to evaluate for autoimmune hepatitis 1, 2
• Alpha-1 antitrypsin level for alpha-1 antitrypsin deficiency 1, 4
• Ceruloplasmin level for Wilson disease (particularly important in patients under 40) 1, 4
• Thyroid function tests to rule out thyroid disorders as a cause of transaminase elevations 2
• Celiac disease screening if clinically indicated 1

Management Based on Most Likely Diagnosis

If NAFLD Is Confirmed (Most Common in Non-Drinkers)

Lifestyle modifications are the cornerstone of treatment 1, 2, 3:

• Weight loss target: 7-10% body weight reduction through caloric restriction 2, 3
• Exercise prescription: 150-300 minutes of moderate-intensity aerobic exercise weekly (50-70% of maximal heart rate) 2
• Dietary changes: Low-carbohydrate, low-fructose diet 2, 3
• Manage metabolic comorbidities: Treat dyslipidemia with statins, optimize diabetes control with GLP-1 receptor agonists or SGLT2 inhibitors, and manage hypertension per standard guidelines 2

For biopsy-proven NASH, consider vitamin E 800 IU daily, which improves liver histology in 43% of patients versus 19% with placebo 2

If Medication-Induced Liver Injury Is Suspected

• Review all medications including prescription drugs, over-the-counter products, herbal supplements, and dietary supplements against the LiverTox® database 2
• Discontinue suspected hepatotoxic medications when possible 2
• Monitor liver enzymes every 3-7 days until declining, with expectation of normalization within 2-8 weeks after drug discontinuation 2

Monitoring Schedule

For Mild Elevations (<2× ULN)

• Repeat liver enzymes in 2-4 weeks to establish trend and direction of change 2, 3
• If values normalize or decrease, no further immediate testing needed 2
• If stable or improving, continue monitoring every 4-8 weeks until normalized 2

Escalation Criteria Requiring More Urgent Follow-Up

• ALT increases to 2-3× ULN: Repeat testing within 2-5 days and intensify evaluation 2
• ALT increases to >3× ULN or >300 U/L: Urgent evaluation within 2-3 days for alternative etiologies 2, 3
• ALT increases to >5× ULN (>235 U/L for males, >125 U/L for females): Immediate hepatology referral 2, 3
• Total bilirubin >2× ULN: More urgent follow-up within 2-3 days 2

Hepatology Referral Criteria

Refer to hepatology if 1, 2, 3:

• Liver enzymes remain elevated for ≥6 months without identified cause
• ALT increases to >5× ULN
• Total bilirubin increases to >2× ULN
• Evidence of synthetic dysfunction (elevated INR, low albumin, thrombocytopenia)
• FIB-4 score >2.67 indicating high risk for advanced fibrosis
• Diagnosis remains unclear after non-invasive evaluation

Critical Pitfalls to Avoid

• Do not assume NAFLD without proper evaluation: ALT elevation ≥5× ULN is rare in NAFLD alone and requires investigation for viral hepatitis, autoimmune hepatitis, or drug-induced liver injury 2, 3
• Do not overlook non-hepatic causes: Intensive exercise, muscle injury, cardiac injury, hemolysis, and thyroid disorders can all elevate transaminases, particularly AST 2
• Do not rely on normal ALT to exclude liver disease: Up to 50% of NAFLD patients have normal liver enzymes, and up to 10% of patients with advanced fibrosis may have normal ALT using conventional thresholds 2
• Remember sex-specific normal ranges: Normal ALT is 29-33 IU/L for males and 19-25 IU/L for females, significantly lower than commercial laboratory cutoffs 2, 3
• Do not order liver biopsy routinely: Biopsy is reserved for cases where diagnosis remains unclear after non-invasive evaluation, enzymes remain elevated >6 months without cause, or there is suspicion for autoimmune hepatitis or advanced fibrosis 2, 3