In a 29‑year‑old man with mildly elevated aspartate aminotransferase, alanine aminotransferase, and gamma‑glutamyl transferase, and abdominal ultrasound showing hepatomegaly with fatty infiltration, what is the most likely diagnosis and what initial evaluation and management steps should be taken?

Nonalcoholic Fatty Liver Disease (NAFLD) with Metabolic Syndrome

This 29-year-old man most likely has nonalcoholic fatty liver disease (NAFLD), and the initial management should focus on aggressive lifestyle modification targeting 7-10% weight loss, complete metabolic and viral hepatitis workup, and risk stratification for advanced fibrosis using the FIB-4 score. 1, 2

Most Likely Diagnosis

The clinical presentation strongly suggests NAFLD based on several key features:

• The AST/ALT ratio is 0.74 (<1), which is characteristic of NAFLD rather than alcoholic liver disease (which typically shows AST/ALT ratio ≥2) 1, 3, 4
• Hepatomegaly with fatty infiltration on ultrasound in a young adult with mildly elevated transaminases points to NAFLD as the most common cause, affecting up to 30% of the population 1, 5, 6
• The GGT elevation (80 U/L) can occur in NAFLD, though it is also sensitive for alcohol use—a detailed alcohol history is essential to distinguish between these etiologies 2, 4

Initial Evaluation Algorithm

Step 1: Detailed Risk Factor Assessment

• Obtain comprehensive alcohol consumption history, including quantity, frequency, and duration—consumption of ≥14-21 drinks/week in men suggests alcoholic liver disease rather than NAFLD 1, 2
• Assess for metabolic syndrome components: measure waist circumference, blood pressure, and evaluate for obesity, type 2 diabetes, hypertension, and dyslipidemia 1, 2
• Complete medication review using the LiverTox® database to exclude drug-induced liver injury, which causes 8-11% of cases with mildly elevated transaminases 2

Step 2: Complete Laboratory Panel

• Comprehensive liver panel: AST, ALT, alkaline phosphatase, GGT, total and direct bilirubin, albumin, prothrombin time/INR to assess synthetic function 1, 2
• Viral hepatitis serologies: HBsAg, anti-HBc IgM, anti-HCV antibody to exclude viral hepatitis 1, 2, 5
• Metabolic parameters: fasting glucose or HbA1c, fasting lipid panel to identify metabolic syndrome 2, 5, 6
• Iron studies: serum iron, ferritin, total iron-binding capacity to screen for hemochromatosis 1, 5, 6
• Additional screening: thyroid function tests, celiac serologies if clinically indicated 2, 5

Step 3: Risk Stratification for Advanced Fibrosis

Calculate the FIB-4 score using age, ALT, AST, and platelet count (available at http://gihep.com/calculators/hepatology/fibrosis-4-score/): 1, 2

• FIB-4 <1.3 (or <2.0 if age >65): Low risk for advanced fibrosis, negative predictive value ≥90% 1, 2
• FIB-4 1.3-2.67: Indeterminate risk, consider transient elastography or MR elastography 1
• FIB-4 >2.67: High risk for advanced fibrosis, requires hepatology referral 1, 2, 3

Alternatively, calculate the NAFLD Fibrosis Score (NFS) using age, BMI, hyperglycemia, platelet count, albumin, and AST/ALT ratio (http://gihep.com/calculators/hepatology/nafld-fibrosis-score/), which has 90% sensitivity and 60% specificity to exclude advanced fibrosis at score <-1.455 1

Management Strategy

Lifestyle Modifications (Cornerstone of Treatment)

• Target 7-10% body weight loss through caloric restriction—this is the most effective intervention for NAFLD 1, 2
• Dietary changes: low-carbohydrate, low-fructose diet 2
• Exercise prescription: 150-300 minutes of moderate-intensity aerobic exercise weekly (50-70% of maximal heart rate), which reduces liver fat even without significant weight loss 2

Monitoring Protocol

• Repeat liver enzymes in 2-4 weeks to establish trend and direction of change 2
• If ALT normalizes or decreases: Continue lifestyle modifications and monitor every 4-8 weeks until stabilized 2
• If ALT increases to 2-3× ULN: Repeat testing within 2-5 days and intensify evaluation for alternative causes 2
• If ALT increases to >5× ULN (>145-165 U/L for males): Urgent hepatology referral required 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
• Evidence of synthetic dysfunction (elevated INR, hypoalbuminemia, thrombocytopenia)
• FIB-4 score >2.67 or transient elastography >12.0 kPa suggesting advanced fibrosis

Critical Pitfalls to Avoid

• Do not assume normal ALT excludes significant liver disease—up to 50% of patients with NAFLD and 10% with advanced fibrosis may have normal ALT using conventional thresholds 2
• Do not overlook alcohol consumption—even moderate alcohol use can exacerbate liver injury and impede recovery; the AST/ALT ratio >1.5 combined with elevated GGT strongly suggests chronic alcohol consumption 4
• Do not delay evaluation if ALT ≥5× ULN—this level is rare in simple NAFLD and warrants investigation for viral hepatitis, autoimmune hepatitis, or drug-induced liver injury 2
• Do not routinely perform liver biopsy for mild elevations—biopsy is reserved for cases where diagnosis remains unclear after non-invasive evaluation or when FIB-4 score suggests advanced fibrosis 1, 2

Special Considerations for This Patient

• The GGT elevation (80 U/L) requires careful alcohol history—while GGT can be elevated in NAFLD, it is 75% sensitive for detecting habitual alcohol use 4
• The AST/ALT ratio of 0.74 argues against alcoholic liver disease (which typically shows ratio ≥2) but does not completely exclude it 3, 4
• At age 29 with hepatomegaly, consider less common causes if initial workup is unremarkable: Wilson disease (check ceruloplasmin), autoimmune hepatitis (ANA, anti-smooth muscle antibody), and alpha-1 antitrypsin deficiency 1, 5, 6