What is the likely cause of elevated alanine transaminase (ALT) and gamma-glutamyl transferase (GGT) levels in a 35-year-old patient with obesity (body mass index (BMI) 32.5), taking Zoloft (sertraline), atorvastatin, and losartan, with mildly elevated alkaline phosphatase and a negative hepatitis C test?

Most Likely Cause: Nonalcoholic Fatty Liver Disease (NAFLD)

The most likely cause of this patient's elevated liver enzymes is nonalcoholic fatty liver disease (NAFLD), given the obesity (BMI 32.5), metabolic risk factors (on losartan suggesting hypertension, on atorvastatin suggesting dyslipidemia), and the pattern of mild transaminase elevation with elevated GGT. 1

Understanding the Enzyme Pattern

The enzyme pattern here is critical for diagnosis:

• ALT 94 IU/L and GGT 170 IU/L with mildly elevated alkaline phosphatase (126 IU/L) suggests a mixed hepatocellular-cholestatic pattern, most consistent with NAFLD in the context of metabolic syndrome 1, 2
• The AST:ALT ratio appears to be <1 (AST not provided but implied), which is characteristic of NAFLD, viral hepatitis, or medication-induced liver injury 1
• GGT elevation is particularly prominent (170 IU/L), which is commonly seen in both alcoholic and non-alcoholic fatty liver disease 2
• The mildly elevated alkaline phosphatase (126 IU/L) with elevated GGT confirms hepatic origin rather than bone disease 1, 3

Why NAFLD is Most Likely

NAFLD is the most common cause of persistently elevated ALT in patients with metabolic risk factors including obesity, diabetes, and hypertension 1:

• BMI 32.5 indicates obesity, a major risk factor for NAFLD 1
• Patient is on losartan (suggesting hypertension) and atorvastatin (suggesting dyslipidemia), both components of metabolic syndrome 1
• The enzyme elevations are mild (<5× ULN for ALT), which is typical for NAFLD 1
• Hepatitis C is negative, ruling out a major alternative diagnosis 1

Medication-Induced Liver Injury: A Secondary Consideration

While NAFLD is most likely, medication-induced liver injury must be considered, particularly from atorvastatin:

• Atorvastatin can cause transaminase elevations in 0.8-3% of patients, typically occurring within the first 1-9 weeks of treatment 4, 5, 6
• However, statin-induced elevations are usually <2× ULN and often resolve with continued therapy 1
• Atorvastatin more commonly elevates ALT rather than alkaline phosphatase, though rare cases of cholestatic patterns have been reported 7
• Sertraline can cause asymptomatic transaminase elevations in approximately 0.8% of patients, usually within 1-9 weeks, which promptly diminish upon discontinuation 5
• Losartan is not typically associated with significant liver enzyme elevations 1

The prominent GGT elevation (170 IU/L) could suggest drug-induced liver injury, as marked GGT increases may indicate DILI even when conventional thresholds are not reached 8. However, GGT is also commonly elevated in NAFLD 2.

Recommended Diagnostic Approach

Immediate Steps:

1. Obtain a complete liver panel including AST, total and direct bilirubin, albumin, and prothrombin time to assess synthetic function and cholestatic patterns 1

2. Perform abdominal ultrasound as first-line imaging with 84.8% sensitivity and 93.6% specificity for detecting moderate to severe hepatic steatosis 1

3. Obtain detailed alcohol history (>14 drinks/week in women suggests alcoholic liver disease) 1

4. Complete medication review checking all drugs against the LiverTox® database, as medication-induced liver injury causes 8-11% of cases with mildly elevated enzymes 1

5. Check fasting glucose or HbA1c and fasting lipid panel to assess for metabolic syndrome components 1

Risk Stratification:

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

• FIB-4 <1.3 indicates low risk for advanced fibrosis (negative predictive value ≥90%) 1
• FIB-4 >2.67 indicates high risk and warrants hepatology referral 1

Management Strategy

If NAFLD is Confirmed:

• Implement lifestyle modifications targeting 7-10% weight loss through caloric restriction, low-carbohydrate/low-fructose diet, and 150-300 minutes of moderate-intensity aerobic exercise weekly 1
• Aggressively manage metabolic comorbidities: continue statin for dyslipidemia, optimize blood pressure control, and screen for diabetes 1
• Continue atorvastatin unless ALT increases to >3× ULN, as statins are safe and beneficial in NAFLD patients 1

If Medication-Induced Liver Injury is Suspected:

• Consider temporary discontinuation of atorvastatin if ALT/AST >3× ULN on repeat testing, with expected normalization within 2-8 weeks 1
• Monitor liver enzymes every 3-7 days until declining if drug is discontinued 1

Monitoring Protocol:

• Repeat liver enzymes in 2-4 weeks to establish trend 1
• If ALT increases to >5× ULN (>125 IU/L for women) or bilirubin >2× ULN, urgent hepatology referral is warranted 1
• If enzymes remain elevated for ≥6 months without identified cause, consider hepatology referral 1

Critical Pitfalls to Avoid

• Do not attribute severe transaminase elevations (>1000 IU/L) to NAFLD alone, as this warrants investigation for acute processes 9
• Do not assume elevated enzymes are benign without proper evaluation, even if mild 1
• Do not discontinue statins prematurely in patients with metabolic syndrome, as benefits typically outweigh risks unless ALT >3× ULN 1
• Do not overlook alcohol consumption, as even moderate intake can exacerbate liver injury 1