What could be the cause of significantly elevated Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) levels in a patient with no other acute abnormalities?

Differential Diagnosis: Isolated Transaminase Elevation

This pattern of significantly elevated AST (205 IU/L) and ALT (291 IU/L) with normal white blood cell count and otherwise normal chemistry most likely represents acute hepatocellular injury from medication-induced liver injury, viral hepatitis, or metabolic dysfunction-associated steatotic liver disease (MASLD), requiring immediate systematic evaluation to identify the underlying cause. 1

Understanding the Clinical Pattern

The laboratory findings reveal:

• ALT elevation to 291 IU/L represents moderate hepatocellular injury (approximately 6-12× upper limit of normal for females, 9-10× for males), which is classified as moderate elevation (5-10× ULN) 1
• AST:ALT ratio of 0.7 (<1) strongly suggests non-alcoholic liver disease, as alcoholic liver disease typically shows AST:ALT ratio ≥2:1 1, 2
• Normal white blood cell count excludes acute systemic infection or sepsis as primary causes 3
• Preserved synthetic function (implied by "no acute abnormalities" in other chemistry values) indicates this is hepatocellular injury without liver failure 1

Most Likely Causes (In Order of Probability)

1. Medication-Induced Liver Injury (8-11% of cases)

• Review ALL medications including prescription drugs, over-the-counter products, herbal supplements, and dietary supplements against the LiverTox® database 1
• Common culprits include statins, antibiotics, NSAIDs, antiepileptics, and herbal products 1
• Naltrexone at high doses (>50 mg/day) can cause transaminase elevations ranging from 3-19× baseline 4
• Discontinue suspected hepatotoxic agents immediately and monitor ALT every 3-7 days until declining, with normalization expected within 2-8 weeks 1

2. Viral Hepatitis (Acute or Chronic)

• Obtain hepatitis B surface antigen (HBsAg), hepatitis B core IgM (HBcIgM), and hepatitis C antibody as initial viral serologies 3, 1
• Acute viral hepatitis typically shows ALT >400 IU/L, but early presentation or chronic hepatitis can show moderate elevations 1
• Chronic hepatitis B and C commonly present with fluctuating transaminase elevations 1

3. Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD/NAFLD)

• Most common cause of chronic transaminase elevation affecting >30% of the general population 2
• Assess metabolic risk factors: obesity (measure waist circumference), type 2 diabetes, hypertension, dyslipidemia 1, 2
• However, ALT ≥5× ULN is rare in NAFLD/NASH alone and should not be attributed to fatty liver without excluding other causes 1
• Typical pattern shows AST:ALT <1, elevated triglycerides, low HDL cholesterol 2

4. Autoimmune Hepatitis

• Less likely given the absence of other acute abnormalities, but check antinuclear antibody (ANA) and anti-smooth muscle antibody (ASMA) if other causes excluded 1
• Typically presents with higher ALT elevations and elevated autoantibodies 1

5. Ischemic Hepatitis ("Shock Liver")

• Consider if recent hypotensive episode, cardiac event, or severe systemic illness 1
• Usually shows very high transaminases (>1000 IU/L) with rapid decline 1

Immediate Diagnostic Workup

Complete the following tests within 2-5 days: 1

1. Complete liver panel: Alkaline phosphatase, GGT, total and direct bilirubin, albumin, PT/INR 1
2. Viral hepatitis serologies: HBsAg, HBcIgM, HCV antibody 3, 1
3. Metabolic parameters: Fasting lipid panel, hemoglobin A1c, fasting glucose 1, 2
4. Autoimmune markers: ANA, ASMA (if other causes excluded) 1
5. Iron studies: Ferritin, transferrin saturation (screen for hemochromatosis) 1
6. Creatine kinase (CK): To exclude muscle injury as source of AST elevation 1
7. Thyroid function tests: TSH to rule out thyroid disorders 1

Obtain abdominal ultrasound to assess for:

• Hepatic steatosis (sensitivity 84.8%, specificity 93.6% for moderate-severe steatosis) 1
• Biliary obstruction or focal liver lesions 1
• Structural abnormalities 1

Management Algorithm

If Medication-Induced Liver Injury Suspected:

• Discontinue offending agent immediately 1
• Repeat liver enzymes every 3-7 days until declining 1
• Expect normalization within 2-8 weeks after drug discontinuation 1

If Viral Hepatitis Confirmed:

• Refer for specific antiviral management based on viral etiology 1
• For chronic HBV with planned immunosuppression, initiate nucleoside analogue prophylaxis 1

If MASLD/NAFLD Identified:

• Target 7-10% body weight loss through caloric restriction 1, 2
• Low-carbohydrate, low-fructose diet 1, 2
• 150-300 minutes of moderate-intensity aerobic exercise weekly (50-70% maximal heart rate) 1
• Aggressively treat metabolic comorbidities: statins for dyslipidemia, GLP-1 receptor agonists or SGLT2 inhibitors for diabetes 1, 2
• Calculate FIB-4 score to assess fibrosis risk: score >2.67 indicates high risk requiring hepatology referral 1

If No Cause Identified:

• Repeat liver enzymes in 2-4 weeks to establish trend 1
• If ALT increases to >5× ULN (>235 IU/L males, >125 IU/L females) or bilirubin >2× ULN, urgent hepatology referral required 1
• If ALT remains elevated >6 months without identified cause, hepatology referral indicated 1

Critical Pitfalls to Avoid

1. Do not attribute ALT ≥5× ULN to NAFLD alone without excluding viral hepatitis, autoimmune hepatitis, and medication-induced injury 1
2. Do not overlook non-hepatic causes of AST elevation including cardiac injury, muscle disorders (check CK), and hemolysis 1, 5
3. Do not assume benign course without proper evaluation - this level of elevation warrants immediate investigation, not watchful waiting 1
4. Do not miss occult alcohol consumption - even moderate intake (≥14-21 drinks/week in men, ≥7-14 drinks/week in women) can cause significant liver injury 1
5. Do not forget to check ALL supplements and herbal products - these are common causes of drug-induced liver injury 1
6. In COVID-19 pandemic context, consider SARS-CoV-2 as potential cause (14-53% incidence of LFT abnormalities), though direct viral hepatotoxicity versus medication effects can be difficult to distinguish 3

Monitoring Strategy

• If ALT 2-3× ULN: Repeat testing within 2-5 days and intensify evaluation 1
• If ALT >3× ULN (current case): Close observation with repeat testing every 3-7 days until declining 1
• If ALT >5× ULN or bilirubin >2× ULN: Urgent evaluation and hepatology referral within 2-3 days 1
• If evidence of synthetic dysfunction (elevated bilirubin, prolonged PT/INR, low albumin): Immediate hepatology referral 1