What is the appropriate management for a 20-year-old patient with elevated Gamma-Glutamyl Transferase (GGT), Alanine Transaminase (ALT), and Aspartate Transaminase (AST), leukocytosis, and negative Hepatitis A, B, and C (hep ABC) serology?

Diagnostic Workup for Elevated Liver Enzymes with Leukocytosis in a Young Adult

This 20-year-old patient requires immediate comprehensive evaluation for acute hepatitis, with priority given to excluding drug-induced liver injury, autoimmune hepatitis, and acute viral hepatitis beyond A, B, and C.

Initial Assessment and Pattern Recognition

The clinical picture shows a hepatocellular injury pattern with elevated ALT, AST, and GGT, accompanied by leukocytosis (11.6 × 10⁹/L) and neutrophilia (7.3 × 10⁹/L), which suggests an acute inflammatory or infectious process 1. The negative hepatitis A, B, and C serologies do not exclude all viral causes or other important etiologies 2.

Critical Diagnostic Considerations

Immediate laboratory workup should include:

• Complete liver panel: Total and direct bilirubin, alkaline phosphatase, albumin, prothrombin time/INR to assess synthetic function and distinguish hepatocellular from cholestatic patterns 1
• Hepatitis E PCR: Acute hepatitis E can present identically to hepatitis A but requires PCR testing, not antibody testing 1
• Epstein-Barr virus (EBV) testing: EBV viral capsid antigen IgM/IgG, as infectious mononucleosis commonly causes hepatitis with leukocytosis in young adults 3
• Cytomegalovirus (CMV) IgM: CMV hepatitis presents with similar laboratory findings 1
• Autoimmune markers: Anti-nuclear antibodies (ANA), anti-smooth muscle antibodies (ASMA), anti-liver kidney microsomal antibodies (anti-LKM), and serum immunoglobulins, as autoimmune hepatitis can present acutely in young adults 1
• Creatine kinase (CK): To exclude rhabdomyolysis or muscle injury as a source of AST elevation 1, 2

Severity Grading and Management Algorithm

Without knowing the absolute values of ALT and AST, the management approach depends on severity:

If ALT/AST are 3-5× ULN (Grade 2):

• Withhold any potentially hepatotoxic medications immediately 1
• Repeat liver function tests within 2-5 days 1
• Perform abdominal ultrasound to exclude biliary obstruction, liver metastases, or vascular thrombosis 1
• Review all medications, supplements, and herbal products for hepatotoxicity 1
• Obtain detailed alcohol history using AUDIT-C screening 4

If ALT/AST are >5× ULN (Grade 3):

• Consider hospitalization for close monitoring 1
• Repeat liver function tests including bilirubin and INR within 2-3 days 1
• If bilirubin >2× ULN or INR elevated, this represents severe hepatitis requiring urgent hepatology consultation 1
• Initiate supportive care and monitor for signs of acute liver failure 1

Critical Diagnostic Pitfalls to Avoid

Do not assume negative hepatitis A, B, C testing excludes viral hepatitis:

• Hepatitis A IgM can be falsely negative in the first few days of symptoms and requires repeat testing if clinical suspicion remains high 5
• Hepatitis E requires PCR testing, not included in standard viral hepatitis panels 1
• EBV and CMV can cause false-positive hepatitis A IgM and autoimmune markers, requiring careful interpretation 3

Do not overlook drug-induced liver injury:

• Review all medications including over-the-counter drugs, herbal supplements, and dietary supplements using the LiverTox® database 1, 2
• Medication-induced liver injury causes 8-11% of cases with elevated liver enzymes 1, 2

Do not ignore the leukocytosis:

• The combination of elevated liver enzymes and leukocytosis with neutrophilia suggests acute bacterial infection, drug reaction with eosinophilia and systemic symptoms (DRESS), or acute viral infection 5
• Check differential white blood cell count for eosinophilia (suggests drug reaction) or atypical lymphocytes (suggests EBV/CMV) 3

Imaging Evaluation

Abdominal ultrasound is mandatory as first-line imaging 1:

• Sensitivity of 84.8% and specificity of 93.6% for detecting hepatic steatosis 2
• Identifies biliary obstruction, focal liver lesions, and vascular abnormalities 1, 2
• If ultrasound shows biliary dilation or focal lesions, proceed to MRCP or CT for further characterization 1

Monitoring Strategy

For Grade 1-2 hepatitis (ALT/AST <5× ULN):

• Repeat liver function tests every 3-7 days until declining trend established 1, 2
• Continue monitoring weekly until normalization 1

For Grade 3 hepatitis (ALT/AST >5× ULN):

• Monitor liver function tests 2-3 times weekly initially 1
• Daily monitoring if bilirubin elevated or synthetic dysfunction present 1

When to Refer to Hepatology

Immediate referral indicated if:

• ALT/AST >10× ULN 1
• Any elevation in bilirubin >2× ULN with elevated transaminases 1
• Evidence of synthetic dysfunction (prolonged INR, low albumin) 1
• Suspicion of autoimmune hepatitis based on elevated immunoglobulins and positive autoantibodies 1

Urgent referral (within 1 week) if:

• ALT/AST 5-10× ULN without improvement after 1 week 1
• No clear etiology identified after initial workup 1, 2
• Persistent symptoms despite supportive care 5

Special Considerations for Young Adults

In a 20-year-old patient, prioritize evaluation for:

• Acute viral infections: EBV, CMV, hepatitis E are more common than hepatitis A/B/C in this age group in developed countries 5, 3
• Autoimmune hepatitis: Can present acutely in young adults, particularly women, with elevated IgG and positive autoantibodies 6
• Drug-induced liver injury: Including recreational drugs, bodybuilding supplements, and weight loss products 1, 2
• Wilson disease: Should be considered in any patient under 40 years with unexplained hepatitis; check ceruloplasmin and 24-hour urinary copper 1