Can Herpes Simplex Virus (HSV) cause transaminitis, an elevation of liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST), in a patient with a positive HSV Immunoglobulin M (IgM) and Immunoglobulin G (IgG) result?

Can HSV Cause Transaminitis?

Yes, Herpes Simplex Virus (HSV) can cause transaminitis, though it is uncommon and occurs primarily in immunocompromised patients, but can also affect immunocompetent individuals.

Epidemiology and Clinical Presentation

HSV hepatitis is a rare but recognized cause of elevated liver enzymes that can range from mild transaminitis to fulminant hepatic failure 1, 2. The condition affects primarily immunocompromised individuals, including solid organ transplant recipients, but documented cases exist in otherwise healthy adults 3, 2.

Patterns of Liver Enzyme Elevation

In immunocompetent patients with genital herpes, mild transaminitis (≤2 times upper limit of normal) occurs in approximately 14% of cases, compared to 2.6% in controls 3. Key characteristics include:

• Most patients are anicteric (without jaundice) 3
• Constitutional symptoms are minimal—only malaise and fatigue reported in some cases 3
• Liver enzyme elevations correlate temporally with active mucocutaneous HSV lesions 3
• Transaminases typically normalize within 1 week after genital lesions resolve 3
• Recurrent episodes of genital herpes can trigger repeated mild transaminase elevations 3

Severe HSV Hepatitis

In immunosuppressed patients, HSV hepatitis presents more severely 1, 2:

• Can occur in the late post-transplant period, not just early post-transplantation 1
• May present with persistent fever without mucocutaneous lesions, making diagnosis challenging 1
• Transaminase elevations can be moderate (AST 198 U/L, ALT 135 U/L documented) 1
• Carries 80% mortality if untreated, requiring prompt recognition and treatment 2
• Can progress rapidly to acute liver failure 2

Diagnostic Approach in Patients with Positive HSV Serology

When evaluating a patient with positive HSV IgM/IgG and transaminitis, consider the following algorithm:

Initial Assessment

Screen for common viral hepatitis causes first 4:

• Hepatitis A, B, C, and E serologies 4
• EBV and CMV testing (IgG, IgM, and PCR) 4
• HSV testing should include HSV-DNA by PCR in addition to serology 4

Clinical Context Matters

Presence of active mucocutaneous HSV lesions strongly suggests HSV-related transaminitis 3. In patients without visible lesions:

• Consider liver biopsy if diagnosis remains unclear, particularly in immunosuppressed patients with persistent fever and transaminitis 1
• Liver biopsy tissue should be tested for HSV by PCR, as histology may show only focal necrosis with vague histiocyte collections 1
• Both HSV-1 and HSV-2 can cause hepatitis 1

Exclude Alternative Causes

The differential diagnosis for transaminitis is broad 4:

• Autoimmune hepatitis: Check ANA, ASMA, quantitative immunoglobulins 4
• Drug-induced liver injury: Review all medications, including over-the-counter drugs and herbal supplements 4
• Biliary obstruction: Obtain hepatobiliary imaging (ultrasound with Doppler) 4
• Ischemic hepatopathy: Assess cardiovascular status 4
• Alcohol-related liver disease: Consider urinary ethyl-glucuronide testing 4

Treatment Implications

If HSV hepatitis is suspected or confirmed, initiate intravenous acyclovir immediately 1, 2:

• Fever typically resolves within 48 hours of acyclovir initiation 1
• Liver enzymes normalize with appropriate antiviral therapy 1
• In acyclovir-resistant cases, foscarnet is an alternative 2
• Valacyclovir (oral formulation) can cause mild ALT elevation (>2× ULN) in <10% of patients, but this is typically self-limiting 5

Important Caveats

Positive HSV IgM and IgG alone do not establish causality for transaminitis—these antibodies indicate exposure but not necessarily active hepatic infection 3. The diagnosis requires:

• Temporal correlation between HSV activity (mucocutaneous lesions or systemic symptoms) and liver enzyme elevation 3
• Exclusion of other common causes of hepatitis 4
• In severe or atypical cases, tissue diagnosis via liver biopsy with HSV PCR 1

Do not delay treatment in immunosuppressed patients with unexplained fever and transaminitis while awaiting confirmatory testing—empiric acyclovir should be considered given the high mortality of untreated HSV hepatitis 1, 2.