Biopsy Findings in HSV Hepatitis
Liver biopsy in HSV hepatitis characteristically shows massive hepatocellular necrosis with viral intranuclear inclusions (Cowdry type A bodies) and positive immunohistochemical staining for HSV antigens.
Characteristic Histopathologic Features
Primary Microscopic Findings
Extensive coagulative necrosis is the hallmark finding, typically presenting as multifocal or massive areas of hepatocellular death that can involve both lobes of the liver 1, 2.
Viral intranuclear inclusions (Cowdry type A bodies) appear as eosinophilic inclusions within hepatocyte nuclei, representing the pathognomonic feature of HSV infection 1, 3.
Ground-glass appearance of infected hepatocyte nuclei may be visible, with margination of chromatin creating a characteristic "smudged" nuclear appearance 3.
Distribution Pattern
The necrosis typically appears multifocal and hemorrhagic, often with a geographic or map-like distribution throughout the liver parenchyma 1, 2.
Areas of necrosis may be surrounded by relatively preserved hepatocytes, creating a patchy pattern that can lead to sampling error if biopsy specimens are inadequate 4.
In some cases, the lesions may demonstrate rim enhancement on imaging, mimicking pyogenic abscesses, which can delay correct diagnosis 1.
Confirmatory Diagnostic Techniques
Immunohistochemistry
Immunoperoxidase staining with anti-HSV antibodies is highly sensitive for detecting both active and previous HSV infection, showing strong positive staining in infected hepatocytes 3.
This technique can identify HSV antigens even in completely necrotic hepatocytes, making it valuable for diagnosis even when viral replication has ceased 3.
Immunostaining can differentiate between HSV-1 and HSV-2, which is clinically relevant as both types can cause hepatitis 1, 5.
In Situ Hybridization
DNA-DNA in situ hybridization is highly specific for detecting viable HSV-DNA within hepatocyte nuclei, but is less sensitive than immunohistochemistry 3.
This technique becomes negative in completely necrotic tissue, even when immunoperoxidase staining remains positive, indicating it detects only active viral replication 3.
In situ hybridization is most useful for confirming active infection rather than detecting residual viral antigens in dead cells 3.
Molecular Testing
PCR testing of liver biopsy tissue provides definitive diagnosis and can detect HSV DNA even when histologic findings are subtle 5.
PCR can identify the specific HSV type (HSV-1 vs HSV-2) and is particularly valuable when immunohistochemistry is unavailable or equivocal 5.
Post-Treatment Histologic Changes
Response to Acyclovir
Following antiviral therapy, liver tissue shows regenerative nodules of hepatocytes surrounded by connective tissue stroma containing necrotic debris 3.
Completely necrotic hepatocytes within the connective tissue may remain positive for HSV by immunoperoxidase but become negative by in situ hybridization, except for rare HSV DNA-positive nuclei 3.
This pattern indicates successful viral clearance with residual architectural changes from the initial injury 3.
Clinical Correlation and Diagnostic Pitfalls
Imaging-Pathology Discordance
CT and MRI findings may mimic pyogenic abscesses with multiple bilobar hepatic lesions showing rim enhancement, leading to initial misdiagnosis and inappropriate antibiotic therapy 1.
The radiologic appearance does not reliably distinguish HSV hepatitis from bacterial abscesses, making biopsy essential when clinical suspicion exists 1.
Timing Considerations
Early biopsy is critical as the diagnostic yield decreases with disease progression and increasing coagulopathy, which may contraindicate the procedure 4.
In cases where biopsy is contraindicated due to coagulopathy, plasma HSV DNA quantification correlates with liver enzyme levels and disease severity, providing an alternative diagnostic approach 4.
Sampling Limitations
Liver biopsies are prone to sampling errors due to the patchy distribution of necrosis, potentially yielding false-negative results if the needle misses affected areas 4.
The sensitivity is particularly low in mild HSV hepatitis cases, where focal necrosis may be easily missed 4.
Additional Histologic Features
Minimal inflammatory infiltrate is typically present, contrasting with the extensive necrosis—this paucity of inflammation relative to the degree of hepatocellular destruction is characteristic 2, 3.
Vague histiocyte collections may be seen at the margins of necrotic areas, representing the host response to tissue destruction 5.
Absence of significant fibrosis in acute cases, though chronic or treated cases may show connective tissue deposition around areas of previous necrosis 3.