Acute Liver Failure Due to Suspected Herpes Simplex Virus Hepatitis: A Call to Consider Empirical Acyclovir in High-risk Cases

Abstract

Background: Although rare, Herpes simplex virus (HSV-2) is a fatal cause of acute liver failure (ALF) if unrecognized or with delayed treatment. The accepted protocol for empirical management of ALF has a well-defined role for N-acetylcysteine (NAC), but none for antivirals. We have encountered three HSV ALF cases recently, with varying clinical courses, compelling us to highlight this unresolved issue. Case: A 25-year-old man with sickle trait presented with 1-week of fever, headache and myalgia. He claimed sexual monogamy and no medication/drug use. On admission, he was tachycardic, hypotensive, oriented mentally, with tender hepatomegaly and abdomen and lymphadenopathy in axilla/groin. Labwork suggested mild renal insufficiency, low platelets, leukopenia, coagulopathy (INR 2.4) with marked transaminasemia (AST/ALT 4009/3504), mild hyperbilirubinemia (1.8mg/dL) and LDH 4400, but negative Tylenol, salicylate and viral hepatitis panel and imaging unrevealing of cause. Patient was initiated on NAC protocol, but worsened hemodynamically, clinically and biochemically, required intubation, DIC management but eventually died due to multi-organ failure. While all serologies were negative, HSV-2 came positive (titer >1x108). Histopathology on autopsy showed HSV-2 (Fig 1).Figure 1Another woman, aged 30 years was admitted with right upper quadrant pain, headache, fever, increased transaminases in hepatocellular pattern (AST/ALT 1721/975), Hyperbilirubinemia (2.3) and LDH 3930, leukopenia, low platelets, high INR (2). The patient was initiated on NAC protocol, additionally started on empirical Acyclovir given her high-risk sexual behavior, while awaiting serologies. On day 4 of admission transaminases started to improve (AST/ALT 303/567) and so did the coagulopathy. Her HSV-2 titers resulted positive on day 3 (titer >1x10 8). Liver biopsy confirmed HSV-2 hepatitis with Cowdry type A bodies. The patient had uneventful recovery after completion of antivirals. Discussion: Mortality with HSV hepatitis progressing to ALF is high (˜90%). Diagnosis is often delayed (HSV PCR), or false negative (serology) or based on Tzank smear (only if rash is present) or liver biopsy (risky because of coagulopathy). Patients can have maculopapular rash, leukopenia, thrombocytopenia, but fever and anicteric hepatitis are the hallmark features of HSV hepatitis, which if seen should serve as red flags. Based on our experiences, we urge clinicians to remain cognizant in young ALF patients to consider Acyclovir, which may be life-saving. This further raises a debate if Acylovir dose should be included as a part of ALF management protocol, while awaiting serologies, especially in high-risk patients with above mentioned suggestive clinical features.