Can cytomegalovirus (CMV) cause fulminant hepatitis, and what are the other common etiologies and characteristic histologic findings of fulminant hepatitis?

Cytomegalovirus and Fulminant Hepatitis

Yes, cytomegalovirus (CMV) can cause fulminant hepatitis, though it is rare even in immunocompromised patients and exceptionally rare in immunocompetent hosts. 1, 2

CMV as a Cause of Fulminant Hepatitis

CMV-induced fulminant hepatitis represents a life-threatening presentation that can occur in both immunocompromised and immunocompetent individuals, though the latter is exceedingly uncommon. 1, 2 Case reports document immunocompetent adults requiring emergency liver transplantation due to CMV-associated fulminant hepatic failure with massive hepatic necrosis. 1

Clinical Context and Risk Stratification

• Immunocompromised patients (transplant recipients, HIV-positive individuals, those on chronic immunosuppression) face the highest risk of severe CMV hepatitis and fulminant presentations. 3
• Immunocompetent adults typically experience self-limited mononucleosis-like illness, but rare cases progress to severe hepatitis or fulminant liver failure requiring transplantation. 1, 2, 4
• Pregnant women represent a special population where severe CMV hepatitis has been documented, though pregnancy-related immunomodulation may contribute. 5
• Neonates and infants with congenital or perinatal CMV infection commonly develop hepatitis (55% with isolated liver involvement), but fulminant presentations are uncommon and most cases resolve spontaneously. 6

Diagnostic Approach for CMV Hepatitis

When evaluating unexplained hepatitis with elevated transaminases (often several thousand IU/L), consider CMV after excluding more common viral hepatitides (HAV, HBV, HCV, HEV) and drug-induced liver injury. 3, 2

Key diagnostic steps include:

• Serologic testing: CMV IgM and IgG to distinguish primary infection from reactivation 3
• Virologic confirmation: CMV PCR (quantitative viral load) or CMV antigenemia from blood 3
• Liver biopsy (when feasible): Giant cells with viral inclusions ("owl's eye" inclusions) confirmed by immunohistochemistry provide definitive diagnosis 3

Histological Pattern of CMV Hepatitis

The characteristic histologic findings include:

• Giant cells with intranuclear and cytoplasmic viral inclusions (pathognomonic "owl's eye" appearance) 3
• Massive hepatic necrosis in fulminant cases 1
• Lobular hepatitis and centrilobular necrosis in acute presentations 3
• Confirmation via immunohistochemistry demonstrating CMV protein in hepatocytes 3, 1

Other Causes of Fulminant Hepatitis

Viral Etiologies

Hepatitis A, B, and E viruses remain the most common viral causes of fulminant hepatitis globally, with HAV carrying a 2.1% fatality rate in adults over 40 years. 3

Additional viral causes include:

• Hepatitis B virus (HBV): Can cause rapid graft loss post-transplant if untreated; reactivation in immunosuppressed patients leads to fulminant presentations 3
• Hepatitis E virus (HEV): Particularly severe in pregnant women 3, 2
• Epstein-Barr virus (EBV): Documented cases of fulminant hepatitis requiring liver transplantation in both immunocompromised and immunocompetent hosts 2
• Herpes simplex virus (HSV): Causes fulminant hepatitis in neonates, pregnant women, and occasionally immunocompetent adults; requires immediate IV acyclovir 2
• Varicella-zoster virus (VZV): Associated with severe acute and fulminant hepatitis in adults; treated with IV acyclovir 2
• Human herpesvirus 6,7, and 8: Less well-characterized but documented causes of acute liver injury and occasional fulminant hepatitis 2
• Adenoviruses and parvovirus B19: Rare causes of fulminant presentations 2

Non-Viral Etiologies

• Autoimmune hepatitis (AIH): Presents as acute liver failure in some cases; 30% of patients classified as having "cryptogenic" or "seronegative" fulminant hepatitis likely have AIH 3
• Drug-induced liver injury: Including acetaminophen toxicity, antibiotics (nitrofurantoin, minocycline), biologics (infliximab), and herbal medications 3
• Wilson's disease: Must be excluded in young patients with acute liver failure 3
• Ischemic hepatitis: From vascular complications including hepatic artery thrombosis, portal vein thrombosis, or hepatic vein thrombosis (Budd-Chiari syndrome) 3
• Acute fatty liver of pregnancy and HELLP syndrome: Pregnancy-specific causes 5

Histological Patterns by Etiology

Viral hepatitis (HAV, HBV, HCV, HEV): Lobular disarray, hepatocyte ballooning, acidophil bodies (apoptotic hepatocytes), and portal/lobular inflammation 3, 2

Autoimmune hepatitis: Interface hepatitis (piecemeal necrosis), plasma cell infiltration, rosette formation of hepatocytes, and variable degrees of fibrosis even at presentation 3

Drug-induced liver injury: Variable patterns including hepatocellular necrosis, cholestasis, mixed patterns, or granulomatous inflammation depending on the agent 3

HSV/VZV hepatitis: Coagulative necrosis with minimal inflammation, ground-glass hepatocyte nuclei, and Cowdry type A inclusions 2

EBV hepatitis: Atypical lymphocytic infiltration in portal and sinusoidal areas, hepatocyte necrosis, and occasional Reed-Sternberg-like cells 2

Treatment Considerations for CMV Fulminant Hepatitis

Initiate IV ganciclovir 5 mg/kg every 12 hours immediately upon diagnosis or strong clinical suspicion in immunocompromised patients; the role in immunocompetent hosts remains controversial but should be considered in severe presentations. 3, 7, 5

• Transition to oral valganciclovir 900 mg twice daily after 3-5 days of IV therapy in adults once clinical improvement occurs 7, 8
• Treatment duration typically 14-21 days, though severe cases may require longer courses 7, 8
• CMV-specific immunoglobulin may be added in severe cases, particularly in transplant recipients 3
• Monitor for ganciclovir-induced neutropenia (common adverse effect) 8
• Emergency liver transplantation may be necessary in fulminant cases with progressive synthetic dysfunction despite antiviral therapy 1

Critical Pitfalls to Avoid

• Delaying antiviral therapy while awaiting histopathologic confirmation in immunocompromised patients with high clinical suspicion—mortality approaches 70% in severe CMV colitis and similar rates likely apply to fulminant hepatitis 7, 9
• Assuming CMV only causes mild disease in immunocompetent hosts—rare but documented cases of fulminant hepatitis requiring transplantation exist 1, 2
• Missing autoimmune hepatitis in patients presenting with "acute hepatitis"—up to 40% of AIH presents acutely, and 30% of cryptogenic fulminant hepatitis cases likely represent AIH 3
• Failing to screen for CMV before initiating immunosuppression—reactivation can be prevented with prophylaxis in high-risk patients 3