been linked with FHF in neonates, pregnancy, immunocom-Members of the herpes virus family and hepatitis B promised patients, and apparently healthy individuals. [5][6][7][8] Epvirus (HBV) have been implicated as etiologic agents in stein-Barr virus (EBV) infection may cause acute liver failure non-A, non-B (NANB) fulminant hepatic failure (FHF), in male infants with X-linked lymphoproliferative disease, but the frequency of infection with these agents has not immunocompromised patients, and those in whom it is acbeen established using appropriate controls. To examine quired sporadically. 9 Rare cases of FHF caused by disseminthis issue, we studied 50 NANB FHF patients and 104 ated viral infection in immunocompromised subjects have liver transplant recipients from North America and Eubeen observed in patients infected with cytomegalovirus rope. Hepatic DNA was analyzed by polymerase chain (CMV) 10 or varicella-zoster virus (VZV). 11-14 Furthermore, a reaction (PCR) for evidence of Epstein-Barr virus (EBV), case report from Japan suggests that human herpes virus-6 cytomegalovirus (CMV), herpes simplex virus I (HSV I)
(HHV-6) may cause FHF in neonates. 15 and II (HSV II), varicella-zoster virus (VZV), and human
In the search for viral agents responsible for NANB FHF, herpes virus-6 (HHV-6) nucleic acid sequences. The previnvestigators from North America have suggested a possible alence of HBV was assessed in North American subjects role for occult hepatitis B virus (HBV) infection. 16,17 However, only. HSV I, HSV II, VZV, and HHV-6 viral sequences European investigators have not been able to corroborate were not observed in any samples. Three of 50 FHF (6%) these findings. 4,18,19 To more accurately define the contribuand 14 of 104 control patients (13%) were positive for tion of the herpes viruses and cryptic HBV infection to NANB CMV DNA. Two of 50 FHF (4%) and 10 of 104 control FHF, we systematically assessed the livers of both patients patients (10%) had EBV DNA, and HBV DNA was obwith acute liver failure and representative controls for eviserved in 3 of 10 North American FHF patients (30%)
dence of viral sequences using the polymerase chain reaction and 3 of 59 controls (5%) without serum markers for HBV (PCR). infection. The finding of HBV DNA in the liver of seronegative controls from North America but not Europe
PATIENTS AND METHODS
suggests that occult hepatitis B sequences in patients
Patients. Liver tissue was obtained retrospectively from the exwith NANB FHF may simply reflect geographic differplanted liver of 104 control patients undergoing orthotopic liver ences. The majority of cryptogenic FHF cases cannot transplantation and 50 patients with NANB FHF who developed be attributed to infection with herpes viruses or HBV. hepatic encephalopathy within 8 weeks of the appearance of the first (HEPATOLOGY 1996;24:1361-1365.) symptoms of liver disease. 20 The study group included 40 patients with FHF referred to the Institute for Study of Liver Disease, Kings College Hospital, London, England, and 10 FHF patients from Wash-Approximately 30% to 40% of patients with acute liver failington University Medical Center, St. Louis, MO, or Ochsner Clinic, ure in North America and Europe are considered to have non-New Orleans, LA, between 1988 and 1992. Liver tissue was collected A, non-B (NANB) fulminant hepatic failure (FHF) because from 91 liver transplant recipients with chronic liver disease to com- they have no obvious precipitating factors or serum markers pare the prevalence of viral detection with the study group. (Table to identify acute viral infection. [1][2][3][4] All members of the Herpes-1 shows the etiology of liver disease.) An additional 13 patients with acute liver failure secondary to acetaminophen overdose, HBV infec-viridae family have been reported to cause acute liver failure tion, and acute fatty liver disease of pregnancy were also included in isolated instances, but the true prevalence of each specific in the control group (Tables 1 and2). herpes virus infection in patients with NANB FHF is un-Nine of the control patients had serological evidence of HBV infecknown. Herpes simplex virus I (HSV I) and II (HSV II) has tion and were used as positive controls for the HBV PCR studies. This HBV-positive control group consisted of 6 patients with cirrhosis, 2 with FHF, and 1 with subacute liver failure (encephalopathy within 5 to 12 weeks of the onset of jaundice). 21 Only patients from North Abbreviations: NANB, non-A, non-B; FHF, fulminant hepatic failure; HSV I, herpes America were studied for evidence of HBV infection by PCR, because simplex virus I; HSV II, herpes simplex virus II; EBV, Epstein-Barr virus; CMV, cytomegalothe results in European patients had been previously reported. 19 virus; VZV, varicella-zoster virus; HHV-6, human herpes virus-6; HBV, hepatitis B virus;
Patients were included in the study group if they developed FHF PCR, polymerase chain reaction; HCV, hepatitis C virus.