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Nassar F, Nasser M and Assy N Epstein-Barr virus-associated fulminant hepatic failure and autoimmune hemolytic anemia
Nassar F, Nasser M and Assy N, 03 December 2008

Epstein-Barr virus (EBV) infection is common worldwide. It is often asymptomatic, with mild self-limited hepatitis reported in 80 to 90% of cases [1]. Less common complications include hemolytic anemia, aplastic anemia, myocarditis, splenic rupture, hemophagocytic syndrome and neurological complications such as guilain barre, encephalitis, and meningitis.

Fulminant hepatitis is a very rare complication and has an overall mortality of 90% [2]. Hemolytic anemia is also rare and occurs in 0.5 to 3% of patients [3].

We report the case of complicated EBV infection, associated with both fulminant hepatic failure and autoimmune hemolytic anemia. This case had a successful outcome after plasmapheresis, acyclovir and prednisolone combination treatment which removed the need for liver transplantation.

Case report

A 20-year-old patient was admitted with fever (38°C), fatigue and sore throat. Physical examination revealed bilateral cervical lymphadenopathy and hepatosplenomegally. There were no signs of chronic liver disease.

His white blood cell count was 15000 per micro liter; with 55% neurophils and 42% lymphocytes. Platelets were 120,000 per micro liter; albumin, 3.4 g per deciliter; total bilirubin, 45 mg per deciliter (predominantly direct; 37 mg per decilitre); alanine aminotransferase, 500 U per liter; and aspartate aminotransferase, 400 U per liter. INR 1.4; Factor V, 30%; Hemoglobin, 6.4 g per deciliter; Lactate dehydrogenase, 6000 U per liter; Haptoglobin, 2.7 mg per deciliter; Reticulocytes count, 5%.

Positive Coombs test, positive cold agglutinins and positive anti-i antibody.

Liver scanning and abdominal ultrasonography revealed hepatosplenomegaly.

Serologic tests were positive for IgM antibodies to EBV (Anti VCA IGM 1/360), and anti EBNA negative, which are diagnostic of a primary infection.

Polymerase chain reaction in mononuclear cells revealed high viral load (EBV DNA 340 copies per 100,000 cells). Flow cytometry showed increased percentage of CD8+ and decreased CD4/CD8 ratio. Tests for IgM antibodies to hepatitis A virus, antibodies to hepatitis C virus, and antibodies to hepatitis delta, Q-fever and HIV virus, ceruloplasmin, alpha-1 antitrypsine, autoimmune markers were all negative.

Gradually, the aminotransferase and bilirubine levels rose, and signs of encephalopathy developed. At this stage, and because of the threat of cerebral edema and impending acute liver failure, we started treatment with intravenous acyclovir (10 mg/kg) and prednisolone (1mg/kg) after informed consent had been obtained.

Two sets of plasmapheresis were also performed due to resistant hemolytic anemia. Gradually, the aminotransferase levels decreased and after 2 weeks became normal; tests for EBV DNA became undetectable; and the bilirubin and albumin levels returned to normal. Tests for EBNA became positive.


The pathogenesis of EBV infection associated with fulminant hepatic failure is unclear, but the BRCF 1 and BARF 1 proteins may help the virus to evade the host’s immune system [4].

Liver failure is the cause of death in half of patients with fatal infectious mononucleosis [2]. Although, plasmapheresis and steroids decreased the rate of hemolysis and hyperbilirubinemia, and acyclovir inhibits EBV replication and reduces viral shedding, there is no convincing evidence to warrant their clinical use in uncomplicated cases [5].

The goals of treatment in complicated cases are the prevention of progressive acute liver failure and liver transplantation by rapid suppression of EBV replication in EBV-infected CD8+ or NK cells. Clearly, there is urgent need for a drug that may prevent these steps in the progression of complicated EBV infection. Meanwhile, the possible use of this promising combination of plasmapheresis, acyclovir, and prednisolone treatment should be considered in selected patients with acute liver failure.

This article was first published on on 3 December 2008.


Nassar F¹, Nasser M¹ and Assy N²,³

1. Department of Internal Medicine E, Western Galilee Hospital, Nahariya, Israel
2. Liver Unit, Ziv Medical Centre, Safed, Israel
3. Rappaport Faculty of Medicine, Technion Institute, Haifa, Israel


Dr Assy Nimer
Liver Unit, Ziv Medical Centre, Box 1008, Safed 13100, Israel;
Ph +972 4682 8441/5
Ph +972 4682 8442


  1. White NJ, Juel-Jensen BE. Infectious mononucleosis hepatitis. Semin Liver Dis 1984; 4(4): 301-6.

  2. Feranchak AP, Tyson RW, Narkewicz MR, et al.Fulminant Epstein-Barr viral hepatitis: orthotropic liver transplantation and review of the literature. Liver Transpl Surg 1998; 4(6): 469-76.

  3. Sevilla J, del Carmen Escudero M, Jimenez R, et al. Severe systemic autoimmune disease associated with Epstein-Barr virus infection. J Pediatr Hematol Oncol 2004; 26(12): 831-3.

  4. Palanduz A, Yildirmak Y, Telhan L, et al. Fulminant hepatic failure and autoimmune hemolytic anemia associated with Epstein-Barr virus infection. J Infect 2002; 45(2): 96-8.

  5. Tynell E, Aurelius E, Brandell A, et al. Acyclovir and prednisolone treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-controlled study. J Infect Dis 1996; 174(2): 324–31.

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