Infectious mononucleosis due to Epstein-Barr virus (EBV) is usually a self-limited disease, most commonly seen in young adults . Hepatitis is a well recognized complication of EBV infection that usually resolves spontaneously [2,3]. Jaundice occasionally results from the unusual complication of autoimmune hemolytic anemia rather than from hepatitis .
We report a 49-year-old man with severe cholestatic hepatitis whose history and laboratory findings suggest EBV infection. The patient developed encephalitis and diplopia leading to diagnostic delay. Physicians need to be aware of this complication and EBV infection should be included in the differential diagnosis of cholestasis and encephalitis.
A 49-year-old man presented with fever, headache and diplopia in the 5 days preceding his admission. In the 2 previous weeks he started therapy with simvastatin and fibrate derivate for dyslipidemia.
Physical examination showed jaundice and hepatomegaly. Neurological examination showed diplopia and obtundation (mild confusion).
Initial laboratory studies yielded AST 167 U per liter, ALT 235 U per liter, ALP 362 U per liter, GGT 591 U per liter, CRP 15 g per deciliter, total bilirubin 0.76 mg per deciliter (direct 0.3 mg per deciliter), triglyceride 342 g per deciliter, albumin 3.5 g per deciliter, INR1.3, WBC 7000 count per micro liter with 38% lymphocytes, and 13% monocytes.
Serologies of HAV, HCV and HBV were negative. Serologic tests were positive for IgM antibodies to EBV (Anti VCA IGM 1/300), and anti EBNA antibody positive (1/4063) by EIA. Polymerase chain reaction in mononuclear cells revealed high viral load (EBV DNA 300 copies per 100,000 cells). Heterophile antibodies were also detected indicating a late primary infection. CMV IgM and IgG were negative. Tests for Q-fever and HIV virus, ceruloplasmin, urinary copper, alpha-1 antitrypsine, autoimmune markers were all negative.
Brain CT was normal. Lumbar puncture (CSF) revealed opening pressure of 20. CSF mononuclear cells 1 and CSF protein level 77 g per deciliter. CSF HSV DNA by PCR was negative. CSF EBV DNA was not done. CT of chest and abdomen showed hepatomegaly with fatty infiltration. No bile duct abnormalities, lymphadenopathy or splenomegaly were noted.
Lipid lowering drugs were discontinued. He was treated initially by acyclovir IV for presumed encephalitis and by fluids management. During follow-up he showed good clinical and biochemical response. Fever and diplopia resolved completely, and liver enzymes returned to normal.
Acute cholestatic hepatitis induced by EBV infection in the immune-competent host is rare . The associated CNS involvement including encephalitis and diplopia should prompt the diagnosis of EBV infection.
The incidence of neurological complications during EBV infection ranges between 0.4 and 7%, and CNS symptoms may be the only clinical manifestation of EBV . Whether neurological manifestation are linked to EBV immune reaction or caused by direct EBV invasion into CNS has remained unclear. The neurological abnormalities are most likely immune mediated .
The issue of primary or reactivated EBV infection in the current case is interesting. EBV antigenemia is usually positive within 2 weeks of primary infection. IgM typically becomes positive 1 week after onset, whereas IgG becomes positive in 3 to 4 weeks and peaks in a couple of months. In the present case, the presence of heterophile antibody (HA), and the strong IgM positive response in the first 2 weeks with marked lymphocytosis, prompted the diagnosis of primary infection .
In conclusion, this rare case illustrates the presentation of EBV infection as a severe multi-system disorder in an immuno-competent host. The severity of hepatitis brought the infection to nearly fulminant scale including encephalitis and diplopia.
This article was first published on GastroHep.com on 22 April 2009.
Murad G1, Shaheen R2, Farah R3 and Assy N1,4.
1. Liver Unit, Ziv Medical Center, Safed, Israel.
2. Neurology, Ziv Medical Center, Safed, Israel.
3. Internal Medicine, Ziv Medical Center, Safed, Israel.
4. Technion Faculty of Medicine, Haifa, Israel.
Dr Assy Nimer
Ziv Medical Center
Phone +972 4682 8441/5 Fax +972 4682 8442
- Edoute Y, Baruch Y, Lachter J, et al. Severe cholestatic jaundice induced by Epstein-Barr virus infection in the elderly. J Gastroenterol Hepatol 1998; 13: 821-4.
- Barreales M, Pérez-Carreras M, Meizoso T, et al. Epstein-Barr virus infection and acute cholestatic hepatitis. An Med Interna 2006; 23: 483-6.
- Ono J, Shimizu K, Harada K, et al. Characteristic MR features of encephalitis caused by Epstein-Barr virus: a case report. Pediatr Radiol 1998; 28: 569-70.
- Shaukat A, Tsai HT, Rutherford R, Anania FA. Epstein-Barr virus induced hepatitis: An important cause of cholestasis. Hepatol Res 2005; 33:24-6.
- Doja A, Bitnun A, Ford Jones EL, et al. Pediatric Epstein-Barr virus-associated encephalitis: 10-year review. J Child Neurol 2006; 21: 384-91.
- Vetsika EK, Callan M. Infectious mononucleosis and Epstein-Barr virus. Expert Rev Mol Med 2004; 6: 1-16.
- Nystad TW, Myrmel H. Prevalence of primary versus reactivated Epstein-Barr virus infection in patients with VCA IgG-, VCA IgM- and EBNA-1-antibodies and suspected infectious mononucleosis. J Clin Virol 2007; 38: 292-7.