Acute Epstein Barr infection presenting with hepatitis and jaundice.
Abstract: Background

Epstein Barr virus (EBV) infection usually presents with the well known constellation of symptoms of infectious mononucleosis.

Case Report Presentation

In this case report a young man presented with jaundice, mild abdominal pain and subjective fever as the only clinical manifestations of acute EBV infection. Further laboratory evaluation revealed that he was EBV-IgM positive. The work up for other types of acute hepatitis was negative. During his hospitalization he was treated conservatively and his liver transaminases and bilirubin were monitored daily and demonstrated steady decline towards normal values. Liver biopsy was not performed since diagnosis was made by serology and careful physical examination. This report is followed by a short review of the literature on acute EBV hepatitis.

Keywords:

Epstein Barr, Hepatitis, Jaundice, Infectious Mononucleosis
Article Type: Report
Subject: Jaundice (Development and progression)
Hepatitis (Development and progression)
Infection (Development and progression)
Bilirubin
Author: Papafragkakis, Haris
Pub Date: 04/01/2010
Publication: Name: Archives: The International Journal of Medicine Publisher: Renaissance Medical Publishing Audience: Academic Format: Magazine/Journal Subject: Health Copyright: COPYRIGHT 2010 Renaissance Medical Publishing ISSN: 1791-4000
Issue: Date: April-June, 2010 Source Volume: 3 Source Issue: 2
Accession Number: 263251119
Full Text: INTRODUCTION

EBV infection presents clinically in adults with symptoms indicative of infectious mononucleosis (IM). Though EBV hepatitis is a common entity, clinically present jaundice with high bilirubin levels is less common. (1-4) We present a case of a young man with jaundice and bilirubin of 3.8 mg/dl, mild abdominal pain and subjective fever as the only clinical manifestations of acute EBV infection.

CASE REPORT

A 19 year old male presented to our hospital with subjective fever and abdominal pain for one week. He had dark urine for 3-4 days prior to presentation. He had no joint pain, skin rash, sore throat or lymphadenopathy. He did not have any past medical or surgical history. The patient was not taking any medications, was sexually active with one female partner for the last one year and denied alcohol abuse, herbal or over the counter medications, blood transfusions, tattoos, piercings, intravenous drug use, needle stick injuries or recent travel to endemic countries. Upon arrival, his vital signs were within normal limits and he was afebrile. He had scleral icterus, had no pharyngeal erythema or tender lymphadenopathy, no hepatosplenomegaly and no abdominal tenderness. The basic metabolic panel was normal and the white blood cell count was 13.2 without left shift. Other laboratory tests revealed acute hepatitis with AST 653 IU/L, ALT 1134 IU/L, alkaline phosphatase (ALP) 340 IU/L, total bilirubin 3.8 mg/dl (direct bilirubin 2.7 mg/dl). Blood tests were negative for acute or chronic hepatitis A, B or C. Acetaminophen level was normal. Biliary obstruction, gallbladder pathology or presence of choledochal cysts were ruled out by ultrasound, HIDA scan and MRCP. During the hospital course the patient remained afebrile and asymptomatic. The second day of admission his WBC count was 10.2. Transaminases and bilirubin levels over the next six days decreased towards normal levels (table 1) and the patient was subsequently discharged home. Results of EBV serology (EBV anti-IgM) became positive after discharge. EBV IgG antibody, Human immunodeficiency virus, cytomegalovirus and herpes simplex virus serology were negative.

DISCUSSION

EBV is a member of the herpes virus family. When it infects children the disease is usually asymptomatic. In adults can manifest with the complex of symptoms of infectious mononucleosis, such as fever, malaise, lymphadenopathy, sore throat, hepatosplenomegaly and abdominal pain. EBV hepatitis usually presents with a two to three-fold elevation in transaminases, elevation of LDH, alkaline phosphatase and bilirubin levels. (5) These liver enzyme abnormalities most commonly present during the second week of infection and most of the times the levels normalize within two to six weeks. (5) In the minority of cases of EBV hepatitis, severe liver injury can be fatal. (6) Immunocompetent patients are usually asymptomatic and recover with only supportive care, but immunosuppressed patients are more likely to develop infectious mononucleosis and lymphomas. Also, malignancies, such as undifferentiated nasopharyngeal adenocarcinomas, especially associated with HBV type 1 and lymphoepithelioma-like gastric carcinomas have been associated with EBV infection. (7)

Jaundice as a feature of acute EBV infection is relatively uncommon and presents in less than 5%-10% of reported cases. (1,7) On the contrary, AST levels can be elevated > 10-fold. (8,9) The pathophysiology behind EBV associated jaundice is not fully illuminated. The most common finding in liver biopsy is portal and intrasinusoidal infiltration of lymphocytes with apoptotic hepatocytes, minimal swelling and vacuolization of hepatocytes and presence of mononuclear cells in the sinusoids in an 'Indian bead' pattern. (10,11,12) The virus does not affect directly the hepatocytes, the biliary epithelium and vascular endothelium (13), but it has been suggested that cytotoxic T-lymphocytes may be responsible through proinflammatory cytokine production (TNF-a, IL-6,2 and 10) and expression of cytotoxic granules such as Perforin/T-cell intracellular antigen. (14) Also has been suggested that jaundice can be a result of centrilobular cholestasis due to dysfunctional mitochondria around the biliary microvilli (15) or due to infection of the biliary epithelial cells, generation of manganese--superoxide dismutase autoantibodies16 and EBV induced hemolysis. (17) The severity of the cholestasis does not correlate with the degree of bile duct injury. (18) Liver biopsy can help establish the diagnosis, but is probably not necessary in the appropriate clinical setting with elevation of liver enzymes and presence of EBV- IgM antibodies. (19) If biopsy is done, in situ hybridization (ISH) and polymerase chain reaction (PCR) can be performed to establish the diagnosis. One study showed that ISH and PCR are equally sensitive in detecting EBV, but immunohistochemical staining for EBV latent membrane proteins that was also studied, was not helpful. (18) Without liver biopsy, EBV infection can be diagnosed based on clinical suspicion and proper laboratory data including EBV IgM antibody, positive monospot and heterophile antibody testing. (20) As in our case, other etiologies of hepatitis must be excluded. As mentioned, treatment is usually supportive, but in some cases steroids and anti-herpetic medications have been used, but no adequate volume of clinical data have clearly supported their use.

CONCLUSIONS

Acute EBV hepatitis is a common and usually self limited disease. Presentation with high levels of bilirubin is uncommon and high level of clinical suspicion is required for correct and prompt diagnosis. Emphasis should be given in excluding other etiologies of elevated bilirubin and transaminases, such as acute hepatitis A, B or C, HIV or other less common viral hepatitides. Liver biopsy, although very helpful in diagnosis, often is unnecessary, since diagnosis can be made by careful history taking and serologic testing and it includes small risk of bleeding, infection or trauma to the liver and other organs.

REFERENCES

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(2.) Barlow G, Kilding R, Green ST. Epstein Barr virus infection mimicking extrahepatic biliary obstruction. J R Soc Med 2000;93:316-8.

(3.) Canovic P, Gajovic O, Todorovic Z, Mijailovic Z. Epstein Barr virus hepatitis associated with icterus- a case report. Med Pregl 2006;59(3-4);179-82.

(4.) Fuhraman SA, Gill R, Horowitz CA. Marked hyperbilirubinemia in infectious mononucleosis. Analysis of laboratory data in seven patients. Arch Intern Med 1987;147:850-3

(5.) Finkel M, Parker GW, Fanselau HA. The hepatitis of infectious mononucleosis: experience with 235 cases. Mil Med 1964;129:533-38

(6.) Papatheodoridis GV, Delladetsima JK, Kavallierou L, Kapranos N, Tassopoulos NC. Fulminant hepatitis due to Epstein Barr infection. J Hepatol 1995;23:348-50.

(7.) Tompson, M, Kurzrock R. Epstein Barr virus and cancer. Clinic Cancer Res 2004;10:803-21.

(8.) Rosalski SB, Jones TG, Verney AF. Transaminase and liver function studies in infectious mononucleosis. Br Med J 1960;1:929-32.

(9.) Horwitz CA, Burke MD, Grimes P, Tombers J. Hepatic function in mononucleosis induced by Epstein Barr virus and cytomegalovirus. Clin Chem 1980;26:243-46

(10.) White NJ and Juel-Jensen BE. Infectious mononucleosis hepatits. Semin Liver Dis 1984;4:301-06

(11.) Tsuchiya S. Diagnosis of Epstein Barr associated diseases. Crit Rev Oncol Hematol 2002;44:227-38

(12.) Tandon BN, Acharya SK. Viral diseases involving the liver. Baillieres Clin Gastroenterol 1987;1:211-30

(13.) Kimura H, Nagasaka T, Hoshino Y, Hayashi N, Tanaka N, Xu JL, et al. Severe hepatitis caused by Epstein Barr virus without infection of hepatocytes. Hum Pathol 2001;32:757-62

(14.) Gilmour KC, Gaspar HB. Pathogenesis and diagnosis of X-linked ly,phoproliferative disease. Expert Rev Mol Diagn 2003;3:549-61

(15.) Popper H. The pathology of viral hepatitis. CMAJ 1972;106(Suppl):447-52

(16.) Juttner HU, Rails PW, Quinn MF, Jenney JM. Thickening of the gallbladder wall in acute hepatitis: ultrasound demonstration. Radiology 1982;142:465-66

(17.) Deaton JG, Skaggs H Jr, Levin WC. Acute hemolytic anemia complicating infectious mononucleosis: The mechanism of hemolysis. Tex Rep Biol Med 1967;25:309-17

(18.) Suh N, Liapis H, Misdraji J, Brunt EM, Wang HL.Epstein Barr virus hepatitis: Diagnostic value of in situ hybridization, Polymerase chain reaction and immunohistochemistry on liver biopsy from immunocompetent patients. Am J Surg Pathol 2007;31(9):1403-1408

(19.) Drebber U, Kasper HU, Krupacz J, Haferkamp K, Kern MA, Steffen HM, et al. The role of Epstein Barr virus in acute and chronic hepatitis. J Hepatology 2006;44:879-885

(20.) Gray J.J., Caldwell J, Sills M. The rapid serological diagnosis of infectious mononucleosis. J Infect 1992;25:39-46

Corresponding author:

Haris Papafragkakis,

Advocate Illinois Masonic Medical Center, Chicago IL, 836 W Wellington Avenue

Department of Internal Medicine

Chicago Illinois, 60657

Tel: Internal Medicine Office 773-296-7635

Cell: 773-329-7785

Fax: 773-296-7486
Table 1. Trend of laboratory values during patient's hospitalization

Day                       1      2     3      4     5     6

SGOT (units/L)            653    483   407    380   265   227
SGPT (units/L)            1134   917   773    806   611   530
Total Bilirubin (mg/dL)   3.8    3.4   3.5    4.0   3.4   3.0
Direct Bilirubin(mg/dL)          2.7          3.2         2.4
Albumin (g/dL)            4.1    3.5   3.1    3.4   3.1   3.1
WBC (K/mcL)               10.6         13.2               12.6
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