Epstein Barr virus hepatitis: case series and review.
Key Words: Epstein Barr virus, EBV, hepatitis, liver dysfunction
Epstein Barr virus (EBV) infection often causes a triad of fever, sore throat, and adenopathy, referred to as infectious mononucleosis. Gastrointestinal manifestations are frequently present, but often unrecognized. These include mild elevations in transaminases (two to three times the upper limit of normal), abdominal pain, and hepatosplenomegaly. Less commonly, jaundice ([less than or equal to] 5% of cases) and hepatitis with moderate levels of transaminase elevation (5 to 10 times) may occur. Rarely, death may ensue from fulminant liver failure or splenic rupture. I report a case series of acute EBV infections among military trainees who presented with significant hepatic involvement, along with a review of the literature.
A 19-year-old Caucasian male presented with a 10-day history of fever of 102[degrees]F, fatigue, nausea, vomiting, and diarrhea. He had no significant medical or surgical history. The patient was found to have a total bilirubin of 3.0 mg/dL (normal, 0.4-2.0 mg/dL), direct bilirubin 1.9 mg/dL, albumin 3.5 g/dL (normal 3.5-4.8 g/dL), alkaline phosphatase 309 U/L (normal 38-126 U/L), alanine aminotransferase (ALT) 276 U/L (normal, 17-63 U/L), aspartate aminotransferase (AST) 246 U/L (normal 15-41 U/L), lactic dehydrogenase (LDH) 412 U/L (normal, 99-192 U/L), prothrombin time of 12.3 seconds, and an INR of 1.2. The patient was instructed to discontinue use of acetaminophen and was empirically treated with ciprofloxacin, loperamide, and promethazine.
On follow-up, the patient reported vomiting as well as pale-colored stools. His vital signs were normal. Remarkable physical examination findings included scleral icterus, jaundice, and hepatomegaly. Laboratory values showed a white blood count of 14,800/[mm.sup.3], with 78% atypical lymphocytes, a total bilirubin of 6.1 mg/dL (direct 3.8 mg/dL), and an alkaline phosphatase of 496 IU/L; transaminase levels were falling. Ultrasound revealed hepatomegaly (17 cm) with diffuse hyperecho-genicity of the portal triads of the liver, consistent with periportal edema/infiltration. There was no ascites or ductal dilation, and the gallbladder was normal. Hepatitis serologies (A, B, and C) as well as human immunodeficiency virus (HIV) and cytomegalovirus (CMV) antibody tests were negative. EBV IgM was elevated with a positive monospot test. The patient's symptoms and abnormal laboratory values resolved without intervention over three weeks.
A 21-year-old male without a significant past medical or surgical history presented with two weeks of headaches, fatigue, sore throat, and fever. He was initially diagnosed with sinusitis, but returned to clinic after the onset of epigastric abdominal pain and nausea. The patient had a low-grade fever of 100.7[degrees]F; examination findings included hepatosplenomegaly, icterus, and jaundice. Laboratory values showed a white blood count of 11,400, with 42% atypical lymphocytes, hemoglobin 13.7 g/dL, platelets 140,000, total bilirubin mg/dL of 6.0 (direct 4.1 mg/dL), albumin 4.2 g/dL, alkaline phosphatase 369 U/L, ALT 400 U/L, AST 294 U/L, LDH 1,010 U/L, ammonia level of 37 [micro]mol/L, prothrombin time 13.5, and an INR of 1.3.
Ultrasound of the right upper quadrant revealed hepatomegaly (20 cm) with adenopathy in the porta hepatis and splenomegaly. The gallbladder appeared small and contracted, but with normal wall thickness; there was no intrahepatic or extrahepatic ductal dilation. A monospot was positive. The patient was admitted for IV hydration; he had complete resolution of his symptoms and laboratory abnormalities within three weeks.
An 18-year-old male presented with fevers, chest pain, cough, dyspnea, nausea, and vomiting. On examination, he had a temperature of 100.7[degrees]F, bilateral respiratory rales, and crepitus of the upper chest. His white blood count was 6,300/[mm.sup.3], with 89% neutrophils, hemoglobin of 13.9 g/dL, platelets 219,000/[mm.sup.3], total bilirubin 0.8 mg/dL, albumin 2.1 g/dL, alkaline phosphatase 57 U/L, ALT 73 U/L, AST 123 U/L, LDH 485 U/L, prothrombin time 17.1, and an INR of 1.4. Chest x-ray revealed multilobar consolidations and pneumomediastinum. He was diagnosed with a community-acquired pneumonia and treated with ceftriaxone and azithromycin. A workup of the etiology of the pneumonia was negative, including respiratory and blood cultures; serologies for Chlamydia pneumoniae and Mycoplasma pneumoniae; ASO titer; and nasopharyngeal swabs for respiratory syncytial virus (RSV), adenovirus, influenza and parainfluenza viruses.
The fevers continued and the patient developed pancytopenia on hospital day #2, with a white blood count of 1,300/[mm.sup.3], hemoglobin 13 g/dL, and platelets 111,000/[mm.sup.3]. Peripheral smear showed no schistocytes. His laboratory studies worsened on day #5, with an albumin of 1.7 g/dL, ALT 441 U/L, AST 847 U/L, LDH 1,134 U/L, and alkaline phosphatase of 126 U/L. Due to these findings, gastroenterology was consulted and additional blood tests were performed including a hepatitis panel for A, B, and C and an HIV viral load, all of which were negative. A monospot and EBV IgM were positive. Ultrasound showed mild splenomegaly without liver or biliary pathology. The patient was diagnosed with acute hepatitis and pancytopenia attributed to EBV and a multilobar pneumonia of uncertain etiology. He was discharged on day #10 with clinical and laboratory improvement.
Epstein-Barr virus infections were first clinically described over a century ago, and the causative agent was described nearly 40 years ago. (1,2) Most EBV infections are asymptomatic and acquired in childhood, with a seropositivity rate of 90 to 95% by age 18. Symptomatic disease typically occurs among adolescents or adults who were not exposed during childhood; it occurs more frequently in developed countries where transmission rates during childhood are lower compared with the developing world. Among military personnel, infection is symptomatic in approximately 10% of cases; the frequency of symptomatic disease among other adult populations is usually higher. (3,4)
The most common presentation of EBV is the constellation of fever, sore throat, and adenopathy, referred to as infectious mononucleosis. Abdominal discomfort and nausea are noted in 2 to 15% of cases. (4-6) Mild hepatic involvement is particularly common, occurring in 80 to 90% of cases as an asymptomatic, self-limited elevation of the hepatocellular enzymes (AST, ALT, and/or LDH). Typically enzymes are two to three times the upper limit of normal; levels elevated greater than 10 times are less likely due to EBV and an alternate etiology should be sought. (7) Alkaline phosphatase is increased in 60% of cases. Bilirubin is mildly increased in 45% of cases, but jaundice is rare ([less than or equal to]5% of cases). Two of the cases presented here had jaundice; cholestatic hepatitis from EBV has recently been reviewed, although the mechanism remains obscure as there is no biliary obstruction noted on imaging studies. (8,9) Liver function abnormalities occur most often during the 2nd week of illness, and resolve within two to six weeks. (7)
On examination, 50 to 60% of patients have splenomegaly, and 6 to 14% have hepatomegaly. (10) Jaundice may be due to either cholestatic hepatitis or hemolytic anemia. Any patient presenting with jaundice should have a complete blood count and peripheral smear evaluation, especially if the indirect bilirubin is high, to exclude hemolysis. (11) Abdominal ultrasound evaluations may show an enlarged liver and/or spleen as well as adenopathy in the porta hepatis or periportal edema. Rarely, gallbladder thickening and ascites have been reported. (12,13)
Histologic findings of EBV-associated hepatitis include minimal swelling and vacuolization of the hepatocytes, as well as infiltration with lymphocytes and monocytes in the periportal areas. Mononuclear cells within the sinusoid areas in an "Indian Bead" pattern have also been described with EBV infections. (14) Bile ducts may be mildly swollen, but obstruction is rare. (15) An evaluation of a case of EBV-associated hepatitis showed that the virus did not infect hepatocytes, but rather, infiltration of CD8 T-cells led to indirect hepatic damage. (16) Although another study did demonstrate the presence of EBV within hepatocytes, (17) the host's B- and T-cells remain implicated as the predominant cause of hepatitis. The immune response may explain the periportal inflammation and adenopathy seen in some of the presented cases.
Severe liver injury is rare; however, when it occurs, it is a leading cause of death among patients with acute EBV infection. (18,19) Most fulminant cases occur post-transplantation or are associated with immunodeficiencies such as HIV, X-linked lymphoproliferative disease, or during cancer chemotherapy. (16,20,21) Other potential abdominal complications associated with acute EBV infection include splenic rupture after rapid enlargement (usually occurring during the 2nd or 3rd week of illness). Pain in the left upper quadrant, which may radiate to the left scapula, and falling hemoglobin are suggestive of splenic rupture; in such cases, an emergent splenectomy is necessary. EBV may also cause lymphoproliferative disorders and lymphoma that may involve the liver and spleen (22); it has been suggested as a trigger for autoimmune hepatitis, although conclusive data is lacking. (23,24)
EBV may rarely cause chronic or recurrent infections lasting over a long period of time (>6 mo) in apparently immunocompetent hosts and is referred to as chronic active Epstein-Barr virus (CAEBV). (25,26) Some patients with CAEBV develop severe, and sometimes fatal, liver disease. (25-27) Recently, chronic EBV infections have been linked to the development of hepatocellular carcinoma (HCC) among Asian patients; its association with HCC in other populations remains debated. (28,29)
The diagnosis of EBV hepatitis is suggested by the appropriate clinical symptoms and laboratory findings and confirmed by a positive EBV IgM antibody, monospot, and/or heterophile antibody test. False-positive monospot tests may occur in association with HIV, endocarditis, and acute hepatitis A. (30) Occasionally, serologic tests are unremarkable, and the diagnosis must be established by the use of polymerase reaction testing. (25) Given overlapping clinical presentations, other potential viral etiologies of hepatitis are typically considered, including CMV, varicella zoster virus, herpes simplex virus, hepatitis A, B, and C, and HIV. Leptospirosis, syphilis, brucellosis, drug-induced, autoimmune, ischemic, Wilson disease, and Q-fever are considered in the appropriate clinical setting.
Treatment of EBV is usually supportive, and most cases of hepatitis resolve spontaneously. Steroids and antiviral medications (eg, acyclovir, ganciclovir) have been utilized to treat cases of severe EBV hepatitis, (25,27) but randomized studies have not been performed. Liver transplantation has been utilized in one case of fulminant EBV hepatitis. (19) It is recommended that patients avoid abdominal trauma in the presence of splenomegaly and refrain from hepatotoxins until liver abnormalities resolve.
Mild EBV-induced hepatitis is a common finding during infectious mononucleosis and usually is asymptomatic. This case series shows that more significant liver involvement may occur including jaundice, moderate transaminase elevations, and periportal inflammation and adenopathy on ultrasound examinations. EBV should be included in the differential of patients presenting with liver abnormalities, especially in the setting of fever and pharyngitis.
1. Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt's lymphoma. Lancet 1964;15:702-703.
2. Henle G, Henle W, Diehl V. Relation of Burkitt's tumor-associated herpes-type virus to infectious mononucleosis. Proc Natl Acad Sci USA 1968;59:94-101.
3. Lehane DE. A seroepidemiologic study of infectious mononucleosis: the development of EB virus antibody in a military population. JAMA 1970;212:2240-2242.
4. Johannsen EC, Schooley RT, Kaye KM. Epstein-Barr virus (infectious mononucleosis). In: Principles and Practices of Infectious Diseases. 6th ed. 2005, p 1801-1820.
5. Mason WR Jr, Adams EK. Infectious mononucleosis: an analysis of 100 cases with particular attention to diagnosis, liver function tests, and treatment of selected cases with prednisone. Am J Med Sci 1958;236:447-459.
6. Hoagland RJ. Infectious mononucleosis. Am J Med 1952;13:158-171.
7. Finkel M, Parker GW, Fanselau HA. The hepatitis of infectious mononucleosis: experience with 235 cases. Mil Med 1964;129:533-538.
8. Hinedi TB, Koff RS. Cholestatic hepatitis induced by Epstein-Barr Virus infection in an adult. Dig Dis Sci 2003;48:539-541.
9. Edoute Y, Baruch Y, Lachter J, et al. Severe cholestatic jaundice induced by Epstein-Barr virus infection in the elderly. J Gastroenterol Hepatol 1998;13:821-824.
10. White NJ, Juel-Jensen BE. Infectious mononucleosis hepatitis. Semin Liver Dis 1984;4:301-306.
11. Whitelaw F. Brook MG, Kennedy N, et al. Haemolytic anaemia complicating Epstein-Barr virus infection. Br J Clin Pract 1995;49:212-213.
12. Sainsbury R, Smith PK, LeQuesne G, et al. Gallbladder wall thickening with infectious mononucleosis hepatitis in an immunosuppressed adolescent. J Pediatr Gastroenterol Nutr 1994;19:123-125.
13. Devereaux CE, Bemiller T, Brann O. Ascites and severe hepatitis complicating Epstein-Barr infection. Am J Gastroenterol 1999;94:236-240.
14. Tandon BN, Acharya SK. Viral diseases involving the liver. Baillieres Clin Gastroenterol 1987; 1:211-230.
15. Nelson RS, Darragh JH. Infectious mononucleosis hepatitis: a clinicopathologic study. Am J Med 1956;21:26-33.
16. Kimura H, Nagasaka T, Hoshino Y, et al. Severe hepatitis caused by Epstein-Barr virus without infection of hepatocytes. Hum Pathol 2001; 32:757-762.
17. Randhawa PS, Jaffe R, Demetries AJ, et al. Expression of Epstein-Barr virus-encoded small RNA (by the EBER-I gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease. N Engl J Med 1992;327:1710-1714.
18. Papatheodoridis GV, Delladetsima JK, Kavallierou L, et al. Fulminant hepatitis due Epstein-Barr virus infection. J Hepatol 1995;23:348-350.
19. Feranchak AP, Tyson RW, Narkewicz MR, et al. Fulminant Epstein-Barr viral hepatitis: orthotopic liver transplantation and review of the literature. Liver Transpl Surg 1998;4:469-476.
20. Donhuijsen-Ant R, Abken H, Westerhausen M, et al. Aggressive hepatitis in a patient with acute myeloid leukaemia during complete remission and detection of Epstein-Barr virus DNA in a liver biopsy. Br J Haematol 1990;76:557-558.
21. Penman HG. Fatal infectious mononucleosis: a critical review. J Clin Pathol 1970;23:765-771.
22. Markin RS. Manifestations of Epstein-Barr virus-associated disorders in liver. Liver 1994;14:1-13.
23. Vento S, Guella L, Mirandola F, et al. Epstein-Barr virus as a trigger for autoimmune hepatitis in susceptible individuals. Lancet 1995;346:608-609.
24. Vento S, Cainelli F. Is there a role for viruses in triggering autoimmune hepatitis? Autoimmun Rev 2004;3:61-69.
25. Yuge A, Kinoshita E, Moriuchi M, et al. Persistent hepatitis associated with chronic active Epstein-Barr virus infection. Pediatr Infect Dis J 2004;23:74-76.
26. Kimura H, Hoshino Y, Kanegane H, et al. Clinical and virologic characteristics of chronic active Epstein-Barr virus infection. Blood 2001; 98:280-286.
27. Chiba T, Goto S, Yokosuka O, et al. Fatal chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis. Eur J Gastroenterol Hepatol 2004;16:225-228.
28. Chu PG, Chen YY, Chen W, et al. No direct role for Epstein-Barr virus in American hepatocellular carcinoma. Am J Pathol 2001; 159:1287-1292.
29. Li W, Wu BA, Zeng YM, et al. Epstein-Barr virus in hepatocellular carcinogenesis. World J Gastroenterol 2004;10:3409-3413.
30. Gray JJ, Caldwell J, Sillis M. The rapid serological diagnosis of infectious mononucleosis. J Infect 1992;25:39-46.
When you are content to be simply yourself and don't compare or compete, everybody will respect you. --Lao-Tzu
Nancy F. Crum, MD, MPH
From the Department of Internal Medicine, Infectious Diseases Division, Naval Medical Center San Diego, San Diego, CA.
Reprint requests to Dr. Nancy F. Crum, c/o Clinical Investigation Department (KCA), Naval Medical Center San Diego, 34800 Bob Wilson Drive, Suite 5, San Diego, CA 92134-1005. Email: NFCrum@nmcsd.med.navy.mil
The views expressed in this article are those of the author and do not reflect the official policy or position of the Department of the Navy, Department of Defense, or the United States Government.
Accepted January 26, 2006.
RELATED ARTICLE: Key Points
* Epstein Barr virus infections are commonly associated with asymptomatic, mildly elevated transaminase levels.
* Gastrointestinal manifestations of EBV infections may also include clinically significant hepatitis, jaundice, splenic rupture, and liver failure.
* Chronic EBV infections may play a role in the development of autoimmune hepatitis and hepatocellular carcinoma, but further data are needed.
* Patients with elevated liver function tests in the setting of symptoms such as fever, sore throat, and adenopathy should be evaluated for EBV.