Epstein Barr virus hepatitis: case series and review.Abstract: Epstein Barr virus (EBV EBV Epstein-Barr virus.
Epstein-Barr virus (EBV)
A virus in the herpes family that causes mononucleosis. ) infection causes asymptomatic liver-associated enzyme abnormalities in 80 to 90% of cases which are often unrecognized. Patients with acute EBV infections may also develop cholestatic hepatitis with associated jaundice and hepatitis with moderate elevations in the transaminase transaminase /trans·am·i·nase/ (-am´i-nas) aminotransferase.
See aminotransferase. levels. Other gastrointestinal complications associated with EBV may include splenic splenic /splen·ic/ (splen´ik) pertaining to the spleen.
Of, in, near, or relating to the spleen.
pertaining to the spleen. rupture, liver failure due to acute and/or chronic EBV infection, and perhaps, autoimmune hepatitis and hepatocellular carcinoma. This article presents a case series of EBV infections with clinically significant hepatitis and reviews the literature on the gastrointestinal complications of EBV.
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 ful·mi·nant
Occurring suddenly, rapidly, and with great severity or intensity, usually of pain.
ful 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 (AST Computer, Irvine, CA) A PC manufacturer founded in 1980 by Albert Wong, Safi Quershey and Tom Yuen (A, S and T). It offered a complete line of PCs that sold through its dealer channel. ) 246 U/L (normal 15-41 U/L), lactic dehydrogenase (LDH LDH -lactate dehydrogenase.
lactic acid dehydrogenase; see lactate dehydrogenase. ) 412 U/L (normal, 99-192 U/L), prothrombin time of 12.3 seconds, and an INR INR
In currencies, this is the abbreviation for the Indian Rupee.
The currency market, also known as the Foreign Exchange market, is the largest financial market in the world, with a daily average volume of over US $1 trillion. of 1.2. The patient was instructed to discontinue use of acetaminophen and was empirically treated with ciprofloxacin, loperamide loperamide /lo·per·amide/ (lo-per´ah-mid) an antiperistaltic used as the hydrochloride salt as an antidiarrheal and to reduce the volume of discharge from ileostomies. , and promethazine promethazine /pro·meth·a·zine/ (-meth´ah-zen) a phenothiazine derivative, used in the form of the hydrochloride salt as an antihistaminic, antiemetic, antivertigo agent, and sedative, and in the prevention and treatment of motion .
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 hepatomegaly /hep·a·to·meg·a·ly/ (hep?ah-to-meg´ah-le) enlargement of the liver.
The abnormal enlargement of the liver. Also called megalohepatia. . 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 human immunodeficiency virus
Human immunodeficiency virus (HIV)
A transmissible retrovirus that causes AIDS in humans. (HIV HIV (Human Immunodeficiency Virus), either of two closely related retroviruses that invade T-helper lymphocytes and are responsible for AIDS. There are two types of HIV: HIV-1 and HIV-2. HIV-1 is responsible for the vast majority of AIDS in the United States. ) 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 epigastric adjective Referring to the body region between the costal margins and the subcostal plane abdominal pain and nausea. The patient had a low-grade fever of 100.7[degrees]F; examination findings included hepatosplenomegaly, icterus icterus /ic·ter·us/ (ik´ter-us) [L.] jaundice.icter´ic
icterus neonato´rum jaundice in newborn children.
See jaundice. , 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 right upper quadrant Physical exam The abdominal region that contains the liver, duodenum and head of pancreas revealed hepatomegaly (20 cm) with adenopathy in the porta hepatis and splenomegaly splenomegaly /sple·no·meg·a·ly/ (-meg´ah-le) enlargement of the spleen.
congestive splenomegaly Banti's disease; splenomegaly secondary to portal hypertension. . The gallbladder appeared small and contracted, but with normal wall thickness; there was no intrahepatic or extrahepatic ex·tra·he·pat·ic
Originating or occurring outside the liver. 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 crepitus /crep·i·tus/ (krep´i-tus)
1. the discharge of flatus from the bowels.
3. crepitant rale.
1. Crepitation. 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 respiratory syncytial virus (sĭnsĭsh`əl): see cold, common. (RSV RSV respiratory syncytial virus; Rous sarcoma virus.
respiratory syncytial virus
RSV 1 Respiratory syncytial virus, see there 2 Rous sarcoma virus, see there ), adenovirus, influenza and parainfluenza viruses.
The fevers continued and the patient developed pancytopenia pancytopenia /pan·cy·to·pe·nia/ (-sit-ah-pe´ne-ah) abnormal depression of all the cellular elements of the blood.
n. 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 HIV viral load AIDS A measure of the amount of HIV RNA in blood, expressed as number of copies/mL of plasma. See AIDS, HIV. , 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 hemolysis (hĭmŏl`ĭsĭs), destruction of red blood cells in the bloodstream. Although new red blood cells, or erythrocytes, are continuously created and old ones destroyed, an excessive rate of destruction sometimes occurs. . (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 monocytes,
n.pl the largest of the white blood cells. They have one nucleus and a large amount of grayish-blue cytoplasm. Develop into macrophages and both consume foreign material and alert T cells to its presence. in the periportal areas. Mononuclear cells within the sinusoid sinusoid /si·nus·oid/ (si´nu-soid)
1. resembling a sinus.
2. a form of terminal blood channel consisting of a large, irregular anastomosing vessel having a lining of reticuloendothelium and found in the liver, 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 left upper quadrant Physical exam The region of the body containing the stomach, spleen and tail of pancreas , which may radiate to the left scapula scapula /scap·u·la/ (skap´u-lah) pl. scap´ulae [L.] shoulder blade; the flat, triangular bone in the back of the shoulder. scap´ular
n. pl. , and falling hemoglobin are suggestive of splenic rupture; in such cases, an emergent splenectomy Splenectomy Definition
Splenectomy is the surgical removal of the spleen, which is an organ that is part of the lymphatic system. The spleen is a dark-purple, bean-shaped organ located in the upper left side of the abdomen, just behind the bottom of the 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 im·mu·no·com·pe·tent
Having the normal bodily capacity to develop an immune response following exposure to an antigen.
im 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 endocarditis (ĕn'dōkärdī`tĭs), bacterial or fungal infection of the endocardium (inner lining of the heart) that can be either acute or subacute. , 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 varicella: see chicken pox. zoster virus, herpes simplex virus Herpes simplex virus
A virus that can cause fever and blistering on the skin, mucous membranes, or genitalia.
Mentioned in: Conjunctivitis
herpes simplex virus , hepatitis A, B, and C, and HIV. Leptospirosis leptospirosis (lĕp'təspīrō`sĭs), febrile disease caused by bacteria of the genus Leptospirae. The disease occurs in dogs, cattle, pigs, sheep, goats, and horses and is transmissible to humans. , syphilis, brucellosis brucellosis (br'səlō`sĭs) or Bang's disease, infectious disease of farm animals that is sometimes transmitted to humans. , drug-induced, autoimmune, ischemic Ischemic
An inadequate supply of blood to a part of the body, caused by partial or total blockage of an artery.
Mentioned in: Antiangiogenic Therapy, Subarachnoid Hemorrhage, Ventricular Fibrillation
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 ran·dom·ize
tr.v. ran·dom·ized, ran·dom·iz·ing, ran·dom·iz·es
To make random in arrangement, especially in order to control the variables in an experiment. 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.
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Liver function tests, or LFTs, include tests for bilirubin, a breakdown product of hemoglobin, and ammonia, a protein byproduct that is normally converted into urea by the liver before being excreted by the kidneys. , and treatment of selected cases with prednisone. Am J Med Sci 1958;236:447-459.
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in full ribonucleic acid
One of the two main types of nucleic acid (the other being DNA), which functions in cellular protein synthesis in all living cells and replaces DNA as the carrier of genetic (by the EBER-I gene) in liver specimens from transplant recipients with post-transplantation lymphoproliferative disease. N Engl J Med 1992;327:1710-1714.
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or deoxyribonucleic acid
One of two types of nucleic acid (the other is RNA); a complex organic compound found in all living cells and many viruses. It is the chemical substance of genes. in a liver biopsy. Br J Haematol 1990;76:557-558.
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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.