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Epstein-Barr viral hepatitis.
Last reviewed: 05.07.2025
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Epstein-Barr viral hepatitis is a term that does not imply the involvement of the liver in the pathological process in general, as, for example, in infectious mononucleosis, but an independent form of Epstein-Barr viral infection, in which liver damage occurs in isolation and is not accompanied by the clinical picture of infectious mononucleosis.
This form of Epstein-Barr virus infection occurs when the Epstein-Barr virus has a tropism not for the biliary tract epithelium, but directly for hepatocytes. Despite the fact that up to 90% of the population is infected with the Epstein-Barr virus, Epstein-Barr viral hepatitis continues to be considered a rare manifestation of the infection.
Epidemiology of Epstein-Barr Viral Hepatitis
The Epstein-Barr virus is widespread among the human population, affecting 80-100% of the world's population. The first encounter with the virus depends on social conditions. In developing countries and socially disadvantaged families, most children are infected by the age of 3, and the entire population - by adulthood. In developed countries and socially advantaged families, the encounter with the Epstein-Barr virus may not occur until adolescence.
The source of infection is sick people and virus excretors. The main route of transmission of the pathogen is airborne, often infection occurs through infected saliva. Blood transfusion and sexual transmission of the Epstein-Barr virus are possible. Cases of vertical transmission of this virus from mother to fetus have been described and it has been suggested that the Epstein-Barr virus causes congenital anomalies.
In Epstein-Barr viral hepatitis, the predominant routes of infection are apparently parenteral and perinatal, when the pathogen enters the blood directly, bypassing the patient's lymphoid apparatus.
What causes Epstein-Barr viral hepatitis?
The Epstein-Barr virus was first cultivated in 1964-1965 by English scientists E. Epstein and I. Barr, after whom it was named. The Epstein-Barr virus belongs to the Herpesviridae family, contains DNA, and has spherical particles with a diameter of 180 nm. The virus is sensitive to ether, and reproduces well in a culture of Burkitt's lymphoma cells, blood of patients with infectious mononucleosis, leukemic cells, and in a culture of brain cells from a healthy person.
The Epstein-Barr virus contains the following antigens: viral capsid antigen (VCA), nuclear antigen (EBMA), early antigen (EA), and membrane antigen (MA). The time of appearance and biological significance of these antigens are not the same. The viral capsid antigen is late. The membrane antigen is a complex of early and late gene products. The nuclear antigen is early because during the lytic phase of infection it precedes the synthesis of viral particles. Detection of antibodies to the nuclear and early surface antigens in the absence of antibodies to late antigens indicates an acute infection. Detection of antibodies to the capsid antigen and late membrane antigen in the absence of antibodies to early antigens serves as a marker of a long-standing infection - latent infection.
There are no disease- or location-specific subtypes of Epstein-Barr virus. Comparisons have shown minimal differences among Epstein-Barr virus strains isolated from certain geographic areas and from different patients.
Pathogenesis of Epstein-Barr viral hepatitis
The pathogenetic mechanism causing hepatocyte destruction and cholestasis development in EBV infection is not fully understood. There are suggestions that the Epstein-Barr virus does not have a direct cytopathic effect, but the destruction of these cells is caused by the toxic effect of free radicals involved in lipid peroxidation. Patients with Epstein-Barr virus infection have autoantibodies to the enzyme superoxide dismutase, neutralizing its antioxidant effect. As a result, free radicals accumulate in hepatocytes and cause their damage.
High concentrations of autoantibodies against superoxide dismutase are found in patients with acute Epstein-Barr viral hepatitis. It has been established that the above-mentioned autoantibodies in vitro reduce the antioxidant capacity of superoxide dismutase by more than 70%, which leads to cytolysis in cell culture due to activation of lipid peroxidation processes. Recovery and normalization of the functional state of the liver in patients with Epstein-Barr viral hepatitis are accompanied by a sharp decrease in the level of antibodies to superoxide dismutase.
In addition, the mechanism of antibody-dependent cellular cytolysis of cells affected by the Epstein-Barr virus, developing under the influence of T-suppressors and natural killers, is described. In icteric forms of acute Epstein-Barr viral hepatitis, EBV DNA is detected mainly in CD3, CD4, and CD8 lymphocytes, whereas in infectious mononucleosis in patients without jaundice, B-lymphocytes of the peripheral blood are mainly infected, indicating the possible participation of T-lymphocytes in the development of severe forms of acute Epstein-Barr viral hepatitis. However, there are also indications that in severe icteric forms of Epstein-Barr viral hepatitis, it is the T-cells of the infiltrate that are infected with the Epstein-Barr virus, not the hepatocytes.
In the formation of isolated damage to hepatocytes in Epstein-Barr viral hepatitis, an important role can be played by direct entry of the pathogen into the blood during parenteral infection. Thus, the question of possible mechanisms of damage to hepatocytes by the Epstein-Barr virus requires further study.
Pathomorphology
Histopathological changes in Epstein-Barr viral hepatitis have not been adequately studied.
In acute Epstein-Barr viral hepatitis, morphological changes in liver tissue are typical for acute hepatitis of other etiologies and may be accompanied by cholangitis and endotheliitis. In this case, the etiology of the disease is confirmed not only by the detection of the Epstein-Barr virus capsid antigen IgM and IgG, EBV DNA in the blood serum, but also by the detection of EBV DNA in hepatocytes using PCR and Epstein-Barr virus antigens (in particular, the latent membrane protein LMP) by immunohistochemical methods.
In the liver along the portal tracts, less often - inside the lobules, there is lymphoid-cell infiltration, hyperplasia of the reticuloendothelial stroma, but without disruption of the lobular structure of the liver. In cases accompanied by jaundice, the formation of bile thrombi, deposition of bile pigment in hepatocytes of the central zones of the lobules, edema, dystrophy of hepatocytes and disseminated necrosis of hepatocyte groups are noted.
A variant of Epstein-Barr virus infection is acute cholestatic hepatitis with acute cholecystitis in school-age children and adults. Morphological changes include necrosis of the liver parenchyma and lymphocytic infiltration.
Morphological changes in chronic Epstein-Barr viral hepatitis are also not fundamentally different from those in viral hepatitis of other etiologies. At the same time, immunocompetent patients are diagnosed with a lower degree of histological activity compared to immunocompromised people. Chronic Epstein-Barr viral hepatitis in children is characterized by mononuclear infiltration and moderate proliferation of connective tissue in the liver. In some cases, the cellular composition of the infiltrate in Epstein-Barr viral hepatitis is represented mainly by CD3 and CD8 lymphocytes.
In Epstein-Barr virus infection of the liver transplant, EBV DNA is detected in hepatocytes using PCR and Epstein-Barr virus antigens are detected using the immunohistochemical method, including the gp220 apside protein. These patients develop Epstein-Barr viral hepatitis, accompanied by lymphohistiocytic and immunoblastic infiltration. In this case, the greatest histopathological activity of the process in the liver is detected in biopsies with maximum concentrations of EBV DNA, which further confirms the etiological role of the Epstein-Barr virus in the development of hepatitis.
Symptoms of Epstein-Barr Viral Hepatitis
Epstein-Barr viral hepatitis can have both acute and chronic course.
Acute Epstein-Barr viral hepatitis
There is reason to believe that liver damage develops in 80-90% of patients with Epstein-Barr virus infection. However, increased activity of hepatocellular enzymes often remains undiagnosed.
Acute Epstein-Barr viral hepatitis can occur in anicteric, mild, moderate, and in isolated cases, severe and even fulminant forms.
The incubation period for Epstein-Barr viral hepatitis has not been precisely established. It is believed to be 1-2 months.
Preicteric period. The disease begins gradually in most cases. During this period of the disease, patients experience decreased appetite, weakness, headache, and abdominal pain. In rare cases, body temperature rises to 38 C. No patient has lesions of the oropharynx, enlarged lymph nodes, or atypical mononuclear cells in the peripheral blood.
The duration of the pre-icteric period of acquired initial manifest Epstein-Barr viral hepatitis is 3-5 days in mild form and 4-7 days in moderate form.
Jaundice period. In patients after the onset of jaundice, the symptoms of intoxication persist and even increase. In some patients, clinical manifestations of the pre-jaundice period are absent. The manifest initial form of Epstein-Barr viral hepatitis in these patients debuts with the onset of jaundice.
Thus, clinical symptoms and laboratory parameters in acute viral hepatitis Epsom-Barr in children are not fundamentally different from those in viral hepatitis B, C, etc. Patients do not exhibit symptoms characteristic of infectious mononucleosis.
The duration of the icteric period is 15-22 days in the mild form and 17-26 days in the moderate form.
The post-icteric period is characterized by normalization of the patient's well-being, a decrease in the size of the liver and spleen, and a significant decrease in enzyme activity.
Outcomes of acute Epstein-Barr viral hepatitis. The course of the disease can be acute (35% of cases) and end in recovery with complete restoration of the functional state of the liver in a period of 1 to 3 months. In 65% of patients, in the outcome of manifest Epstein-Barr viral hepatitis, the disease takes a chronic course
Chronic Epstein-Barr viral hepatitis
Chronic Epstein-Barr viral hepatitis can develop as a primary chronic process or as a result of initial manifest Epstein-Barr viral hepatitis. In this case, the patients do not have a history of infectious mononucleosis.
In patients, minimal activity of the process predominates (about 70%), 20-25% of patients are diagnosed with low activity and 6-10% with moderate activity of the process in the liver.
In 3/4 of patients, mild liver fibrosis is diagnosed, in 12-15%, moderate liver fibrosis. Approximately 10% of patients have no liver fibrosis. Signs of severe liver fibrosis and cirrhosis are detected only in isolated patients with acquired chronic Epstein-Barr viral hepatitis.
Clinical manifestations and laboratory parameters during the exacerbation period of acquired chronic Epstein-Barr viral hepatitis do not have fundamental differences from those in children with viral hepatitis of other etiologies.
During the remission period, intoxication symptoms in patients with acquired chronic Epstein-Barr viral hepatitis are practically absent. Extrahepatic manifestations disappear in most patients. The liver and spleen shrink in size, but their full normalization is not observed. No lesions of the oropharynx, enlarged lymph nodes, or atypical mononuclear cells are detected in the peripheral blood. Enzyme activity in the blood serum does not exceed normal values.
Acquired Epstein-Barr viral hepatitis can develop both as a primary chronic process and as a result of the initial manifest infection. Clinical symptoms in this case correspond to those in acute and chronic viral hepatitis of varying severity. In 3/4 of cases, mild liver fibrosis is diagnosed. Lesions of the oropharynx, enlarged lymph nodes, and atypical mononuclear cells in the peripheral blood of patients are not detected.
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Congenital viral hepatitis Epstein-Warr
Congenital Epstein-Barr viral hepatitis almost always has a primary chronic course, in some cases combined with damage to other organs and systems (CNS, biliary tract, etc.).
Among children with congenital chronic Epstein-Barr viral hepatitis, approximately 60% are diagnosed with minimal, 20% with low, 10% with moderate, and 6-8% with severe activity of the process in the liver.
Half of the children have mild liver fibrosis, and 1/4 have moderate liver fibrosis. Signs of severe liver fibrosis and cirrhosis are found in 20% of children with congenital chronic Epstein-Barr viral hepatitis.
Clinical manifestations and laboratory parameters in congenital chronic viral hepatitis Epstein-Barr do not have fundamental differences from those in viral hepatitis B, C, etc.
During the remission period, symptoms of intoxication in children with congenital chronic Epstein-Barr viral hepatitis are practically absent. In most children, extrahepatic manifestations disappear. The liver and spleen sizes decrease, but their full normalization is not observed. In the blood serum, enzyme activity does not exceed normal values. Lesions of the oropharynx, enlarged lymph nodes, and atypical mononuclear cells in the peripheral blood are not detected.
Congenital Epstein-Barr viral hepatitis always develops as a primary chronic process. Liver damage may be combined with other developmental defects. Clinical manifestations of acquired Epstein-Barr viral hepatitis correspond to those of acute and chronic viral hepatitis of varying severity. In 3/4 of cases, mild and moderate liver fibrosis develops.
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Epstein-Barr viral hepatitis in patients undergoing liver transplantation
In patients who have undergone liver transplantation. Epstein-Barr viral hepatitis is observed in approximately 2% of cases, which is confirmed by histological examination and detection of EBV DNA in liver biopsy. Epstein-Barr viral hepatitis develops on average 45 days after liver transplantation. Liver damage can develop in the first 6 months after organ transplantation. The greatest risk of developing Epstein-Barr viral hepatitis is observed in recipients who have received antilymphocyte therapy.
In this case, the Epstein-Barr virus can cause rejection of the infected transplant. In such cases, the diagnosis is confirmed morphologically and by identifying the Epstein-Barr virus genome in hepatocytes. The levels of EBV DNA in such patients do not differ from the viral load in patients with post-transfusion lymphoproliferative syndrome of Epstein-Barr viral etiology, a long-standing and well-studied infectious complication in organ transplantation. Early diagnosis of Epstein-Barr viral hepatitis allows preventing transplant rejection or promptly starting the fight against rejection.
Diagnosis of Epstein-Barr viral hepatitis
Epstein-Barr viral hepatitis is diagnosed based on a combination of clinical, biochemical and serological data. The onset of the disease in the form of asthenodyspeptic symptoms - malaise, weakness, loss of appetite, accompanied by an enlarged liver and hyperfermentemia - allows one to suspect hepatitis, especially if the anamnesis indicates the presence of parenteral manipulations 1-2 months before the current disease and in the absence of markers of viral hepatitis (A, B, C, D, G, TT), etc. in the blood serum. The final diagnosis is established based on the detection of specific antibodies to Epstein-Barr virus antigens of the IgM class in the blood serum, EBV DNA in the blood, saliva, urine.
Cytolysis syndrome is typical for acute and chronic viral hepatitis Epstein-Barr. Determination of aminotransferase activity (ALT, AST) and LDH fractions (LDH-4, LDH-5) is widely used to indicate cytolysis syndrome. Increased activity of liver cell enzymes is typical for acute hepatitis and the exacerbation stage of chronic hepatitis Epstein-Barr of viral etiology. The degree of increase in the activity of liver cell enzymes in various forms of Epstein-Barr viral hepatitis corresponds to that in viral hepatitis of other etiologies.
In the presence of jaundice, it is important to determine the level of total bilirubin and the ratio of its conjugated and unconjugated fractions.
The activity of the inflammatory process in the liver is reflected to a certain extent by the protein spectrum of the blood serum. In most cases, children with chronic Epstein-Barr viral hepatitis have a normal level of total protein in the blood serum (65-80 g/l). In patients with chronic Epstein-Barr viral hepatitis, dysproteinemia is formed due to a decrease in the albumin level and an increase in the γ-globulin fraction. The nature of dysproteinemia is moderate, it reaches significant severity only in some patients, when the albumin level falls below 45%, and the γ-globulin level exceeds 25%.
During exacerbation of chronic Epstein-Barr viral hepatitis, the decrease in the indices of protein-synthetic function of heme is more significant, the more severe the inflammatory process in the liver. Disorders in the blood coagulation system (hypocoagulation) of varying degrees develop in patients with chronic hepatitis mainly due to a reduction in the synthetic function of the liver.
The ultrasound picture in the liver in acute and chronic Epstein-Barr viral hepatitis is no different from that in viral hepatitis of other etiologies.
The Doppler ultrasound method is used to determine blood flow in the portal vein system and the presence of portocaval anastomoses, which allows for the diagnosis of portal hypertension, including in patients with EBV-etiology liver cirrhosis.
Morphological studies allow an objective assessment of the nature of the pathological process in the liver, its direction, and also serve as one of the mandatory criteria for the effectiveness of the therapy. The results of a puncture biopsy can have a decisive differential diagnostic value. With a sufficient size of the liver puncture, the obtained morphological information is of decisive importance in assessing the activity, the degree of fibrosis of chronic hepatitis and in choosing therapeutic tactics.
Treatment of Epstein-Barr Viral Hepatitis
Acyclovir and ganciclovir are used as etiotropic therapy for Epstein-Barr virus infection. Antiviral treatment is successfully combined with intravenous immunoglobulins for the treatment of isolated Epstein-Barr viral hepatitis in liver transplant recipients against the background of cytostatic therapy.
Recently, there has been successful experience with the use of rituximab, which is an anti-CD20 monoclonal antibody, in chronic Epstein-Barr viral hepatitis in recipients of donor kidneys. In this case, there is an elimination of peripheral B-lymphocytes and cells producing EBV-encoded mRNA. During the treatment, the level of liver cell enzymes is normalized and the morphological picture in the liver improves. Recombinant interferon a preparations are used for the same purpose.
Under observation in one of the clinics where treatment of Epstein-Barr viral hepatitis was carried out, there were 21 children receiving Viferon therapy for chronic Epstein-Barr viral hepatitis. Among them, 12 children with acquired and 9 with congenital Epstein-Barr viral hepatitis. 17 children were under 1 year old, 2 - from 1 to 3 years old, 2 - over 3 years old.
For the treatment of chronic Epstein-Barr viral hepatitis, 16 children received monotherapy with Viferon in rectal suppositories, 5 - Viferon in combination with intravenous immunoglobulins. The dose of interferon is 5 million IU/m2, 3 times a week.
The duration of the treatment course was 6 months in 11 patients, 9 months in 6 and 12 months in 4 children. The criteria for the effectiveness of interferon therapy were determined in accordance with the EUROHEP consensus.
The control group consisted of 23 children, including 16 patients with acquired acute and 7 with acquired chronic Epstein-Barr viral hepatitis. These children received basic therapy, including only choleretic, vitamin preparations and hepatoprotectors.
Against the background of viferon therapy, 2 children (9.5%) had primary biochemical, 2 (9.5%) had primary virological, 1 (4.8%) had stable virological, 1 (4.8%) had long-term virological, and 7 (33.3%) had long-term complete remission. There was no remission in 8 (38.1%). No significant differences in the effectiveness of treatment of children with congenital and acquired Epstein-Barr viral hepatitis were found.
Thus, the proportion of children with chronic Epstein-Barr viral hepatitis who developed complete remission against the background of viferon therapy was low - about 30%. However, the combined group of children who developed some remission constituted 61.9% of the total number of patients. At the same time, remission was absent in more than 1/3 of patients. In the same time frame, spontaneous remission did not develop in any child from the control group.
In order to answer the question about the dependence of the frequency of achieving remission in Epstein-Barr viral hepatitis during therapy on the treatment regimen, 2 groups were identified. The first included patients who received monotherapy with Viferon, the second - those who received Viferon in combination with intravenous immunoglobulins.
There were no significant differences in the severity of cytolysis in patients from different groups. Only a tendency toward lower cytolysis severity was noted against the background of combined treatment with Viferon and intravenous immunoglobulins. The p values ranged from p>0.05 to p>0.1.
A similar pattern was observed when assessing the replicative activity of the virus in chronic Epstein-Barr viral hepatitis in children treated according to different schemes. The frequency of EBV DNA detection during dynamic observation was practically the same in children from both groups. Only slightly lower replicative activity of the virus was observed in patients treated with Viferon in combination with intravenous immunoglobulins. The p values ranged from p>0.05 to p>0.2.