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Epstein-Barr virus viral hepatitis
Last reviewed: 23.04.2024
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Epstein-Barr virus viral hepatitis is a term that implies not involving the liver in the pathological process in general, as, for example, in infectious mononucleosis, but an independent form of Epstein-Barr virus infection, in which liver damage appeared in isolation and was not accompanied by a clinical picture of infectious mononucleosis.
This form of Epstein-Barr virus infection occurs if the Epstein-Barr virus has tropism not to the epithelium of the biliary tract, but directly to the hepatocytes. Despite the fact that the Epstein-Barr virus infected up to 90% of the population, Epstein-Barr virus hepatitis continues to be considered a rare manifestation of infection.
[Epidemic Epstein-Barr Virus Hepatitis
The Epstein-Barr virus is ubiquitous among the human population, it affects 80-100% of the world's population. The first encounter with a virus depends on social conditions. In developing countries and socially disadvantaged families, most children are infected by 3 years, and the entire population by age. In developed with grains and socially-advantaged families, a meeting with the Epstein-Barr virus may not occur until adolescence.
The source of infection is sick and virus extractors. The main route of transmission of the pathogen is airborne, often infection occurs through infected saliva. Possible hemotransfusion and genital transmission of the Epstein-Barr virus. Cases of vertical transmission of this virus from mother to fetus are described and it is suggested that Epstein-Barr virus causes congenital anomalies.
In Epstein-Barr virus hepatitis, the primary routes of infection are apparently parenteral and perinatal, when the pathogen enters the bloodstream directly, bypassing the patient's lymphoid apparatus.
What causes Epstein-Barr virus hepatitis?
The Epstein-Barr virus was first cultivated in 1964-1965, by the English scientists E. Epstein and I. Barr, after which they got their name, Epstein-Barr virus belongs to the family Nepresviridae, contains DNA, has a spherical shape of particles 180 nm in diameter. The virus is sensitive to the action of the ether, it multiplies well in the culture of Burkitt's lymphoma cells, the blood of infectious mononucleosis patients, leukemia cells and in the brain cell culture of a healthy person.
Epstein-Barr virus contains the following antigens: viral capsid antigen (USA), 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 antigen of the viral capsid is late. Membrane antigen is a complex of products of early and late genes. The nuclear antigen is early, because during the lytic phase of the infection it precedes the synthesis of viral particles. Detection of antibodies to nuclear and early surface antigens in the absence of antibodies to late antigens testifies to acute infection. Identification of antibodies to the capsid antigen and late membrane in the absence of antibodies to early antigens serves as a marker for long-term infection, a latent infection.
Subtypes of the Epstein-Barr virus, specific for a particular disease or terrain, do not exist. When comparing, minimal differences among Epstein-Barr strains of viruses isolated from certain geographical areas and from different patients were found.
Pathogenesis of epstein-Barr virus viral hepatitis
The pathogenetic mechanism that causes the destruction of hepatocytes and the development of cholestasis 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. In patients with Epstein-Barr virus infection, autoantibodies to the superoxide dismutase enzyme are found to neutralize its antioxidant effect. As a result, free radicals accumulate in the hepatocytes and cause their defeat.
In patients with acute Epstein-Barr virus hepatitis, high concentrations of autoantibodies against superoxide dismutase are found. It was found 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. Recovering and normalization of the functional state of the liver in patients with Epstein-Barr virus hepatitis are accompanied by a sharp decrease in the level of antibodies to superoxide dismutase.
In addition, the mechanism of antibody-dependent cell cytolysis of cells infected with Epstein-Barr virus, which develops under the influence of T-suppressors and natural killers, is described. In icteric forms of acute Epstein-Barr virus hepatitis, EBV DNA is detected mainly in CD3, CD4 and CD8 lymphocytes, whereas in infectious mononucleosis, in patients without jaundice, B-lymphocytes of peripheral blood are mainly infected, indicating a possible involvement of T-lymphocytes in the development of severe forms of acute Epstein-Barr virus viral hepatitis. However, there are indications that in the case of severe icteric forms of Epstein-Barr virus hepatitis Epstein-Barr virus is infected with the T-cell infiltrate, not hepatocytes.
In the formation of an isolated lesion of hepatocytes in the Epstein-Barr virus hepatitis, an immediate entry of the causative agent into the blood during parenteral infection can play an important role. Thus, the issue of possible mechanisms of hepatocyte damage by the Epstein-Barr virus needs further study.
Pathomorphology
Histopathological changes in Epstein-Barr virus hepatitis have not been adequately studied.
In acute Epstein-Barr virus hepatitis, morphological changes in liver tissue are typical of acute hepatitis of another etiology and may be accompanied by cholangitis and endotheliitis. Moreover, 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 serum, but also by the detection of EBV DNA in hepatocytes by PCR and Epstein-Barr virus antigens (in particular, 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 disturbing the lobular structure of the liver. In cases accompanied by jaundice, formation of biliary thrombi, deposition of bile pigment in hepatocytes of the central zones of the lobules, edema phenomena, hepatocyte degeneration and disseminated necrosis of hepatocyte groups are noted.
Variant Epstein-Barr virus infection is acute cholestatic hepatitis with acute cholecystitis in school-age children and adults. Morphological changes include necrosis of liver parenchyma and lymphocytic infiltration.
Morphological changes in chronic Epstein-Barr virus hepatitis are also not fundamentally different from those in viral hepatitis of another etiology. In immunocompetent patients, a lower degree of histological activity is diagnosed compared with immunocompromised people. Chronic Epstein-Barr virus hepatitis in children is characterized by mononuclear infiltration and a moderate expansion of connective tissue in the liver. In a number of cases, the cellular composition of the infiltrate with Epstein-Barr virus hepatitis is represented predominantly by CD3 and CD8 lymphocytes.
In the Epstein-Barr virus infection of liver transplant in hepatocytes, EBV DNA is detected by PCR and Epstein-Barr virus antigens - by immunohistochemical method, including the protein to the apse of gp220. Epstein-Barr virus viral hepatitis develops in these patients, accompanied by lymphohistiocytic and immunoblastic infiltration. In this case, the greatest histopathological activity of the process in the liver is found 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 Virus Hepatitis
Epstein-Barr virus hepatitis can have both acute and chronic course.
Acute Epstein-Barr virus viral hepatitis
There is reason to believe that liver damage develops in 80-90% of patients with Epstein-Barr virus infection. At the same time, an increase in the activity of hepatic cell enzymes often remains undiagnosed.
Acute Epstein-Barr virus hepatitis can occur in anicteric, mild, moderate, and in isolated cases - in severe and even fulminant form.
The incubation period for Epstein-Barr virus hepatitis is not exactly established. Presumably, it is 1-2 months.
Preglozhtushny period. The disease begins in most cases gradually. In this period of the disease, patients have decreased appetite, weakness, headache, abdominal pain. In rare cases - an increase in body temperature to 38 C. No oropharyngeal lesions, lymph node enlargement, atypical mononuclear cells in peripheral blood are not detected in any patient.
The duration of the pre-jaundiced period of the acquired initial manifest Epstein-Barr virus viral hepatitis is approximately 3-5 days, with an average form of 4-7 days,
The icteric period. In patients with jaundice, the symptoms of intoxication persist and even increase. In some patients, there are no clinical manifestations of the pre-jaundiced period. The manifest form of viral hepatitis Epstein-Barr in these patients makes its debut with the appearance of jaundice.
Thus, the clinical symptoms and laboratory parameters for acute viral hepatitis Eppsyna-Barr in children are not fundamentally different from those in viral hepatitis B, C, etc. Patients do not have symptoms typical of infectious mononucleosis.
The duration of the icteric period is 15-22 days in mild form, and 17-26 days in the case of a moderate form.
Post-jelly period is characterized by normalization of the patient's well-being, decrease in the size of the liver and spleen, a significant decrease in the activity of enzymes.
Outcomes of acute Epstein-Barr virus hepatitis. The course of the disease can be acute (35% of cases) and result in recovery with complete restoration of the functional state of the liver in terms of 1 to 3 months. In 65% of patients in the outcome of the manifest Epstein-Barr virus hepatitis the disease takes a chronic course
Chronic Epstein-Barr virus viral hepatitis
Chronic Epstein-Barr virus hepatitis can form as a primary chronic process or in the outcome of the initial manifest Epstein-Barr virus hepatitis. At the same time, the patient does not have an infectious mononucleosis
The minimal process activity prevails in patients (about 70%), in 20-25% of patients is diagnosed low and in 6-10% - moderate activity of the process in the liver.
In 3/4 patients, mild-to-moderate is diagnosed, and moderate liver fibrosis in 12-15%. Approximately 10% of patients have no liver fibrosis. Signs of severe fibrosis and cirrhosis of the liver are revealed quietly in single patients with acquired chronic Epstein-Barr virus hepatitis.
Clinical manifestations and laboratory indicators in the period of exacerbation with acquired chronic Epstein-Barr virus hepatitis do not differ in principle from those in children with viral hepatitis of another etiology.
In the remission period, symptoms of intoxication in patients with acquired chronic Epstein-Barr virus hepatitis are practically absent. In most patients, extrahepatic manifestations disappear. Dimensions of the liver and spleen are reduced, but complete their normalization is not observed. Lesions of the oropharynx, enlarged lymph nodes, atypical mononuclear cells in the peripheral blood are not detected. In the blood serum, the activity of the enzymes does not exceed normal values.
Acquired Epstein-Barr virus hepatitis can develop both as a primary chronic process and in the outcome 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 cases, mild liver fibrosis is diagnosed. Lesions of the oropharynx, enlarged lymph nodes, atypical mononuclear cells in peripheral blood are not detected in patients.
Congenital viral hepatitis Epstein-Warr
Congenital Epstein-Barr virus hepatitis almost always has a primary chronic course, in some cases combined with the defeat of other organs and systems (CNS, bile ducts, etc.).
Among children with congenital chronic Epstein-Barr virus hepatitis, about 60% are diagnosed with minimal, 20% - low, 10% - moderate and 6-8% - pronounced activity of the process in the liver.
Half of the children show mild symptoms, in 1/4 - moderate liver fibrosis. Signs of severe fibrosis and liver cirrhosis are found in 20% of children with congenital chronic Epstein-Barr virus hepatitis.
Clinical manifestations and laboratory indices with congenital chronic viral hepatitis Epstein-Barr do not differ in principle from those in viral hepatitis B.S. Et al.
In the remission period, the symptoms of intoxication in children with congenital chronic Epstein-Barr virus hepatitis are practically absent. In most children, extrahepatic manifestations disappear. Dimensions of the liver and spleen are reduced, but complete their normalization is not observed. In the blood serum, the activity of the enzymes does not exceed normal values. Lesions of the oropharynx, enlarged lymph nodes, atypical mononuclear cells in the peripheral blood are not detected.
Congenital Epstein-Barr virus hepatitis always develops as a primary chronic process. The defeat of the liver can be combined with other developmental malformations. The clinical manifestations of acquired Epstein-Barr virus hepatitis correspond to those in acute and chronic viral hepatitis of varying severity. In 3/4 cases, mild and moderate liver fibrosis is formed.
Epstein-Barr virus hepatitis in patients who underwent liver transplantation
In patients who underwent liver transplantation. Epstein-Barr virus hepatitis is observed in about 2% of cases, which is confirmed by histological examination and detection of EBV DNA in liver bioptag. Epstein-Barr virus hepatitis develops on average 45 days after liver transplantation. The defeat of the liver can develop in the first 6 months after organ transplantation. The greatest risk of development of Epstein-Barr virus hepatitis is noted in recipients receiving antilymphocyte therapy.
In this case, the Epstein-Barr virus can cause rejection of an infected transplant. The diagnosis in such cases is confirmed morphologically and by revealing the genome of the Epstein-Barr virus in hepatocytes. The levels of EBV DNA in such patients do not differ from the viral load in patients with post-transfusion lymphoproliferative Epstein-Barr syndrome of viral etiology for a long time and a well-studied infectious complication in organ transplantation. Early diagnosis of Epstein-Barr virus hepatitis can prevent rejection of the transplant or timely start a fight with rejection.
Diagnosis of epstein-Barr virus viral hepatitis
Epstein-Barr virus hepatitis is diagnosed by a combination of clinical, biochemical and serological data. The onset of the disease in the form of asthenodyspeptic phenomena - malaise, weakness, deterioration of appetite, accompanied by an increase in the liver and hyperfermentemia, - allows you to suspect hepatitis, especially when given anamnesis for parenteral manipulation for 1-2 months before the present disease and in the absence of serum markers of viral hepatitis (A, B, C, D, G, TT), etc. The final diagnosis is established based on the detection in the serum of blood specific antibodies to Epstein-Barr virus antigens of IgM class, EBV DNA in the blood, with lune, urine.
The day of acute and chronic viral hepatitis Epstein-Barr is characterized by cytolysis syndrome. For the indication of cytolysis syndrome, the determination of the activity of aminotransferases (ALT, ACT) and LDH fractions (LDG-4, LDG-5) is widely used. Increased activity of hepatic cell enzymes is characteristic of acute hepatitis and the stage of exacerbation of chronic hepatitis Epstein-Barr virus etiology. The degree of increase in the activity of hepatic cell enzymes in various forms of Epstein-Barr virus hepatitis corresponds to that of viral hepatitis of another etiology.
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 to a certain extent reflects the protein spectrum of blood serum. In most cases, children with chronic Epstein-Barr virus hepatitis maintain a normal level of total protein in the blood serum (65-80 g / l). In patients with chronic viral hepatitis Epstein-Barr, disproteinemia is formed by lowering the level of albumins and increasing the fraction of y-globulins. The nature of disproteinemia is moderate, it reaches a significant extent only in some patients, when the albumin level falls below 45%, and the level of y-globulin exceeds 25%.
With exacerbation of chronic Epstein-Barr virus hepatitis, the decrease in the indicators of the protein-synthetic function of heme is more significant, the heavier the inflammatory process in the liver. Violations in the blood coagulation system (hypocoagulation) of varying degrees develop in patients with chronic hepatitis mainly by reducing the synthetic function of the liver.
The ultrasonic picture in the liver with acute and chronic Epstein-Barr virus hepatitis does not differ from that in viral hepatitis of another etiology.
The method of Doppler sonography is used to determine blood flow in the portal vein system and the presence of portocaval anastomoses, which allows to diagnose portal hypertension, including in patients with cirrhosis of EBV-aetiology.
Morphological studies allow an objective assessment of the nature of the pathological process in the liver, its orientation, and also serve as one of the mandatory criteria for the effectiveness of the therapy. The results of puncture biopsies can have a decisive differential-diagnostic significance. With a sufficient amount of punctate liver, the obtained morphological information is of decisive importance in assessing the activity, the degree of fibrosis of chronic hepatitis, and in the choice of therapeutic tactics.
Epstein-Barr treatment of viral hepatitis
As etiotropic therapy for Epstein-Barr virus infection, acyclovir and ganciclovir are used. Antiviral treatment is successfully combined with intravenous immunoglobulins for the treatment of isolated Epstein-Barr virus hepatitis in liver transplant recipients on the background of cytostatic therapy.
Recently, there has been a successful experience with the use of rituximab, an anti-CD20 monoclonal antibody, in chronic Epstein-Barr virus hepatitis in recipients of the donor kidney. At the same time, peripheral B lymphocytes and cells producing EBV-encoded mRNA are eliminated. Against the background of treatment, the level of hepatic cell enzymes normalizes and the morphological pattern in the liver improves. For the same purpose, preparations of recombinant interferon a are used.
Under supervision in one of the clinics where Epstein-Barr virus hepatitis was treated, there were 21 children who received viferon therapy for chronic Epstein-Barr virus hepatitis. Among them, 12 children with acquired and 9 - with congenital Epstein-Barr virus hepatitis. 17 children were under the age of 1 year, 2 - from 1 to 3 years, 2 - over 3 years.
For the treatment of chronic Epstein-Barr virus 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 treatment was 6 months in 11 patients, 9 months in 6 and 12 months in 4 children. Criteria for the effectiveness of interferon therapy were determined in accordance with the consensus of EUROHEP.
The control group consisted of 23 children, including 16 patients with acquired acute and 7 acquired chronic hepatitis Epstein-Barr virus aetiology. These children received basic therapy, including only choleretic, vitamin preparations and hepatoprotectors.
Against the backdrop of viferonotherapy in 2 children (9.5%), the primary biochemical, in 2 (9.5%) - primary virologic, 1 (4.8%) - stable virologic, 1 (4.8%) - prolonged virologic, in 7 (33.3%) - long-term complete remission. In 8 (38.1%) there was no remission. There were no significant differences in the effectiveness of treatment of children with congenital and acquired Epstein-Barr virus hepatitis.
Thus, the proportion of children with chronic Epstein-Barr virus hepatitis, who developed complete remission against viferon therapy, was low - about 30%. However, the combined group of children who developed any remission constituted 61.9% of the total number of patients. At the same time, there were no remissions in more than 1/3 of the patients. At the same time, no children from the control group had spontaneous remission.
In order to answer the question about the dependence of the frequency of achieving remission with Epstein-Barr virus hepatitis against the background of therapy from the treatment regimen, two groups were identified. The first included patients who received monotherapy with viferon, the second - 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 to a lower cytolysis was observed against a background of combined treatment with viferon and intravenous immunoglobulins. The values of p varied from p> 0.05 to p> 0.1.
This pattern was also observed in the evaluation of the replicative activity of the virus in chronic Epstein-Barr virus hepatitis in children treated with different regimens. The frequency of detection of EBV DNA in the entry of the dynamic observation was practically unchanged in children from both groups. Only slightly less replicative activity of the virus was observed in patients on the background of treatment with viferon in combination with intravenous immunoglobulins. The values of p varied from p> 0.05 to p> 0.2.