Barr virus and hepatitis

Spleen had been enlarged with mm length. Portal vein diameter was 10 mm with normal flow, and suprahepatic inferior vena cava was normal. Gallbladder and biliary tree were normal, without any signs of cholestasis. Mild ascites was present in the abdominal cavity. With due attention to the prior tests which had revealed hepatitis, seeking for the cause started. Complementary tests were Ceruloplasmin: 0.

The patient was closely observed for probable fulminant hepatic failure during her hospital stay. Her general condition improved significantly during that time.

Fever, nausea, vomiting and malaise ceased and her appetite became normal. Finally, she was discharged under good general conditions and normal liver function tests, and was asked to refer one month later for general assessments and future evaluations for autoimmune and HCV hepatitis. During six months of follow-up, all hematologic and liver function tests were normal, and the EBV viral load become negative.

The rest converts mostly in young adulthood with presentation of EBV infectious mononucleosis characterized by fever, tonsillitis exudative or non-exudative and lymphadenopathy. Other common manifestations are prolonged malaise, fatigue, nausea, vomiting and anorexia.

On physical examination, splenomegaly and maculopapular generalized rash may be present. Less common complications include psychological and respiratory problems, meningitis, encephalitis, Guillain-Barre syndrome, aplastic and auto-immune hemolytic anemia, splenic rupture, myocarditis and hepatic necrosis 1 - 3. Abnormal liver function tests, especially elevated transaminases and hyperbilirubinemia, are common in primary infection occurring particularly in adult populations and EBV is known as an important cause of cholestasis in those patients; nevertheless, considering some reports which have shown EBV induced cholestatic hepatitis in children, it is invaluable to emphasize that Epstein-Barr virus infection should be part of the differential diagnoses in all age groups 4 , 5.

In uncomplicated EBV infectious mononucleosis syndrome, the rates of mortality and morbidity are very low. There is no effective antiviral therapy available for EBV infectious mononucleosis in immunocompetent persons. Acyclovir and ganciclovir are used to reduce EBV shedding but are clinically ineffective. In one study, complicated EBV infection, associated with both fulminant hepatic failure and auto-immune hemolytic anemia, was managed successfully by plasmapheresis, acyclovir and prednisolone, but there is no convincing evidence to warrant their clinical use in uncomplicated cases 6.

To the best of our knowledge, abnormal liver function tests without symptomatic hepatitis are widely seen in acute EBV infection although self-limiting, and acute symptomatic hepatitis is rare 7.

On the other hand, some reports and studies have revealed the coincidence of acute hepatitis and IM syndrome due to primary EBV infection 8 - 10 , and one presented fatal hepatitis due to reactivation of Epstein-Barr virus Some reports and review articles have revealed the relationship between EBV and autoimmune liver disease and suggested EBV to be a trigger agent for autoimmune hepatitis; therefore, chronic liver disease might be a manifestation of chronic EBV infection with frequent reactivations and persistent, moderate or low levels of viral load 12 , Thus, to the best of our knowledge, isolated EBV hepatitis and cholestasis without IM syndrome is a very rare manifestation of primary EBV infection and only a few reports have introduced cases with acute fulminant hepatitis without IM syndrome According to these reports and ours, EBV induced isolated hepatitis should be considered in all patients presenting with typical symptoms and signs of acute hepatitis, especially significant hyperbilirubinemia and cholestatic hepatitis.

Furthermore, the data provide evidence for the need to test the presence of EBV in cryptogenic hepatitis even if it remains difficult to prove a causative role for EBV Considering the wide range of viral causes of acute hepatitis, after exclusion of common viral agents, EBV should be considered as an important factor. National Center for Biotechnology Information , U. Gastroenterol Hepatol Bed Bench.

B, Kupffer cells showing erythrophagocytosis. C, Portal inflammation with bile duct damage. These methods have equivalent sensitivity for detecting EBV in formalin-fixed, paraffin-embedded specimens of native livers from immunocompetent patients. It is important to note that EBV-associated hepatitis is not excluded by a negative EBER, especially in the setting of a small biopsy because staining may be focal. Immunohistochemical staining for EBV latent membrane proteins is not useful in establishing a diagnosis; it is typically absent in immunocompetent patients, 4 whereas in patients with posttransplant lymphoproliferative disorder, latent membrane protein staining may be present but is a less-sensitive test than PCR or EBER.

The differential diagnosis includes autoimmune liver diseases, transplant rejection, lymphomas, and drug-induced liver injury. Distinguishing between these entities may not be possible with histologic findings alone, and correlation with clinical and laboratory data is usually necessary to establish the correct diagnosis. As noted, autoimmune antibody production has been associated with EBV, 14 and the presence of positive autoimmune antibodies and elevated serum transaminase levels will often raise the possibility of autoimmune liver disease.

The presence of positive EBV serologies, elevated levels of IgG, and the presence of other autoantibodies anti—smooth muscle cell antibodies or liver—kidney—microsomal antibodies can help distinguish EBV hepatitis from autoimmune hepatitis.

In contrast, EBV hepatitis lacks prominent plasma cells and the lobular architecture is generally intact, with only spotty necrosis of hepatocytes. Immunosuppressive therapy reduces the risk of liver transplant rejection but predisposes liver transplant recipients to latent EBV reactivation and increases the possibility of clinically significant primary EBV infection.

When EBV hepatitis does occur in a liver transplant recipient, it may be difficult to distinguish from acute cellular rejection on histologic grounds, particularly as EBV hepatitis can cause endothelial inflammation. In EBV hepatitis, the portal-based inflammatory infiltrate is almost entirely lymphocytic. Activated and atypical forms may be present, but eosinophils and neutrophils are rare. In acute rejection, the infiltrate is mixed and is composed primarily of lymphocytes, but there are abundant eosinophils, with interspersed neutrophils and plasma cells.

Bile duct injury can occur in EBV hepatitis, but it is typically less severe than that seen in acute rejection. As mentioned, venular endotheliitis is also characteristic of rejection; however, it can also be seen in EBV hepatitis. The sinusoidal infiltration of atypical T cells in EBV hepatitis can mimic lymphoproliferative disorders, making it difficult to distinguish the 2 entities on histologic grounds alone.

This is particularly true of hepatosplenic T-cell lymphoma HSTL , which preferentially involves the sinuses of the liver; however, this pattern is also commonly reported in adult human T-cell leukemia, natural killer cell leukemia, and hairy cell lymphoma. Microscopically, liver involvement is characterized by diffuse sinusoidal infiltration by intermediate-sized monomorphic lymphocytes with irregular nuclear contours, condensed chromatin, inconspicuous nucleoli, and a moderate amount of pale cytoplasm.

Associated sinusoidal dilation is variably prominent Figure 4 , A through C. In contrast to EBV hepatitis, involvement of the portal tracts is typically mild or absent. With disease progression, the lymphocytes may become larger and more pleomorphic. Hepatosplenic T-cell lymphoma has overlapping clinical features with EBV hepatitis with hepatosplenomegaly and a peak incidence in adolescents and young adults, although HSTL shows a male predominance.

In contrast to EBV, patients with HSTL typically have cytopenias without lymphadenopathy, and bone marrow involvement is usually present. T-cell receptor gene rearrangements, identified by PCR, are somewhat limited in specificity and sensitivity but may still be helpful in recognizing T-cell clonality. Hepatosplenic T-cell lymphoma. A, Sinusoidal infiltration by lymphocytes with minimal portal involvement. B, Atypical lymphoid infiltrate filling and distending the sinuses.

Lymphoproliferative disorders can also be associated with EBV infection in the context of immunosuppressive therapy after transplant. In hepatic posttransplant lymphoproliferative disorder, there is a characteristic, maplike expansion of the portal tracts. Drug-induced liver injury should always be considered in the differential diagnosis of EBV hepatitis. Diagnosis of drug-induced liver injury is challenging, and it is often difficult to completely exclude other possible causes of liver injury because the histologic features of drug-induced liver injury can emulate any pattern of primary liver disease, including hepatocellular injury, cholestatic injury, mixed hepatocellular-cholestatic injury, steatosis, and vascular lesions.

Although the timing of drug use is important, liver toxicity may not become evident for weeks or months after ingestion; drug interactions or dose increases can also influence toxicity. Hepatic involvement with EBV infection is very common, although it is often subclinical.

Most cases of EBV hepatitis are self-limited, but severe and potentially fatal disease has been reported. The differential diagnosis is fairly broad and includes autoimmune hepatitis, transplant rejection, lymphomas, and drug-induced liver injury. The clinical scenario is also an important clue to the diagnosis.

Unusual clinical and laboratory features such as lack of signs and symptoms of mononucleosis, positive antinuclear antibodies, or negative serologies in young children or immunocompromised patients can confound the clinical picture. The authors have no relevant financial interest in the products or companies described in this article. Recipient s will receive an email with a link to 'Epstein-Barr Virus Hepatitis: A Review of Clinicopathologic Features and Differential Diagnosis' and will not need an account to access the content.

Sponsored Video. Two patients died of progressive multi-organ EBV involvement. To determine the risk of developing EBV hepatitis, we reviewed our experience with the administration of antilymphocyte preparations in patients. The patients found to have a significantly greater risk of developing EBV hepatitis included those receiving more than one course of antilymphocyte therapy or greater than a total dose of 70 milligrams of OKT3 in a single course.

Conclusions: EBV hepatitis after liver transplantation is an infrequent event, which may be treated successfully. The occurrence of EBV hepatitis appears closely linked to the use of antilymphocyte preparations.