—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 2 - Fulminant Adenovirus Hepatitis

Hanlin L. Wang
Washington University
St. Louis, Missouri


Click on each slide thumbnail image for an enlarged view
Clinical History:
The patient was a 21-year-old man, status post allogeneic bone marrow transplantation (BMT) for acute T cell leukemia. His clinical course was complicated by gastrointestinal graft-versus-host disease (GVHD), grade ¾, one month after transplantation diagnosed by colonoscopic biopsies. Four months later, the patient developed fulminant hepatic failure with jaundice. Laboratory studies showed a total bilirubin level of 9.8 mg/dL, aspartate transaminase 7352 U/L, alanine transaminase 2501 U/L, alkaline phosphatase 1074 U/L, plasma ammonia 53.0 _ mol/L, prothrombin time 26.5 seconds, partial thromboplastin time 67.1 seconds, total plasma protein 4.8 g/dL, and albumin 2.2 g/dL. Serologic tests were negative for hepatitis A, B and C viruses, and negative for anti-Epstein-Barr virus IgM antibody. A clinical diagnosis of hepatic GVHD was suspected and a transjugular liver biopsy was performed. Liver tissue and blood cultures were also sent. The patient died next day following liver biopsy despite supportive measures. An autopsy was not performed.

Diagnosis: Fulminant Adenovirus Hepatitis
The diagnosis was further confirmed by liver tissue and blood cultures, which were both positive for adenovirus, and negative for cytomegalovirus and herpes simplex viruses and negative for bacterial and fungal growth.


Case 2 - Figure 1 - Low power view
Case 2 - Figure 2 - Intranuclear inclusions
Case 2 - Figure 3 - Immunohistologic stain for adenovirus

Pathologic Findings
Histologic sections of the liver biopsy exhibited random foci of coagulative hepatocyte necrosis. Mild canalicular and cytoplasmic cholestasis and mild steatosis were seen. No significant inflammatory response was present. The portal tracts showed only minimal mononuclear cell infiltrates composed of lymphocytes admixed with rare eosinophils and neutrophils. No bile duct damage or loss and no endotheliitis were evident to suggest a diagnosis of acute or chronic GVHD. On higher power view, there was a slight variation in the size of hepatocyte nuclei. Some of the hepatocytes, particularly those surrounding the necrotic foci, contained smudgy nuclei with chromatin margination. These histologic findings are highly suggestive of a diagnosis of adenovirus hepatitis. Immunohistochemical staining for adenovirus was then performed, which demonstrated a strong and predominantly nuclear staining (with some cytoplasmic positivity) in approximately 30% of the hepatocytes, more concentrated around the necrotic foci.

Discussion
Adenoviruses are a group of nonenveloped double stranded DNA viruses that have been recovered from virtually every organ system in humans. In immunocompetent individuals the viruses may cause mild, self-limited illnesses including respiratory infection, keratoconjunctivitis, hemorrhagic cystitis, and gastroenteritis. Adenovirus infections occur more often in immunocompromised patients, where more severe diseases, such as pneumonia, nephritis, hepatitis, encephalitis, pancreatitis or disseminated disease, may be encountered.

The reported incidence of adenovirus infections in BMT recipients varies from 3% to 21%. The mortality is largely attributed to pneumonia, renal failure or fulminant hepatitis, and the lack of effective therapy, even though successful treatment with ribavirin, cidofovir, or serum immunoglobulin containing high titers of neutralizing antibody to adenovirus has been reported.

The most common adenovirus species isolated from BMT patients are serotypes 5, 11/34/35, and 1. Other serotypes, such as 2, 4, 6, 7, 12, 29 and 31, have also been reported. It is postulated that adenovirus infections in pediatric cases, usually occurring within the first 30 days after transplantation, are most likely to be acquired due to a recent exposure; whereas in adults, many of the infections may represent reactivation since the time of onset is usually after 90 days. A few studies have identified the presence of moderate to severe GVHD, isolation of the virus from two or more anatomic sites, and receipt of concurrent immunosuppressive therapy, to be the risk factors for adenovirus infections and for the severity of the disease in BMT patients. These findings are not confirmed by other investigators, however.

Fulminant hepatic failure as seen in this case is not a common presentation of adenovirus infection in BMT patients. In fact, most cases described in the literature are single case reports. In the study by Shields et al with 51 cases of adenovirus infections,only 2 patients had adenovirus hepatitis. One patient died of pneumonia and the other died of GVHD and sepsis. In the series reported by Flomenberg et al and Carrigan, where 42 cases of adenovirus infections were identified, fulminant hepatitis as the initial presentation was seen in only one case, although mild hepatitis as a later component of disseminated disease was observed in 3 patients. A more recent study by Baldwin et al included 100 BMT patients with adenovirus infections and in only one patient were characteristic nuclear inclusions found in hepatocytes. In other smaller series, liver involvement by the virus was either not documented or occurred in only rare cases. As in other immunocompromised groups, fulminant adenovirus hepatitis in BMT recipients usually has a fatal overcome.

Histologically, adenovirus hepatitis is characterized by small or large areas of coagulative necrosis with no particular zonal distribution. Inflammatory response is usually sparse or absent. Intranuclear viral inclusions with characteristic smudgy appearance and chromatin margination are unique but can be overlooked at low power. When viral inclusions are identified on H&E slides, differential diagnosis may include herpes simplex virus and cytomegalovirus and immunohistochemical studies are very useful for the distinction.

Other important differential diagnoses for adenovirus hepatitis in BMT recipients include acute and chronic GVHD and drug toxicity. In acute GVHD (less than 90 days after transplantation), portal inflammation, dystrophic changes in bile duct epithelium with lymphocytic infiltrate, endotheliitis, and apoptosis in hepatocytes may be prominent. These histologic features somewhat resemble those seen in acute cellular rejection in liver transplants or hepatitis C virus infection. In chronic GVHD (after 90 days), ductopenia and portal fibrosis may be characteristic, reminiscent of chronic liver allograft rejection. Extensive hepatocyte necrosis with little or no bile duct damage is usually not typically seen in GVHD. However, the presence of necrosis, particularly when associated with cholestasis and steatosis, should raise the possibility of drug toxicity. Again, the presence of characteristic "smudgy cells" should point to the right direction and ancillary studies (immunohistochemistry, culture and polymerase chain reaction) should aid the diagnosis.

References

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