Cytomegalovirus in liver biopsies of marrow transplant recipients: detection methods, clinical, histological and immunohistological features

Abstract

In a retrospective analysis liver biopsy specimens obtained from 44 marrow transplant recipients were studied to evaluate the frequency of local presence of human cytomegalovirus (CMV) and graft-versus-host disease (GvHD)-like histological and immunohistological alterations in patients with and without liver dysfunction following bone marrow transplantation (BMT). In 22 of 28 patients with marked liver dysfunction after BMT and histopathological alterations described as typical for acute GvHD CMV could be detected in the liver biopsy specimen. The polymerase chain reaction (PCR) technique revealed the highest sensitivity for CMV detection in liver biopsy samples, but in 20 of 22 PCR-positive specimens CMV infection could be confirmed by at least one additional technique. All the liver biopsies obtained from 16 patients with normal liver function lacking histopathological signs of GvHD were CMV negative. In all 3 patients with CMV-positive liver biopsy started on antiviral therapy liver function improved and no generalized CMV disease occurred. All the 4 patients without local presence of CMV started on severe immunosuppressive therapy showed an improvement of liver dysfunction without occurrence of CMV infection. Local CMV infection of the liver could not be differentiated from hepatic GvHD by clinical and histopathological features, nor by immunohistological analysis of the bile duct epithelium. In contrast, only in liver biopsy with local viral presence could an increase in HLA class II- and ICAM-1 expression be demonstrated on hepatocytes. Thus, especially the high negative predictive value of the PCR technique helps to manage the patient with liver dysfunction after BMT.

Human Cytomegalovirus Cell Tropism and Pathogenesis

“…Liver dysfunction due to systemic HCMV infection is frequent after liver transplantation or BMT [22,23,160], and it occurs occasionally in recipients of other solid organ transplants [161][162][163]. Viral replication has been detected in hepatocytes and bile duct cells [40,120,121], However, the extent of viral replication in most instances was moderate, and symptoms might be mediated by indi rect rather than direct pathogenesis.…”

The hepatologist in the haematologists' camp

“…Diffuse intra‐ and extrahepatic duct strictures, as well as ampulla of Vater obstruction, can also occur but these are rarely seen now (Murakami et al , 1997). When CMV infection needs to be excluded or confirmed, in situ PCR techniques show the highest sensitivity for CMV detection in liver specimens with a high negative predictive value (Einsele et al , 1994). Immunohistochemical methods are also very sensitive.…”

Cytomegalovirus infection after orthotopic liver transplantation is restricted by a pre‐existing antiviral immune response of the recipient

“…HCMV liver infection also occurs after bone marrow (BMT) or stem cell transplantation (SCT), although less frequently [Reusser, 1991[Reusser, , 1996Einsele et al, 1994;Hebart et al, 1998]. Hepatitis is one of the predominant manifestations of HCMV primary infection in the immunocompetent host [Snover and Horwitz, 1984;Ten Napel et al, 1984;Laskus et al, 1990;Alford and Britt, 1993;Funato et al, 2001].…”

“…Infection of the liver by the human cytomegalovirus (HCMV) is a frequent complication in immunocompromised patients [Ten Napel et al, 1984;Emery, 2001], especially after orthotopic liver transplantation (OLT) [Bronsther et al, 1988;Singh et al, 1988;Paya et al, 1990;Stratta et al, 1992;Barkholt et al, 1994;Brainard et al, 1994]. HCMV liver infection also occurs after bone marrow (BMT) or stem cell transplantation (SCT), although less frequently [Reusser, 1991[Reusser, , 1996Einsele et al, 1994;Hebart et al, 1998]. Hepatitis is one of the predominant manifestations of HCMV primary infection in the immunocompetent host [Snover and Horwitz, 1984;Ten Napel et al, 1984;Laskus et al, 1990;Alford and Britt, 1993;Funato et al, 2001].…”