Cytomegalovirus Infection Persists in the Liver Graft in the Vanishing Bile Duct Syndrome

Abstract

Cytomegalovirus infection is one factor implicated in the cause of the vanishing bile duct syndrome complicating liver transplantation. To further investigate the role of cytomegalovirus in this syndrome, we studied serial liver biopsy material by in situ hybridization for cytomegalovirus DNA using a highly sensitive technique that allows the localization of viral replication. Cytomegalovirus DNA was identified in hepatocytes in 10 of 12 patients with the vanishing bile duct syndrome, 1 of whom had no serological evidence of cytomegalovirus infection. It was also present in all 18 patients with uncomplicated cytomegalovirus infection but was not identified in any of 10 subjects with transplants who had neither complication. Nine of the patients in this series underwent a diagnostic liver biopsy at 1 wk and subsequently had cytomegalovirus infection develop; cytomegalovirus DNA was identified in liver tissue of all nine patients, indicating that cytomegalovirus replication commences at an early stage. In those with uncomplicated cytomegalovirus, infection occurred earlier (p less than 0.05) but was eliminated more quickly (p less than 0.0005), and the number of infected hepatocytes was greater (p less than 0.05) when compared with those with the vanishing bile duct syndrome; in these, cytomegalovirus DNA was detectable until death or retransplantation. Cytomegalovirus DNA was never identified in either biliary or endothelial tissue. These data indicate that the vanishing bile duct syndrome is associated with persistent cytomegalovirus replication within hepatocytes.

Intrahepatic cholestasis after liver transplantation

“…89 Other risk factors include lack of azathioprine (in the cyclosporine era), few histocompatibility leukocyte antigen A and B matches, and grafting a liver from a male donor into a female recipient. 60,89,90 A close relationship has also been found between CMV infection and chronic rejection, as previously mentioned 60,61 ; one study reported a persistent CMV genome in the bile ducts of patients with chronic rejection. 91 Ductopenic rejection is characterized histologically by progressive destruction of the small (interlobular and septal) intrahepatic bile ducts.…”

“…59 Indeed, CMV infection may be a risk factor for vanishing bile duct syndrome 59 and chronic liver graft rejection. 60,61 The latter suggestion is supported by in situ hybridization and immunohistochemistry findings of CMV in patients with chronic graft rejection. 62 However, the CMV may not be a causal factor, but rather a consequence of graft injury or an "innocent bystander."…”

Evolving concepts in the diagnosis, pathogenesis, and treatment of chronic hepatic allograft rejection

“…61 In addition, in a number of studies, CMV has been identified as a distinct risk factor for chronic rejection in liver transplantation. 28,53,61,62 Two of these studies have shown the persistence of CMV DNA in the epithelium of bile ducts and endothelial cells of chronically rejected hepatic allografts. 35,62 Although the mechanisms by which CMV infection may cause chronic rejection are uncertain, many investigators believe the combination of direct actions on in- …”

The Impact of Infection on Chronic Allograft Dysfunction and Allograft Survival After Solid Organ Transplantation

“…VBDS seems to be mediated by immunological factors (T cell-mediated cytotoxicity and alloantibodies) and may be triggered by initial ischemic injury (71). Persistence of CMV DNA in hepatocytes of liver allografts was found only in liver transplant recipients who developed VBDS (72). An increased risk of allograft loss or death has also been related to CMV infection after liver transplantation (45,(73)(74)(75).…”