Cytomegalovirus infection of bile duct epithelial cells, hepatic artery and portal venous endothelium in relation to chronic rejection of liver grafts

Abstract

Background/Aim: Chronic rejection is an important cause of graft loss following liver transplantation. A number of risk factors for chronic rejection have been identified previously, albeit inconsistently. These include cytomegalovirus infection detected by a number of different techniques, including immunohistochemical staining and in situ hybridisation of liver grafts. However, tissue-based techniques for the detection of CMV have not been applied to grafts lost to conditions other than chronic rejection. The purpose of this study was to investigate the relationship between the presence of cytomegalovirus infection detected by in situ hybridisation and immunohistochemistry with respect to graft outcome, the presence of cytomegalovirus infection detected by other techniques and in addition, the type of infected cell. Methods: The 29 patients studied included 15 patients who lost their primary liver graft to chronic rejection in 8 cases, to hepatic artery thrombosis in 4 cases and to causes other than chronic rejection or hepatic artery thrombosis in 3 further cases. In each case, sections containing septal or large ducts and vessels were selected (usually blocks) since these may be more representative. Needle biopsies from 14 further patients who ultimately achieved satisfactory graft function served as control tissue. Of these, ten had evidence of cytomegalovirus infection at the time of study by serum/urine PCR, DEAFF testing or seroconversion, while 4 patients had no evidence of cytomegalovirus infection according to these techniques. Results: Cytomegalovirus infection was detected in the liver of 12 of the 29 patients. These included 8/15 grafts lost, which comprised 3/8 with chronic rejection, 2/3 with hepatic artery thrombosis and 3/4 with grafts lost to other causes, as well as 4/14 who retained grafts. CMV was detected most commonly in association with symptomatic infection and notably was detected only by in situ hybridisation in two cases. Predominant cell types that contained cytomegalovirus were hepatocytes and mononuclear cells. However, bile duct epithelial cells, hepatic artery endothelial cells and portal venous endothelial cells also contained cytomegalovirus in some cases. Conclusions: These data support previous studies that cytomegalovirus infection is detectable in patients with chronic rejection and are consistent with the theory that CMV is involved in chronic rejection. However, cytomegalovirus infection was detected in explanted grafts lost to conditions other than chronic rejection, and the association may not be causal but a consequence of graft injury.