Gregory J. Gores

Chronic infection and inflammation are risk factors for the development of cholangiocarcinoma, a highly malignant, generally fatal adenocarcinoma originating from biliary epithelia. However, the link between inflammation and carcinogenesis in these disorders is obscure. Because nitric oxide (NO) is generated in inflamed tissues by inducible nitric oxide synthase (iNOS) and because DNA repair proteins are potentially susceptible to NO-mediated nitrosylation, we formulated the hypothesis that inflammatory cytokines induce iNOS and sufficient NO to inhibit DNA repair enzymes leading to the development and progression of cholangiocarcinoma. iNOS and nitrotyrosine were demonstrated in 18/18 cholangiocarcinoma specimens. Furthermore, iNOS and NO generation could be induced in vitro by inflammatory cytokines (mixture of interleukin-1beta, IFN-gamma, and tumor necrosis factor alpha) in three human cholangiocarcinoma cell lines. NO-dependent DNA damage as assessed by the comet assay was demonstrated during exposure of the three cholangiocarcinoma cell lines to cytokines. Moreover, global DNA repair activity was inhibited by 70% by a NO-dependent process after exposure of cells to cytokines. Our data indicate that activation of iNOS and excess production of NO in response to inflammatory cytokines cause DNA damage and inhibit DNA repair proteins. NO inactivation of DNA repair enzymes may provide a link between inflammation and the initiation, promotion, and/or progression of cholangiocarcinoma.

Nonanastomotic biliary strictures that involve only the biliary tree of the graft occur after orthotopic liver transplantation in patients with hepatic artery thrombosis, chronic ductopenic rejection and ABO blood group incompatibility. This complication may also occur in the absence of these known risk factors. The major focus of our study was to evaluate the risk factors for nonanastomotic biliary stricturing of unknown cause after orthotopic liver transplantation. Results demonstrate that the development of biliary strictures is strongly associated with the duration of cold ischemic storage of allografts in both Euro-Collins solution and University of Wisconsin solution. Results also demonstrate that strictures are not associated with the type of biliary reconstruction, the primary liver disease, cytomegalovirus infection, allograft rejection or the presence of a positive lymphocytotoxic crossmatch. More recently, we have markedly reduced the occurrence of nonanastomotic biliary stricturing by decreasing the ischemia time of our allografts. Thus nonanastomotic biliary strictures appear to be the result of the ischemia/reperfusion-induced tissue injury associated with the harvest and implantation of allografts.

OBJECTIVES: The diagnosis of cholangiocarcinoma is often difficult, making management approaches problematic. A reliable serum tumor marker for cholangiocarcinoma would be a useful additional diagnostic test. Previous studies have demonstrated that elevated serum concentrations of CA 19-9, a tumor-associated antigen, have good sensitivity and specificity for cholangiocarcinoma in patients with primary sclerosing cholangitis. However, the value of this tumor marker for cholangiocarcinoma unassociated with primary sclerosing cholangitis is unclear. Thus, the aims of this study were to determine the usefulness of a serum CA 19-9 determination in the diagnosis of de novo cholangiocarcinoma. METHODS: We prospectively measured serum CA 19-9 concentrations in patients with cholangiocarcinoma (n = 36), nonmalignant liver disease (n = 41), and benign bile duct strictures (n = 26). Serum CA 19-9 concentrations were measured by an immunoradiometric assay (CIS Bio International) without knowledge of the clinical diagnosis. RESULTS: The sensitivity of a CA 19-9 value >100 U/ml in diagnosing cholangiocarcinoma was 53%. When compared with the nonmalignant liver disease and the benign bile duct stricture groups, the true negative rates were 76% and 92%, respectively. Patients with unresectable cholangiocarcinoma had significantly greater mean CA 19-9 concentrations compared to patients with resectable cholangiocarcinoma. CONCLUSIONS: These data suggest that the serum CA 19-9 determination is a useful addition to the available tests for the differential diagnosis of cholangiocarcinoma.