Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited. Serum Nitric Oxide Levels in Patients With Benign and Malignant Biliary Disease A Prospective Single Center Study Yavuz Beyazit, MD,* Abdurrahim Sayilir, MD,* Seyfettin Koklu, MD,w Serkan Torun, MD,* Burak Suvak, MD,* Adnan Tas, MD,w Tugrul Purnak, MD,z Ismail H. Kalkan, MD,* Yusuf Yesil, MD,* and Mehmet Ibis, MD* Background: Despite advances in new diagnostic modalities, the differentiation of malignant from benign causes of biliary obstruction still remains difficult. The nitric oxide (NO) system is considered to be an important component in mediating cytokine activation of mac- rophages in inflammation. It also modulates tumorigenesis and reg- ulates cell proliferation, angiogenesis, survival, and DNA repair. Although NO and its role in pancreatobiliary disorders has not been studied previously, the present study is designed to evaluate NO synthesis and metabolism in patients with biliary obstruction and to determine its usefulness in differentiating between benign and malignant causes of biliary obstruction. Materials and Methods: Seventy-nine consecutive patients (60 malignant and 19 benign) with a history of biliary obstruction either with a benign or a malignant cause and 23 age-matched and sex-matched controls were included in this prospective study. NO metabolites, and conventional inflammation and tumor markers were determined. Results: In patients with malignant biliary obstruction (MBO), serum NO metabolites were found to be significantly elevated (P < 0.001). The receiver operating characteristic analysis showed that an NO level of 1.095 was the best cut-off value for predicting a malignant biliary stricture with a sensitivity of 78.3% and a spe- cificity of 84.2% (area under the curve = 0.821). Correlation analysis suggested that carbohydrate antigen 19-9 and carcinoem- bryonic antigen levels were correlated with NO levels for differ- entiating benign from malignant cause of biliary obstruction. Conclusions: Serum NO-associated tissue injury might be associated with the development of pancreatobiliary neoplasia by creating a local environment that is enriched with reactive oxygen species, cytokines, and other growth factors that may promote endothelial cell apoptosis. Moreover, serum NO levels may be used as an adjunctive marker to identify malignant causes of the obstructive jaundice. Key Words: nitric oxide, nitrite, oxidative stress, biliary obstruction (J Clin Gastroenterol 2012;00:000–000) B ile duct obstruction, which is an interruption of bile flow from the liver to the small intestine, may occur at any level within the biliary system, and may result from intraluminal or extraluminal benign or malignant causes. 1 Although physical findings and laboratory work-up with endoscopic and radiologic modalities such as endoscopic retrograde cholangiopancreatography (ERCP) and mag- netic resonance cholangiopancreatography may be useful for clinicians to differentiate benign from malignant causes of biliary obstruction, the differential diagnosis is not always easy. 2 In this context, carbohydrate antigen (CA 19-9) and carcinoembryonic antigen (CEA) are the most com- monly used tumor markers, with a lack of high sensitivity and specificity. 3 The adjunctive use of additional markers may be significantly beneficial for diagnostic accuracy. For this reason, additional markers such as nitric oxide (NO) measurement may be valuable to achieve a better diagnostic result. Moreover, evaluation of the role of NO in disease pathophysiology may provide new therapeutic avenues for disease management. Subclinical inflammation in the tumor microenviron- ment contributes toward the proliferation and survival of malignant cells, modulating apoptosis along multiple path- ways. In this context, NO seems to be directly involved in this process as a tumor inducer through its role in DNA dam- age. 4,5 NO as a mediator of cytokine activation is produced by cytokine-activated cells in inflammation. Neutrophils and macrophages generate NO by NO synthase that is inducible by endotoxin and various cytokines. It is a highly reactive molecule that possesses proinflammatory and anti-inflam- matory effects depending on its concentration and the source. 6 Moreover, it is potentially cytotoxic to the host, because it can react with superoxide and form peroxynitrite, which has been implicated in a variety of immunopathologic situations including septic shock, necrotizing pancreatitis, autoimmune disorders, and atherosclerosis. 7–10 However, the data in this field are limited and present inconsistent results in different parameters. To the best of our knowledge, there is no study in the literature evaluating the diagnostic role of NO in biliary obstructions. In view of the potential implications of these data, we carried out a prospective study to assess serum NO levels and its correlation with other tumor markers in patients with biliary obstruction. In addition, we also discussed whether these endogenous molecules are associated with the pathogenesis of malignant causes of biliary disorders. MATERIALS AND METHODS We carried out a prospective study of 79 patients diagnosed with biliary obstruction because of a malignant Received for publication December 29, 2011; accepted June 8, 2012. From the *Department of Gastroenterology, Turkiye Yuksek Ihtisas Education and Research Hospital; wDepartment of Gastro- enterology, Ankara Training and Research Hospital; and zDepartment of Gastroenterology, Ankara Numune Education and Research Hospital, Ankara, Turkey. The authors declare that they have nothing to disclose. Reprints: Adnan Tas, MD, Feneryolu sokak 19/16 As ¸ag˘ıeylence, Etlik, Kec ¸io¨ren, Ankara, Turkey (e-mail: dradnantas@gmail.com). Copyright r 2012 by Lippincott Williams & Wilkins ORIGINAL ARTICLE J Clin Gastroenterol  Volume 00, Number 00, ’’ 2012 www.jcge.com | 1