Role of Appendicitis and Appendectomy in the Pathogenesis of Ulcerative Colitis: A Critical Review *Ioannis E. Koutroubakis, †Ioannis G. Vlachonikolis, and *Elias A. Kouroumalis *Department of Gastroenterology, University Hospital of Heraklion, Crete; and †Department of Social Medicine, University of Crete, Crete, Greece Summary: Besides a genetic predisposition, a causal role of various environmental factors has been considered in the eti- ology of ulcerative colitis (UC). The association between ap- pendectomy and UC has recently been the subject of intense scrutiny in the hope that it may lead to the identification of important pathogenetic mechanisms. Published data from ani- mal models of colitis demonstrated reduction in experimental colitis after appendectomy, especially if performed at an early age. Several epidemiological case control and cohort studies have shown a strong and consistent relationship. The metaan- alysis of 17 case-controlled studies showed an overall odds ratio 0.312 (95% confidence intervals  0.261–0.373) in favor of appendectomy (p < 0.0001). One of the two recent large cohort studies is in agreement with these results, but the other failed to confirm them. All these studies have suggested that alterations in mucosal immune responses leading to appendi- citis or resulting from appendectomy may negatively affect the pathogenetic mechanisms of UC. Further investigation of the role of appendectomy in UC is expected to open new fields for basic scientific research and may lead to the improvement of our understanding for the disease pathogenesis. Key Words: Appendicitis—Appendectomy—Epidemiology—Mucosal im- munity—Ulcerative colitis. INTRODUCTION The etiology of ulcerative colitis (UC) is believed to be multifactorial. Genetically susceptible subjects de- velop the disease, which may be triggered by environ- mental factors, and perpetuated by an abnormal host im- mune response (1). Numerous epidemiological studies have been performed to determine environmental risk factors that might contribute to the development of UC. The significant geographic variation in UC incidence, the increased incidence of UC in urban areas in comparison to rural areas, and the low rate in concordance of mono- zygotic twins are epidemiological observations suggest- ing an important role for factors such as diet, lifestyle, or infections (2,3). The most consistent associations that have been found so far are the inverse relationships of UC with smoking habits (4–6) and a history of appen- dectomy (7–20). Recently the association between ap- pendectomy and UC has been a subject of intense scru- tiny in the hope that it may lead to the identification of important pathogenic mechanisms responsible for this relationship (21,22). To review and analyze the existing data in the literature, we identified all the studies con- cerning the role of appendectomy in UC published be- tween 1987–2001, using the MEDLINE and EMBASE databases. Reference lists from published articles, re- views, and abstracts from major gastrointestinal meet- ings were also reviewed. Based on these data, historical, epidemiological, methodological, clinical, experimental, and therapeutic aspects of this association are reported here. IS THE APPENDIX A VESTIGIAL ORGAN? The appendix is a highly vascular organ that embryo- logically arises from the cecum and represents an impor- tant part of the gut-associated lymphoid tissue system, together with Peyer’s patches and tonsils. However, for a long period it was considered as an evolutionary mis- fit; a redundant organ that served little, if any, purpose in humans. Recently it has been identified as an impor- tant component of mammalian mucosal immune func- Received January 14, 2002; accepted March 27, 2002. Address correspondence and reprint requests to Dr. I. E. Koutroubakis, Department of Gastroenterology, University Hospital Heraklion, P.O Box 1352, 71110 Heraklion, Crete, Greece. E-mail: ktjohn@her.forthnet.gr Inflammatory Bowel Diseases 8(4):277–286 © 2002 Crohn’s & Colitis Foundation of America, Inc. 277