NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 1 Internal Medicine Institute (F. Franceschi, G. Zuccalà, D. Roccarina), Internal Medicine and Gastroenterology (A. Gasbarrini), Catholic University of Rome, Policlinico A. Gemelli Largo A. Gemelli, 8‑00168 Rome, Italy. Correspondence to: F. Franceschi francesco.franceschi@ rm.unicatt.it Clinical effects of Helicobacter pylori outside the stomach Francesco Franceschi, Giuseppe Zuccalà, Davide Roccarina and Antonio Gasbarrini Abstract | The discovery of Helicobacter pylori infection in the stomach could be considered as one of the most important events of modern gastroenterology. Understanding of the natural history of many disorders of the upper gastrointestinal tract, including chronic gastritis, peptic ulcer disease, gastric cancer and MALT lymphoma, was altered by this discovery. Interestingly, epidemiological studies have also revealed a correlation between H. pylori infection and some diseases localized outside the stomach, especially those characterized by persistent and low‑grade systemic inflammation. Of note, H. pylori has an important role in iron deficiency anaemia, idiopathic thrombocytopenic purpura and vitamin B 12 deficiency. Moreover, the association of this bacterial pathogen with many other diseases, including hepatobiliary, pancreatic, cardiovascular and neurodegenerative disorders is currently under investigation. In this Review, we summarize the results of the most important studies performed to date surrounding the association of H. pylori infection with extragastric diseases, as well as the strength of the evidence. We also provide information concerning bacterial–host interactions and the mechanisms implicated in the pathogenesis of each of these extragastric diseases. Franceschi, F. et al. Nat. Rev. Gastroenterol. Hepatol. advance online publication 17 December 2013; doi:10.1038/nrgastro.2013.243 Introduction The discovery of H. pylori colonization of the stomach and its associated pathogenic effects is a crucial landmark in modern gastroenterology. Indeed, the natural history of many disorders of the upper gastrointestinal tract, such as chronic gastritis, peptic ulcer disease, gastric cancer and MALT lymphoma are all linked with the presence of this bacterium. 1 Since its discovery, many researchers have clearly demonstrated that approximately one-half of the worldwide population is infected with H. pylori and that its prevalence is mostly linked with socioeconomic status. 2,3 Epidemiological studies have also revealed a cor- relation between H. pylori infection and some diseases localized outside the stomach, especially those charac- terized by persistent and low-grade systemic inflam- mation (Box 1). 4,5 H. pylori has been suggested to affect the development and progression of multiple diseases outside the stomach through a variety of mechanisms including the following: the production of a low-grade inflammatory state; induction of molecular mimicry mechanisms by expressing proteins that mimic host pep- tides; and interference with the absorbance of different nutrients and drugs. 4,5 For this reason, a large number of papers have been published in this area during the past few years and the European Helicobacter Study Group dedicate a session to the extragastric manifestations of H. pylori infection each year during their international annual meeting. Considering the high number of papers published on these extragastric diseases, the scope of this Review is to summarize the results obtained by the most important studies published so far about a possible role of H. pylori in non-gastrointestinal diseases. Cardiovascular diseases Ischaemic heart disease Ischaemic heart disease (IHD) was the first extragastric disorder to be studied for a possible association with H. pylori infection. In 1994, Mendall et al. 6 reported an increased prevalence of H. pylori infection in patients with documented IHD when compared with healthy controls, even after adjustment for all known confounding factors, such as high blood pressure, high levels of cholesterol, dia- betes, smoking and current social class (odds ratio [OR] 2.15; P = 0.03). These findings stimulated many other researchers to investigate this association, either from the epidemiological or pathogenic point of view, some- times with discordant findings. A prospective study by Whincupp and co-workers showed that determining the association between H. pylori infection and myocardial infarction might be substantially confounded by the rela- tionship between H. pylori infection, social class and major cardiovascular risk factors. 7 Similar results were obtained by Rathbone et al. 8 in a case–control study involving 342 patients with acute myocardial infarction.On the other hand, Pasceri et al. 9 first introduced the concept that the correlation between H. pylori infection and IHD is more significant when the data are stratified for the presence of more virulent strains of H. pylori, such as those express- ing the cytotoxin CagA (cytotoxin associated gene A) (OR 3.8; 95% CI 1.6–9.1; P <0.001). Therefore, the reported epidemiological association seems to be limited to only a subgroup of patients infected with this bacterium. Competing interests The authors declare no competing interests. REVIEWS © 2013 Macmillan Publishers Limited. 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