Association between Systemic Diseases and Apical Periodontitis Navid Khalighinejad, DDS,* M. Reza Aminoshariae, MD, † Anita Aminoshariae, DDS, MS,* James C. Kulild, DDS, MS,* Andre Mickel, DDS, MSD,* and Ashraf F. Fouad, DDS, MS ‡ Abstract Introduction: To date, the relationships between sys- temic diseases and periapical microbial infection remain unknown. Thus the purpose of this systematic review was to evaluate the relationship between host modifying factors and their association with endodon- tic pathosis. Methods: Two reviewers independently conducted a comprehensive literature search. The MEDLINE, Embase, Cochrane, and PubMed databases were searched. In addition, the bibliographies of all relevant articles and textbooks were manually searched. There was no disagreement between the 2 reviewers. Results: Sixteen articles were identified and included. The overall quality of the studies and the risk of bias were rated to be moderate. Only 3 studies demonstrated a low level of bias. Conclusions: The results of this review suggest that there may be a moderate risk and correlation between some systemic diseases and endodontic pathosis. More prospective and longitudinal research in this area is warranted to determine greater specificity in these possible interac- tions to potentially decrease or minimize the effects of systemic disease on the formation of apical periodonti- tis. (J Endod 2016;42:1427–1434) Key Words Correlation, endodontic pathosis, pathogenesis, system- atic review, systemic diseases M any associated risk factors are shared by systemic diseases and oral infections that could confound a relationship between them (1–3). As these studies have noted, periodontal disease has received considerable interest when these relationships were studied. Endodontic infections have received much less attention, despite the fact that many of microbial pathogens are common in those 2 diseases. Khader (4) conducted a study to investigate factors that were associated with peri- odontal patients. The author reported that increased age, low level of education, increased plaque index score, not routinely brushing their teeth, smoking more than 15 pack-years, and having diabetes were significantly associated with increased severity of periodontal disease. These are all clearly risk factors for cardiovascular disease as well, and the degree to which they have been controlled for in the aforementioned studies has been mixed. Several systemic diseases were found to affect the outcome of endodontic treat- ment. Diabetes mellitus was found to be associated with significantly reduced endodon- tic treatment outcome of teeth with preoperative infections, suggesting that diabetes may serve as a disease modifier (5, 6). Also, both diabetes and hypertension were found to be associated with reduced survival of endodontically treated teeth (7). Therefore, at this time, systemic conditions and disorders can be considered modulating factors affecting oral infection progression rather than acting as the causative etiologic factor (1, 8, 9). A number of observational studies (8, 10–12) and a longitudinal cohort study (13) have described, at least in part, a possible association between systemic involve- ment and endodontic periapical infection. However, one case-control study did not identify a correlation between periapical infection and atherosclerotic disease. Those authors also reported that calcified carotid artery atheromas observed in radiographs had a greater burden of chronic dental infection specifically with advanced mesial and distal periodontal bony defects $4 mm (14). To date, the role of systemic medical conditions as a modulating factor in the development of endodontic periapical infection has been a subject of controversy with authors who found a strong association (15–17) and those who found weak to no association (8, 14, 18). A recent systematic review reported that although the evidence is limited, endodontic periapical infection and certain molecular markers of systemic inflammation could be closely related (19). Another systematic review examining the relationship between polymorphism and apical pathosis also suggested a plausible relationship between genetic polymorphism and apical pathosis (20). Therefore, the purpose of this systematic review was to evaluate the pathogenesis and scientific evidence reporting any relationships between lesion of endodontic origin and risk of systemic diseases. From the *Department of Endodontics, School of Dental Medicine, Case Western Reserve University, Cleveland, Ohio; † Department of Medicine, International American University College of Medicine, Banse, St Lucia; and ‡ Department of End- odontics, School of Dentistry, University of North Carolina, Chapel Hill, North Carolina. Address requests for reprints to Dr Anita Aminoshariae, 2123 Abington Road A 280, Cleveland, OH 44106. E-mail address: AAminoshariae@yahoo.com 0099-2399/$ - see front matter Copyright ª 2016 American Association of Endodontists. http://dx.doi.org/10.1016/j.joen.2016.07.007 Significance One of the current clinical healthcare challenges is to lower costs by controlling factors that may lead to systemic disease. If a definite cause-effect rela- tion is confirmed between endodontic pathosis and systemic diseases, oral healthcare providers might be able to help lower the cost of treating such disease by prevention of chronic oral infec- tions. The current systematic review reported that there may be moderate risk and correlation be- tween systemic diseases and endodontics. Review Article JOE — Volume 42, Number 10, October 2016 Pathogenesis of Endodontics and Systemic Disease 1427