Periodontal Disease and Age-Related Macular Degeneration: A Novel Hypothesis for a Complex Disease
Age-related macular degeneration (AMD) is a complex disease with a multifactorial etiology, and is a leading cause of irreversible vision loss in the elderly.1 Cellular damage due to age-associated changes from oxidative stress has been proposed as one of the pathogenic mechanisms in AMD. The body’s immune response to the changes caused by oxidative stress further aggravates cellular damage, and may lead to advanced stages of AMD that manifest as geographic atrophy, choroidal neovascularization, or both.2
An inflammatory/infectious etiology underlying the pathogenesis of AMD has been studied widely.3 Elevated inflammatory markers such as C-reactive protein (CRP) have been associated with AMD.4,5 Similarly, the association between infections and AMD has been documented previously.
Infections with Cytomegalovirus (CMV), Helicobacter pylori (H. pylori), and Chlamydia pneumoniae (C. pneumoniae) have been shown to be associated with AMD.6,7 In one study, C. pneumoniae was isolated from choroidal neovascular membranes (CNVM) excised from eyes with AMD. These microbes were capable of inducing increased production of pro-inflammatory cytokines, such as interleukin-8 (IL-8), monocyte chemotactic protein-1 (MCP-1), and vascular endothelial growth factor (VEGF).6 Persistent infection and the resulting inflammation may further potentiate the risk for developing advanced stages of AMD.
Periodontal Disease and AMD
The association between periodontal disease and AMD is a novel theory related to the inflammatory/infectious hypothesis. Recent studies have shown that periodontal disease is significantly associated with an increased risk of AMD in certain populations. A cross-sectional study from Finland by Karesvuo et al reported an increased risk of AMD in males with periodontal disease; this significance was not present in women.8
Similarly, a recently published cross-sectional analysis of data from the National Health and Nutrition Examination Survey in the United States found an independent association between periodontal disease and AMD in individuals ≤ 60 years of age. While this association was present in both men and women, the significance was lost in individuals > 60 years of age. The authors hypothesized that increasing age resulted in increased influence of covariates, thus diluting the effects of periodontal disease on AMD in the older age group.9
Periodontal disease is a highly prevalent, infectious, and inflammatory condition.10 As its prevalence increases with age, periodontal disease can range from simple inflammation of the gingiva — in its less severe and reversible form called gingivitis — to loss of supporting connective tissue and alveolar bone in more advanced forms.11 The accumulation of bacterial biofilms (more commonly known as dental plaque) adjacent to the gums results in bacteria-induced inflammation and eventual damage of the periodontal tissues, leading to the formation of periodontal pockets. These pockets expose bacterial biofilms to the circulation.12
There are more than 500 distinct microorganisms in the human oral cavity, and exposure of these organisms and their biologically active compounds into the circulation, alongside chronic local periodontal inflammation, can lead to increased systemic inflammation.13
The association between periodontal disease and other inflammatory systemic conditions, particularly cardiovascular disease, has been well established.14 Many of the risk factors associated with atherosclerotic vascular disease (ASVD) have also been identified to be independently associated with AMD.15 Further, histopathological analyses of atherosclerotic plaques have identified organisms similar to those observed in CNVM excised from eyes with AMD.16,17
The direct pathway (vascular infection by a periodontal pathogen) and indirect pathway (systemic inflammation or molecular mimicry) in the development of ASVD share similarities to the mechanisms hypothesized in the infection and the subsequent inflammatory reaction in AMD. Furthermore, compositional and histological similarities between drusen in AMD and plaques in ASVD lend further support to this inflammatory/infectious theory.18
While there is robust research investigating the inflammatory nature behind the development and progression of AMD, we are only beginning to identify and understand the link between periodontal disease and AMD. Studies have identified independent associations between the two conditions, but additional research is necessary.
As the link between periodontal disease and AMD continues to be investigated, it is important to encourage good oral health habits for patients at risk for AMD. Good oral health is beneficial regardless of its connection to systemic disease and, given the emerging evidence, it might also aid in preventing the development and progression of AMD.
Reference(s):1. Congdon N, O’Colmain B, Klaver CC, et al; Eye Diseases Prevelance Research Group. Causes and prevalence of visual impairment among adults in the United States. Arch Ophthalmol. 2004;122:477-485.
2. Jager RD, Mieler WF, Miller JW. Age-related macular degeneration. N Engl J Med. 2008;358:2606-2617.
3. Barouch FC, Miller JW. The role of inflammation and infection in age-related macular degeneration. Int Ophthalmol Clin. 2007;47:185-197.
4. Seddon JM, Gensler G, Milton RC, Klein ML, Rifai N. Association between C-reactive protein and age-related macular degeneration. JAMA. 2004;291:704-710.
5. Hong T, Tan AG, Mitchell P, Wang JJ. A review and meta-analysis of the association between C-reactive protein and age-related macular degeneration. Surv Ophthalmol. 2011;56:184-194.
6. Kalayoglu MV, Bula D, Arroyo J, Gragoudas ES, D’Amico D, Miller JW. Identification of Chlamydia pneumoniae within human choroidal neovascular membranes secondary to age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 2005;243:1080-1090.
7. Robman L, Mahdi OS, Wang JJ, et al. Exposure to Chlamydia pneumoniae infection and age-related macular degeneration: the Blue Mountains Eye Study. Invest Ophthalmol Vis Sci. 2007;48:4007-4011.
8. Karesvuo P, Gursoy UK, Pussinen PJ, et al. Alveolar bone loss associated with age-related macular degeneration in males. J Periodontol. 2013;84:58-67.
9. Wagley S, Marra KV, Salhi RA, et al. PERIODONTAL DISEASE AND AGE-RELATED MACULAR DEGENERATION: Results from the National Health and Nutrition Examination Survey III. Retina. 2015;35:982-988.
10. Eke PI, Dye BA, Wei L, et al; CDC Periodontal Disease Surveillance workgroup. Prevalence of periodontitis in adults in the United States: 2009 and 2010. J Dent Res. 2012;91:914-920.
11. Pihlstrom BL, Michalowicz BS, Johnson NW. Periodontal diseases. Lancet. 2005;366:1809-1820.
12. Hujoel PP, White BA, Garcia RI, Listgarten MA. The dentogingival epithelial surface area revisited. J Periodontal Res. 2001;36:48-55.
13. Moore WE, Moore LV. The bacteria of periodontal diseases. Periodontol 2000. 1994;5:66-77.
14. Lockhart PB, Bolger AF, Papapanou PN, et al. Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association. Circulation. 2012;125:2520-2544.
15. Arroyo JG. A 76-year-old man with macular degeneration. JAMA. 2006;295:2394-2406.
16. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ. Identification of periodontal pathogens in atheromatous plaques. J Periodontol. 2000;71:1554-1560.
17. Rosenfeld ME, Campbell LA. Pathogens and atherosclerosis: update on the potential contribution of multiple infectious organisms to the pathogenesis of atherosclerosis. Thromb Haemost. 2011;106:858-867.
18. Donoso LA, Kim D, Frost A, Callaghan A, Hageman G. The role of inflammation in the pathogenesis of age-related macular degeneration. Surv Ophthalmol. 2006;51:137-152.
About our author(s):
College of Human Medicine,
Michigan State University
Jorge G. Arroyo, MD, MPH
Harvard Medical School, Boston
Division of Ophthalmology,
Beth Israel Deaconess
Medical Center, Boston