Oral-Periodontal and Systemic Relationships: Part I—Cardiovascular and Diabetes

The body is a complex structure composed of numerous biological processes. The mouth is a part of the body and is the window to its health,¹ indicating that oral health is inextricably linked to systemic health. Health is defined not only as the absence of disease but being in a state of complete physical, mental, and social well-being.² When the mouth is unhealthy, so too is the body. In 1900, Hunter introduced the concept of oral sepsis to the medical community and described the link between oral infection and systemic disease.³

Today, the medical and dental community is aware that maintaining optimal oral health is a crucial part of achieving and maintaining overall health. The oral cavity receives blood supply, innervation, and lymphatics from blood vessels, nerves, and components of the immune and circulatory systems that serve other parts of the body.

A detailed examination of the oral cavity can help provide the oral healthcare practitioner with information on oral diseases, lesions, and abnormalities to help discern systemic diseases, nutritional deficiencies, disorders of the immune system, and certain cancers.⁴ In 1996, Offenbacher coined the term periodontal medicine,⁵ which is a branch of periodontology that focuses on the strong associations between periodontal health and systemic health. Another periodontist, Miller, founded the American Academy of Oral Medicine in 1945 and the American Board of Oral Medicine in 1956.⁶

Periodontal disease is perhaps the most common chronic infection⁷ and is caused by dental plaque. Dental plaque is the well-organized, heterogeneous structure composed of microbial pathogens, which are the primary etiologic agents for periodontal disease.

The two main forms of the disease are gingivitis and periodontitis, arising from pathologic inflammatory processes triggered by an accumulation of dental plaque. The more common of the two, gingivitis, is reversible.⁸ Periodontitis, which is a destructive, irreversible, chronic inflammation, results in a loss of the underlying bone and connective tissue supporting the teeth.⁸

More than 500 microbial species have been implicated as primary etiologic agents.⁹ Despite the potential for many pathogens to be associated with periodontal disease, a small number are most frequently linked with the condition. Socransky et al¹⁰ divided the pathogens into red and orange complexes. The red complex includes the following Gram-negative anaerobic pathagens: Porphyromonas gingivalis, Treponema denticola, and Tanneralla forsythia. The orange complex includes Fusobacterium nucleatum, Prevotella intermedia, Prevotella nigrescens, Peptostreptococcus micros, Campylobacter rectus, Centruroides gracilis, Campylobacter showae, Eubacterium nodatum, and Streptococcus constellatus. Other microbial pathogens highly associated with periodontal disease are Aggregatibacter actinomycetemcomitans and Eikenella corrodens.

The putative periodontal pathogens reside in the gingival tissue collar of the tooth, forming the periodontal pocket.¹¹ An ulceration of the periodontal gingival pocket is a pathway for the spread of dental plaque into the systemic circulation.¹² The plaque biofilm’s presence triggers the activation of an inflammatory response, resulting in the production of inflammatory cytokines and mediators, such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor-alpha (TNF-α).¹³ These mediators, whose effects are also systemic, are the means by which periodontal disease may increase one’s susceptibility to systemic diseases.^14,15

Although dental plaque is the main cause for developing the disease, the condition also has several risk factors, including age, genetics, medication use, poor nutrition, obesity, other systemic disease, bruxism, and smoking.¹⁶ Smoking may be one of the most significant risk factors because of its negative impacts on periodontal health.^17,18 People under psychological stress may also be at an increased risk¹⁹ because this population may be less likely to perform optimal oral hygiene. The interactions of pathogenic microbes, a susceptible host, and the presence of risk factors elicit an immune-inflammatory response, which causes an impact on connective tissue and bone metabolism, ultimately resulting in periodontal disease. The activation of an inflammatory response and the subsequent production of mediators are all means by which periodontal disease may affect a person’s susceptibility to systemic diseases.

Periodontal Medicine

Periodontal disease is thought to be a risk factor associated with several systemic diseases and conditions. Cardiovascular disease, stroke, and diabetes will be discussed in this article.

Cardiovascular Disease

Cardiovascular disease refers to a group of disorders associated with the heart and vasculature and includes hypertension, coronary heart disease, congestive heart failure, heart valve diseases, stroke, and myocardial infarction.²⁰

Atherosclerotic disease, or hardening of the arteries, can affect different vessels in the body. When it impacts the arteries of the heart, it is called coronary heart disease and is manifested by heart attack and angina pectoris. When it affects the vessels of the brain, it is called cerebrovascular disease and is manifested by stroke. When atherosclerosis occurs in the arteries of the legs, arms, and organs, it is called peripheral arterial disease.

Atherosclerotic disease is a specific type of atherosclerosis in which the walls of a vessel thicken as a result of the invasion and accumulation of white blood cells, cellular waste products, cholesterol, and triglycerides. Plaques, or atheromas, can form.²¹

Periodontal microbial pathogens such as P gingivalis, T denticola,C rectus, and A actinomycetemcomitans have been isolated from atherosclerotic plaques and in the arterial walls of coronary arteries.²⁰ P gingivalis has also been isolated in higher concentrations in patients with more severe periodontitis compared with those with milder disease.²² It has been suggested that the lipopolysaccharides found on the cell walls of Gram-negative periodontal pathogens such as P gingivalis stimulates an inflammatory response through the release of inflammatory cytokines such as interleukin and TNF-α in the walls of coronary blood vessels.²³ The presence of IL-6 has been observed to be an important prognostic factor for an occurrence of a major cardiovascular event.²⁴

Stroke

Poor oral health and periodontal disease have been found to be risk factors for cerebrovascular disease, especially in ischemic stroke.^25-27 Poor oral health, especially periodontal disease that increases the level of C-reactive protein (CRP), a marker for systemic inflammation, has been found to be a risk factor for stroke.²⁸ P gingivalis has been found in atherosclerotic plaques from ischemic stroke.²⁹ Studies have suggested that periodontal pathogens such as P gingivalis induce an inflammatory response by eliciting macrophages to produce and secrete proinflammatory cytokines, such as IL-1, IL-6, and TNF-α. These cytokines stimulate the production of acute-phase proteins, such as fibrinogen, which plays a role in arterial clot formation, contributing to atherosclerotic events.³⁰ Such events may result in ischemic stroke/cerebral vascular accident.

Diabetes

Diabetes mellitus is a group of metabolic diseases in which high blood-glucose levels occur for a prolonged period.³¹ The onset of diabetes is preceded by inflammation, leading to pancreatic beta-cell dysfunction and eventual apoptosis.³² The disease is associated with alterations in carbohydrate, fat, and protein metabolism as a result of defects in insulin secretion by the pancreas, beta cells of the body not responding properly to the insulin that is produced by the pancreas, or both.³¹ Long-term, poorly controlled disease can result in damage, dysfunction, or failure of various organs and systems.³¹ The goal of treatment for some patients is to maintain blood-glucose levels at 7% or lower, as measured by a laboratory test known as HbA1C, which assesses glycemic control over time.³³

The main types of diabetes are type 1, type 2, and gestational diabetes. Type 1 diabetes is an autoimmune disease³⁴ and is characterized by the body’s inability to produce enough insulin. The body’s immune system attacks and destroys pancreatic beta cells, the cells that produce insulin.³⁵ Over time, chronic hyperglycemia develops. Type 2 diabetes, the most common form, usually starts as insulin resistance, which means certain cells of the body, specifically muscle, fat, and liver cells, do not respond properly to the insulin being made.^35,36 This results in glucose building in the blood instead of being absorbed. Over time, as the body’s need for insulin increases, the pancreas slowly loses its ability to produce insulin. Risk factors for type 2 diabetes include excess weight, obesity, age, family history, physical inactivity, metabolic syndrome, and race/ethnicity.³⁵ Gestational diabetes occurs in pregnant women who have no history of diabetes but develop high blood-glucose levels.³⁵

Periodontitis is associated with an increased risk for diabetic complications. Studies have shown a direct relationship between the severity of periodontitis and complications of type 2 diabetes.³² Moderate-to-severe periodontitis is associated with an increased risk for macroalbuminuria, end-stage renal disease, calcification of atherosclerotic plaques, thickening of carotid vessels, and cardio-renal mortality.³² Researchers have found that patients with diabetes and periodontitis had more cardiovascular, cerebrovascular, or peripheral vascular events compared with diabetics without periodontal disease.³⁷ Others have found that the death rate from ischemic heart disease is 2.3 times higher in those with severe periodontitis than those without periodontitis or mild periodontitis.³⁸

Inflammation is the central mechanism that links periodontal disease and diabetes. It has been suggested that type 2 diabetes is a manifestation and exaggeration of the host’s inflammatory response due to a cytokine-induced acute-phase response to the periodontal microflora.³⁹ Type 1 and type 2 diabetes are both associated with increased levels of systemic inflammatory markers.⁴⁰ Increases in inflammatory markers such as IL-6 and TNF-α have been found in the obese and those with diabetes.⁴⁰ These inflammatory cytokines are also associated with periodontal inflammatory disease and are the main ones associated with up-regulation of acute-phase proteins, such as CRP. Increases in CRP levels have been linked with insulin resistance, type 2 diabetes, and cardiovascular disease.⁴¹ IL-6 and CRP levels are also elevated in patients with periodontitis, with the levels of IL-6 correlating with disease severity in periodontitis.⁴²

Bidirectionally, diabetes increases inflammation in periodontal tissues. PGE2 and IL-1β are elevated in patients with type 1 diabetes who have either gingivitis or periodontitis compared with patients without diabetes with the same degree of periodontal disease.⁴³ Research has shown that patients with diabetes and severe periodontitis have depressed neutrophil function, specifically a reduction in polymorphonuclear activity, impairment with chemotaxis, and phagocytosis, allowing bacteria to persist in the periodontal gum pocket; thus, these patients exhibit a significant increase in destruction of the periodontal attachment apparatus compared with diabetic patients with mild periodontitis.^44,45 There is a prolonged inflammatory response to P gingivalis as denoted by an increase in production of IL-6 and TNF-α in patients with diabetes compared with those without diabetes.^45,46 These altered host-defense mechanisms and increases in proinflammatory mediators in patients with diabetes result in an increase in the level of peridontal inflammation present as well as contribute to increased insulin resistance and poor diabetic metabolic glycemic control.^45,47,48 Improving periodontal health through treatment has shown to reduce the levels of inflammatory mediators, such as IL-6, TNF-α, and CRP in patients with and without diabetes.^49,50 In addition, it has been suggested that enhanced apoptosis may contribute to periodontitis as a complication of diabetes, rendering the effect of delayed wound healing.^51,52

Conclusion

Although more research regarding cause and effect is needed, many researchers have established an association between periodontal disease and cardiovascular disease, stroke, and diabetes. Periodontal disease is a chronic infection that contributes to an inflammatory response in the oral cavities of susceptible individuals. Support has been provided describing plausible biologic mechanisms by which periodontal disease may also contribute to the chronic systemic inflammatory burden. A vast amount of data shows an association between periodontal disease and these conditions. Additional randomized, controlled studies are needed to demonstrate causality. Also, prospective, randomized controlled efficacy studies are necessary. Future studies may show the efficacy of periodontal therapy related to positive outcomes with regard to these conditions.

ABOUT THE AUTHOR

Dr. Glascoe is an associate professor in the Department of Periodontics and Preventive Services at Howard University College of Dentistry, Washington, DC.

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