The Oral-Systemic Relationship

Although periodontal diseases are well known as an oral problem, in the past decade, there has been a shift in perspective. Research has been focusing on the potential impact of periodontal diseases on systemic health. The relationship between periodontal inflammatory disease and systemic diseases such as cardiovascular disease, diabetes, respiratory disease and adverse pregnancy outcomes has been closely investigated. The basis for the biological mechanism of this relationship is beginning to emerge and further study may lead to an understanding of whether or not a true causal relationship exists.

Cardiovascular disease (CVD) is characterized by the build-up of inflammatory plaques that may cause thromboses and eventual myocardial infarction. Atherosclerosis is the term used for the thickening and hardening of the arteries that is produced by this plaque build-up. It represents a chronic inflammatory response that causes injury to the endothelium of elastic and muscular arterial tissue. One of the hallmarks of the early atherosclerotic lesion is the presence of neutrophils followed by monocytes and lymphocytes.10 These leukocytes can affect the vascular endothelial lining and can cause oxidation of low-density lipoprotein (LDL) levels. Monocytes are induced to become macrophages, which take up modified lipoproteins and become lipid-laden “foam cells.”11 The local inflammation is sustained by secreting chemical mediators, and the atherosclerotic lesion begins to bulge within the luminal wall. As this lesion progresses, the extracellular matrix is degraded by proteolytic enzymes and becomes susceptible to rupture. Thromboses can occur, occluding blood flow to the heart, which may eventually lead to infarction.

Since atherosclerosis is considered to be inflammatory in nature, identifying inflammatory markers that correlate with disease state is beneficial. One of the most recognized and consistent markers of systemic inflammation and poor cardiovascular prognosis is the acute-phase protein CRP.12,13 It is produced by the liver and released into the blood stream. It is positively correlated to IL-6, activates complement and accounts for LDL uptake by macrophages.14-16

It has been proposed that bacteria or viruses may directly infect atherosclerotic lesions contributing to the inflammatory process. Further, distant infections may increase systemic inflammation through the release of toxins or the leakage of chemical mediators into the circulation.17 It has been reported that studies of atheromatous lesions in the carotid arteries have found over 40% of atheromas contain antigens from periodontal pathogens including Porphyromonas gingivalis, Tannerella forsythensis, and Prevotella intermedia.18 In addition, P. gingivalis can induce platelet aggregation, a component of atheroma and thrombus formation.19 This suggests a possible invasion of atheromas by oral pathogens as well as a possible contribution to their development. However, causality has yet to be established.

Animal model studies investigating the relationship between CVD and periodontal disease have demonstrated that clinically induced oral infection with P. gingivalis will increase atheroma size and elevate CRP levels.20 More recently, a study of humans reported a positive independent association between carotid intima-media thickness (IMT) and bacterial burden including P. gingivalis, Actinobacillus actinomycetemcomitans, Treponema denticola, and Tannerella forsythensis.21 Figure 2 represents the proposed connection between periodontal disease and atherosclerosis. It is also thought that an autoimmune response may be involved in the development of atherosclerosis. Most humans have immune reactions against microbial heat-shock protein 60 (HSP60). Antibodies against bacterial versions of this protein may cross-react with human HSP60, causing an autoimmune response and stimulating athersosclerosis.4

Diabetes mellitus is another systemic condition with oral inflammatory connections. One of the major complications of diabetes is periodontitis.22 While diabetes increases the probability of developing periodontal disease,22-24 periodontitis also increases the risk of poor glycemic control in people with diabetes when compared to those individuals with diabetes without periodontitis.25 Fortunately, periodontal treatment can improve glycemic control by reducing the bacterial burden and the inflammatory response.26-28

There are several biological mechanisms proposed to explain the increased incidence and severity of periodontal disease in individuals with diabetes. Diabetes tends to increase susceptibility to infection--including oral infection--and the disease itself decreases the effectiveness of cells that kill bacteria.

Another explanation is that inflammation is enhanced in those with diabetes. Research has demonstrated elevated levels of inflammatory mediators in the gingival crevicular fluid of periodontal pockets of poorly controlled patients with diabetes as compared to those without diabetes or those with diabetes who are well controlled. These patients had significant periodontal destruction with an equivalent bacterial challenge.24,29,30 In particular, the proinflammatory cytokine, TNF-α, plays a major role in this process. TNF- α has a significant role in insulin resistance, the primary cause of type 2 diabetes. It is produced in large quantities by fat cells. Periodontitis has also been associated with increased levels of TNF-α. Elevated levels of TNF-α may lead to greater bone loss by killing cells that repair damaged connective tissue or bone and may exacerbate insulin resistance and worsen glycemic control.31-33

It has also been hypothesized that diabetes interferes with the capacity to form new bone after periodontal diseases have caused bone resorption. Graves, et al., studied genetically diabetic mice with type 2 diabetes and nondiabetic littermates by injecting them with P. gingivalis. The death of osteoblasts was measured, and results indicated that there was a higher and more prolonged rate of osteoblast cell death in the diabetic group. It was concluded that the capacity to repair a bony defect by producing new bone would be severely limited when osteoblasts died prematurely. Yet further study is needed in this area to refine this concept.34

As with CVD and diabetes mellitus, there is a relationship between oral infection and respiratory disease. In particular, chronic obstructive pulmonary disease (COPD) and pneumonia have been associated with poor oral health.35-38 It is likely that oral biofilm serves as a reservoir of infection for respiratory bacteria. Specifically, Pseudomonas aeruginosa, Staphylococcus aureus, and enteric bacteria that has been shown to colonize the teeth of patients admitted to hospitals or long-term care facilities. These bacteria may be released into saliva and then aspirated into the lower airway causing infection.4 Another vehicle by which bacteria from the oral cavity can be introduced into the respiratory system is intubation.

Inflammatory mediators, such as cytokines produced by the periodontium, may be another mechanism by which respiratory disease are associated with oral health. These mediators present in inflamed gingival tissues enter the gingival crevicular fluid and then the saliva. Once aspirated, these mediators can have proinflammatory effects in the lower airway.

Further, studies have demonstrated that periodontal diseases have been shown to increase the risk of adverse pregnancy outcomes such as premature birth and low birth weight.39-41 Uterine contractions are stimulated by oxytocin, which is produced by the hypothalamus, and by prostaglandins produced by the placenta. This process normally occurs in the third trimester and leads to birth. However, chronic infection can stimulate the inflammatory process, which leads to elevated amniotic levels of prostaglandins, TNF-α, and IL-1 and IL-6. These mediators then lead to premature rupture of membranes and preterm labor. Other work has suggested that periodontal pathogens may travel from the gingival sulcus to the placenta and stimulate preterm birth. Specifically, Han and colleagues found that periodontal bacteria, including Fusobacterium nucleatum, entered the bloodstream from the oral cavity and directly affected the birth process.42 A summary of the biological mechanisms by which gingival inflammation effects systemic health appears in Figure 3.