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The mouth is a part of the body and often provides a glimpse into overall health.1 Health is defined not only as the absence of disease but also as a state of complete physical, mental, and social well-being.2 In 1900, Hunter introduced the concept of oral sepsis to the literature in a paper entitled “Oral Sepsis as a Cause of Disease”3 and wrote about the association of oral infection and systemic disease.
A thorough examination of the oral cavity can help a clinician detect oral diseases, lesions, and abnormalities, as well as signs of systemic diseases and disorders, nutritional deficiencies, disorders of the immune system, and cancers.4 Miller, a periodontist, started the American Academy of Oral Medicine in 1945 and the American Board of Oral Medicine in 1956.5 In 1996, Offenbacher coined the term periodontal medicine,6 which is a branch of periodontology that focuses on the relationship between periodontal health and systemic disease.
Periodontal disease is perhaps the most common chronic infection7 and is caused by dental plaque. Dental plaque is the well-organized, heterogeneous structure comprised of microbial pathogens, which are the primary etiologic agents for the condition.
Gingivitis and periodontitis are the two main forms of the disease. Both are pathologic periodontal inflammatory processes that result from an accumulation of dental plaque. Gingivitis, the most common plaque-induced gingival disease, is reversible.8 As the second most common form, periodontitis is destructive, irreversible, and chronic. Periodontal disease is caused by dental plaque, which leads to atrophy or loss of bone and connective tissue support around the teeth.8
More than 500 microbial species are associated with periodontal disease.9 Despite this, just a small number are commonly linked. Socransky et al10 segregated the pathogens into red and orange complexes. The red complex includes the following Gram-negative, anaerobic pathogens: Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia. Orange includes Fusobacterium nucleatum, Prevotella intermedia, Prevotella nigrescens, Peptostreptococcus micros, Campylobacter rectus, Centruroides gracilis, Campylobacter showae, Eubacterium nodatum, and Streptococcus constellatus. Other pathogens strongly associated with periodontal disease are Aggregatibacter actinomycetemcomitans and Eikenella corrodens.
In disease, the putative periodontal pathogens colonize in the gingival tissue around the tooth. When ulceration of the periodontal pocket occurs, the pathogens gain access into the systemic circulation. The inflammatory response is activated, resulting in the production of inflammatory cytokines and mediators, such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α).11 These mediators, whose effects are also systemic, may play a role in a person’s susceptibility to systemic illnesses.
Periodontal Medicine
Periodontal disease is thought to be a risk factor associated with several systemic diseases and conditions such as preterm delivery, low birth weight, preeclampsia, erectile dysfunction, osteoporosis, cognitive impairment, and cancer.
Reproductive Issues
Preterm labor occurs between Week 20 and Week 36 of gestation.12 Preterm birth is a major cause of infant mortality and morbidity. Low birth weight refers to a child weighing less than 5.5 pounds at birth.13 Low birth weight applies to premature birth or babies being too small.13
Studies have shown that the risk factors for preterm and low-birth-weight deliveries are similar to those for periodontitis, such as smoking, low socioeconomic status, lower levels of education, and ethnicity.14 Researchers have found that women who delivered prematurely had poorer oral health and worse periodontal disease compared with those without periodontal disease.15 Offenbacher et al16 found that mothers of preterm and low-birth-weight babies had significantly worse periodontal disease than mothers of normal-weight babies. Research has also indicated that mothers of preterm babies had higher levels of prostaglandin E2 (PGE2) and periodontal microbial pathogens, such as C rectus, F nucleatum, and P gingivalisin the amniotic fluid than those without periodontal disease.15,17,18 The appearance of fusobacteria may be due to types of sexual activity with a new partner.19
Researchers have a theory regarding the process. The oral infection activates a cell-mediated inflammatory response that triggers the production of pro-inflammatory cytokines such as IL-1 and TNF-α. This then begins the synthesis and release of PGE2. This prostaglandin not only stimulates bone resorption, but it also can affect labor by softening the cervix, relaxing smooth muscles, and causing contractions.20
Preeclampsia, as defined by the American Congress of Obstetricians and Gynecologists, is associated with a hypertension level of ≥140 mm Hg systolic and ≥ 90 mm Hg diastolic on two occasions at least 4 hours apart after Week 20 coupled with proteinuria.21,22 Periodontal disease increases the risk for the development of preeclampsia and, thus, preterm delivery.12,23,24
Erectile Dysfunction
Erectile dysfunction (ED) is characterized by the inability to develop or maintain an erection during sexual activity.25 Common causes include medication side effects, diabetes mellitus, cardiovascular disease, atherosclerosis, hypertension, obesity, metabolic syndrome, cancer, Parkinson’s disease, inadequate blood flow to the penis, excessive alcohol consumption, smoking, physical exhaustion, and stress.26
Researchers have found a possible relationship between chronic periodontitis and ED.27,28 It is theorized that ED is associated with damage from endothelial dysfunction and systemic inflammatory changes associated with periodontal disease.27,29
Osteoporosis
Osteoporosis is a progressive, chronic, systemic skeletal disease characterized by low bone mass and density with deterioration of bone structure that increases the risk for fracture.30 Osteoporosis may also affect the jaw bones.31 The condition can occur without a known cause or can be secondary to another condition, such as hyperthyroidism, or to medications, such as steroids.32 It is strongly believed that estrogen deficiency can lead to osteoporosis.33 Postmenopausal women, women who have had their ovaries surgically removed, young women with secondary amenorrhea (exercise- or anorexia nervosa-associated), and men with testosterone deficiency are at higher risk for developing osteoporosis.33 Men require both testosterone and estrogen for bone health because they convert testosterone into estrogen.33 Risk factors for osteoporosis include older age, female gender, postmenopausal status, Caucasian or Asian race, inadequate intake of calcium, smoking, alcohol consumption, and physical inactivity.34,35
Periodontitis and osteoporosis share some common risk factors such as age, genetics, smoking, poor nutrition, alcohol consumption, and stress. Both conditions are silent, meaning that patients usually do not develop symptoms until late in the disease when destruction has already begun. They are also bone-resorptive diseases.36 Despite the fact that both osteoporosis and periodontal disease ultimately result in bone destruction and loss, research has not definitively determined that osteoporosis is a causative factor for periodontal disease but it may be a risk factor for the progression.
Hypothetical models suggest that as bone density is reduced from osteoporosis, more rapid bone resorption from periodontal disease occurs from the periodontal microbial pathogens.31 This further reduces local and systemic bone density as a result of the release of systemic inflammatory mediators such as IL-1, IL-6, and TNF-α.31 These mediators not only stimulate an inflammatory response but also bone resorption through the activation of osteoclasts, which are specialized cells that reabsorb bone.31 Researchers have found tooth loss to be greater in those with osteoporosis compared with those without.37,38 Others have observed a positive association between osteoporosis and periodontal disease.35,38 von Wowern et al surmised that osteoporosis reduces the mineral content that may be associated with less favorable levels of attachment in patients with periodontitis.38,39
Cognitive Impairment
Dementia is a broad term used for brain diseases that result in the long-term loss of the ability to think, remember, and reason such that it interferes with daily functioning.40 Alzheimer’s disease is an irreversible, progressive disease of the brain that slowly affects memories, thinking skills, and daily functioning.41 The condition is the most common form of dementia in the elderly.42
Researchers have found the inflammatory mediators associated with periodontal disease, bacteria, and their byproducts can reach the brain through systemic circulation and neural pathways.43-45 In addition, studies have shown these inflammatory changes contribute to brain amyloid accumulation and cognitive dysfunction.44,46 Others have demonstrated that infections from bacterial pathogens and spirochetes have been associated with cognitive brain decline and increases in brain amyloid deposits.46-48 Periodontal microbial pathogens have also been identified in the brains of patients with Alzheimer’s disease and from those with amyloid deposits.46,49,50
Researchers are studying how Alzheimer’s disease and cognitive decline may be associated with vascular and metabolic conditions such as heart disease, stroke, diabetes, and obesity. It is suspected that one of the links is systemic inflammation.51 Various studies have suggested that systemic inflammation may be a risk factor for the progression of Alzheimer’s disease.51-53 Some systemic inflammatory mediators such as IL-6, IL-1β, TNF-α, and C-reactive protein, which are associated with periodontal disease, have been thought to increase the risk for Alzheimer’s disease and/or cognitive decline.51-53 Researchers have found an association that suggests periodontitis is a risk factor for cognitive impairment and/or Alzheimer’s disease in older adults.54-56
Cancer
Cancer refers to diseases that are associated with abnormal cell growth and the potential for these cells to spread to other parts of the body, which is known as metastasis.57 Cancer is thought to begin with a single cell in which genetic alterations occur, resulting in tumor growth (known as a malignancy), invasion, metastasis, and eventual drug resistance.58 Risk factors for cancer include smoking, obesity, alcohol consumption, poor diet, and an inactive lifestyle. Similar risk factors were noted for those at risk for atherosclerotic diseases, diabetes, osteoporosis, and rheumatoid arthritis.
Some evidence suggests that chronic infections and inflammation may be associated with an increased risk for cancer. Many patients with poor oral health have periodontal disease. Hujoel et al59 found a link between periodontitis and various cancers, with lung cancer as the strongest. Michaud et al60 conducted a study that showed an increased risk for the development of pancreatic cancer in men with periodontal disease. Treponema denticola, a red-complex periodontal pathogens, has been associated with various upper gastrointestinal tract cancers.61 Several investigators have noted a relationship between periodontal disease and oral cancers.62-64
Helicobacter pylori commonly causes gastric infections and has been associated with gastric cancers.65 H pylori, although not considered a red- or orange-complex periodontal pathogen, has been isolated from the subgingival microflora of patients with periodontal disease. Fusobacterium species are known periodontal pathogens and have been reported to be co-aggregants with H pylori in the subgingival plaque of patients with periodontal disease.66 This suggests a possible association between subgingival plaque biofilm, periodontal disease, and H pylori infection, which may be instrumental in the development of gastrointestinal cancers.65
Researchers have speculated on possible mechanisms linking poor oral health and periodontal disease with an increased risk for cancers. They believe that two pathways link inflammation with cancer. The first is an extrinsic mechanism in which a constant inflammatory state exists and contributes to the increased risk for cancer.67,68 The second is an intrinsic mechanism in which acquired genetic alterations trigger tumor development.67,68 Periodontal disease may contribute to the development of systemic inflammation and if left untreated, a chronic, smoldering inflammatory response occurs in reaction to periodontal microbial pathogens and their products such as endotoxin. The infection will ultimately stimulate the production of pro-inflammatory cytokines and mediators such as IL-1β, IL-6, TNF-α, and matrix metalloproteinases. IL-6, in particular, has tumor-inducing actions, by promoting growth and proliferation in both healthy and malignant cells in those genetically susceptible.69 IL-1 stimulates tumor growth and metastasis by inducing matrix metalloproteinase activity and other growth factors.70
Studies have also demonstrated that bacteria associated with poor oral health and periodontal disease produce nitrates, which cause genetic damage to cells. This damage decreases the cell’s ability to fight infection, thus increasing the risk for cancer.71
Conclusion
Many researchers have established an association between periodontal disease and other diseases such as reproductive issues, osteoporosis, cognitive impairment, and cancer; however, a cause-and-effect relationship has yet to be established.
Periodontal disease is a chronic infection that contributes to a chronic inflammatory response in the oral cavities of those who are susceptible. 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 demonstrates an association between periodontal disease and these systemic conditions. Further randomized, controlled studies are needed to determine causality between periodontal disease and systemic diseases such as reproductive issues, osteoporosis, cognitive impairment, and cancer. In addition, the gold standard in determining whether periodontal therapy will have a positive influence on medical outcomes is prospective, randomized, controlled, efficacy studies. Future research may demonstrate the efficacy of periodontal therapy related to positive outcomes with regard to these medical conditions. However, current data and risk-benefit ratios support the importance of periodontal therapy.
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