International Journal of Research and Review www.ijrrjournal.com E-ISSN: 2349-9788; P-ISSN: 2454-2237

Review Article

Relationship between Periodontitis and Systemic Diseases: A Review

Dr. Kamal Kishor Mankar1, Dr. Sushil Naik2, Dr. Swapnil Patil3

1Associate Professor, Department of Periodontics and Implantology, VSPM Dental College and research centre, Nagpur. 2Lecturer, Department of Public Health Dentistry, VSPM Dental College and Research Centre, Nagpur. 3Lecturer, Department of Conservative Dentistry and , VSPM Dental College and Research Centre, Nagpur.

Corresponding Author: Dr. Kamal Kishor Mankar

ABSTRACT

The potential impact on the periodontium of many systemic diseases have been well documented, much less is known about the consequences of diseased periodontium on systemic status. Periodontal medicine is a rapidly emerging branch of periodontology, based on abundance of evidence establishing a strong relationship between periodontal health or disease and systemic health or disease. Research has established that periodontal infection is a probable risk factor for , including atherosclerosis, myocardial infarction and stroke. Many studies also suggest that periodontitis may also contribute to adverse pregnancy outcomes, diabetes, respiratory diseases and other conditions. The anatomic closeness of this micro-flora to the blood stream can facilitate bacteremia and systemic spread of bacterial products, components and immune complexes. The findings from cross-sectional and longitudinal epidemiological studies are supported by in vitro and animal studies describing the plausible mechanism linking periodontal infection to development of atherosclerotic diseases, to the triggering of clinical coronary events or to both. It is possible that periodontal infection may serve as initiator or propagators of insulin resistance in a way similar to obesity, thereby aggravating glycemic control. Based upon the criteria that have been used to establish risk, data from animal and human studies support the biological plausibility that untreated moderate to severe periodontitis may increase the risk for adverse pregnancy outcome.

Keywords: Periodontitis, atherosclerosis, diabetes mellitus, inflammation,

INTRODUCTION the . Since many teeth William Hunter a British were extracted without evidence of infection in 1900 put forth the concept of “oral thereby providing no relief of symptoms the as a cause of wide range of systemic theory was discredited and ignored for many diseases” [1] Frank billings in 1911 replaced years. The potential impact on the the term oral sepsis with focal infection, and periodontium of many systemic diseases advocated removal of all foci of infection. [2] have been well documented, much less is The theory of focal infection stated that foci known about the consequences of diseased of sepsis were responsible for initiation and periodontium on systemic status. progression of variety of inflammatory Periodontal medicine is a rapidly emerging diseases such as arthritis, peptic ulcers, and branch of periodontology, based on appendicitis. [3] Therapeutic edentulation abundance of evidence establishing a strong was common as a result of the popularity of relationship between periodontal health or

International Journal of Research & Review (www.ijrrjournal.com) 172 Vol.5; Issue: 11; November 2018 Kamalkishor Mankar et.al. Relationship between Periodontitis and Systemic Diseases: A Review disease and systemic health or disease. The powerful and lethal poisons known. [9] term periodontal medicine was first conversely; endotoxins are part of the outer suggested by Offenbacher. [4] Recent membranes released after cell death. research has established that periodontal Endotoxins is compositionally a infection is a probable risk factor for lipopolysaccharide (LPS) that when cardiovascular disease, including introduced into the host, give rise to a atherosclerosis, myocardial infarction and variety of pathological manifestations. LPS stroke. Many studies also suggest that is continuously shed from periodontal gram- periodontitis may also contribute to adverse negative rods during their growth in vivo. pregnancy outcomes, diabetes, respiratory [10] diseases and other conditions. [5] Recent Metastatic inflammation. progress in classification and identification Soluble may enter the of oral micro-organism and that certain bloodstream, react with circulating specific micro-organism are normally found only in , and form a macromolecular the oral cavity have opened the way for a complex. These immunocomplexes may more realistic assessment of importance of give rise to variety of acute and chronic oral focal infection. Oral cavity can act as inflammatory reactions at the sites of site of origin for dissemination of the deposition. [11] pathogenic organism to distant body sites Periodontitis and systemic disease especially immunocompromised hosts. susceptibility: Human periodontal infections are associated Roy C. Page proposed that periodontitis with complex microfloras in which may affect the host’s susceptibility to approximately 200 species (in apical systemic disease in three ways. [12] periodontitis’ [6] and more than 500 species Shared risk factors (in marginal periodontitis) have been Factors that place the individual at encountered. [7] The anatomic closeness of high risk for periodontitis may also place this micro-flora to the blood stream can them at high risk for systemic diseases such facilitate bacteremia and systemic spread of as cardiovascular disease. Among the bacterial products, components and immune environmental risk factors and indicators complexes. Three mechanisms have been shared by periodontitis, and systemic proposed to link oral infection with systemic diseases such as cardiovascular disease, are diseases. [8] tobacco smoking, stress, aging, race or ethnicity, and male gender. It seems likely Metastatic infection: that the polymorphisms in the IL-1β and Oral infection and dental procedures TNF-α gene, families are likely to can cause transient bacteremia. The associated with cardiovascular disease as microorganisms that gain entrance to the well as with periodontitis. blood and circulate throughout the body are Subgingival biofilms usually eliminated by the Subgingival biofilms constitute an reticuloendothelium system within minutes enormous and continuing bacterial load. (transient bacteremia). However if the They present continually renewing disseminated microorganisms find favorable reservoirs of LPS and other gram-negative conditions, they may settle at a given site, bacteria with ready access to the periodontal and after a certain time lag start to multiple. tissues and circulation. Systemic challenge Metastatic injury. with gram-negative bacteria or LPS induces Some microorganisms have the vascular responses, including an ability to produce diffusible proteins, or inflammatory cell infiltrate in the vessel exotoxins, which include cytolytic enzymes wall, vascular smooth muscle proliferation, and dimeric toxins with A and B subunits. vascular fatty degeneration, and The exotoxins are considered the most intravascular coagulation. [13,14] PS

International Journal of Research & Review (www.ijrrjournal.com) 173 Vol.5; Issue: 11; November 2018 Kamalkishor Mankar et.al. Relationship between Periodontitis and Systemic Diseases: A Review upregulates expression of endothelial cell involved, the association of high peripheral adhesion molecules and secretion of fibrinogen and WBC count. [19] interleukin-1 (IL-1), tumor necrosis factor Mechanisms: alpha (TNF-α), and thromboxane, which There are several mechanism results in platelet aggregation and adhesion, proposed by which may formation of lipid-laden foam cells, and trigger pathways leading to cardiovascular cholesterol and cholesterol esters. disease through direct and indirect effects of Periodontium as cytokine reservoir oral bacteria. Evidence indicates that oral The proinflammatory cytokines bacteria such as Streptococcus sanguis and TNF-α, IL-1β, and gamma interferon as Porphyromonas gingivalis induce platelet well as prostaglandin E2 (PGE2) reaches aggregation which leads to thrombus high tissue concentrations in periodontitis. formation. [20] These organisms have a The periodontium can serve as a renewing collagen like molecule, the platelet reservoir for spillover of these mediators, aggregation associated protein on their which can enter the circulation and induce surface. [21] The second factor in this process and perpetuate systemic effects. IL-1β could be an exaggerated host response to a favors coagulation and thrombosis and given microbial or LPS challenge as retards fibrinolysis. [15] IL-1, TNF-α, and reflected in the release of high levels of thromboxane can cause platelet aggregation proinflammatory mediators such as PGE2, and adhesion, formation of lipid-laden foam TNF-α, IL-1β. [22] These mediators have cells and deposition of cholesterol. These been related to interindividual differences in mediators from the diseased periodontium the T-cell repertoire and the secretary may also account for preterm labour and capacity of monocytic cells. Peripheral low-birth weight infants. monocytes from individuals with the Cardiovascular diseases: Cardiovascular hyperinflammatory monocyte phenotype diseases (CVD) such as atherosclerosis & secrete 3 to 10 fold greater amounts of these myocardial infarction occur as a result of mediators in response to LPS than those complex set of genetic and environmental from normal monocyte phenotype factors. [16] Genetic factors include age, lipid individuals. [23] Patient with certain forms of metabolism, obesity, hypertension, diabetes, periodontal disease, such as aggressive increased fibrinogen levels. Environmental periodontitis, refractory periodontitis factors include socio-economic status, possess a hyperinflammatory monocyte exercise stress, non steroidal anti phenotype. [24] A third mechanism possibly inflammatory drugs, smoking and chronic involves the relationship between bacterial infection. The classical risk factors of and inflammatory products of periodontitis Cardiovascular diseases such as and CVD. LPS from periodontal organisms hypertension, hypercholesterolemia and being transferred to the serum as a result of cigarette smoking can only account for one bacteremia or bacterial invasion may have a half to two third of variation in the direct effect on endothelium so that incidence of CVD. Among other possible atherosclerosis is promoted. [25] LPS may risk factors evidence linking chronic also elicit recruitment of inflammatory cells infection and inflammation to CVD has into major blood vessels and stimulates been accumulating. [17,18] It is clear that proliferation of vascular smooth muscle, periodontal disease is capable of vascular fatty degeneration, intravascular predisposing individual to CVD, given the coagulation and blood platelet function. abundance of gram negative species These changes are the result of the action of involved, the readily detectable levels of various biological mediators, such as PGE2, proinflammatory cytokines, the heavy TNF-α, IL-1β on vascular endothelium and immune and inflammatory infiltrate smooth muscle. [26] Fibrinogen and WBC count increases noted in periodontitis

International Journal of Research & Review (www.ijrrjournal.com) 174 Vol.5; Issue: 11; November 2018 Kamalkishor Mankar et.al. Relationship between Periodontitis and Systemic Diseases: A Review patient may be a secondary effect of the primary diabetes, environmental factors above mechanisms or a constitutive feature interact with a genetic susceptibility to of those at risk for both CVD and determine which of those with the genetic periodontitis. [27] Periodontitis as an predisposition actually develops the clinical infection may stimulate the liver to produce syndrome and the timing of its onset. C- reactive protein (CRP) a marker of Environmental factors in insulin- dependent inflammation, which in turn forms deposits diabetes include , diet, immunological on injured blood vessels. CRP binds to cells factors and pancreatic diseases. In non- that are damaged and fixes complement, insulin- dependent diabetes, environmental which activates , including factors include life style, age, pregnancy, neutrophils. These cells release nitric oxide, pancreatic pathology, and insulin secretion there by contributing atheroma formation. In and resistance. Severe periodontal disease a study of 1043 apparently healthy men, often coexists with severe diabetes mellitus. baseline plasma concentrations of CRP Diabetes is a risk factor for severe predicted the risk of future myocardial periodontal disease. The converse infarction and stroke. Ebersole et al. found possibility that periodontal disease either that patient with adult periodontitis have predisposes or exacerbates the diabetic higher levels of CRP and haptoglobin than condition has received more and more subjects without periodontitis. A specific attention. heat shock protein Hsp65 has been reported Mechanism to link cardiovascular risks and host A model was presented by Grossi response. [28] It has been suggested that and Genco, in which severe periodontal chronic oral infection stimulates high levels disease increases the severity of diabetes of Hsp65 in subjects with high mellitus and complicates metabolic control. cardiovascular risk. [29] Thus, if [31] They propose that an infection-mediated directed towards bacterial shock proteins upregulation cycle of cytokine synthesis and cross-react with heat shock proteins secretion by chronic stimulus from LPS and expressed in the host tissue, especially if products of periodontopathic organisms may they are found in the lining of blood vessels, amplify the magnitude of the advanced then some oral species might well be the glycation end products (AGE) mediated link between oral infection and cytokine response that is operative in cardiovascular disease. diabetes mellitus. The combination of these Diabetes mellitus: Diabetes mellitus is a two pathways, infection and AGE mediated clinical syndrome characterized by cytokine upregulation, helps explain the hyperglycemia due to an absolute or relative increase in tissue destruction seen in deficiency of insulin. Diabetes mellitus is diabetic periodontitis, and how periodontal characterized by metabolic abnormalities infection may complicate the severity of and long-term complications involving the diabetes and the degree of metabolic eyes, kidneys, nervous system, vasculature control, resulting in a two-way relationship and periodontium. [30] Diabetes is commonly between diabetes and periodontal disease or categorized as type 1, or insulin dependent infection. It is well established that diabetic diabetes, and type-2, non- insulin are more likely to develop periodontal dependent. The fundamental derangement in disease than nondiabetics [32] and the disease insulin dependent diabetes is the severity is related to the duration of hypoproduction of insulin due to destruction diabetes. One plausible biologic mechanism of beta cells of the pancreas. In non-insulin- for why diabetics have more severe dependent diabetes, the derangement periodontal disease is that glucose-mediated involves resistance of the target tissue to AGE accumulation affects the migration insulin action. Although the precise etiology and phagocytic activity of the mononuclear is still uncertain in both main types of and polymorphonuclear phagocytic cells,

International Journal of Research & Review (www.ijrrjournal.com) 175 Vol.5; Issue: 11; November 2018 Kamalkishor Mankar et.al. Relationship between Periodontitis and Systemic Diseases: A Review resulting in establishment of a more treatment outcome is strict improvement in pathogenic subgingival flora. The periodontal status or a local effect. On the maturation and gradual transformation of contrary, when systemic are the subgingival microflora into an essential included with mechanical therapy, an gram-negative flora. This provides a chronic improvement in diabetes control, measured source of systemic challenge via the as a reduction in glycated hemoglobin or ulcerated pocket epithelium. This in turn reduction in insulin requirement is achieved. triggers an “infection mediated” pathway of Therefore one may propose that control of cytokine upregulation, especially with chronic gram-negative periodontal infection secretion of TNF-α & IL-1, and a state of should be a part of standard treatment of the insulin resistance, affecting glucose utilizing diabetic patient. pathway. The interaction of mononuclear Adverse pregnancy outcome: phagocytes with AGE- modified proteins Recently the impact of periodontal induces upregulation of cytokine expression disease on adverse pregnancy outcome has and induction of oxidative stress. received much attention. Pre-term low birth Simultaneously periodontal infection may weight (PLBW) is a problem encountered in induce a chronic state of insulin resistance, most world communities at varying levels of contributing to the cycle of hyperglycemia, prevalence. There is emerging interest and nonenzymatic irreversible glycation, and increasing amount of the evidence that AGE- protein binding and accumulation, support the inter-relationship between amplifying the classical pathway of diabetic periodontitis and adverse pregnancy connective tissue degradation, destruction, outcome. Growth in uterus is a balance and proliferation. [31] Hence the relationship between the genetic potential of each between diabetes mellitus and periodontal individual fetus and the maternal disease or infection becomes two ways. A environment. The maintenance of a normal self-feeding two-way system of catabolic pregnancy for approximately nine months response and tissue destruction ensues, represents the balance of the maternal and resulting in more severe periodontal disease fetal nutritional, hormonal, and and increased difficulty in controlling blood immunological systems. The international sugar. definition of low birth weight adopted by Epidemiological Evidence: the 29th World Health assembly in 1976 is a The results of a longitudinal study birth weight <2500 g. Birth weight <2500 g indicated that severe periodontitis at results in rapid increase in risk of infant baseline is associated with increased risk of mortality. Low birth weight can be a result poor glycemic control at follow-up two or of a short gestational period and/or retarted more years later. [33] These finding suggest intrauterine growth. These low birth weight that severe periodontitis may be an infants are more likely to die during the important risk factor in progression of neonatal period, and low birth weight diabetes, and control of periodontal survivors are more likely to develop neuro- infection is essential to achieve long term developmental problems, respiratory control of diabetes mellitus. Grossi and problems and congenital problems. The Genco reexamined the studies that neonatal and long term health care cost of addressed the effect of periodontal treatment pre- term infants impose a considerable on metabolic control of diabetes mellitus economic burden both on individual and concluded that the effect of periodontal families and taxpayers. Many risk factors on diabetic metabolic control is dependent have been proposed for pre-term rupture of on the mode of therapy. When mechanical membrane and preterm labour, including periodontal treatment alone is provided, infection and inflammation. [34] 25% to 50% regardless of the severity of periodontal of PLBW deliveries occur without any disease or degree of diabetes control, the known etiology, and there is increasing

International Journal of Research & Review (www.ijrrjournal.com) 176 Vol.5; Issue: 11; November 2018 Kamalkishor Mankar et.al. Relationship between Periodontitis and Systemic Diseases: A Review evidence that infection may play a disease is a gram-negative anaerobic significant role in pre- term delivery. Both infection, which may lead to bacteraemia generalized infections, including viral and induce pregnancy complication. In a respiratory infections, diarrhea and malaria, series of landmark animal studies, they and more localized infections of the genital demonstrated that in a hamster chamber and urinary systems can affect the model, chronic exposure to Porphyromonas gestational length. Association between gingivalis led to 15% to 18% decrease in chorioamnionitis, infection of amniotic fluid fetal weights along with a local increase of and PLBW has been established. [35] PLBW PGE2 and TNF-α within the chamber fluid. is multifactorial in nature. The traditional Later they studied the association between risk factors are smoking, genetics, and use infection and pregnancy by inducing of alcohol, prenatal care, poor maternal periodontal disease in the hamster model. nutrition and urinary tract infection. About These animal studies provided vital proof- 25% of PLBW cases occur without a of-principle experiments and suggested the candidate or suspected risk factors. Gibbs in possibility that low-grade oral infections his review article provides an excellent may trigger off maternal-fetal inflammation outline of the possible association between and result in adverse pregnancy events. In infections and adverse pregnancy outcomes. subsequent landmark human study, The infection hypothesis suggest that during Offenbacher et al. show that periodontitis a subclinical infection, the micro-organisms was a significant risk factor for PLBW. The and their lipopolysaccharides enter the adjusted odd ratios were 7.9 and 7.5 for all uterine cavity during pregnancy by the PLBW and primiparous PLBW cases ascending route from the lower genital tract respectively. Jeffcoat et al conducted a or by the blood- borne route from a non- prospective cohort study of 1313 pregnant genital route, hence causing pre-term birth. women with severe periodontitis. [39] There [36] It has been suggested that spontaneous was an adjusted odd ratio of 4.45 for pre- term labour is commonly associated preterm delivery before 37 weeks’ gestation with bacterial vaginosis, a vaginal condition age, 5.28 before 35 weeks and 7.07 for characterized by a prevalence of anaerobes. delivery before 32 weeks. Bacterial invasion of the choriodecidual Summary: space can activate the fetal membranes or The findings from cross-sectional trigger the maternal immune system to and longitudinal epidemiological studies are produce a variety of cytokines and growth supported by in vitro and animal studies factors. This has been shown to be eliciting describing the plausible mechanism linking an inflammatory burden resulting in periodontal infection to development of placental damage and distress and, hence atherosclerotic diseases, to the triggering of fetal growth restriction. In addition the clinical coronary events or to both. The cascade of disordered cytokine response can cumulative evidence supports, but does not lead to stimulation of prostaglandin prove, a causal association between synthesis and release of matrix periodontal infection and atherosclerotic metalloprotinases (MMPs), which account cardiovascular disease or its sequelae. for the uterine contractions and membrane Consequently, more focused studies are rupture, respectively leading to the needed to elucidate the mechanism induction of labour. [37] involved. Periodontal infection and diabetes Epidemiological Evidence: In the early mellitus are closely associated and are 1990s Offenbacher et al. hypothesized that highly prevalent chronic diseases with many oral infection, such as periodontitis, could similarities in pathobiology. Related represent a significant source of both antecedent conditions including obesity and infection and inflammation during insulin resistance may play an important pregnancy, [38] they noted that periodontal role in this relationship; inflammation is a

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How to cite this article: Mankar KK, Naik S, Patil S. Relationship between periodontitis and systemic diseases: a review. 2018; 5(11):172-179.

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International Journal of Research & Review (www.ijrrjournal.com) 179 Vol.5; Issue: 11; November 2018