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Metabolic syndrome (MetS) is generally described as a common cluster of conditions that occur together, all of which increase the risk for cardiovascular diseases (CVD), cerebrovascular disease (including stroke), and type 2 diabetes mellitus (T2DM).1 These conditions include: hypertension (HTN), hyperglycemia, visceral fat deposits and increased waist circumference, and abnormal cholesterol or triglyceride levels.1 Further, patients with MetS often demonstrate increased systemic levels of proinflammatory mediators, such as interleukin-1 (IL-1), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-), and C-reactive protein (CRP).1,2 Periodontitis is initiated by infectious agents resulting in tissue destruction caused by host inflammation within the supporting structures of the teeth.3,4 It has been shown to be associated with numerous systemic conditions in a bidirectional manner.5 This association is related to the systemic inflammation produced by chronic periodontal infection. Bacteremias in the systemic circulation and bacterial byproducts (eg, endotoxins), as well as the resultant proinflammatory cytokines produced in response to those bacteria, may result in a systemic immune response, dyslipidemia, and an increased risk of atherosclerotic lesion formation.6 Further, evidence suggests that the odds of periodontitis increase with the number and severity of MetS conditions present in an individual.7,8 It is critical that dental healthcare providers understand the interactions of periodontal disease and the components of MetS, as well as the potential impact of periodontal therapy on its development and severity (Figure 1).
Pathophysiology and Prevalence
MetS is a spectrum of conditions that result in elevated risk for myriad impactful systemic diseases, including CVD, cerebrovascular disease, and T2DM. The underlying risk factors that predispose a patient to MetS include obesity, physical inactivity, and insulin resistance.2 Further, aging, hormonal imbalance, genetic predisposition, sleep apnea, certain medications, and smoking have been associated with higher rates of MetS.1,2 In parallel with obesity rates, prevalence of MetS has increased in the US over time. In data from the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2016, adults 20 years old reported overall rates of MetS of 34.7%.9 The prevalence of MetS significantly rose with increasing age among all subgroups; prevalence was 19.5% among those aged 20 to 39 years and increased to 48.6% among those aged at least 60 years.9
It should be noted that insulin resistance, which is a known consequence of prolonged obesity, is a component of MetS etiology and has been hypothesized to be a link between the various conditions that make up MetS.10 MetS is theorized to be initiated through a systemic proinflammatory state, which may occur as a result of obesity and/or insulin resistance. Insulin resistance is associated with increasing body mass index (BMI), waist circumference, and dysglycemia, and results in low-grade increases in serum levels of proinflammatory cytokines that are produced by adipocytes and macrophages, including TNF-, IL-1, and IL-6.10 Insulin resistance has also been associated with increased levels of oxidative stress, which may be mediated through the production of advanced glycation end products (AGEs) during periods of hyperglycemia and, when bound to specific receptors (RAGEs), induce local oxidative damage.10,11
While the current definition of clinical MetS differs based upon diagnostic criteria,12-14abdominal obesity, hypertension, and hyperglycemia are the most common components. Severity of MetS and frequency of the secondary sequelae (eg, CVD, T2DM, and cerebrovascular diseases) appear to be related to the involvement and severity of MetS components.10 It has been demonstrated that the presence of three MetS components increases the risk of development of CVD by 2.7-fold and the presence of four or more MetS components increases the risk of CVD 5.9-fold. The incidence of T2DM appears to be tied to MetS components in an even more robust fashion with a 10-fold increase in T2DM seen in individuals with 3 MetS components and a 35-fold increase in T2DM seen in individuals with 4 or more MetS components.15 Table 1 describes commonly used diagnostic criteria for MetS.
Periodontitis is a chronic multifactorial inflammatory disease of the hard and soft tissues supporting the teeth associated with a dysbiotic dental plaque biofilm. This dysbiotic biofilm then initiates a host immunoinflammatory response that, over time, may result in progressive destruction of the periodontal ligament and alveolar bone if not adequately resolved.3,16 Average progression of periodontal disease demonstrates a slow to moderate rate of disease progression with approximately 0.1 mm of attachment loss and 0.2 teeth lost annually.17 Groups with the fastest and slowest disease progression differed considerably, with accelerated attachment loss associated with access to comprehensive dental care as well as local and/or systemic factors.3,18 In an updated classification system from the American Academy of Periodontitis (AAP) and European Federation of Periodontitis (EFP), individuals are classified with a Stage and Grade to characterize disease severity and risk of future disease progression.3,18 Periodontitis Stage is assigned as I-IV and is assessed by patients' current disease presentation, including attachment, bone, and tooth loss, and the case complexity.3,18 Periodontitis Grade is defined as A-C and is based upon risk and evidence of the rapidity of disease progression over time.3,18
The prevalence of periodontitis has been estimated to be over 42% of US adults over 30 years of age.19 Of those individuals, 7.8% had severe periodontitis, which was most prevalent among adults 65 years or older, Mexican Americans, non-Hispanic Black Americans, and smokers.19 These statistics suggest that the prevalence of periodontitis among US adults is nearly 4-fold greater than that of diabetes mellitus20 and over 6-fold greater than that of coronary artery disease.21 Periodontitis is extremely prevalent and, after initiation by bacteria and bacterial virulence factors, disease progression and tissue destruction occurs through host-mediated immunoinflammatory pathways, which may vary based upon genetic, environmental, and other risk factors.3 The result is a chronic immunoinflammatory disease that may pose a significant systemic burden for individuals.5
The Relationship Between Periodontal Disease and Metabolic Syndrome
Cross-sectional studies demonstrate an association between periodontal disease and MetS.10 However, such study designs cannot demonstrate causation and/or the directionality of influence. Furthermore, given the known common risk factors shared between MetS and periodontal disease and the known interaction of periodontal disease with other systemic diseases, such as CVD and T2DM, the risk for confounding may be elevated. It should be noted that in many existing studies, periodontal disease severity was correlated with an increased prevalence of MetS.8,22,23 The odds ratios (OR) describing the association between MetS and periodontal disease reported in the literature range from 1.54-10.54, and many of these investigations elucidated that increasing numbers of MetS components were associated with an increased likelihood of periodontal disease.10 MetS components have also been associated with tooth loss, increased proportion of probing depths 5 mm, clinical attachment loss (CAL), radiographic alveolar bone loss, and tooth mobility.10,24 Further, other investigations have demonstrated that increasing MetS component involvement was correlated to worsening periodontal conditions.25
Both increased systemic inflammation and oxidative stress have been hypothesized as links between MetS and periodontal disease.10,11 Both of these underlying etiologies have been associated with CVD, obesity, and dysglycemia/insulin resistance. This report will further elucidate the interaction of periodontal conditions with the individual components of MetS including: 1) diabetes mellitus and dysglycemia, 2) obesity, 3) atherosclerosis and dyslipidemia, and 4) hypertension. While it is currently unclear if the interactions between MetS and periodontal disease are uni- or bidirectional, current research has established an association in cross-sectional and population cohort studies, and it is critical to understand the underlying components that may relate to that relationship.
Diabetes Mellitus and Dysglycemia and Periodontal Disease
Diabetes mellitus and dysglycemia have a well-established bidirectional relationship with periodontal disease. Diabetes and periodontitis both involve significant dysregulation of the immune system. Periodontal tissue breakdown occurs in response to bacterial stimuli as a result of host inflammatory response. Periodontal tissue breakdown seen in disease is mediated by proinflammatory cytokines and mediators. There are significant differences in the inflammatory response among individuals, which influences susceptibility to disease as well as severity of disease progression.26 The immunologic dysregulation seen in diabetes is associated with both metabolic and physiologic changes in tissues. In patients with diabetes mellitus or other dysglycemia, sustained hyperglycemia leads to the formation of AGEs, which then activates the RAGE and receptor activator of nuclear factor kappa B ligand (RANKL)/osteoprotegrin (OPT) pathways, inducing immune dysfunction and cytokine imbalance.27 Furthermore, diabetic subjects have an increased hyperinflammatory state and demonstrate increased serum levels of proinflammatory cytokines. As proinflammatory cytokines increase, a patient's glycemic control becomes worse in a dose-dependent manner. Common proinflammatory biomarkers implicated in both periodontal disease and diabetes mellitus include interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), prostaglandin E2 (PGE2), RANKL, and matrix metalloproteinases (MMPs).27
Due to these underlying interactions, it has been long established that subjects with diabetes demonstrate an approximately 3-fold increase in odds of having periodontitis compared to healthy subjects, after adjusting for confounding factors including age, gender, and oral hygiene.26-28 Additionally, diabetic subjects with poor glycemic control demonstrated greater progressive bone loss compared with subjects with diabetes that was well-controlled.25-27 Periodontitis has even been referred to as the "sixth complication of diabetes," indicating that much like the classic complications of diabetes, periodontitis may be a result of extended hyperglycemia on the periodontal tissues.29 Further, the 2017 AAP/EFP WWDC identified smoking and diabetes mellitus as grade modifiers for the Staging and Grading of Periodontitis. The classification system categorizes individuals with diabetes mellitus as demonstrating a moderate-to-high risk for either Grade B (moderate) or Grade C (rapid) rate of future periodontal disease progression and establishes an HbA1c of > 7% as the cut-off rate for categorization into a Grade C risk level.18
Obesity and Periodontal Disease
Epidemiologic studies have demonstrated an association between overweight/obesity and its anthropomorphic measurements, in particular BMI (kg/m2) and waist circumference, with worsening periodontal clinical parameters over time, increased gingival inflammation, higher levels of serum proinflammatory markers, and periodontitis diagnosis.30 The underlying mechanism of this association has been mediated by the production of proinflammatory markers by adipocytes. Adipose tissue secretes a host of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). TNF-α and IL-6 are the main inducers of acute-phase hepatic protein production, including C-reactive protein (CRP). Additionally, both TNF-α and IL-6 have been shown to impair intracellular insulin signaling, which may lead to insulin resistance.30 Human plasma levels of TNF-α, IL-6, and CRP are associated with obesity and insulin resistance,10,27,30as well as periodontal inflammation and destruction of periodontal tissues,30 and periodontal treatment has been demonstrated to reduced levels of circulating TNF-α.31 In persons with periodontal disease, bacterial pathogens, endotoxins, and inflammatory cytokines may systemically trigger an upregulated leukocytosis, synthesis of acute-phase proteins (eg, CRP, Amyloid A), and enhanced lipid metabolism, as well as increase serum cholesterol and triglyceride levels.32
Additionally, periodontal therapy in overweight and obese patients has shown decreased efficacy than in normoweight controls, and obese patients with periodontitis have been shown to have higher rates of serum leptin (a protein that is generally produced in adipocytes and directs the central nervous system to manage the body's overall metabolism) and lower adinectin that are unaffected by periodontal therapy.33 It is notable that both leptin resistance and decreased systemic adiponectin levels have been hypothesized to play roles in the development of type 2 diabetes, obesity, and cardiovascular disease in humans.34
Atherosclerosis and Dyslipidemia and Periodontal Disease
The role of inflammation in the pathogenesis of atherosclerosis is highlighted by the associations between systemic proinflammatory biomarkers and measurements of CVD and its outcomes.35While atherosclerosis contributes to the elevation of systemic inflammatory biomarkers, population studies have found that smoking, age, and adiposity are more highly associated with proinflammatory mediators than atherosclerotic plaque thickness.36 Adiposity, in particular, has been shown to be associated with up to 30% of the systemic inflammation in large-scale population studies.36 Many of these proinflammatory risk factors are associated with increased risk of both periodontal disease and CVD.1,2,5,6,36 The action of these risk factors on CVD demonstrates that inflammation from a distant site, such as the periodontium, can increase systemic levels to a point that conveys increased cardiovascular risk.
It is also known that dyslipidemia, in particular, elevated levels of serum triglycerides and low-density lipoproteins (adiponectin), as well as decreased serum levels of high-density lipoproteins (HDL), is a potent risk factor in the development of atherosclerosis and major cardiovascular events.36 Periodontal disease has been associated with an increase in the odds of elevated triglycerides37 and serum antibody levels to Porphyromonas gingivalis (P. gingivalis) were associated with low HDL levels.38 These findings suggest that periodontal disease may contribute to increased oxidative stress and a hyperinflammatory state that can predispose a patient to development of or worsening atherosclerosis and dyslipidemia. Further, it has also been proposed that in patients with established periodontitis, bacteremias and systemic circulation of bacterial byproducts, such as lipopolysaccharide (LPS), may cause endothelial injury and stimulate triglyceride production.5,10,26,39
Hypertension and Periodontal Disease
It is well established that elevated arterial blood pressure, particularly if it is chronic, increases the risk of complications from cardiovascular diseases (CVD), such as stroke and myocardial infarction, and is an impactful component of MetS.1,2,10,12 In the US, approximately 30% of adults have hypertension, and it has been estimated that 15% to 50% of these individuals may be unaware of this condition.40,41 Inflammation is considered an important driver of vascular dysfunction and implicated in the development and progression of hypertension.6
It should be noted that a recent report demonstrates a link between severe periodontitis and high blood pressure in younger individuals without a previous diagnosis of hypertension.42 Individuals with severe periodontitis demonstrated two-fold higher risk of elevated systolic blood pressure (> 140 mmHg) than those without periodontitis (14% v. 7%, respectively).42 Established and emerging evidence suggest that this relationship and the predisposition to major cardiovascular events is mitigated through a mechanism of periodontal inflammation.6,43
Impact of Periodontal Therapy on Systemic Inflammation
Periodontal therapy has been shown to be an effective intervention to reduce oral inflammation and improve clinical periodontal parameters for patients.44 However, despite adequate therapy, it is estimated that 20% to 25% of individuals with periodontitis do not respond predictably to standard periodontal therapies and are not well-maintained despite compliance with therapy.45 This variation may be related to underlying systemic disease, genetic differences between individuals, environmental factors, and/or other risk factors.18,33,45 Evidence does exist to suggest that periodontal therapy positively influences many factors associated with MetS including: 1) levels of proinflammatory cytokines, 2) concentrations of CRP in patients with and without coronary heart disease, 3) levels of fibrinogen and white blood cells, 4) levels of total cholesterol, 5) serum dyslipidemia, 6) hemoglobin A1c levels, 7) endothelial function, especially in people with diabetes and CVD, 8) systolic and diastolic blood pressure, 9) left ventricular mass, 10) pulse-wave velocity as a measure of arterial function, and 11) carotid intima-media thickness.46,47 Given the positive outcomes associated with periodontal treatment on myriad markers of MetS, periodontal therapy and continued maintenance in at-risk patients may provide additional systemic benefits.
Clinical Implications for Dental Care
It is estimated that in 2019, 64.9% of US adults visited their dentist,48 while only approximately 59% of adults reported a yearly visit to their physician.49 This means that 20 million Americans are seen in a dental office, but not by their primary care physician.49 This offers a unique opportunity to provide much needed screening and referral for interprofessional care for patients who present for dental examinations and treatment.49 Promoting understanding of the relationship of MetS and periodontal disease among both dental and medical healthcare providers can allow for referral of patients diagnosed by a physician for dental examination and treatment and, conversely, the assessment of the components of MetS in the dental office could allow for referral to a treating physician for definitive diagnoses. In combination, this type of interprofessional interaction could provide an opportunity to improve oral and overall health outcomes.
Within the dental practice, screening for MetS risk factors, including overweight/obesity status, dysglycemia, hypertension, and dyslipidemia can allow dental healthcare providers to develop risk profiles for patients and provide individualized treatment plans based upon underlying systemic conditions. It is also critical to routinely evaluate all patients, and particularly those who demonstrate MetS components for periodontal diseases. Early identification and treatment of periodontal disease, along with ongoing individualized maintenance protocols. can allow dental healthcare professionals to positively impact oral and overall health for patients.
Understanding the relationship between MetS and periodontal disease allows dental healthcare professionals to provide screening and assessment for impactful systemic health conditions in the dental office. Patient evaluation and diagnosis are essential to the practice of dentistry and the primary prevention of dental disease, but with the ever-expanding body of knowledge that demonstrates the connection between oral and periodontal health and overall health, it is critical to fully ground oral disease in the context of systemic health. Not only can dental healthcare providers assess and treat oral diseases and conditions, but they can also play a critical role in the evaluation, risk assessment, referral, and treatment of systemic conditions as well.
About the Authors
Machell Hudson, RDH, FAAOSH
Granbury Dental Center
Maria L. Geisinger, DDS, MS
American Board of Periodontology
Professor and Director
Advanced Education Program in Periodontology
University of Alabama at Birmingham
School of Dentistry
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