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For decades, researchers have been critically evaluating the evidentiary links between diseases of oral origin and their impact on systemic disease. Likewise, the impact of various systemic diseases on oral health has been heavily scrutinized. Within this research, it is the infectious and inflammatory process of periodontitis as well as genetic and acquired risk factors that provide the biological plausibility of associations between periodontitis and subsequent systemic diseases.1 Currently, upwards of 57 various diseases and conditions have been studied with regards to their biological connection with periodontitis.2
The American Academy of Periodontology has classified systemic disease and conditions known to affect the periodontal attachment apparatus in which this collection of relatively rare diseases have been described with regards to their association to diseases of the periodontium (Table 1).3 The observation of these associations is noted in the influence periodontal disease has on host factors, including immune response, genetic profile, environmental etiological factors, and the impact these systemic diseases can have on the presentation and severity of periodontitis.
This article critically outlines the causative mechanisms that play a substantial role in the evolution of a localized to systemic effect, as well as systemic diseases that contribute to periodontitis and conversely, the role periodontitis plays in increasing the risk for systemic disease in susceptible individuals.
Periodontitis is defined as a polymicrobial, dysbiotic oral disease4 in which the coordinated effort of disease-producing microorganisms and a subsequent host response create destruction of the periodontium in susceptible hosts.5
Localized effects on the periodontium may include increased pocket depths, bleeding on probing, furcation involvement, mobility, and ultimately tooth loss.6 Moreover, research has determined that the presence of this bacteria-initiated host response contributes to a systemic burden of inflammation.
The systemic consequences of periodontitis begin with the introduction of bacteria into the bloodstream, a decline in host immunity, and an increase in concentration of inflammatory markers including C-reactive proteins and erythrocyte sedimentation rate, among others.
Bacteremia is loosely defined as the presence of bacteria within the bloodstream. The dysbiotic nature of periodontitis describes an imbalance of health-producing and disease-producing microorganisms, indicating a high concentration of bacteria capable of destruction. During active periodontal infections, ulceration of the sulcular lining as well as host-affiliated margination and widening of the microvasculature walls create an ideal portal of entry for disease-producing bacteria to easily enter the circulatory system.
Research is rapidly determining the clinical significance of bacteremia of oral origin, which has certainly instituted evolutions in decisions of premedication guidelines during at-risk procedures in the dental operatory. However, it is also believed that daily episodes of dumping of disease-producing microorganisms originating from periodontal lesions exacerbate the changes in systemic markers in periodontitis7 and have the potential to elevate the risk for systemic disease.
The host response to the presence of biofilm of oral origin includes a cascade of inflammatory processes. These processes include the release of lipopolysaccharides (endotoxins), chemotactic peptides, proteolytic enzymes, protein toxins, and organic acids from oral bacteria, as well as the simulation of host cells to release potent agents termed inflammatory cytokines.
Inflammatory cytokines of interest include, but are not limited to: interleukin-1, interleukin-6, prostaglandins, leukotrienes, and tumor necrosis factor-alpha.8 The release of inflammatory cytokines initiates the inflammatory response and aims to regulate the host defenses against pathogens by mediating an immune response in an attempt to protect the host.
It should be noted that most systemic inflammatory markers associated with periodontal inflammation are also considered predictive markers for cardiovascular disease.9 This association provides a potential explanation as to why periodontitis is associated with cardiovascular and/or cerebrovascular events and may provide insight as to the links to other systemic diseases.
Following the inflammatory response, the immune system is further activated to continue the delicate process of systematically addressing the bacterial threat on the host. The activation of the specific host response aims to improve the ability to recognize a foreign antigen, communicate with other defense cells, and suppress or completely destroy the antigen. Through humoral and cellular immunity, the host system begins integrating key elements of the immune response such as B lymphocytes, plasma cells, antibodies, macrophages, cytokines, and T lymphocytes (T killer and T helper) to aid in the immune mechanism.10,11
It is well documented that the chronic inflammatory condition of periodontitis leads to a burden and subsequent drain on the immune components of the host as key elements of the immune response are budgeted for the management of this ongoing, progressive disease.
Commonly evaluated blood markers have been used as diagnostic tools to assess the status of various systemic diseases and infections for decades to indicate overall systemic health and disease. Cellular and molecular components of blood can change in the presence of various diseases, disorders, and conditions. These markers are not only served as diagnostic mechanisms but also to guide treatment.
The inflammatory response has an adverse impact on commonly assessed blood parameters such as white blood cells (WBC), polymorphonuclear lymphocytes (PMNs), and lymphocyte counts from differential leukocyte count, as well as hemoglobin (Hb), and bleeding time (BT).
Various studies have evaluated the effect of scaling and root planing on these parameters and have demonstrated both significant and insignificant reduction in these values without conclusive but suggestive evidence.12 This infers that there is an effect on plaque-induced chronic periodontal disease and its treatment with scaling and root planing.
Several inflammatory markers are very useful indicators for diagnoses and monitoring the progress of treatment of various conditions, whether acute or chronic, such as bacterial infections, fungal infections, autoimmune disorders, inflammatory bowel disease, trauma, surgery, burns, and advanced cancer. Moderate changes in inflammatory markers can be observed after strenuous exercise, heatstroke, and childbirth, as well as after physiological stress and psychiatric illness.
C-reactive protein (CRP) is a plasma protein made by the liver. Erythrocyte sedimentation rate (ESR) is a test that measures how quickly erythrocytes settle to the bottom of a test tube over the course of one hour. Normally erythrocytes settle relatively slowly but a faster rate may indicate inflammation. Research has indicated strong evidence that these inflammatory markers are elevated in the presence of periodontitis, and modest evidence has demonstrated a link between integrating periodontal therapy and the subsequent lowering of levels of CRP13 and ESR.14
Systemic Risk Factors
As research rapidly unpacks connections amongst periodontal disease and systemic diseases, it is imperative to acknowledge that many systemic diseases serve as significant risk factors for periodontal disease. The "two-way street" of many systemic diseases clarifies that there are multifactorial complexities within periodontal disease.
While it is impossible to list every systemic condition that has an impact on the progression of periodontal disease, it is imperative to understand the common factors which elevate the susceptibility of periodontal disease in some populations.
The complications of diabetes are broad and can lead to cardiovascular disease including peripheral vascular disease, hepatic disease, renal disease, neuropathy, ophthalmologic problems including retinopathy, osteoporosis, and oral disease.
Oftentimes patients will present with secondary oral manifestations even prior to diagnosis of diabetes. Oral manifestations of diabetes may include: diminished salivary flow, elevated caries risk, altered taste, burning mouth syndrome, enlarged parotid glands, halitosis, candidiasis, stomatitis, lichen planus, lichenoid reaction, benign migratory glossitis, angular cheilitis, and increased risk of traumatic ulcers.15
Diabetes mellitus is associated with a reduced immune function and subsequent impaired wound healing response. As such, research suggests that patients with type I and type II diabetes are at an elevated risk for experiencing severe gingivitis and periodontitis. While this relationship is well observed in poorly controlled individuals, studies suggest that persons with optimal diabetic control are at equal risk for developing diseases of the periodontium.16
Certain oral markers influence the periodontium in diabetic patients, such as the subgingival microflora containing high levels of Capnocytophaga, anaerobic Vibrios, and Actinomyces species.17 An increase in inflammatory mediators caused by periodontitis can also systematically influence glycemic control.18
The integration of utilizing glycosylated hemoglobin A1c (HbA1c) or blood glucose readings as vital signs permits the clinician to better understand the controlled or uncontrolled status of diabetes in prediabetic, type I, type II, or pregnancy-induced diabetes. This working knowledge better guides the clinician in understanding the potential delay in wound healing as well as the suspected progression of periodontal disease as outlined in the American Academy of Periodontology Staging & Grading guide.19
Episodic experiences of gingivitis and periodontitis are also observed in patients during hormonal imbalances of estrogen and progestin levels.20 Although pregnancy itself is not associated with an increased risk of periodontitis, it is suggested that pregnant patients experience exaggerated inflammatory responses. Oral contraceptives acting to elevate hormonal levels thus simulating pregnancy to prevent ovulation may also lead to increased inflammation and gingival enlargement, particularly in the first few months of initiating contraception. Hormonal imbalances during puberty also contribute to severity and an exaggerated response to the presence of oral biofilm, and menopause may also provide hormonal challenges linked to increased severity of periodontal disease.
Dental patients with osteoporosis, a reduction in bone mass due to loss of calcium, as well as those with Paget's disease or metastasis of the bone associated with various types of cancer may be prescribed a bisphosphonate drug intended to inhibit bone resorption and reduce the levels of calcium in the blood. Bisphosphonates act to inhibit the breakdown of bone by osteoclasts and as such, patients on bisphosphonates do not have osteoclasts readily available to resorb necrotic bone which results in new bone being laid down beside diseased bone. The presence of necrotic bone leads to impaired healing and reduced blood supply to the area, termed osteonecrosis of the jaw (ONJ).21
Dental procedures such as extractions, implant placement, periodontal therapy, endodontic or orthodontic therapy elevate the risk of triggering ONJ. In addition, the following factors are believed to elevate the risk for ONJ: chemotherapeutic drugs, corticosteroid therapy, diabetes, tobacco habit, high alcohol use, and poor oral hygiene in the presence of periodontitis.
Human immunodeficiency virus (HIV) and acquired immunodeficiency syndrome (AIDS) have rendered patients vulnerable to advanced stages of necrotizing diseases, including necrotizing ulcerative gingivitis and necrotizing ulcerative periodontitis.22 It is believed that this vulnerability results from an impairment of the host response in which the degree of immunodeficiency plays a vital role in the severity and prevalence of oral disease.
The introduction of antiretroviral23 drugs has helped modify the overt disease associated with HIV and subsequently AIDS, thus improving survival rates, quality of life, and better control over the exacerbation of oral disease.
Persons living with HIV or AIDS acquire vital signs from their physician to better identify potential complications associated with these diseases. These vital signs include a CD4 count and a viral load, of which a snapshot of these trending counts is continually evaluated for fluctuation.
• CD4 count:HIV damages the immune system by targeting CD4 cells. As such, acquiring a CD4 count from a patient can clarify the level of control or advancement of disease status. • Viral load:In addition, acquiring a viral load provides a measurement of HIV particles in the blood. A high viral load indicates either a recent HIV transmission or an uncontrolled status whereas a low or undetectable viral load indicates a relatively controlled person.
The positive associations between diseases of the periodontium and obesity have been well documented. Of note: a positive correlation was found in obese patients who presented with increased probing depth and advanced clinical attachment loss. The presence of obesity significantly increased the risk of periodontitis.24
The interdependent relationships between various co-morbidities often observed in obese patients may explain some of these causalities. Associations modified by risk factors such as hypertension, hyperlipidemia and elevated fasting blood glucose or HbA1c readings were associated with advanced periodontal pockets. Finally, the management and prevention of obesity may provide not only optimal systemic health but could lend to prevention or arresting the rate of progression of periodontal disease in this complex, bidirectional relationship.25
Cardiovascular Disease (CVD) refers to diseases of the circulatory system to include advanced acute outcomes such as myocardial infarction and stroke. The underlying cause of CVD in the majority of cases is atherosclerosis. Of note: upwards of 50% of individuals with CVD do not present with traditional risk factors such as hypercholesterolemia, hypertension, tobacco habits and obesity, however, the roles of infection and inflammation in atherosclerosis cases have become apparent and may play a key factor in better understanding how highly prevalent chronic inflammatory conditions of the periodontium may compensate for a vast majority of cardiovascular cases.26
Within the context of CVD, research has demonstrated a robust group of evidentiary pieces linking chronic periodontitis to an increased risk of atherosclerosis27 and individuals with periodontitis are reported to have a subsequently increased risk of experiencing coronary artery disease, stroke, and myocardial infarction.28
It is believed that bacterial burden from Porphyromonas gingivalis, Actinobacillus actinomycetemcomitans, Treponema denticola, and Tannerella forsythia as well as the release of bacterial endotoxins and proteolytic enzymes are responsible not only for the exacerbation of periodontal disease but also for advanced cardiovascular episodes. As such, periodontal therapy has been linked to improved biomarkers and subsequent cardiovascular disease outcomes.29
Cerebrovascular damage is loosely characterized as a blockage or rupture of the vessels providing blood supply to the central nervous system. Subclassifications of cerebrovascular accidents (CVA) include: subarachnoid hemorrhage, cerebral venous thrombosis, and spinal cord stroke. While these subclassifications present with different origins and pathogenesis, the presence of vascular changes unites each of these subclassifications in similarities.
Systematic literature reviews have yielded a link between periodontitis and CVA,30 specifically noting that individuals with periodontitis have about a twice greater chance of suffering from some form of CVA. This link is due in nature to the chronic and infectious origin of periodontitis. Specifically, the cascade of a wide spectrum of inflammatory markers has the ability to increase the risk of a stroke episode while also notating that these biomarkers are found to trigger the aggravation of the stroke process including changes in tissue phenotype and an increase in neuroinflammation and neurodegeneration leading to cell death.31
Adverse Pregnancy Outcomes
The burden of periodontal disease with regards to the wide range of adverse pregnancy outcomes has been well documented. Adverse pregnancy outcomes can describe primary outcomes such as maternal mortality, preterm delivery and perinatal mortality or secondary outcomes, such as miscarriage, preterm prelabor rupture of membranes, pregnancy-induced hypertension, preeclampsia, clinical chorioamnionitis, histologic chorioamnionitis, stillbirth, very preterm delivery, low birth weight, small for gestational age, early onset neonatal sepsis, or neonatal death.32
An increase on bacterial counts of Prevotella intermedia, a microorganism known to feed on sex steroid hormones may be responsible for a plausible link between pregnant women with periodontal disease and the increased risk of adverse pregnancy outcomes. Of note: periodontal scalings in pregnant women with active disease reduced the risk of adverse pregnancy outcomes.32
Rheumatoid arthritis symptoms are due to an overactive autoimmune response leading to joint damage and synovitis through pro-inflammatory pathways of unknown etiology. Periodontal disease is a common complication and can be present in all stages of rheumatoid arthritis (RA). Patients with periodontitis are up to four times more likely to have a self-reported history of rheumatoid arthritis than those without periodontal disease.33
Rheumatoid arthritis and periodontal disease share common risk factors and common pathologic processes.34 Risk factors for both diseases include: smoking, socio-economic status, obesity, poorly controlled diabetes, certain ethnicities.35 Certain serum antibodies directed to citrullinated peptides have been associated with RA disease severity, periodontal disease, periopathic microbiota, atopic autoimmune structures, and smoking. The underlying mechanisms of synovial inflammation and bone resorption demonstrate a biologic interrelationship between RA and periodontitis. In both diseases, the inflammatory response in which the pro-inflammatory cytokines and inflammatory mediators share a common pathway that results in gingival, collagen, and bone destruction.36
The inflammatory microenvironment in oral disease including specific oral bacteria strains such as P. gingivalis (P.g.), Treponema denticola (T.d.), and Tannerella forsythia (T.f.) may augment the systemic immune response and propagate rheumatoid arthritis.37 A common inflammatory response activates osteoclast function and vascular damage in both diseases. Similar proinflammatory mediators are present in both diseases including IL-1, IL-6, CRP, TNF-α, INF-γ, and RANK ligand (RANKL). When RA and periodontal disease exist together, they cyclically exacerbate systemic inflammation worsening both disease processes. Individuals with RA demonstrate 45% increased risk of myocardial infarctions.38,39
Symptom management of RA can be done with disease modifying anti-rheumatic drugs (DMARDs) and anti-tumor necrosis factor alpha (TNF-α), steroids, or non-steroidal anti-inflammatories (NSAIDs).40 The use of many antirheumatic medications do pose a risk to undergoing periodontal treatment, potentially leading to decreased immune response and higher infection rates.41 When managing periodontal therapy of patients with RA, consultation with their rheumatologist or treating physician should be performed as well as an understanding of their host modulation therapy for customization of treatment strategies. Of note, studies have demonstrated that mechanical nonsurgical periodontal therapy is effective in improving periodontal clinical parameters as well as systemic RA markers.42
The interdependent relationship between periodontitis and respiratory disease results from both a bacterial and inflammatory influence. It is widely accepted that oral bacteria are easily aspirated and has a subsequent opportunity to reside within the respiratory tract. Bacteria such as porphyromonas gingivalis, bacteroides oralisand fusobacterium nucleatum have demonstrated a contribution to respiratory diseases such as bronchitis, pneumonia, and emphysema.43
Specifically, the links between active periodontal infection and nosocomial pneumonia have been evaluated. Of note, the specific association between active periodontal treatment and decreased pneumonia cases throughout the United States has been well documented.44
Physiologically, high levels of interleukin-6(IL-6) have been known to accurately predict respiratory failure. Moreover, individuals presenting with high quantities of IL-6 are at a 22 times higher risk for respiratory complications than of those without.45 Current research indicates that IL-6 levels are significantly higher in concentration in individuals with extensive periodontal disease.46
As the global pandemic initiated by the severe acute respiratory syndrome coronavirus (SARS-CoV-2 virus) continues, clinicians are evaluating the possible links between active oral infection and the contraction of the 2019 coronavirus (COVID-19) in individuals.
One consideration is the known similarities in risk factors of individuals experiencing COVID-1947 and periodontitis48 that include but are not limited to: age of 65 years and older, cardiovascular conditions, diabetes, smoking habit, and severe obesity. It has been discussed that cytokine storm syndrome and subsequent immunosuppression may provide another rationale as to the role of periodontitis in the outcome of this current pandemic.49
Researchers began considering a possible link between oral hygiene and SARS-CoV-2 infections,50 and most notably it was discovered that periodontitis increases the risk of dying after a COVID-19 infection by nine times.51 The conclusion indicated that periodontitis presented with increased blood levels of biomarkers which linked to worse disease outcomes.
Current epidemiologic studies on the links between diseases of the periodontium and incident total cancers exist within a positive association. Notably, there is a statistically significant increased risk of total cancer amongst those with a history of diseases of the periodontium.
Associations were observed in cancers of the following systems: digestive tract, colorectal, pancreatic, prostate, and corpus uteri, as well as less common malignancies such as cancers of: gallbladder, liver, prostate, hematological/hematopoietic, and genitourinary systems. In addition, research has notated a positive association between tooth loss and risk of head and neck, esophageal, and lung cancers.52
Current plausibly mechanistic links between periodontal disease and cancers involve the release of free radicals and intermediates responsible for inducing oxidative stress from inflammatory cells. In addition, the presence of inflammatory cells and metabolites of the arachidonic acid pathway may demonstrate an affinity for advanced inflammatory cells and subsequent risk of cancers.
Associative clinical trials have demonstrated positive findings with regards to periodontal disease treatment in cohort studies and subsequent reduction in overall cancer risk. Additional studies have identified a significant risk of cancer associated with individuals who have chronic periodontitis yet did not receive periodontal treatment when compared with those who did not have chronic periodontitis. While evidence of the links between periodontal disease and cancer are primarily observational at the moment, plausible mechanisms are currently being evaluated.
One additional note observed in clinical trials is the challenges associated with advanced periodontal disease and accompanying tooth loss in which reduced masticatory efficacy often leads to a reduction in the consumption of fibrous, nutritious, cancer-fighting foods containing antioxidants. As such, advanced tooth loss has the capability of contributing to potential systemic challenges as well.53
Clinical Decision Making
Research has unpacked the importance of high-quality assessments, accurate diagnostics, appropriate planning, efficient interventions, and subsequent evaluation in the control of diseases of the periodontium. The multivariable model of treating periodontal disease requires a comprehensive evaluation of the complexities of oral inflammation, understanding that disease-susceptible and treatment-non-responsive individuals may require additional considerations in when, how, and how often to integrate periodontal therapy.54
Of note, non-surgical periodontal therapy has demonstrated a potential to reduce systemic levels of inflammation. Specifically, non-surgical therapy has demonstrated an impact on serum levels of inflammation55 as well as reducing the risk for other systemic inflammatory conditions.56
As such, the prudent clinician must consider familial and genetic risks as detected in the medical history and utilize this working knowledge to better understand treatment modalities and modifications to appraise.
Practitioners have an obligation to their patients to treat them comprehensively. Inflammation can be controlled, even reversed, with a healthy lifestyle and diet. Weight loss, exercise, blood sugar control, and stress management are all essential facets to discuss with patients. Eliminating inflammatory foods such as red meats, processed foods, refined sugars and carbohydrates, and trans fats such as margarine, corn oil, and deep-fried foods is advised.
Food choices are just as important as the medications one takes. A diet of fresh fruits, vegetables and foods containing omega-3 fatty acids such as fish, tofu, walnuts, flax seeds, soybeans, and olive oil is suggested. Some teas and spices such as black pepper, cardamom, cinnamon, clove, cumin, fenugreek, fennel, garlic, ginger, onion, rosemary, and turmeric57 have demonstrated anti-inflammatory properties and can be consumed as cooking seasoning or in an over-the-counter tablet form purchased from a pharmacy.
Evidence has demonstrated there are distinct links between diseases of the periodontium and various systemic illnesses. It is the infectious and inflammatory process of periodontitis as well as genetic and acquired risk factors that demonstrate associations between periodontitis and subsequent systemic diseases.
The "two-way street" of many systemic diseases clarifies that there are multifactorial complexities within periodontal disease. It is imperative to understand the common factors which elevate the susceptibility of periodontal disease.
The systemic consequences of periodontitis begin with the introduction of bacteria into the bloodstream, a declined in host immunity, and an increase in inflammatory markers. Common blood parameters such as white blood cell count (WBC), polymorphonuclear lymphocytes (PMNs) and lymphocyte counts, hemoglobin (Hb), and bleeding time (BT) have been adversely impacted by periodontal disease. Inflammatory markers such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are useful indicators for diagnosis and monitoring the progress of treatment of various conditions.
Links between periodontal health have been documented to be associated with 57 various diseases and conditions, but there are likely more. We are just beginning to understand these connections.
As such, the prudent clinician must consider all associated risks as detected in the medical history and utilize this working knowledge to better understand treatment modalities and modifications for patients with periodontal disease and other systemic diseases. A comprehensive, multi-disciplinary approach to optimize patient care should be utilized to treat these patients when appropriate.
About the Authors
Katrina M. Sanders, RDH, BSDH, MEd, RF Private Practice
Elizabeth A. Sanders, DPM, DABPM, AACFAS
San Juan, Puerto Rico
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