Periodontal Disease and Overall Health: A Clinician's Guide

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CHAPTER 3 Infection and Inflammation 33for the initiation and progression of a varietyof inflammatory diseases, including arthritis,peptic ulcers, and appendicitis. As a result,therapeutic full-mouth extractions became acommon dental practice. However, many teethwere extracted without evidence of infection.When it was finally realized that there wasno therapeutic benefit, the theory was finallydiscredited and the practice abandoned. Duringthe final two decades of the twentiethcentury—as our knowledge concerning theinflammatory component of systemic diseaseswas enriched and our understanding ofthe relationship of periodontal disease tosystemic inflammation increased—the ideathat periodontal infection may affect theprogression of systemic disorders such ascardiovascular disease, adverse pregnancycomplications, diabetes mellitus, and otherdiseases re-emerged.In this possible association, systemicinflammation seems to play a key role.Specifically, on one hand, periodontal diseasemay induce systemic inflammation andon the other, there is increasing evidencesuggesting that elevated levels of the markersof systemic inflammation are associatedwith an increased risk for systemic diseases.Cardiovascular Disease (CVD)There is now abundant clinical evidencedemonstrating that many biomarkers of inflammationare elevated years in advance offirst-ever myocardial infarction (MI) orthrombotic stroke, and that these same biomarkersare highly predictive of recurrentMI, recurrent stroke, and death due to CVD. 2Moreover, studies demonstrate that serumIL-6 levels were significantly elevated insubjects who subsequently experienced anMI compared to age-matched controls. 34Similarly, plasma levels of soluble P-selectin,soluble CD40L, and macrophage-inhibitorycytokine-1 were all significantly increased inhealthy subjects who subsequently developedCVD events compared to matched controls. 35Elevated plasma concentrations of TNF-αhave also been associated with CVD, andspecifically with recurrent nonfatal MI orother CVD events. Moreover, TNF-α levelswere persistently higher among post-MIpatients at increased risk for recurrent coronaryevents.Besides these pro-inflammatory cyto -kines, several acute-phase reactants have alsobeen associated with CVD. One of the factorswith the strongest evidence as a biomarkerfor predicting CVD events is CRP(specifically, high sensitivity CRP, hsCRP).When measured in the blood, hsCRP provedto be a strong, independent predictor of futureMI and stroke among apparently healthyasymptomatic men. Also, the relative riskfor first MI and ischemic stroke increasedsignificantly with each increasing quartileof baseline concentrations of CRP. 36 As describedalready, CRP may contribute to theinitiation and development of atherothromboticlesions not only by up-regulating theexpression of pro-inflammatory cytokines,but also by mediating proliferation and activationof SMCs and by activating the procoagulantsystem. This last property may befurther enhanced by another acute-phase protein,fibrinogen, which is often found to beelevated in CVD patients.Adverse Pregnancy OutcomesSystemic inflammation has also beenimplicated in adverse pregnancy outcomes,since elevated concentrations of CRP in earlypregnancy are associated with an increasedrisk of preterm birth and very-preterm birth.Diabetes MellitusFinally, systemic inflammation hasbeen associated with both Type 1 and Type2 diabetes mellitus. Recent studies suggestthat in Type 1 diabetes, the levels of systemicmarkers of inflammation, such as CRP,do not differ between healthy individualsand subjects for which Type 1 diabetes has
34 Periodontal Disease and Overall Health: A Clinician's Guidebeen just diagnosed. However, the levels ofcirculating CRP are significantly higher inindividuals with long-term diabetes. 37 It isalso believed that inflammatory processesmay have a more pronounced effect on thedevelopment of complications of Type 1 diabetes.Thus, elevated levels of plasma CRPand of the pro-inflammatory soluble adhesionmolecule, vascular cell adhesion molecule-1(VCAM-1), have been found in patientswith microvascular disease comparedto those without.In Type 2 diabetes, inflammatoryprocesses are more strongly associated withthe development of the disease. Systemicmarkers of inflammation are found to be increasedin healthy individuals who developType 2 diabetes later in their lives. AmongPima Indians, a population with a high prevalenceof Type 2 diabetes, subjects with whiteblood cell counts within the highest tertilewere more likely to develop Type 2 diabetesover a period of 20 years compared to those inthe lowest tertile. Moreover, in two other studies,healthy individuals demonstrating serumlevels of CRP and IL-6 within the highestquartiles were more likely to develop Type 2diabetes in the next four to seven years comparedto subjects in the lowest quartile. 4 Similarresults were found with increased levelsof another acute-phase protein, PAI-1.Insulin resistance, which is associatedwith Type 2 diabetes and usually procedesthe development of frank diabetes, may alsobe affected by pre-existing systemic inflammationsince several pro-inflammatory andacute-phase proteins, such as TNF-, IL-6,MCP-1, PAI-1, and SAA are associated withthe induction of insulin resistance. 38Summary of Part IIBased on available evidence, it is possiblethat systemic inflammation may actuallybe the link that associates periodontaldisease with other systemic diseases. Detailsof the plausible biological mechanisms thatmay associate periodontal disease with varioussystemic diseases are further analyzed inother chapters of this book.PART III: RESOLUTION OFINFLAMMATION IN PERIODONTITISAND OTHER SYSTEMIC DISEASESInflammation is thought to play a centralrole in the progression of periodontaland a number of systemic diseases. Experimentsin animal models and in man havedemonstrated that periodontal destruction ismediated primarily by the inflammatory response,although periodontal pathogens area necessary etiologic factor. 20,39,40 Geneticpolymorphisms and other factors may alsobe responsible for a “hyperinflammatoryphenotype” that may further affect the susceptibilityof the host to periodontal diseaseand tissue destruction. Currently, it is believedthat in chronic periodontal disease, destructiondoes not follow a linear pattern withtime, but occurs in “random bursts” with periodsof remission and exacerbation. However,the reasons behind this random progressionare not fully understood. Diseaseprogression becomes even more enigmaticconsidering that it is not always clear why achronic inflammation of the gingiva may remainas gingivitis in some patients andprogress to periodontitis in others. Irrespectiveof the nature of periodontal disease progression,the perpetuation of the inflammatoryprocess in the gingiva may lead to achronic low-grade systemic inflammatory response,which in turn potentially contributesto the progression of systemic diseases.The Process of Inflammatory ResolutionThe landmark events during inflammationinclude the accumulation of leukocytesin the infected area and phagocytosis of thebacteria and/or their virulence factors. Aspart of the inflammatory process, activationof neutrophil lysosomal phospholipase releasesfree arachidonic acid from membrane
Page 5: ivCONTRIBUTORSSrividya Kidambi, MDA
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