2-D The Importance of Oral Health Systemic Health Connections

University of Manitoba University of Manitoba Faculty of DentistryFaculty of Dentistry


Traditions of Excellence: Traditions of Excellence: Horizons of ChangeHorizons of Change

Anthony M. Iacopino Anthony M. Iacopino Dean Dean Professor, Restorative Professor, Restorative

DentistryDentistry

Periodontitis and Systemic Periodontitis and Systemic Disease “The Perio-Disease “The Perio-Systemic Connection”Systemic Connection”

Alzheimer Society of ManitobaAlzheimer Society of Manitoba

Winnipeg – March 10, 2008Winnipeg – March 10, 2008

Basic Basic OverviewOverview

Relationship Between Relationship Between Periodontitis Periodontitis

and Systemic and Systemic Diseases/ConditionsDiseases/Conditions

Grand Rounds in Oral Systemic MedicineGrand Rounds in Oral Systemic Medicine Gapski and Cobb Gapski and Cobb

1(1):14-23, 2006; Moritz and Mealy 1(1):14-23, 2006; Moritz and Mealy 1(2):13-21, 2006; 1(2):13-21, 2006; Iacopino 1(3):25-37, 2006; Iacopino 1(3):25-37, 2006; Paquette 1(4):14-25, 2006; Paquette 1(4):14-25, 2006; Tae-Ju Oh et al., 2(1):10-21, Tae-Ju Oh et al., 2(1):10-21,

20072007

• respiratory diseaserespiratory disease

• arthritisarthritis • Alzheimer’s diseaseAlzheimer’s disease

• strokestroke • adverse pregnancy outcomeadverse pregnancy outcome

• heart diseaseheart disease • diabetesdiabetes

• osteoporosisosteoporosis

Periodontal Disease: Periodontal Disease: PeriodontitisPeriodontitis

Chronic inflammatory diseaseChronic inflammatory disease• primarily gram negative anaerobic oral infectionprimarily gram negative anaerobic oral infection• gingival inflammationgingival inflammation• destruction of periodontal supporting tissues destruction of periodontal supporting tissues • exfoliation of teeth in severe casesexfoliation of teeth in severe cases• organisms within microbial flora of dental plaque are organisms within microbial flora of dental plaque are

the major etiologic agents (the major etiologic agents (Porphyromonas gingivalis, Porphyromonas gingivalis, Bacteriodes forsythus, and Treponema denticolaBacteriodes forsythus, and Treponema denticola))

• microorganisms and endotoxins generate localized microorganisms and endotoxins generate localized host-mediated tissue destructive immune response host-mediated tissue destructive immune response (cellular, inflammatory cytokines)(cellular, inflammatory cytokines)

(Socransky et al., J Periodontol 63:322-331, 1992; Liljenberg et al., J Clin Periodontol 21:720-727, 1994)

Periodontitis: Systemic Periodontitis: Systemic EffectsEffects

Transient bacteremia/endotoxemiaTransient bacteremia/endotoxemia

• demonstrations of periodontitis-induced demonstrations of periodontitis-induced bacteremia/endotoxemia linked to periodontitis bacteremia/endotoxemia linked to periodontitis severity and periods of progression/exacerbationseverity and periods of progression/exacerbation

• organisms invade deep connective tissues/endothelium organisms invade deep connective tissues/endothelium and coronary vasculatureand coronary vasculature

• tissue destructive responses not limited to oral cavitytissue destructive responses not limited to oral cavity


Transient bacteremia/endotoxemiaTransient bacteremia/endotoxemia

• creates systemic “exposure” creates systemic “exposure”

• elevation of serum pro-inflammatory cytokines and elevation of serum pro-inflammatory cytokines and acute phase reactants have many biologic effectsacute phase reactants have many biologic effects

– leads to elevations of serum lipid levels (FFA, LDL/TRG)leads to elevations of serum lipid levels (FFA, LDL/TRG)

– ““systemic inflammatory state” may adversely effect many systemic inflammatory state” may adversely effect many organ systems leading to systemic diseases/conditions organ systems leading to systemic diseases/conditions associated with chronic inflammationassociated with chronic inflammation


Link to systemic healthLink to systemic health• determined prevalence of systemic diseases/conditions determined prevalence of systemic diseases/conditions

in patients with periodontitisin patients with periodontitis

• 420 random patients over a two-year period with 420 random patients over a two-year period with periodontal disease) periodontal disease)

• hypertension, respiratory disease, diabetes, and hypertension, respiratory disease, diabetes, and arthritis significantly more prevalent in subjects with arthritis significantly more prevalent in subjects with periodontitis (p < 0.05)periodontitis (p < 0.05)

• subjects with more severe periodontitis were four subjects with more severe periodontitis were four times more likely to have three or more systemic times more likely to have three or more systemic conditionsconditions

(Al-Emadi et al., Quintessence Int 37: 761-765, 2006)


Link to medical costsLink to medical costs• investigated effect of periodontal treatment on investigated effect of periodontal treatment on

medical expenditures for diabetes, cardiovascular medical expenditures for diabetes, cardiovascular disease, and cerebrovascular diseasedisease, and cerebrovascular disease

• measured per member per month costs for 144,225 measured per member per month costs for 144,225 enrollees of a PPO by aggregating ICD-9 expenditures enrollees of a PPO by aggregating ICD-9 expenditures over a two-year periodover a two-year period

• controlled for differences in disease burden between controlled for differences in disease burden between groups with and without history of periodontal caregroups with and without history of periodontal care

• periodontal treatment significantly decreases medical periodontal treatment significantly decreases medical costs (p < 0.05) with greater reductions when care is costs (p < 0.05) with greater reductions when care is provided earlier in lifeprovided earlier in life

(Albert et al., BMC Health Services Res 6: 103-109, 2006)

Periodontitis Causes Periodontitis Causes Systemic InflammationSystemic Inflammation

Treatment of periodontitis reverses systemic Treatment of periodontitis reverses systemic inflammationinflammation• 65 healthy subjects with severe generalized PD65 healthy subjects with severe generalized PD

• blinded randomized control clinical trial blinded randomized control clinical trial

• measured CRP, IL-6, LDL cholesterol at baseline and measured CRP, IL-6, LDL cholesterol at baseline and two months after treatment (standard therapy)two months after treatment (standard therapy)

– at baseline, markers were significantly elevated at baseline, markers were significantly elevated

– after treatment, significant reductions in CRP (p=0.03), after treatment, significant reductions in CRP (p=0.03), IL-6 (p=0.006), and LDL (p=0.002)IL-6 (p=0.006), and LDL (p=0.002)

– reductions were independent of age, gender, BMI, ethnicityreductions were independent of age, gender, BMI, ethnicity

(D’Aiuto et al., J Clin Perio 34:124-129, 2007)

Respiratory DiseaseRespiratory Disease

Direct linkages through aspirationDirect linkages through aspiration• aspiration pneumoniaaspiration pneumonia

– major cause of morbidity, hospitalization, and mortality in major cause of morbidity, hospitalization, and mortality in institutional settings (~50% of all infections)institutional settings (~50% of all infections)

– tremendous health care coststremendous health care costs and decreased quality of lifeand decreased quality of life

– frequently caused by gram negative organisms in dental frequently caused by gram negative organisms in dental plaque around diseased teeth/poorly maintained denturesplaque around diseased teeth/poorly maintained dentures

– indisputable evidence and acceptance by medical communityindisputable evidence and acceptance by medical community

– requires changes in interprofessional patient managementrequires changes in interprofessional patient management

Rheumatoid Rheumatoid ArthritisArthritis

Some preliminary studies indicate:Some preliminary studies indicate:• patients with PD and RA exhibit similar pro-patients with PD and RA exhibit similar pro-

inflammatory cytokine profilesinflammatory cytokine profiles• periodontal pathogens may initiate formation of periodontal pathogens may initiate formation of

rheumatoid factor immune complexesrheumatoid factor immune complexes• patients with moderate to severe periodontitis are at patients with moderate to severe periodontitis are at

higher risk for rheumatoid arthritishigher risk for rheumatoid arthritis• dose-response relationship between PD and RAdose-response relationship between PD and RA• periodontal treatment reduces the severity of periodontal treatment reduces the severity of

rheumatoid arthritis rheumatoid arthritis • requires further investigation, may warrant closer requires further investigation, may warrant closer

monitoring of periodontal status of RA patientsmonitoring of periodontal status of RA patients

Stroke/CVA/TIAStroke/CVA/TIA

Several credible studies indicate PD is a Several credible studies indicate PD is a significant risk factor for CVAs, especially strokesignificant risk factor for CVAs, especially stroke• dose-response relationship (gingivitis, PD severity)dose-response relationship (gingivitis, PD severity)

• closely tied to mechanisms underlying initiation and closely tied to mechanisms underlying initiation and progression of atherosclerosisprogression of atherosclerosis

– dysregulation of lipid metabolismdysregulation of lipid metabolism

– interaction of periodontal pathogens with vascular wallsinteraction of periodontal pathogens with vascular walls

– endothelial cell dysfunction and damageendothelial cell dysfunction and damage

– initiation and/or exacerbation of atheroma formationinitiation and/or exacerbation of atheroma formation

– thickening of intimal-medial vessel wallsthickening of intimal-medial vessel walls

Stroke/CVA/TIAStroke/CVA/TIA

Periodontitis associated with stroke in the Periodontitis associated with stroke in the elderly, even partially edentulous patientselderly, even partially edentulous patients

• NHANES III database for patients aged NHANES III database for patients aged ≥ 60 years≥ 60 years

• used “new” index to account for number of teethused “new” index to account for number of teeth– weighs “exposure burden” based on past periodontitis weighs “exposure burden” based on past periodontitis

• periodontitis significantly associated with strokeperiodontitis significantly associated with stroke– relationship just as strong for subjects with few teethrelationship just as strong for subjects with few teeth– ““cumulative effects” of periodontitis are importantcumulative effects” of periodontitis are important

(Lee et al., J Periodontol 77:1744-1754, 2006)

Cardiovascular Cardiovascular DiseaseDisease

8 separate longitudinal studies from 2000-2004 8 separate longitudinal studies from 2000-2004 indicated that PD is associated with the onset of indicated that PD is associated with the onset of coronary heart diseasecoronary heart disease• controlled for other established risk factorscontrolled for other established risk factors

• periodontitis associated with intimal-medial wall periodontitis associated with intimal-medial wall thickness (a measure of sub-clinical atherosclerosis)thickness (a measure of sub-clinical atherosclerosis)

• links between systemic inflammation, PD, and links between systemic inflammation, PD, and atherosclerosis/CHD as gingival index and dental atherosclerosis/CHD as gingival index and dental infections (microbial burden) were positively infections (microbial burden) were positively correlated to onset of new CHD eventscorrelated to onset of new CHD events

Cardiovascular Cardiovascular DiseaseDisease

Since 2000:Since 2000:• 16 associative studies linking PD to presence of 16 associative studies linking PD to presence of

vascular plaquesvascular plaques• 9 studies demonstrating presence of periodontal 9 studies demonstrating presence of periodontal

pathogens in atheromas pathogens in atheromas • 16 associative studies concerning inflammatory PD-16 associative studies concerning inflammatory PD-

cardiovascular mechanistic linkcardiovascular mechanistic link– significant association between PD-induced elevations in significant association between PD-induced elevations in

serum inflammatory biomarkers (pro-inflammatory serum inflammatory biomarkers (pro-inflammatory cytokines, CRP, fibrinogen) and CHDcytokines, CRP, fibrinogen) and CHD

– levels of inflammatory biomarkers and extent of CHD levels of inflammatory biomarkers and extent of CHD directly proportional to PD severitydirectly proportional to PD severity

– treatment of PD reduces levels of serum inflammatory treatment of PD reduces levels of serum inflammatory biomarkers biomarkers

DiabetesDiabetes The most well defined perio-systemic connectionThe most well defined perio-systemic connection

• The “sixth major complication” of diabetesThe “sixth major complication” of diabetes

• similar changes in systemic physiology and blood similar changes in systemic physiology and blood biochemistry (a bi-directional relationship between biochemistry (a bi-directional relationship between pro-inflammatory cytokines and serum lipids)pro-inflammatory cytokines and serum lipids)

• definitive evidence that uncontrolled diabetes definitive evidence that uncontrolled diabetes exacerbates PD and that PD exacerbates some diabetic exacerbates PD and that PD exacerbates some diabetic complications (reversible with treatment of PD)complications (reversible with treatment of PD)

• preliminary evidence that untreated PD may actually preliminary evidence that untreated PD may actually cause diabetes in otherwise healthy patientscause diabetes in otherwise healthy patients

Periodontitis and Insulin Periodontitis and Insulin Resistance Resistance Periodontitis and Insulin Periodontitis and Insulin Resistance Resistance

Recent studies demonstrate links between PD and insulin resistance (case control and randomized trials)

• PD causes insulin resistance and significant elevations in serum glucose/HbA1c levels (degree of insulin resistance directly related to severity of PD)

• treatment of PD improves glycemic status in diabetic patients (significant decreases in serum glucose/HbA1c levels, reduced insulin requirements, effects more pronounced for severe PD)

• significantly more PD in non-diabetic patients with documented insulin resistance

• documented relationship between PD and pre-diabetes (impaired fasting glucose and impaired glucose tolerance)

OsteoporosisOsteoporosis Conflicting results from initial studies for:Conflicting results from initial studies for:

• periodontal status and systemic bone mineral densityperiodontal status and systemic bone mineral density• BMD and number of remaining teethBMD and number of remaining teeth• systemic bone loss as a predictor of risk for alveolar systemic bone loss as a predictor of risk for alveolar

bone loss (vice-versa)bone loss (vice-versa) Positive studies outnumber negative studies for Positive studies outnumber negative studies for

associations/relationshipsassociations/relationships Both conditions involve physiologic mechanisms Both conditions involve physiologic mechanisms

mediated through pro-inflammatory cytokinesmediated through pro-inflammatory cytokines Current thought is that patients would benefit Current thought is that patients would benefit

from “bi-directional” screening from “bi-directional” screening

Alzheimer’s DiseaseAlzheimer’s Disease

Inflammatory hypothesis (no biologic evidence)Inflammatory hypothesis (no biologic evidence)• systemic inflammation associated with signals that systemic inflammation associated with signals that

cross blood-brain barrier via perivascular cross blood-brain barrier via perivascular macrophages/microgliamacrophages/microglia

• activated macrophages/microglia initiate a neuro-activated macrophages/microglia initiate a neuro-inflammatory processinflammatory process

• resultant neuro-inflammatory responses and secretion resultant neuro-inflammatory responses and secretion of neurotoxic factors cause cell injury/deathof neurotoxic factors cause cell injury/death

• chronic inflammation in the brain destroys sufficient chronic inflammation in the brain destroys sufficient neurons to cause the clinical signs of dementia neurons to cause the clinical signs of dementia

• several recent population-based, prospective cohort several recent population-based, prospective cohort studies have demonstrated that serum CRP and pro-studies have demonstrated that serum CRP and pro-inflammatory cytokine levels are increased prior to inflammatory cytokine levels are increased prior to the clinical onset of dementia the clinical onset of dementia

PeriodontitisElevated Serum

Pro-Inflammatory

Cytokines

Hyperlipidemia

Diabetes

BacteremiaEndotoxemia

Insulin Resistance

β-Cell Destruction

Cardiovascular/ Cerebrovascular

Disease

Arthritis

Respiratory Infection

Aspiration

Dementia

Microglia Activation

Synovial Inflammatio

n

Atherosclerosis

Altered Lipid Metabolism

Rheumatoid Factor

Atherosclerosis

Vascular Endothelium

Linkage Between PD and Systemic Linkage Between PD and Systemic Diseases/Conditions in the ElderlyDiseases/Conditions in the Elderly

Iacopino, Grand Rounds Oral-Sys Med 1(3):25-37, 2006Iacopino, Grand Rounds Oral-Sys Med 1(3):25-37, 2006



Questions, Comments, Concerns?Questions, Comments, Concerns?

Traditions of Excellence: Traditions of Excellence: Horizons of ChangeHorizons of Change

Documents

2-D The Importance of Oral Health Systemic Health Connections