University of Manitoba Faculty of Dentistry

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University of Manitoba Faculty of Dentistry
Traditions of Excellence Horizons of Change
Anthony M. Iacopino
Dean

Professor, Restorative Dentistry
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Periodontitis and Systemic Disease The
Perio-Systemic Connection
Basic Overview
Alzheimer Society of Manitoba Winnipeg March
10, 2008
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Relationship Between Periodontitis
and Systemic
Diseases/Conditions
Grand Rounds in Oral Systemic Medicine
Gapski and Cobb
1(1)14-23, 2006 Moritz and Mealy 1(2)13-21,
2006
Iacopino 1(3)25-37,
2006 Paquette 1(4)14-25, 2006
Tae-Ju Oh et al.,
2(1)10-21, 2007
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Periodontal Disease Periodontitis
(Socransky et al., J Periodontol 63322-331,
1992 Liljenberg et al., J Clin Periodontol
21720-727, 1994)

• Chronic inflammatory disease
• primarily gram negative anaerobic oral infection
• gingival inflammation
• destruction of periodontal supporting tissues
• exfoliation of teeth in severe cases
• organisms within microbial flora of dental plaque
  are the major etiologic agents (Porphyromonas
  gingivalis, Bacteriodes forsythus, and Treponema
  denticola)
• microorganisms and endotoxins generate localized
  host-mediated tissue destructive immune response
  (cellular, inflammatory cytokines)

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Periodontitis Systemic Effects

• Transient bacteremia/endotoxemia
• demonstrations of periodontitis-induced
  bacteremia/endotoxemia linked to periodontitis
  severity and periods of progression/exacerbation
• organisms invade deep connective
  tissues/endothelium and coronary vasculature
• tissue destructive responses not limited to oral
  cavity

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Periodontitis Systemic Effects

• Transient bacteremia/endotoxemia
• creates systemic exposure
• elevation of serum pro-inflammatory cytokines and
  acute phase reactants have many biologic effects
• leads to elevations of serum lipid levels (FFA,
  LDL/TRG)
• systemic inflammatory state may adversely
  effect many organ systems leading to systemic
  diseases/conditions associated with chronic
  inflammation

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Periodontitis Systemic Effects
(Al-Emadi et al., Quintessence Int 37 761-765,
2006)

• Link to systemic health
• determined prevalence of systemic
  diseases/conditions in patients with
  periodontitis
• 420 random patients over a two-year period with
  periodontal disease)
• hypertension, respiratory disease, diabetes, and
  arthritis significantly more prevalent in
  subjects with periodontitis (p lt 0.05)
• subjects with more severe periodontitis were four
  times more likely to have three or more systemic
  conditions

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

• Link to medical costs
• investigated effect of periodontal treatment on
  medical expenditures for diabetes, cardiovascular
  disease, and cerebrovascular disease
• measured per member per month costs for 144,225
  enrollees of a PPO by aggregating ICD-9
  expenditures over a two-year period
• controlled for differences in disease burden
  between groups with and without history of
  periodontal care
• periodontal treatment significantly decreases
  medical costs (p lt 0.05) with greater reductions
  when care is provided earlier in life

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Periodontitis Causes Systemic Inflammation
(DAiuto et al., J Clin Perio 34124-129, 2007)

• Treatment of periodontitis reverses systemic
  inflammation
• 65 healthy subjects with severe generalized PD
• blinded randomized control clinical trial
• measured CRP, IL-6, LDL cholesterol at baseline
  and two months after treatment (standard therapy)
• at baseline, markers were significantly elevated
  
• after treatment, significant reductions in CRP
  (p0.03), IL-6 (p0.006), and LDL (p0.002)
• reductions were independent of age, gender, BMI,
  ethnicity

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Respiratory Disease

• Direct linkages through aspiration
• aspiration pneumonia
• major cause of morbidity, hospitalization, and
  mortality in institutional settings (50 of all
  infections)
• tremendous health care costs and decreased
  quality of life
• frequently caused by gram negative organisms in
  dental plaque around diseased teeth/poorly
  maintained dentures
• indisputable evidence and acceptance by medical
  community
• requires changes in interprofessional patient
  management

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Rheumatoid Arthritis

• Some preliminary studies indicate
• patients with PD and RA exhibit similar
  pro-inflammatory cytokine profiles
• periodontal pathogens may initiate formation of
  rheumatoid factor immune complexes
• patients with moderate to severe periodontitis
  are at higher risk for rheumatoid arthritis
• dose-response relationship between PD and RA
• periodontal treatment reduces the severity of
  rheumatoid arthritis
• requires further investigation, may warrant
  closer monitoring of periodontal status of RA
  patients

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Stroke/CVA/TIA

• Several credible studies indicate PD is a
  significant risk factor for CVAs, especially
  stroke
• dose-response relationship (gingivitis, PD
  severity)
• closely tied to mechanisms underlying initiation
  and progression of atherosclerosis
• dysregulation of lipid metabolism
• interaction of periodontal pathogens with
  vascular walls
• endothelial cell dysfunction and damage
• initiation and/or exacerbation of atheroma
  formation
• thickening of intimal-medial vessel walls

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Stroke/CVA/TIA
(Lee et al., J Periodontol 771744-1754, 2006)

• Periodontitis associated with stroke in the
  elderly, even partially edentulous patients
• NHANES III database for patients aged 60 years
• used new index to account for number of teeth
• weighs exposure burden based on past
  periodontitis
• periodontitis significantly associated with
  stroke
• relationship just as strong for subjects with few
  teeth
• cumulative effects of periodontitis are
  important

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Cardiovascular Disease

• 8 separate longitudinal studies from 2000-2004
  indicated that PD is associated with the onset of
  coronary heart disease
• controlled for other established risk factors
• periodontitis associated with intimal-medial wall
  thickness (a measure of sub-clinical
  atherosclerosis)
• links between systemic inflammation, PD, and
  atherosclerosis/CHD as gingival index and dental
  infections (microbial burden) were positively
  correlated to onset of new CHD events

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Cardiovascular Disease

• Since 2000
• 16 associative studies linking PD to presence of
  vascular plaques
• 9 studies demonstrating presence of periodontal
  pathogens in atheromas
• 16 associative studies concerning inflammatory
  PD-cardiovascular mechanistic link
• significant association between PD-induced
  elevations in serum inflammatory biomarkers
  (pro-inflammatory cytokines, CRP, fibrinogen) and
  CHD
• levels of inflammatory biomarkers and extent of
  CHD directly proportional to PD severity
• treatment of PD reduces levels of serum
  inflammatory biomarkers

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Diabetes

• The most well defined perio-systemic connection
• The sixth major complication of diabetes
• similar changes in systemic physiology and blood
  biochemistry (a bi-directional relationship
  between pro-inflammatory cytokines and serum
  lipids)
• definitive evidence that uncontrolled diabetes
  exacerbates PD and that PD exacerbates some
  diabetic complications (reversible with treatment
  of PD)
• preliminary evidence that untreated PD may
  actually cause diabetes in otherwise healthy
  patients

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Periodontitis and Insulin 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)

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Osteoporosis

• Conflicting results from initial studies for
• periodontal status and systemic bone mineral
  density
• BMD and number of remaining teeth
• systemic bone loss as a predictor of risk for
  alveolar bone loss (vice-versa)
• Positive studies outnumber negative studies for
  associations/relationships
• Both conditions involve physiologic mechanisms
  mediated through pro-inflammatory cytokines
• Current thought is that patients would benefit
  from bi-directional screening

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Alzheimers Disease

• Inflammatory hypothesis (no biologic evidence)
• systemic inflammation associated with signals
  that cross blood-brain barrier via perivascular
  macrophages/microglia
• activated macrophages/microglia initiate a
  neuro-inflammatory process
• resultant neuro-inflammatory responses and
  secretion of neurotoxic factors cause cell
  injury/death
• chronic inflammation in the brain destroys
  sufficient neurons to cause the clinical signs of
  dementia
• several recent population-based, prospective
  cohort studies have demonstrated that serum CRP
  and pro-inflammatory cytokine levels are
  increased prior to the clinical onset of dementia

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Linkage Between PD and Systemic
Diseases/Conditions in the Elderly
Respiratory Infection
Dementia
Microglia Activation
Aspiration
Atherosclerosis
Elevated Serum Pro-Inflammatory
Cytokines
Bacteremia
Periodontitis
Hyperlipidemia
Endotoxemia
Altered Lipid Metabolism
Rheumatoid Factor
Synovial Inflammation
Atherosclerosis
ß-Cell Destruction
Insulin Resistance
Arthritis
Diabetes
Cardiovascular/ Cerebrovascular Disease
Vascular Endothelium
Iacopino, Grand Rounds Oral-Sys Med 1(3)25-37,
2006
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University of Manitoba Faculty of Dentistry
Traditions of Excellence Horizons of Change
Questions, Comments, Concerns?