periodontal systemic interrelationships

Periodontal-Systemic Periodontal-Systemic InterrelationshipsInterrelationships

Antonio J. Moretti, DDS, MSAntonio J. Moretti, DDS, MS

The University of Texas Houston The University of Texas Houston Health Science Center Dental BranchHealth Science Center Dental Branch

Periodontal Diseases and Periodontal Diseases and Systemic DiseasesSystemic Diseases

• A “two-way street”

• Is the old focal infection theory rearing its head?

• Are we getting closer to become true oral physicians?

Periodontal Diseases and Periodontal Diseases and Systemic DiseasesSystemic Diseases

• Dentists need to know more about systemic diseases and physicians need to increase their knowledge of oral diseases

Periodontal DiseasePeriodontal Disease

• 10 to 15% of US adults have severe periodontal disease

• The same is true for the rest of the world

• Factors other than chance or poor dental habits predispose people to periodontal disease

Moderate to Severe Periodontitis

with at least 28 teeth present

Moderate to Severe Periodontitis

with at least 28 teeth present

72 cm2 of pocket epithelium in

contact with biofilms

72 cm2 of pocket epithelium in

contact with biofilms

Roy Page,1998Roy Page,1998

Systemic conditions as risk Systemic conditions as risk factors for periodontal diseasefactors for periodontal disease

• DiabetesDiabetes

• SmokingSmoking

• HIVHIV

• OsteoporosisOsteoporosis

• MenopauseMenopause

• Angst-Related Psychosocial FactorsAngst-Related Psychosocial Factors

Diabetes - short reviewDiabetes - short review

• IDDM (type 1):– 5 to 15% of cases. Abrupt onset, commonly at puberty

– Destruction of insulin production beta cells in the pancreas via autoimmune process

• NIDDM (type 2):– 2 to 3% of population. Recognized only 50% of cases

– Reduced insulin production

– Control with diet, hypoglycemic drugs, or combination

Diabetes Mellitus - HypothesisDiabetes Mellitus - Hypothesis• Hyperglycemia produces oxidation of protein and

lipids. This will result in advanced glycation end products (AGE)

• AGEs are primarily responsible for collagen cross-links leading to macrovascular complications (hardening of arteries)

• AGEs bind to endothelial cells and macrophages• Macrophages that interact with AGE will increase

secretion of TNF-, IL-6, and IL-1

Diabetes Mellitus - HypothesisDiabetes Mellitus - Hypothesis• Interaction of AGE and endothelial cells will

result in endothelin-1 (a potent vasoconstrictor)• The previous cellular reactions may take place in

the periodontium, thus accounting for increased risk for severe attachment loss

• Tissues from retina, kidney, and nerves have shown permeability to glucose

• Pathogenesis of periodontal disease in diabetics might also be glucose-mediated

DiabetesDiabetes

• IDDM and NIDDM are risk factors for periodontal disease

• Progression is faster and tooth loss is higher in poorly controlled patients

• PMN function might be impaired

• Thickening of the basement membrane and the vessel walls

DiabetesDiabetes

• Interference with delivery of nutrients

• Decreased oxygen diffusion

• Decreased elimination of metabolic waste

• Increased collagen breakdown

• Altered collagen synthesis

Diabetes Diabetes • Well-controlled diabetics who receive

regular periodontal care and have good oral hygiene are NO more likely to develop severe periodontitis than non diabetics.

Seppala et al., 1993 and 1994

• Well-controlled diabetics have been shown to respond equally as well to periodontal therapy as non diabetics.

Westfelt et al., 1996 Telervo et al., 1997

Effect of Periodontitis on Effect of Periodontitis on DiabetesDiabetes

• Hypothesis:– Bacterial infection releases hormones that

increase glucose levels– Inflammatory mediators (TNF- and IL-1)

induce cell resistance to insulin

Effect of Periodontitis on Effect of Periodontitis on DiabetesDiabetes

• Periodontal treatment might improve the metabolic control of the disease

Williams and Mahan, 1960; Miller et al., 1992;

Aldridge et al., 1996; Grossi et al., 1997

• Severe Periodontitis has been associated with a 6 fold increased risk of poor glycemic control Taylor et al.,

1996

Cigarette Smoking

• Accounts for approximately half the cases of periodontitis in young adults

• Smokers are, in average, close to three times more likely to show severe periodontal disease

• Current smokers are 3.3 times more likely to attend a periodontist’s office

SmokingSmoking

• Light smokers have a relative risk of developing periodontal disease that is 2 times higher than non smokers

• Heavy smokers have a relative risk of developing periodontal disease that is 7 times higher than non smokers

Grossi et al. 1994, 1995

SmokingSmoking

• Decreases cell-mediated and humoral immune responses

• Alters PMN function

• Decreases serum IgG2

• Modulates subgingival microbiota

• Increases levels of certain microorganisms

Smoking CessationSmoking Cessation

• Seems to yield periodontal benefits

• Long term studies are still missing

• After a year, gingival tissues revert from fibrotic to normal anatomy and contour

Haber, 1996

HIVHIV

• Conflicting evidence to be considered a risk factor for conventional periodontal disease

• Small percentage of HIV+ patients develop a severe rapidly progressive form of gingivitis/periodontitis (NUG/NUP)

• Lesions are usually associated with pronounced immunosuppression

HIVHIV

• Regulation of PMN recruitment in GCF is hindered

• Suggested that PMN dysfunction allows subgingival colonization of Candida and subsequent risk increase for periodontal destruction

Lamster et al., 1998

Candidiasis and Periodontal DiseaseCandidiasis and Periodontal Disease

Short-Term Success of Short-Term Success of Osseointegrated Dental Implants Osseointegrated Dental Implants

in HIV-Positive Individualsin HIV-Positive Individuals

Riano PC, Stevenson GC, Engelmeier RL, Flaitz CM, Moretti AJ, Nichols CM

Master of Sciences Thesis at UTDB Houston

HypothesisHypothesis

• The null hypothesis for this study was: “There are no differences between the HIV infected and uninfected populations in the clinical behavior and biologic integration of endosseous dental implants as measured by descriptive parameters of assessment.

Study InformationStudy Information

• Prospective, cohort, multi-center pilot study• Compare short-term success rate of

osseointegrated dental implants in HIV infected versus uninfected populations to justify the use of implants in the HIV positive population

• Clinical study to glean other important clinical information related to implant dentistry in HIV infected individuals to assist dentists in contributing to the improvement of the quality of life for these individuals

Materials and MethodsMaterials and Methods• 15 HIV+ patients• 8 HIV- patients• Inclusion criteria:

– >18 years old, edentulous for at least 2 years– Occlusion type I or III– Minimum of 10mm crestal height– Hemoglobin >8g/dl– Absolute neutrophil count >750 cells/L– Platelet count >75,000/L– AST<5 times the upper limit of normal (ULN)– Bilirrubin <2.5 times ULN– Alkaline phosphatase <5.0 times ULN– Creatinine <2.5 mg/ml

Materials and MethodsMaterials and Methods

• Exclusion criteria:– Heavy smoking (>30 cigarettes/day)– Individuals with high recurrence of opportunistic

infections– Patients with uncontrolled diabetes mellitus– Pregnant patients– Occlusion class II and/or bruxism– Inadequate bone availability– Poor oral hygiene


• Panoramic radiograph• Surgical drill guide for mandible only• Amoxicillin 500mg/chlorhexidine rinses• Mandibular right and left block anesthesia• Full thickness flaps• Two BioHorizons® implants Maestro™ System (#s

22 and 27) length: 11 or 12 mm, diameter: 3.5 to 5.0mm

• Conventional surgical protocol according to Branemark

Tooth Loss and OsteoporosisTooth Loss and Osteoporosis

• Systemic bone loss can be a risk for edentulism Daniell et al., 1983

• In a 7-year longitudinal study, the rate of systemic bone loss was a predictor for tooth loss in menopausal women Krall et al., 1996

• Women that are at risk for or suffer from osteoporosis are also at risk for tooth loss

Grossi et al., 2000

Periodontal Disease and Periodontal Disease and OsteoporosisOsteoporosis

• Mandibular bone mass is not related to age but to skeletal bone mass Kribbs et al., 1990

• Controversy still exists on the association between osteoporosis and periodontal disease:– Small sample size, age of population– Definitions of diseases, methods used

Grossi et al., 2000

MenopauseMenopause

• Postmenopausal women with no hormonal replacement have shown greater tooth loss

Grodstein et al., 1996

• Women who received estrogen replacement had much lower risk for edentulism

Pagaini-Hill, 1995

MenopauseMenopause

• Alendronate has shown to lower the risk of bone height and density loss by half

• This difference was shown to remain for at least three months after stopping treatment

Jeffcoat and Reddy, 1996

Angst-Related Psychosocial Angst-Related Psychosocial FactorsFactors

• Chronic stress

• Depression

• Financial problems

• Social Isolation

Angst-Related Psychosocial Angst-Related Psychosocial FactorsFactors

• People with good coping strategies show less periodontal disease

Moss et al., 1996; Marcenes and Sheiham, 1992

Genco et al., 1999

• Studies needed: establish the time course of stress, distress, and inadequate coping with respect to onset and progression of periodontal disease

Periodontal disease as a risk Periodontal disease as a risk factor for systemic conditionsfactor for systemic conditions

• Cardiovascular DiseaseCardiovascular Disease

• PregnancyPregnancy

• RespiratoryRespiratory

Cardiovascular DiseaseCardiovascular Disease

• Increased risk for atherosclerosis and thromboembolisms due to periodontal disease

• Men with periodontitis is 25% more likely to develop coronary heart disease (CHD)

• The risk is particularly high for men under age 50 with a relative risk for CHD

DeStefano et al., 1993

Mechanisms by which infections Mechanisms by which infections contribute to atherosclerosiscontribute to atherosclerosis

• Direct effects of infectious agents in atheroma formation

• Indirect or host-mediated effects triggered by infection

• Common genetic predisposition to periodontal disease and atherosclerosis

• Common risk factors such as life style

Direct effects of infectious agents Direct effects of infectious agents in atheroma formationin atheroma formation

• P. gingivalis has been found in carotid and coronary atheromas

Haraszthy et al. 1998; Chiu et al., 1999

• P. gingivalis has shown to invade and proliferate in endothelial cells Deshpande et al., 1998

• P. gingivalis is able to induce aggregation of platelets

Herzberg and Meyer, 1996

Indirect or host-mediated effects Indirect or host-mediated effects triggered by infectiontriggered by infection

• Periodontitis induces production of C-reactive protein and fibrinogen

• Periodontal microorganisms contain proteins which cross-react with the heart

Common genetic predisposition Common genetic predisposition to periodontal disease and to periodontal disease and

atherosclerosisatherosclerosis

• Beck et al., 1996 proposed a model of genetically determined hyperinflammatory macrophage phenotype in periodontal disease, which contributes to the susceptibility for atherosclerosis


• Meta-analyses of prospective studies on coronary heart disease (CHD) and periodontal disease: Danesh,

1999

– Five main studies with 2369 cases– Weighted mean age at baseline of 55 years– Weighted mean follow-up of 12 years


– Different methods to measure disease (including self reported)

– Different criteria based on clinical examination (e.g., missing teeth, alveolar bone loss, attachment loss, probing depth)

– There was no significant heterogeneity among the 5 articles (p > .1)


– This analyses did not find any strong correlation between periodontal disease and CHD

– Reliable investigation requires:• larger sample size

• socially homogeneous population

• serial measurements of infective agents

• studies of early-onset cases

PregnancyPregnancy

• Fetuses of pregnant hamsters infected with P. gingivalis weighted up to 25% less than the fetuses of healthy controls

• 124 pregnant mothers with periodontal disease were seven times more likely to deliver a preterm low-birth weight (PLBW) baby

Offenbacher et al., 1996

PregnancyPregnancy

• F. nucleatum is the most frequent isolate from the amniotic fluid (AF)

• F. nucleatum may spread to the AF via a transient bacteremia in the presence of periodontal disease

• IL-1, IL-6, and TNF- may target the placenta

PregnancyPregnancy

• Mothers with a higher mean of GCF-PGE2 level were 9 times more likely to be in PLBW

• There is also a trend of higher mean of GCF-IL-1 level and an increase in PLBW

Offenbacher et al., 1998

RespiratoryRespiratory

• Hospitalized or nursing home patients may increase the risk for bacterial pneumonia

Scannapieco et al., 1998

• There is evidence of correlation between increased alveolar bone loss and increased risk for chronic obstructive pulmonary disease

Hayes et al., 1998

Evaluation of Oral Soft Tissue Evaluation of Oral Soft Tissue Lesions in Ventilated PatientsLesions in Ventilated Patients

Moretti AJ, Flaitz CM, Peninger M, Rex JH, Milano M, Harrison N, and Nates JL

UTHSC-H Dental Branch and Medical School,Memorial Hermann Hospital, Houston, TX

PurposePurpose

• To document the frequency of oral soft tissue lesions in ventilated patients, who were receiving care in a tertiary care and level I trauma center. This report is part of a larger study on oral hygiene care for these patients, using the oral suction toothbrush and oral swab.


• Study features:– Pilot study, convenience sample, short term– Neurosurgical Intensive Care Unit patients– Treatment groups: oral hygiene by two-sided

sponge or sponge/toothbrush– Oral hygiene q 4-6 h. or minimum 3 x/day– Initial evaluation by oral pathologist and

periodontist within 24 hours– Follow up q 3-4 days– High intensity light, mouth mirror, cheek

retractors, photos of accessible lesions


• Inclusion criteria:– Assisted ventilation >48 h.– Age >18 years-old– > 2 teeth

• Exclusion criteria:– Non-ventilated patients– Trauma to jaws or neck to limit oral access– Transfer to another unit in less than 24 h.– Life expectancy less than 24 h.– Edentulous patients


• Parameters:– Plaque Index (Silness and Löe, 1964)– Gingival Index (Löe and Silness, 1963)– Tongue assessment (amount, distribution and color of

coating)– Halitosis (Organoleptic scores, Rosenberg et al 1991)– Trauma associated oral lesions– Other oral and perioral lesions

Ventilated Patient

Swab & Toothbrush

Herpes Labialis

Purpura/Sloughing

NUP/Candidiasis

Spontaneous bleeding

Summary of ResultsSummary of Results

• At least one lesion per patient

• Observation time was similar for all patients

• More male patients in toothbrush group

• Similar PI and GI for both groups

• No difference in improvement of halitosis

• No difference in lesions in both groups

Weaknesses of StudyWeaknesses of Study

• Very small sample size and limited time of observation

• Periodontal status not assessed prior to randomization

• More males in toothbrush group. Males usually have decreased periodontal health in comparison to females

• Limited accessibility to evaluate parameters

ConclusionsConclusions

• Lesions were very common but not associated with the oral hygiene devices

• Potential for oral lesions and periodontal disease to contribute to systemic complications exists because many of these lesions are ulcerative and infectious

• Medical and nursing staff needs to recognize and manage a variety of oral lesions for improved patient care and quality of life for ventilated patients

Future knowledge in Periodontal Future knowledge in Periodontal Systemic InterrelationshipsSystemic Interrelationships

• In vitro studies

• Animal studies

• Intervention studies

Modulation of Host Modulation of Host Inflammatory Mediators as a Inflammatory Mediators as a

Treatment Strategy for Treatment Strategy for Periodontal DiseasesPeriodontal Diseases

Antonio J. Moretti, DDS, MSAntonio J. Moretti, DDS, MS

Historical ReviewHistorical Review• Until 1970s bacteria and their products

were seen as the most important factors in periodontal diseases.

• Page & Schroeder (1976): pathogenesis of inflammatory periodontal disease.

• Inflammatory mediators (i.e., arachidonic acid metabolites and cytokines) directly cause local tissue destruction.

• Matrix metalloproteinases imbalance.

Pharmaceutical Inhibition of Pharmaceutical Inhibition of Host Response PathwaysHost Response Pathways

• NSAIDs

• Cytokine receptor antagonists

• Anti-collagenolytic agents

Modulation of Arachidonic Acid Modulation of Arachidonic Acid MetabolitesMetabolites

• Vane (1971) published landmark discovery that aspirin and NSAIDs blocked cyclooxygenase.

• El Attar (1976) PGE2 levels were observed 20 times higher in the inflamed gingiva.

• Offenbacher et al. (1981) found elevated PGE2 levels in the GCF of periodontitis patients.


• Williams et al. (1985) NSAIDs in animal model.

• Williams et al. (1989) NSAIDs in humans showed significant lower bone loss rates up to 24 months.

• Jeffcoat et al. (1995) NSAID rinse with positive results.


• Standard NSAIDs inhibit both cyclooxygenase 1 and 2.

• Side effects: gastrointestinal tract, kidney, and platelets.

• New classes of agents (i.e., cyclooxygenase 2 inhibitors and lipoxins) might selectively inhibit the isoenzyme associated with inflammation rather than that of tissue homeostasis.

Modulation of Host CytokinesModulation of Host Cytokines• Cytokines literally “cell proteins” transmit

information from one cell to another.

– IL-1– TNF-

• Assuma et al. (1998) animal research on cytokine (i.e., IL-1 and TNF-) receptor antagonists found 80% inhibition.

Modulation of Other Host Modulation of Other Host Inflammatory MediatorsInflammatory Mediators

• Nitric Oxide (NO)- free radical with important physiological functions including cardiovascular, nervous system and immune homeostasis.

• NO is elevated in inflammation to protect against antigens. It causes deleterious host effects such as DNA damage, peroxidation, protein damage, and release of cytokines.

Modulation of Other Host Modulation of Other Host Inflammatory MediatorsInflammatory Mediators

• Lohinai et al. (1998) - animal study with injection of mercaptoethylguanidine. Test group exhibited less plasma extravasation and less bone loss as compared with controls.

Matrix Metalloproteinases (MMPs)Matrix Metalloproteinases (MMPs)

• MMPs are a family of at least 12 Ca++ and Zn ++ dependent enzymes that degradate extracellular matrix macromolecules (i.e., interesticial and basement membrane collagens, fibronectins, laminin, and proteoglycan core proteins).

MMPsMMPs

• Matrix metalloproteinases are produced by both infiltrating and resident cells of periodontium.

• They play a role in both physiological (i.e., tooth eruption) and pathological (i.e., periodontitis) events.

Tetracyclines

• Non-antimicrobial properties have application in the treatment of:– Cancer– Complications of diabetes– Arthritis– Wound healing

MMPs (studies)MMPs (studies)

• Golub et al. 1980 – tetracycline binding to Zn++ and Ca++ on collagenases.

• Animal studies (Ciancio et al. 1998)

• Human studies (Caton et al. 1997, 2000)

Sub antimicrobial dose doxycyclineSub antimicrobial dose doxycycline(SDD) (SDD)

• 20 mg bid (no antimicrobial action)

• No change in bacterial flora after 18 months

• No induction of resistance after 18 months

• Side effect profile similar to placebo

Sub antimicrobial dose doxycyclineSub antimicrobial dose doxycycline(drawbacks)(drawbacks)

• Compliance

• Cost

• Statistical x Clinical Significance

Modulation of Host Modulation of Host Inflammatory Mediators - Inflammatory Mediators -


• Animal and human studies support the basic hypothesis that inhibition of local arachidonic acid metabolites with NSAIDs slows periodontal disease progression.

• Data on modulation of cytokines and Nitric Oxide appear promising.



• Despite the finding that SDD provides some benefit in arresting periodontal disease progression, there are numerous issues that need to be addressed before its widespread use with any form of periodontitis.



• Clinicians need to decide which patients are at greatest risk of future disease progression. We still lack proper diagnostic tools for this matter.

• These adjunctive forms of therapy may become a valid option for a small percentage of our patients.

periodontal systemic interrelationships

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