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Periodontal medicine

Periodontal medicine. “When you have eliminated the impossible, whatever remains, however improbable, must be the truth!!”. FOCAL INFECTION ACUTE PHASE REACTANTS CARDIOVASCULAR DISEASE DIABETES PRETERM LOW BIRTH WEIGHT RESPIRATORY DISEASES

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Periodontal medicine

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  1. Periodontal medicine

  2. “When you have eliminated the impossible, whatever remains, however improbable, must be the truth!!”

  3. FOCAL INFECTION • ACUTE PHASE REACTANTS • CARDIOVASCULAR DISEASE • DIABETES • PRETERM LOW BIRTH WEIGHT • RESPIRATORY DISEASES • RHEUMATOID ARTHRITIS • OBESITY

  4. DEFINITION • Offenbacher (1996) defined periodontal medicine as a rapidly emerging branch of periodontology focusing on the wealth of new data establishing a strong relationship between periodontal health or disease and systemic health or disease • This establishes a two way relationship!! • The impact of oral infection on systemic health.

  5. Because of :- • Extensive microbial plaques • Chronic nature • Exuberant local and systemic host response to the microbial assault HYPOTHESIS

  6. History… • Ancient Civilizations – Hebrew Book – Sefer haolsmot o maaseh tovia Hippocrates described a patient of ‘rheumatism’ whose arthritis was cured by the extraction of a tooth. • Roman physician Galen (166-201 A.D.) – Head is the source of all ills. • In 1768, Thomas Berdmore in A Treatise on the disorders and deformities of the teethand gums described the relation between teeth and the entire body

  7. ORAL SEPSIS …. Modern times • Miller, a dentist working with Koch published an article titled “The human mouth as a focus of Infection” (1891) • “Bacterial infections can produce a metastatic abscess, thus periodontal disease, tonsils and uterus formed the foci of infection” • William Hunter 1900 – “oral sepsis as a cause of disease” • 1902 – Colyer suggested “Better no teeth than septic ones”. • Charles Mayo of Mayo Clinic advocated the Focal infection theory

  8. ACUTE PHASE REACTANTS • Host response to variety of injuries like bacterial, viral or parasitic infections, mechanical or chemical trauma, ischemic necrosis or malignant growth. • Macrophage is the cell responsible for initiating the response. • Characteristic features.. fever, neutrophilia, increased (muscle) protein catabolism, activation of the complement and coagulation pathways, hormonal changes, and induction of acute-phase proteins

  9. Periodontal pathogens LPS Release of IL-6, TNF- α Enters blood Act on liver Serum acute phase proteins

  10. TRIGGERING FACTORS LOCAL REACTION MEDIATORS SECONDARY SYSTEMIC REACTION INFECTION, NECROSIS SURGERY, NEOPLASIA RADIATION STIMULATION OF MACROPHAGES, FIBROBLASTS, ENDOTHELIAL AND OTHER CELLS PRODUCTION AND RELEASE OF INFLAMMATORY CYTOKINES: TNF-α IL-1, IL-6, IFNγ FEVER, LEUKOCYTOSIS, COMPLEMENT ACTIVATION, INC SERUM GLUCOCORTICOIDS, SYNTHESIS OF ACUTE PHASE PROTEINS

  11. Acute phase proteins • Type 1(IL-1) • C reactive protein • Serum Amyloid A • Complement C3 • Type 2(IL-6) • Fibrinogen • Haptoglobulin • Anti chymotrypsin • Strong … • C reactive protein • Serum Amyloid A • alpha2 macroglobulin • Moderate • haptoglobin • Fibrinogen • Alpha 1anti trypsin • Weak • Complement C 3 • Ceruloplasmin

  12. PERIODONTAL DISEASE AND CVD • WHO statistics indicate that in 1995, CVD were responsible for 20% of deaths worldwide, numbering 14 million people. • Principle cause of death in developed countries – accounts for 50% of deaths while in developing countries accounting for 16% of deaths.

  13. CVD and Atherosclerosis • Atherosclerosis – A progressive degenerative condition involving large and medium sized arteries. • Atheromatous plaques composed of lysed cells, cholesterol ester crystals, foam cells occlude the artery or cause infarction …

  14. Socioeconomic Factors Chronic infections: Periodontitis (mixed) Lung (C. Pneumoniae) Stomach (H.Pylori) Dietary Smoking Endothelial injury Pro inflammatory cytokines Viscosity Fibrinogen, VWF, Tpa, D-dimer WBCC Atherosclerosis Thrombosis Rheology Cardiovascular Disease

  15. HYPOTHESIS • Presence of an MØ+ phenotype…. • Certain factors such as diet may exacerbate the MØ+ phenotype • Finally, periodontal infections may directly contribute to the pathogenesis of atherosclerosis and thromboembolic events by providing repeated systemic vascular challenges with LPS and inflammatory cytokines.

  16. Association between CVD and Periodontitis as measured in M.I patients, patients with Stroke and CHD…. Positive.. Mattilla and Neiminen – 1989 DeStefano – 1993 Beck - JP 1996 Grau and Buggle - 1997

  17. MECHANISMS • Factor VIII activity and its cofactors (Von Willebrand factor antigen) – were associated with poor dental status, linking chronic dental infection with increased thrombogenicity. • Mattila - 1997 • Individuals with periodontitis had significantly elevated leukocyte counts and circulating fibrinogen. • Lowe GD -1992 • Platelets bind to strains of Strep. Sanguis, a common component of supragingival plaque and result in thrombus formation. (PAAP) • Herzberg et al 1996

  18. MECHANISMS • Infection produces a hypercoagulable state and increased blood viscosity; INFECTION LIPOPOLYSACCHARIDES INFLAMMATORY MEDIATORS INCREASED BLOOD VISCOSITY CHANGES IN TUNICA MEDIA AND ADVENTITIA ATHEROSCLEROSIS ARTERIAL THICKENING

  19. MECHANISMS • The increased influx of inflammatory mediators results in alteration in synthesis and degradation of collagen and elastin…. • The IL-1 production alters the blood compatible surface of the endothelial cells which retards fibrinolysis and enhances cellular adhesion and coagulation • The presence of gram negative infection leads to bacteremia.

  20. OFFENBACHER AND BECK MODEL PERIODONTAL DISEASE HYPER RESPONSIVE MONOCYTIC PHENOTYPE INCREASED INFLAMMATORY MEDIATORS INCREASED BACTEREMIA CORONARY HEART DISEASE LPS INTERACTIONS WITH LDL ATTRACTION OF MONOCYTES PLATELET PLUG THROMBUS FORMATION FORMATION OF FOAM CELLS VESSEL WALL THICKENING

  21. Scannapieco F, Bush R &Paju S ’03 • systematic review …. 1,526 articles scanned …31 • ONLY modest association • Several studies showed no association • Absence of a standard definition & measures • Large scale epidemiologic studies and intervention trials required….

  22. Summary • Periodontal and cardiovascular diseases share many risk factors. • The chronicity of periodontal infections provides a rich source of microbial and host products. • Two main processes providing a causative link include; lipopolysaccharide and monocyte-related responses.

  23. PERIODONTITIS AND DIABETES Pathogenic aspects!! • 17 million people affected by Diabetes • Periodontitis recognized as the 6th major complication (Loe H 1993) • TYPE I and TYPE II; Impaired glucose tolerance, gestational diabetes and drug or chemical induced diabetes. • Characterized by hyperglycemia, hyperlipidemia and assoc complications. • 5 classic major complications include; microangiopathy, nephropathy, neuropathy, macrovascular disease and delayed wound healing

  24. Hypothesis – severe periodontitis in persons with NIDDM increases the conc of glycated Hb in serum. • Data were collected from Gila river indian community – Pima tribe – prevalence of 50% - highest reported in the world. • Poor glycemic control defined – occurrence of glycated Hb of 9% or more at follow up. • Results suggested that severe periodontitis at baseline was assoc with increased risk of having poor glycemic control at follow up 2 or more years later. • Shlossman – JADA 1990 • Elimination of periodontal inflammation. • Grossi’96…. Effect of periodontal treatment on glycated Hb levels

  25. hyperglycemia and its Direct consequences • Increased production of sorbitol and fructose by the enzyme aldose reductase. • Polymorphisms.. Aldose reductase gene (Engerman’93) • Inhibitors.. No effects on complications • Diacylglycerol and it’s importance …production of protein kinase C-beta (Koya’97)

  26. Indirect consequences • Nonenzymatic glycation and oxidation, the Schiff bases and Amadori products. (reversible) • The best-known of these products is glycosylated hemoglobin A1c whose measurement is used as a clinical barometer of glucose control over weeks to months • Complex rearrangement leads to the formation of Advanced Glycation End products (AGE). • These include carboxymethyl (lysine), pentosidine, pyralline and methyglyoxal. • Recent investigations reveal that AGEs can also form in response to an inflammatory milieu (Anderson 1999)

  27. Indirect consequences • AGEs result in significant alteration of normal cellular composition and structure. • Alters the function of ECM components, • Affect the collagen stability and vascular integrity. • Monocytes, macrophages and endothelial cells possess high affinity receptors for AGEs. • the AGEs have a direct effect on the cell surfaces. RAGE…. STRUCTURE • Binding sites for AGEs….. RAGE • Consists of a 332 amino acid region containing a “V” type domain and two “C” domains followed by hydrophobic transmembrane and finally a highly charged cytosolic tail of 42 amino acids, essential for signal transduction.

  28. EFFECTS OF RAGE • Smooth Muscle Cells • Binding lead to increased migration and activation, which may have important implications in vascular perturbations and injury. • Fibroblasts: • Binding led to reduced production of Type I collagen mRNA • Endothelial cells: • Present at low levels, inc. on cellular perturbation • Increased permeability of the endothelial lining • Increased expression of VCAM • Mononuclear Phagocytes: • increased chemotaxis of the macrophages. • increased release of TNF-α

  29. Studies of RAGE • Schmidt (1996) demonstrated that AGEs accumulate in human diabetic gingiva as compared to nondiabetics. • Lalla (1998) demonstrated that diabetic mice injected with P.gingivalis strains showed more periodontal destruction than non diabetic mice • The diabetic patients showed greater periodontal destruction as compared to non diabetics. (Mealey et al, Genco et al) • Thus suggesting that accumulation of AGEs might play a role in pathogenesis of periodontal disease.

  30. Summary of Hyperglycemic interactions DIRECT CONSEQUENCE SORBITOL DIACYLGLYCEROL ALDOSE REDUCTASE PROTEIN KINASE C RETINOPATHY, NEUROPATHY

  31. Summary of Hyperglycemic interactions INDIRECT CONSEQUENCE INCREASED HYPERGLYCEMIA REVERSIBLE GLYCATION PRODUCTS IRREVERSIBLE AGEs POORER METABOLIC CONTROL ALTER COLLAGEN STABILITY AND VASCULAR PERMEABILITY INCREASED PERIODONTAL DESTRUCTION EXAGGERATED RESPONSE TO PERIODONTAL PATHOGENS STIMULATION OF MONOCYTES INCREASING RELEASE OF CYTOKINES AGE- RAGE INTERACTION WITH DIFFERENT CELLS

  32. Grossi’96 and others have suggested that effective control of periodontal infection in diabetic patients reduces the level of AGEs in the serum.

  33. DIABETES, PERIODONTITIS AND LIPID METABOLISM

  34. Hyperglycemia is accompanied by hyperlipidemia Disruption of fatty acid metabolism leading to accumulation of omega 6 –PUFA Formation of LDL and TRG Elevations of (LDL), triglycerides (TRG) and omega – 6 free fatty acids.

  35. Conversion of PUFA to active metabolites is impaired because of reduced 6-desaturase enzyme activity brought about by insulin deficiency. • Present on the surface of the membrane of cells • Pociot (1993), Offenbacher (1994), Yalda (1994) Salvi (1997 and 1998) have shown the existence of a hyper responsive monocytic phenotype which has been postulated to be related to hyperlipidemia

  36. Periodontitis as a risk factor!! • Earlier studies could not document a role of infection causing hyperlipidemia (Lopes 1990). • Recent studies have documented a positive relationship between infection and hyperlipidemia • Samra (1996) found that periodontal infections induced profound changes in the plasma concentration of cytokines and hormones leading to a catabolic state characterized by hypertriglyceridemia and lipid oxidation • Casey (1993) demonstrated that chronic low level exposure to gram negative LPS could induce a similar response

  37. Also the increased presence of cytokines (for e.g. periodontal disease) stimulates the production of ACTH by modifying the hypothalamic-pituitary-adrenal axis resulting in elevated levels of (FFA), LDL and TRG – Gwosdow – 1990. • There is evidence of enhanced hepatic lipogenesis, increased adipose lipolysis, increased synthesis and reduced clearance of TRG. • There is reduction in the lipoprotein lipase activity

  38. Summary of Hyperlipidemic Interactions INCREASED SERUM PRO-INFLAMMATORY CYTOKINES HYPERLIPIDEMIA INFECTION Enhanced lipogenesis CHRONIC LOCALIZED (PERIODONTITIS) ACUTE SYSTEMIC (SEPSIS) Bacteremia IL-1α,TNF-α FFA,LDL,TRG Endotoxemia Reduced Lipid clearance

  39. IACOPINO AND CUTLER HYPOTHESIS PERIODONTAL DISEASE HYPER RESPONSIVE MONOCYTIC TRAIT ENHANCED PROD OF PRO-INFLAMMATORY CYTOKINES ELEVATION OF SERUM LIPID LEVELS INCREASED SEVERITY OF DIABETES

  40. PRETERM LOW BIRTH WEIGHT AND PERIODONTAL DISEASE

  41. WHAT IS PRETERM? • NORMAL GESTATION TIME IS 40 WEEKS. • Birth at Lesser than 37 weeks is called as preterm delivery WHAT IS LOW BIRTH WEIGHT? • International definition adopted at the 29th WHA in 1976 is birth weight less than 2500 g is termed low birth weight

  42. Preterm distribution

  43. Maternal age less than 17 or greater than 34 years • Low socio-economic status • Inadequate prenatal care • Drug abuse • Malnutrition • Alcohol and tobacco use • Diabetes • Genitourinary tract infections • Hypertension and multiple pregnancies. • In spite of this wide range of risk factors, about 25% of PLBW cases remain unexplained. This has motivated further research into the causes of PLBW. • Surviving infants are at increased risk of developing :- • Respiratory distress syndrome • Anemia • Jaundice • Mental retardation • Cerebral palsy • Impaired sight and hearing • Intracranial hemorrhage • Malnutrition • Congestive heart failure • Epilepsy • Learning disabilities and impaired lung function.

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