Periodontal medicine

Oral-systemic link has been termed Periodontal Medicine. Significance: Periodontal disease is preventable and readily treatable, thus providing many new opportunities for preventing and improving several systemic diseases.

FOCAL INFECTION: Localized or Generalized infection caused by dissemination of microorganisms or toxic products from focus of infection.
FOCUS OF INFECTION Confined area that
(1) contains pathogenic microorganisms
(2) can occur anywhere in body

Diseases/Conditions affected by periodontitis
A PREGNANCY, PREECLAMPSIA
B ISCHEMIC HEART DISEASES, STROKE
C DIABETES MELLITUS
D PNEUMONIA, COPD
E OSTEOPOROSIS
F CANCER
G ALZHEIMER’S DISEASE
H. RHEUMATOID ARTHRITIS

1. PERIODONTAL MEDICINE 1

2. Perio Files

3. Index Focal infection theory Diseases/Conditions affected by periodontitis A PREGNANCY, PREECLAMPSIA B ISCHEMIC HEART DISEASES, STROKE C DIABETES MELLITUS D PNEUMONIA, COPD E OSTEOPOROSIS F CANCER G ALZHEIMER’S DISEASE H. RHEUMATOID ARTHRITIS

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5. INTRODUCTION The emerging field of periodontal medicine offers new insights into the concept of oral cavity as one system interconnected with whole human body. Evidence has shed light on the converse side of the relationship between systemic health and oral health i.e. the potential effects of periodontal disease on a wide range of organ systems.

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8. FOCAL INFECTION THEORY In 1900 William Hunter, a British physician first developed the idea that oral micro organisms were responsible for a wide range of systemic conditions. According to this theory, he claimed restoration and extraction of teeth with caries, pulpal necrosis and periapical abscesses to eliminate the source of sepsis.

9. He believed that the degree of systemic effect produced by oral sepsis depended on the virulence of oral infection and individual ’ s degree of resistance. For next 40 years, physicians & dentists believed that infections , especially those originating in mouth , caused most of man’s suffering & illness leading to extractions of infected teeth . That era came to be known as era of focal infection

10. The focal infection theory fell into disrepute in 1940 ’ s and 1950 ’ s when wide spread extraction, often of entire dentition failed to reduce the systemic diseases. Focal infection theory as proposed & defended in that period was based on almost no evidence . Todays era of evidence based medicine & dentistry provides an excellent environment to examine possible relationship b/w oral infections & systemic diseases.

11. Mechanism of interaction between periodontal infection and systemic disorders Subgingival environment act as reservoir of bacteria. The subgingival microbiota in patients with periodontitis provides significant and persistent gram negative bacterial challenge to host. Production of products like lipopolysaccharide (LPS) occurs. Periodontal tissue mount an immunoinflammatory response to bacteria. Ready access of LPS, bacteria, immunoinflammatory cells from periodontal tissues to circulation via sulcular epithelium occurs which is frequently ulcerated and discontinuous, causing systemic manifestations. Even with treatment, complete eradication of these organisms is difficult and their reemergence is rapid.

12. Bacterial Plaque Host Inflammatory Response, LPS Systemic Diseases

13. MECHANISM OF ORAL FOCAL INFECTION 13

14. ORAL INFECTION AND SYSTEMIC DISEASE: A PARADIGM SHIFT 14

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16. Diseases/conditions possibly influenced by periodontal infection A Reproductive system DISEASES Preterm low birth weight (LBW) infants Preeclampsia B Cardiovascular system DISEASES Angina Myocardial infarction (MI) Cerebrovascular accident or Stroke C Endocrine SysteM DISEASES Diabetes mellitus D Respiratory SysteM DISEASES Chronic obstructive pulmonary disease (COPD) Acute bacterial pneumonia E OSTEOPOROSIS F CANCER G ALZHEIMER’s DISEASE h. Rheumatoid arthritis

17. PERIODONTITIS & PREGNANCY 17

18. Periodontitis and Pregnancy Periodontal disease during pregnancy has been linked to preterm low birth weight (PLBW) infants, early pregnancy loss, and preeclampsia .

19. Preterm low birth weight (PLBW) infants Periodontitis is a remote gram negative infection that may play role in PLBW infants (PLBW < 2500gm) Premature and low-birth-weight (PLBW) infants are 40 times more likely to die during the neonatal period. Such infants who survive the neonatal period, face a higher risk of several neurodevelopment disturbances, health problems (such as asthma, upper and lower respiratory infections and ear infections ) and congenital anomalies.

20. Offenbacher and co-authors in 1996 from a case controlled study suggested that women who delivered preterm low birth weight (PLBW) infants had poorer periodontal health than mothers with normal birth weight infants.   They found the presence of higher levels of  Porphyromonas gingivalis ,  Bacteroides forsythus ,  Actinobacillus actinomycetemcomitans  and  Treponema denticola organisms normally associated with periodontal disease in mothers of PLBW babies as compared to normal controls.

21. In periodontal disease, transient bacteremia can occur leading to selective colonization of undesired sites. Study by Han et al (2004) have shown that hematogenous injection of orally related  F. nucleatum   in mice resulted in preferential localization to placental blood vessels from which it crossed the endothelium to the amniotic fluid and induced premature delivery and stillbirths in a pattern similar to that seen in humans. This supports the hypothesis that after transient bacteremia, oral  bacteria like F.nucleatum   translocates to pregnant uterus and possibly to the fetus hematogenously .  

22.   Bacterial migration from periodontal tissues into blood circulation, also stimulate the production of inflammatory mediators   and increased prostaglandin PGE2 production responsible for uterine contraction and the onset of preterm delivery. F. nucleatum and P. gingivalis had been isolated from amniotic fluid and cord blood in cases of preterm birth and neonatal sepsis by Gauthier S et al (2011) and Katz J et al (2009) respectively.

23. Proposed mechanisms are- Translocation of the periodontal bacteria to fetoplacental unit Systemic dissemination of endotoxins on fetoplacental unit Systemic dissemination of inflammatory mediators (IL-1, IL-6, TNF-α, PGE2) on fetoplacental unit .

24. MECHANISM: 24 Periodontal Infection Bacteria & their products in amnion Inflammatory response with cytokine production in amnion Increased amniotic prostaglandin production Preterm labour with LBW infants

25. PREVENTION Hence periodontal disease appears to be an independent risk factor for PLBW (preterm low birth weight infants) and there is need to expand preventive measures by introducing oral health programs as an integral component of prenatal care for pregnant mothers.

26. Preeclampsia Preeclampsia is a pregnancy-specific disorder characterized by increase in systolic arterial pressure (≥140 mmHg) and/or diastolic pressure (≥90 mmHg) and proteinuria (≥300 mg/24 h), after 20 weeks of gestation. It is dangerous for both mother and fetus. Periodontitis is considered as a risk factor for it. Etiology: An increased systemic inflammatory response to pregnancy

27. Preeclampsia It is characterized by an abnormal vascular response to placentation, manifesting as generalized vasospasm, activation coagulation system and reduced organ perfusion affecting the kidney, liver and brain. Periodontal disease burden pregnant women systemically with endotoxins, inflammatory cytokines and oxidative stressors at the maternal-fetal interface, thus acting as vascular stressor that plays a role in development of Preeclampsia in pregnancy.

28. Normal pregnancy is considered as mild pro-inflammatory state whereas preeclampsia indicate more severe level of inflammation. The subgingival bacteria, their products and pro-inflammatory cytokines may enter the bloodstream, reach maternal–fetal interface, trigger/worsen maternal inflammatory response, increases prostaglandin and cytokines levels in the plasma, causing complications in pregnancy .

29. Prevention Maternal periodontal disease is a preventable disease in contrast to preeclampsia, which can be treated but is difficult to prevent .  Hence, maternal periodontal disease must be taken as an independent risk factor for adverse pregnancy outcomes during evaluation of the pregnant women.

30. The study by Jaiman G et al (2018) showed that birth weight of newborn was significantly less in the preeclamptic group suggesting that maternal preeclampsia could increase risk for low birth weight infants.

31. PERIODONTITIS & CARDIOVASCULAR DISEASES 31

32. Periodontal Infection Links to Heart Disease and Stroke Researchers have found that people with periodontitis are almost twice as likely to suffer from coronary artery disease.

33. Coronary Heart D isease MECHANISM Atherosclerosis Thromboembolism Narrowing of coronary arteries Occlusion of arteries by platelets Myocardial ischaemia Angina Myocardial infarction

34. EFFECT OF PERIODONTAL INFECTION Periodontal infection may affect the onset or progression of Ischemic heart disease (Angina, Myocardial infarction) through certain mechanisms. 1. INCREASED VISCOSITY 2. THROMOEMBOLISM 3. ATHEROSCLEROSIS

35. 1. Increased viscosity Increased viscosity of blood may promote ischaemic heart disease by increasing the risk of thrombus formation. The factors promoting hypercoaguable state are: Fibrinogen White blood cell count von Willebrand factor

36. INCREASE IN Plasma fibrinogen von Willebrand factor White blood cell count INCREASE Blood viscosity

37. PERIODONTAL INFECTION Fibrinogen levels and WBC counts are often increased in patients with periodontal disease. Individuals with poor oral health may also have significant elevations in von Willebrand factor , increasing the risk of thrombus formation. Thus periodontal infection may lead to increased risk for coronary artery disease.

38. 2. THROMBOGENESIS It is the process of formation of a solid mass in circulation from the constituents of blood, the mass itself is called a thrombus. Blood vessel wall can rupture and then get thrombus formed at region of ulceration by aggregation of platelets.

39. Platelet aggregation plays a major role in thrombogenesis and most cases of acute MI are precipitated by thromboembolism . Oral organisms may be involved in thrombogenesis. Platelets selectively bind some strains of Streptococcus sanguis, a common component of supragingival plaque, and Porphyromonas gingivalis , a pathogen mostly found in periodontitis.

40. Aggregation of platelets is induced by the platelet aggregation –associated protein(PAAP) expressed on some strains of these bacteria. PAAP – positive bacteria cause aggregation of circulating platelets, resulting in formation of thromboemboli and thus coronary artery disease. Thus periodontitis associated bacteraemia with certain strains of Streptococcus sanguis and Porphyromonas gingivalis may promote acute thromboembolic events .

41. Sharma A et al in 2000 showed only P gingivalis expressed virulence factors that can induce platelet aggregation.

42. 3. ATHEROSCLEROSIS It is the focal thickening of the arterial intima , the innermost lining of vessel lumen and the media, the thick layer under the intima consisting of smooth muscle, collagen and elastic fibres.

43. Early in the formation of atheromatous plaques, circulating monocytes adhere to the vascular endothelium. The adherence is mediated through several adhesion molecules on endothelial cell surface, including intercellular adhesion molecule-1(ICAM-1), endothelial leukocyte adhesion molecule-1(ELAM-1), vascular cell adhesion molecule-1(VCAM-1).

44. PATHOGENESIS OF ATHEROSCLEROSIS M onocytes adhere to vascular endothelium. It penetrate into arterial media producing proinflammatory cytokines and growth factors Low Density Lipids (LDL) pass through damaged endothelium into blood vessel wall Ingestion of oxidized low density lipoproteins(LDL) enlarges monocytes to form foam cells. Smooth muscle cell proliferation and atheromatous plaque formation thicken vessel wall and narrow the lumen.

45. LDL’s are oxidized and then induce production of bio-active molecules such as Interleukin 1, Interleukin 6, Matrix Metalloproteases, Prostaglandins, Platelet Derived Growth Factor, Tumor Necrosis Factor Alpha.

46. Monocytes transform to macrophages and take up LDL to form foam cells. Monocytes trigger chronic inflammatory reaction with lymphocytes and this results in tissue necrosis and fibrosis. Blood vessel wall becomes distended and continues to accumulate cholesterol, some areas become calcified.

47. P eriodontal infection leads to production of several factors like LPS, proinflammatory cytokines that upregulate the adhesion molecules, which help in adherence of monocytes to vascular endothelium After binding of monocytes they migrate under arterial intima. Monocytes ingest low density lipoprotiens (LDL) and form foams cells which are characteristics of atheromatous plaques

48. DNA from periodontal pathogens like Porphromonas gingivalis , Actinomyces actinomycetemcomitans , Prevotella intermedia, T. forsythia had been isolated from human atherosclerotic plaques. This suggested migration of oral pathogens from oral cavity to distant sites. ( Haraszthy VI et al; 2000)

49. Velsko IM et al in 2014 and Chukkapalli SS et al in 2014 showed presence of Treponema denticola and P gingivalis in aortic artherosclerosis of hyperlipidemic mice .

50. Periodontal infection Gram-negative bacteraemia /LPS Endothelial damage Platelet adhesion Monocyte infiltration/proliferation Cytokine /growth factor production Thrombus formation Atheroma formation Vessel wall thickening Thromboembolitic events

51. Direct effect Direct effect Indirect effect 52 PERIODONTAL INFECTION Monocytes Macrophages Liver CRP, Fibrinogen, lipid abnormalities, coagulating factors IL-1,IL-6 TNF- α Vascular Lesion

52. STROKE P eople diagnosed with acute cerebrovascular ischemia (in brain) were found more likely to have an oral infection when compared to those in the control group.

53. Role of periodontal infection in cerebral infarction or stroke Ischemic cerebral infarction or stroke is often preceded by systemic bacterial or viral infection. Periodontitis is greater risk factor for stroke than smoking. Periodontal infection contribute by same three mechanisms atherosclerosis thromboembolism elevated production of fibrinogen and CRP

54. PERIODONTITIS & DIABETES 55

55. Periodontal Infection and Diabetes Severe periodontal disease can increase blood sugar, contributing to increased periods of time when the body functions with a high blood sugar. This puts diabetics at increased risk for diabetic complications. Thus, diabetics who have periodontal disease should be treated to eliminate the periodontal infection.

56. The Risk of Periodontal Disease in Diabetics A naerobic bacteria that live in the deep crevices and periodontal pockets , get into the blood system and make it more difficult for a diabetic to control their blood sugar. Additionally, the loss of teeth is a real problem for diabetics since their support for a denture erodes away more rapidly (more bone loss) than in the non-diabetic person. Diet and nutrition are usually compromised with an undesirable increased intake of refined carbohydrates. Periodontal disease increases the rate of C-Reactive Protein, which also causes problems for diabetics and combines with elevations in blood sugar to greatly increase the rate of heart attacks .

57. Role of periodontal infection in diabetes mellitus In T ype 1 diabetes The gram negative periodontal infection occurs Increases in the insulin resistance of tissues preventing glucose from entering targets cells Causing elevated blood glucose levels Requiring increased pancreatic insulin production to maintain normoglycemia There is a poor glycemic control.

58. In T ype 2 diabetes There is already significant insulin resistance Further tissues resistance to insulin occurs induced by gram negative infection Worsened glycemic control

59. Diabetes Prevention Bacteria living in the periodontal pockets increase blood sugar, which would lead one to suspect that people with periodontal disease would be more likely to develop diabetes.

60. HOST MODULATORY AGENTS

61. SUBANTIMICROBIAL DOSE OF DOXYCYCLINE

62. BISPHOSPHONATES

63. PERIODONTITIS & RESPIRATORY DISEASES 72

64. Periodontal Infection and Respiratory Diseases Bacteria in our mouth can be aspirated into the lungs to cause respiratory diseases such as pneumonia, chronic obstructive pulmonary disease (COPD) especially in people with periodontal disease.

65. ORAL BACTERIA AS ETIOLOGIC AGENTS OF RESPIRATORY INFECTION Variety of oral anaerobes & facultative species have been cultured from infected lung fluids including P. gingivalis , Bacteroides gracilus , Bacteroides oralis , Bacteroides buccae , Eikenella corrodens , Fusobacterium nucleatum , A actinomycetemcomitans , Peptostreptococcus , Clostridium. Most, if not all, of these organisms have been implicated as etiologic agents in pathogenesis of periodontal disease (Moore et al 1994).

66. ORAL BACTERIA AS ETIOLOGIC AGENTS OF RESPIRATORY INFECTION Pneumonia is an important cause of morbidity and mortality in all ages but more so in immunocompromised and older individuals. Periodontitis patients are three times more susceptible to develop nosocomial pneumonia (Gomes- Filho IS et al in 2014)

67. ROLE OF PERIODONTAL INFECTION IN RESPIRATORY DISEASE Bacterial respiratory infections are thought to be acquired through aspiration (inhaling) of fine droplets from the mouth and throat into the lungs. These droplets contain germs that can breed and multiply within the lungs to cause damage. Recent research suggests that bacteria found in the throat, as well as bacteria found in the mouth, can be drawn into the lower respiratory tract. This can cause infections or worsen existing lung conditions. People with respiratory diseases, such as chronic obstructive pulmonary disease, typically suffer from reduced protective systems, making it difficult to eliminate bacteria from the lungs.

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69. DENTAL PLAQUE AS RESERVOIR OF RESPIRATORY PATHOGENS 78

70. POTENTIAL MECHANISMS OF ACTION OF ORAL BACTERIA IN PATHOGENESIS OF RESPIRATORY INFECTION 79

71. PERIODONTITIS & OSTEOPOROSIS 80

72. OSTEOPOROSIS

73. Periodontal Infection and Osteoporosis Researchers have suggested that a link exists between osteoporosis and bone loss in the jaw. Studies indicate that osteoporosis may lead to tooth loss because the density of the bone that supports the teeth may be decreased, which means the teeth no longer have a solid foundation. However, hormone replacement therapy may offer some protection.

74. Relationship between Periodontal disease and Osteoporosis Many studies have shown positive association between osteoporosis and alveolar crest resorption . Fractures are very common in these patients Calcium and Vitamin D supplements have shown positive impact on osteoporosis and periodontal disease.

75. Osteoporosis is frequently seen in women during menopause due to decreased production of estrogen. It causes suppression of calcium absorption, increase in calcium excretion and osteocyte apoptosis. Periodontitis in such patients release TNF-α that induce collagenase activity, resulting in more bone loss

76. Harmone relacement therapy (HRT) is estrogen therapy that decrease osteoclast formation and increase lifespan of osteoblasts and osteocytes. D entist should refer to medical practitioner for this. N asal and subcutaneous calcitonin are available for postmenopausal osteoporosis. Calcitonin is inhibitor of osteoclastic activity. HRT, Parathyroid harmone (PTH), Teriparatide improve osteoporosis and periodontal regeneration TREATMENT

77. PERIODONTITIS & CANCER 86

78. P. gingivalis and F. nucleatum directly interact with oral epithelial cells and stimulate tumor progression in oral specific chemical carcinogenesis model. (Binder Gallimidi A et al in 2015) P. gingivalis increases aggressiveness by promoting invasion and metastasis of oral squamous cells via inducing pro-MMP9 expression in oral squamous cell carcinoma case. ( Inaba H et al in 2014)

79. Colorectal carcinoma is leading cause of death nowadays. F. nucleatum has been shown to promote pro-inflammatory microenvironment contributing to neoplasia progression. (Yu YN et al in 2015) More studies are awaited to prove their relationship.

80. PERIODONTITIS & ALZHEIMER DISEASE 89

81. Progressive neurodegenerative disease characterized by progressive irreversible impairment of thinking, memory, learning capacity, ending in death. Alzheimer disease and Periodontitis have bidirectional relationship just as Diabetes mellitus and periodontitis.

82. Increase in inflammatory cytokines are hallmark of both Alzheimer disease and Periodontitis. Periodontitis release cytokines contributing to inflammation in brain , characterizing Alzheimer disease. Studies conducted showing relationship between the two diseases are: LPS from P. gingivalis and T. denticola ( Poole S et al in 2013) ; Bacteria T. denticola (Ellen RP In 2005), C.pneumonia ( Roulis E et al 2015) have been isolated from postmortem human brains suffering from Alzheimer disease.

83. Patients suffering from Alzheimer disease lose their ability to maintain proper oral hygiene with enhancement of risk of periodontitis. Also poor oral hygiene causing periodontitis increase the risk of Alzheimer disease. More studies are awaited to prove their relationship.

84. PERIODONTITIS & RHEUMATOID ARTHRITIS 93

85. Autoimmune chronic inflammatory disease causing inflammation of synovial membranes in joints. Anti- citrullinated protein antibodies are autoantibodies that are unique of this disease. Its pathogenesis involve an enzyme that transforms arginine into citrulline that causes posttranslational modifications in structural proteins.

86. In periodontitis P.gingivalis release deaminase that induce protein citrullination. Chronic exposure of citrullinated proteins develop anti-citrullinated protein antibodies (ACPA) that can aggravate disease in RA patients. ( Mikulis TR et al, 2014) Association between two diseases is not clear and more studies are required.

87. Periodontal medicine in clinical practice The concept of periodontal diseases as localized entities affecting only the teeth and supporting apparatus is over simplified and in need of revision now. Rather than being confined to the periodontium, periodontal diseases may have wide ranging systemic effects. Furthermore periodontal infection may exacerbate existing systemic disorders. Proper use of knowledge of potential relationship between periodontal disease and systemic health requires the dentists to expand their horizons to step back from technically demanding aspects of dental art and to recognize the oral cavity as one of many inter related organ systems.

88. Patient education Patient must be educated in disease prevention. Just as patient knows that lowering cholesterol levels may decrease their risk for heart disease, prevention of periodontal infection must also be emphasized. Controlling the risk factor of periodontal infection requires the dentist to emphasize personal and professional preventive measures focused on thorough oral hygiene and regular recall .