ปาก: ประต ส ส ขภาพ MOUTH: GATEWAY TO HEALTH AND DISEASE รศ.ทพ. ส พจน ตามสายลม อ.ทพ.ดร. อรรถว ฒ เล ศพ มลช ย อ.ทพญ. พ มพ ชนก ส ทธ บ ณยพ นธ

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1 ปาก: ประต ส ส ขภาพ MOUTH: GATEWAY TO HEALTH AND DISEASE รศ.ทพ. ส พจน ตามสายลม อ.ทพ.ดร. อรรถว ฒ เล ศพ มลช ย อ.ทพญ. พ มพ ชนก ส ทธ บ ณยพ นธ ภาคว ชาปร ท นตว ทยา คณะท นตแพทยศาสตร จ ฬาลงกรณ มหาว ทยาล ย

2 OUTLINE Background & history Update concept Microbiome Literature reviews:- - ASVD DM CVD

3 In ancient Greece, Hippocrates reported cure of an arthritis case by tooth extraction ( B.C.E)

4 PLAQUE BACTERIA

FOCAL INFECTION THEORY (1890-1930) Willoughby Dayton Miller (1853 1907) Miller (1890) proposed that oral microorganisms or their products have a role in the development of a variety of diseases in

5 FOCAL INFECTION THEORY ( ) Willoughby Dayton Miller ( ) Miller (1890) proposed that oral microorganisms or their products have a role in the development of a variety of diseases in sites removed from the oral cavity, including brain abscesses, pulmonary diseases and gastric problems. Miller WD. The human mouth as a focus of infection. The Dental Cosmos 1891;33(9): advocated extraction of known healthy teeth to prevent focal infection. 1950s the Focal infection theory was abandoned

6 1990s' emergence of epidemiological associations between dental infections and systemic diseases

7 Publications of association studies between oral diseases and systemic disease Number of Publications Years

8 Publications of association studies between periodontal disease/dental caries and systemic disease Number of Publications Periodontal disease vs Systemic disease Caries vs Systemic disease Years

Human microbiome is composed of the microbes that live in and on the human body 10 13 human

10 Human microbiome is composed of the microbes that live in and on the human body human cells microbial cells Huge amount and diverse 100x more bacterial genes than human genes!

11 THE HUMAN MICROBIOME Oral ~600 different species Colon = 5 x10 12 bacteria per cm 3 >1,000 different species Skin = 10 6 bacteria per cm 2

12 The human microbiome influences our nutrition, health, & development Nutrition: digesting complex polysaccharides Keep away potential infectious & Shapes immune system Organ development eg. brain

13 Changes in human microbiome influence health and disease Changes in gut microbiome lead to many diseases Nature Reviews Immunology 16, (2016) doi: /nri

14 GUT MICROBIOME & OBESITY

15 The specific niches of oral microbiome

16 Periodontal health, gingivitis and periodontitis George Hajishengallis Nat Rev Immunol doi:

18 Periodontitis >> Systemic inflammation

19 EGAT STUDY Observational cohort study Aim: CVD incidence/ risk factors Sample: EGAT employee (~8,000) every 5 years Facebook 2002 to present (14-year-follow-up)

20 Prin Vathesatogkit, et al. (2010)

21 EGAT STUDY

22 EGAT STUDY Registration Check-OUT Blood and Urine Oral Examination Interview Physical Examination

23 EGAT STUDY Registration Check-OUT Blood and Urine Oral Examination Interview Physical Examination

24 EGAT STUDY Registration Check-OUT Blood and Urine Oral Examination Interview Physical Examination

Health behaviors (smoking, alcohol, exercise,

25 EGAT STUDY Registration Check-OUT Blood and Urine Interview Demographic data Oral Examination Interview Health behaviors (smoking, alcohol, exercise, nutrition) Physical Examination Underlying diseases & Treatment

26 EGAT STUDY Registration Check-OUT Oral Examination Blood and Urine Interview Physical exam Pulse Blood pressure Body measurement (height, weight, waist, hip) EKG BMD Body fat Physical Examination Chest x-ray

27 EGAT STUDY Periodontal exam: Registration Mobile units Check-OUT Blood and Urine Calibrated examiners Trained recorders Oral Examination Interview Physical Examination

28 PERIODONTAL DISEASE EXAMINATION

29 PerioExam EGAT EGAT Overview of EGAT Cohorts EGAT

30 AtheroSclerotic Vascular Diseases (ASVD)

31 สำน กโรคไม ต ดต อ กรมควบค มโรค พ.ศ. ๒๕๕๘

32 MECHANISM

33 LITERATURE REVIEW Association with Periodontitis Clinical events Surrogate markers Effects of Perio-Tx

34 Survival analysis of 35 years among 1203 men Outcome: Myocardial infarction, angina pectoris, and fatal CHD Exposure (Periodontitis): Clinical Examination & Radiography 3yr Circulation 2008

35 Table 2. Association Between Periodontitis and Total Incident CHD by Age (<60, >60 Years) Age 60 y Age 60 y MBLS Median Teeth Remaining, Median, n CHD Events, n Person- Years HR (95% CI)* HR (95% CI) Median Teeth Remaining, Median, n CHD Events, n Person- Years HR (95% CI) HR (95% CI) (Reference) 1.00 (Reference) (Reference) 1.00 (Reference) ( ) 1.68 ( ) ( ) 0.84 ( ) ( ) 1.55 ( ) ( ) 0.98 ( ) ( ) 2.12 ( ) ( ) 1.81 Edentulous ( ) 1.90 ( ) ( ) 1.61 ( ) CPD 0 to 4 mm (Reference) 1.00 (Reference) (Reference) 1.00 (Reference) 4 20 mm ( ) 1.26 ( ) ( ) 1.11 ( ) mm ( ) 1.42 ( ) ( ) 1.23 ( ) 40 mm ( ) 1.94 ( ) ( ) 0.73 ( ) Edentulous ( ) 1.71 ( ) ( ) 1.72 ( ) MBLS indicates mean bone loss score; CPD, cumulative probing depth. *Adjusted for age. Trend: MBLS, P 0.001; CPD, P Adjusted for age, body mass index, high-density lipoprotein cholesterol, total cholesterol, triglycerides, hypertension, mean systolic and diastolic blood pressure, diabetes mellitus, fasting glucose, smoking, alcohol intake, occupation and education, income, and marital status. Trend: MBLS, P 0.02; CPD, P Adjusted for age. Trend: MBLS, P 0.56; CPD, P Adjusted for age, body mass index, high-density lipoprotein cholesterol, total cholesterol, triglycerides, hypertension, mean systolic and diastolic blood pressure, diabetes mellitus, fasting glucose, smoking, alcohol intake, occupation and education, income, and marital status. Trend: MBLS, P 0.99; CPD, P 0.33.

36 ความส มพ นธ ระหว าง โรคปร ท นต อ กเสบและโรคห วใจและหลอดเล อด : การศ กษาเช งระบาดว ทยาในพน กงานการไฟฟ าฝ ายผล ตแห งประเทศไทย (13 ป ) อ.นพ.ส ก จ แย มวงษ ผศ.ทพญ.อรวรรณ จร สก ลางก ร อ.ทพ.ดร.อรรถว ฒ เล ศพ มลช ย

37 Survival curve: CHD - Periodontitis

38 Multivariate COX Regression model Variables Adjusted OR (95% CI) Moderate periodontitis NS 3.6 ( ) Severe periodontitis 4.8 ( ) Adjusted: age, sex, SES, smoking, alcohol, HT, DM, Lipid profile, obesity

39 LITERATURE REVIEW Association with Periodontitis Clinical events Surrogate markers Effects of Perio-Tx

40 SURROGATE MARKERS Systemic inflammatory markers: CRP, sst2 carotid intima-media thickness (IMT) Endothelial dysfunction

41 C-Reactive Protein: CRP Rhodes 2011 (Nature Reviews Rheumatology)

42 THE ASSOCIATION BETWEEN C-REACTIVE PROTEIN LEVEL AND PERIODONTAL DISEASE IN WORKERS OF ELECTRICITY GENERATING AUTHORITY OF THAILAND (EGAT) Cross-sectional study (EGAT 2009) n = 2,394 Periodontal classification (Albandar 2007) CRP: Categorised by CVD risk level (AHA) ผศ.ทพ.ขจร ก งสดารพ ภพ ทพ.เร องยศ จ วราหะวงศ

43 One-way ANOVA Significance

44 Study or sub-category WMD (random) 95% CI Weight % WMD (random) 95% CI Bizzarro 2007 SeP Bizzarro 2007 MoP Salzberg 2006 GaP Salzberg 2006 LaP Havemose-P 2006 GaP Havemose-P 2006 LaP Joshipura 2004 Buhlin 2003 Amar 2003 Craig 2003 Noack 2001 Loos 2000 * Frederikkson 1998 Total (95% CI) Test for heterogeneity: Chi² = 51.41, Test for overall effect: Z = 5.42 (P < 0 a [ 0.33, 2.73] [0.11, 2.29] [1.34, 3.02] [0.19, 1.87] [0.71, 3.29] [ 0.61, 4.61] [ 0.15, 0.95] [0.17, 2.91] [0.13, 2.47] [2.67, 3.97] [0.75, 3.97] [0.66, 2.20] [0.14, 3.36] [1.05, 2.24] Study WMD (random) Weight WMD (random)

45 Association between Chronic Periodontitis and Serum sst2, a novel cardiac biomarker, in a Thai population ศ.ดร.นพ.ป ยม ตร ศร ธรา รศ.ทพ.ดร.ก ตต ต.ร งเร อง ศ.ทพญ.ดร.ร งส น มหานนท ทพ.ด ษยวด เกต ท ต

Association between Chronic Periodontitis and Serum sst2, a novel cardiac biomarker,in a Thai population Releases in response to IL-1α, IL-1β, TNF-α and supernatants derived from LPS-stimulated

46 Association between Chronic Periodontitis and Serum sst2, a novel cardiac biomarker,in a Thai population Releases in response to IL-1α, IL-1β, TNF-α and supernatants derived from LPS-stimulated peripheral blood mononuclear (PBMC) Good prognostic marker to predict mortality of heart disease Inflammatory cytokines led to increase of sst2 secretion from cardiac myocyte and alveolar epithelial cells

47 Association between Chronic Periodontitis and Serum sst2, a novel cardiac biomarker,in a Thai population ng/ml * ng/ml * ng/ml No/Mild Perio Moderate Perio Severe Perio * Significant difference (Ref: No/Mild Perio)

48 LITERATURE REVIEW Association with Periodontitis Clinical events Surrogate markers Effects of Perio-Tx

49 PERIODONTAL TREATMENT Prevent new CVD event:

50 PERIODONTAL TREATMENT Prevent new CVD event: Pilots: Periodontitis and Vascular Events study (PAVE)

51 PERIODONTAL TREATMENT Improve surrogate markers (short-term) reduced CRP: 0.37 mg/dl (95%CI: 0.11, 0.64) (Demmer, 2013) reduced the carotid IMT (Piconi, 2009) improved endothelial dysfunction (EDD & EID) (Mercanoglu, 2004) EDD: Brachial artery responses to reactive hyperemia (endothelium-dependent dilatation EID: Sublingual nitroglycerin (endothelium-independent dilatation IMT: intima-media thickness

52 CONSENSUS EFP/AAP There is consistent and strong epidemiologic evidence that periodontitis imparts increased risk for future cardiovascular disease

AHA Scientific Statement Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independent Association?

53 AHA Scientific Statement Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independent Association? A Scientific Statement From the American Heart Association The American Dental Association Council on Scientific Affairs Concurs With the Lockhart et al. 2012(Circulation)

54 AHA Scientific Statement Periodontal Disease and Atherosclerotic Vascular Disease: Does the Evidence Support an Independent Association? A Scientific Statement From the American Heart Association The American Dental Association Council on Scientific Affairs Concurs With the Although periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction in short-term studies, there is no evidence that they prevent ASVD or modify its outcomes. Lockhart et al. 2012(Circulation)

55 DIABETES MELLITUS

56 Diabetes: A global emergency

57 Diabetes around the world

59 BI-DIRECTIONAL RELATIONSHIP

60 Tissue repair Bone & collagen homeostasis Host response BI-DIRECTIONAL RELATIONSHIP

62 13 studies in review & 6 studies in Meta-analysis Diabetes increased the risk of incidence or progression of periodontitis by 86% (RR 1.86 [95% CI ])

63 Risk effects of DM on Periodontitis Nascimento GG, et al. 2018

64 Glycemic control >> Periodontitis Cross-sectional (N ~ 4,500) US General population (45 years old ++)

65 Effects of Glycemic controlled on Periodontitis Poorly-controlled DM: It is associated with greater prevalence of severe periodontitis. Well-controlled DM: ~ No sig. There was a tendency for a higher prevalence of severe periodontitis Tsai C, et al. 2002

66 Insulin resistant BI-DIRECTIONAL RELATIONSHIP

67 Periodontitis >> DM Increased DM incidence Worsen glycemic controlled in DM patients Increased risk of diabetic complications Taylor GW, et al Shultis WA, et al Saremi A, et al. 2005

risk ratio for incident diabetes in severe

68 Periodontitis >> DM Increased DM incidence - EGAT study - 10-year - Cohort: Adults with non-dm at baseline (N~2,100) - Results: After adjusting for other risk factors, the adjusted risk ratio for incident diabetes in severe periodontitis was 1.24 (95% CI: 1.07, 2.06) รศ.ทพ. ส พจน ตามสายลม

69 Periodontitis >> DM Increased DM incidence Worsen glycemic controlled in DM patients Increased risk of diabetic complications Taylor GW, et al Shultis WA, et al Saremi A, et al. 2005

70 Effect of Periodontitis treatment on glycemic controlled Reduction in HbA1c at 3 4 months was reported in all reviews for the treatment group ranging from 0.27% to 1.03% Madianos & Koromantzos, 2018

71 CHRONIC KIDNEY DISEASE

73 ประเทศ น พน N Prevalence of CKD (%) Stage 1-2 Stage 3-5 Stage 1-5 สหร อเมร กา Coresh J ละคณะ (2007) นอร เวย (HUNT II) Hallan SI ละคณะ (2006) ออสเตรเล ย (The AusDiab Kidney Study) Chadban SJ ละคณะ (2003) จ น Zhang L ละคณะ (2012) ญ ป น Imai E ละคณะ (2009) เกาหล Kim S ละคณะ (2009) 22 2, ไต หว น Hsu CC ละคณะ (2006) 21 NA. NA ส งคโปร Sabanayagam C ละคณะ 4, (2010) 28 อ นเด ย (Indian SEEK study) Singh AK ละคณะ (2013) 24 5, ไทย (Thai SEEK study) CKD PREVALENCE Ingsathit A ละคณะ 3, (2010)

75 LITERATURE OVERVIEW Cross-sectional studies

76 LITERATURE OVERVIEW Cohort studies Sample: Japanese Elderly f/u 2 years Outcome: Decrease in kidney function

78 PERIO-CKD: EGAT-STUDY 10 years cohort study: EGAT sample (n-2635) Aim: Casual effect of Periodontitis on CKD รศ.นพ.ดร.ชาคร ย ก ตต ยากร รศ.ทพ.ส พจน ตามสายลม ผศ.ทพญ.ดร.จ นทรกร แจ มไพบ ลย ทพ.อรรถว ฒ เล ศพ มลช ย

79 Incidence of CKD Cumulative incidence of CKD 1.03 cases per 100 persons per year (95% CI: 0.91, 1.16) Non-CKD 2635 CKD: 167 CKD: 105

80 Cumulative incidence of CKD: EGAT No Perio Moderate Perio Severe Perio

81 Casual pathways DM Periodontitis CKD

82 Casual pathways DM indirect effect Periodontitis direct effect CKD Effect of Periodontitis on CKD mediated through DM

83 Casual pathways DM 0.7% indirect effect Periodontitis direct effect 1% CKD Effect of Periodontitis on CKD mediated through DM % site with CAL >= 5mm

84 Casual pathways DM direct effect Periodontitis indirect effect CKD effect of DM on CKD mediated through periodontitis

85 Periodontal Disease and Adverse Pregnancy Outcomes

86 Periodontitis and Arthritis (Reynolds, 2012)

Alzheimer s & Dementia 4 (2008) 242 250 Inflammation and Alzheimer s disease: Possible role of periodontal diseases Angela R. Kamer a, *, Ronald G. Craig a,b, Ananda P.

87 Alzheimer s & Dementia 4 (2008) Inflammation and Alzheimer s disease: Possible role of periodontal diseases Angela R. Kamer a, *, Ronald G. Craig a,b, Ananda P. Dasanayake c, Miroslaw Brys d, Lidia Glodzik-Sobanska d, Mony J. de Leon d,e a Department of Periodontology and Implant Dentistry, College of Dentistry, New York University, New York, NY, USA b Department of Basic Sciences and Craniofacial Biology, College of Dentistry, New York University, New York, NY, USA c Department of Epidemiology and Health Promotion, College of Dentistry, New York University, New York, NY, USA d Department of Psychiatry, School of Medicine, New York University, New York, NY, USA e Nathan Kline Institute, Orangeburg, NY, USA

Erectile Dysfunction Might Be Associated With Chronic Periodontal Disease: Two Ends of the Cardiovascular Spectrum Yehuda Zadik, DMD,* Ron Bechor, DMD,* Shay Galor, MD,* Dan Justo, MD,* and Rafi J.

University, Jerusalem, Israel; Reuth Medical Center and Sackler Faculty of Medicine, Sexual Rehabilitation Clinic, Tel Aviv, Israel Dr. Dan Justo s contribution was equal to Dr. Rafi Heruti.

88 Erectile Dysfunction Might Be Associated With Chronic Periodontal Disease: Two Ends of the Cardiovascular Spectrum Yehuda Zadik, DMD,* Ron Bechor, DMD,* Shay Galor, MD,* Dan Justo, MD,* and Rafi J. Heruti, MD* *Center for Health Promotion and Preventive Medicine, Medical Corps, Israel Defense Forces, Zrifin, Israel; Department of Oral Medicine, Hadassah School of Dental Medicine, Hebrew University, Jerusalem, Israel; Reuth Medical Center and Sackler Faculty of Medicine, Sexual Rehabilitation Clinic, Tel Aviv, Israel Dr. Dan Justo s contribution was equal to Dr. Rafi Heruti. J Periodontol December 2011 J Sex Med 2009;6: Association Between Chronic Periodontitis and Vasculogenic Erectile Dysfunction Anuj Sharma,* A.R. Pradeep,* and Arjun Raju P. A nationwide population-based study on the association between chronic periodontitis and erectile dysfunction Joseph J. Keller 1, Shiu-Dong Chung 2 and Herng-Ching Lin 3 1 School of Medical Laboratory Sciences and Biotechnology, Taipei Medical University, Taipei, Taiwan; 2 Division of Urology, Department of Surgery, Far Eastern Memorial Hospital, Taipei, Taiwan; 3 School of Health Care Administration, Taipei Medical University, Taipei, Taiwan Keller JJ, Chung S-D, Lin H-C. A nationwide population-based study on the association between chronic periodontitis and erectile dysfunction. J Clin Periodontol 2012; 39: doi: /j X x.

89 PERIODONTAL MEDICINE Monsarrat, et al. 2016

90 PERIODONTAL MEDICINE Fifty-seven systemic conditions have been hypothesized to be linked with periodontal diseases. Monsarrat, et al. 2016

91 Publications of association studies between oral diseases and systemic disease Number of Publications Years

92 MOUTH: GATEWAY TO HEALTH AND DISEASE

93 Acknowledgement จ ฬาลงกรณ มหาว ทยาล ย สำน กงานคณะกรรมการว จ ยแห งชาต สำน กงานกองท นสน บสน นการสร างเสร มส ขภาพ (สสส.) คณะแพทยศาสตร โรงพยาบาลรามาธ บด มหาว ทยาล ยมห ดล การไฟฟ าฝ ายผล ตแห งประเทศไทย ภาคว ชาปร ท นตว ทยา คณะท นตแพทยศาสตร จ ฬาลงกรณ มหาว ทยาล ย

Plaque sample Saliva sample Treatment recommended

Plaque sample Saliva sample Treatment recommended ผศ.ทพ.ส พจน ตามสายลม ภาคว ชาปร ท นตว ทยา คณะท นตแพทยศาสตร จ ฬาลงกรณ มหาว ทยาล ย Oral health and Systemic health connection Several epidemiological and clinical studies have revealed significant associations