# Presentation: 236093

## The Role of Oral Disease in Systemic DisordersG. Todd Smith, DDS, MSDIHS Periodontal ConsultantJuly, 2004

## Oral Disease and Systemic Disorders

- Periodontitis has an association with:
- Diabetes
- Infective Endocarditis
- Cardiovascular Disease
-  Pre-Term, Low Birth Weight Infants
-  Pulmonary Disease

## Oral Disease and Systemic Disorders

**Infectious diseases can cause inflammatory changes at distance body sites.                **Hippocrates
**“****Focal Infection Theory” in the 1920’s-1940’s.**
**The oral cavity is a portal of entry as well as the site of disease for microbial infections that affect general health status.**
**                   **Surgeon General’s Report on Oral Health in America, 2000
**The mouth can become a source of disease or pathological**** ****processes affecting other parts of the body......**
-                 Surgeon General’s Call to Action to Promote Oral Health,  2003

## Common infections in the oral cavity

**Caries**
**Periapical lesions- nonvital teeth**
**Fungal and viral infections**
**Periodontitis**

## Initiation and Progressionof Periodontitis

**	****Periodontitis is a gum infection, initiated by specific bacteria that activate a series of inflammatory and immunologic changes leading to destruction of connective tissue and bone, and possible loss of teeth.**

## Pathway to Periodontal Disease

**Genetic Risk Factors**

**Host Immuno-**
** ****inflam-matory**
**Response**

**Microbial**
**Challenge**

**Connective**
**Tissue**
**and**
**Bone Destruction**

**Clinical Signs of**
**Disease**

**PMN**

**Antigens**

**LPS**

**Other Virulence**
**Factors**

**Environmental ****& Acquired****Risk Factors**

**Tissue Breakdown Products & Ecological ****Factors**

**Antibody**

**MMPs**

**Prostanoids**

**Cytokines**

## Progression of Periodontal Disease

**Risk Factors**

**Rate of Progression**
**Severity of Disease**

## Biofilm Bacteria

## Microbiota of periodontal sites associated with 

- initiation &/or progression of disease:

- Porphyromonas gingivalis
- Tannerella forsythensis
- Treponema denticola
- Actinobacillus actinomycetemcomitans
- Peptostreptococcus micros
- Prevotella intermedia
- Campylobacter rectus
- Selenomonas
- Viruses:  EBV and HSV are immunosuppressive and support the overgrowth of the periopathogens.

## Localized moderate gum disease (periodontitis)

## Localized Severe Periodontitis

## Generalized Severe Caries and Periodontitis

## Deep subgingival scaling

## Generalized Moderate to Severe Periodontitis

## 6 months after deep cleaning

## Severe chronic anaerobic periodontal infection

## 2 cm foot ulcer- smaller than the ulcerated epithelium within infected periodontal pockets

## Oral Disease and Systemic Disorders

- Periodontal disease needs to be viewed more broadly in terms of systemic inflammation, either as a consequence of an underlying hyperinflammatory trait _or_ as a factor contributing to systemic inflammation.

- Slade, Offenbacker, Beck et al
- J. Dent Res 2000

## Oral Disease and Systemic Disorders

- Pro-inflammatory cytokines (IL-1, IL-6, TNF-A) and prostaglandins (PgE2) accumulate in the gum tissues in active periodontitis at extraordinary levels and can enter the circulation.

- Salvi et al, Annals of Perio 97

- Periodontitis is an anaerobic infection flooding the
- blood stream 24 hours a day with endotoxins and
- inflammatory mediators.

- Offenbacher, 1998

- Following dental scaling, the low grade bacteremia
- resulted in increased circulating TNF-A  and IL-6.

- Ide 2004

## 		         Dr. Gordon Douglas, President AAP, 9/2003

- 		         Dr. Gordon Douglas, President AAP, 9/2003

- Periodontitis and Surgical Complications

## Slide 21

## Oral Disease and Systemic Disorders

- Periodontitis has an association with:
- Diabetes
- Infective Endocarditis
- Cardiovascular Disease
-  Pre-Term, Low Birth Weight Infants
-  Pulmonary Disease

##  IL-1, IL-6, & TNF-A

- PMN’s-

- AGE
- RAGE

- High glucose
- Abnormal lipids

-  IL-1, IL-6, & TNF-A
-  collagenase
-  O2 free radicals
**Susceptibility to severe periodontitis**

**Periodontal Destruction Through Cytokine Aberration in Diabetes**

- chemocytosis
- phagocytosis

- Glycation

- Hyper-responsive
- monocyte; endothelial
- cells, collagen

## Epidemiologic Studies in the Pimas:                                     				Shlossman,  Emrich, Knowler, and others

-   Diabetics had more severe periodontitis than non-diabetics.
-   Destructive periodontitis occurred much earlier in life in the diabetics (27% of diabetics 15-19 years old).
-  Diabetics were 15X more likely to lose all their teeth.

## Diabetes and periodontitis

- A recent review of 55 studies involving subjects with diabetes found consistent evidence of greater periodontitis:
- Prevalence
- Incidence
- Severity
- Extent
- Progression
- Dose-response relationship- as glycemic control worsens, periodontitis worsens.

- Taylor, CCED 2004

## Severe Periodontitis and Risk for Poor Glycemic Control in Subjects with NIDDM			Pima study.  Taylor et al, J Perio 96

-    Patients were twice as likely to have a worsening of HbA1c over 2-3 years when severe periodontitis was present at baseline.

## Medical status and complications in relation to periodontal disease experience in insulin-dependent diabetics. Thorstensson J Clin Perio 1996

- Case-control study compared the medical status of diabetics with and without severe periodontitis; median F/U 6 years.
- There was a sig. higher prevalence of proteinurea and cardiovascular complications such as stroke, TIA, angina, and MI in those with severe perio at baseline.

## DM and Periodontitis- The 2 Way Relationship

-  serum lipids
-  blood glucose

- DM

- AGE binding/accumulation
- Inflammatory State
- Destructive Environment

- Further aggravated lipid metabolism &  insulin resistance

- Periodontitis,  with additional  PgE2 & cytokines  IL- 1ß,  IL-6, & TNF- A

- Increased
- Periodontal
- Destruction

**DM and Periodontitis- The 2 Way Relationship**

- Periodontal
- Pathogens

## Periodontal therapy aimed at eliminating infection and reducing inflammation can improve diabetic control, at least in the short term.				Williams and Mahan, JAMA 1960		(Mean insulin decrease of 30 units)	Grossi et al, J Perio 97. Pima study		(Mean HbA1c 10% to 9% at 3 months)			Stewart et al JCP 2001		(Mean HbA1c 9.5% to 7.6%  at 9 months)	Rodrigues et al J Perio 2003		(Mean HbA1c 9.5 to 9.2 and 8.8 to 7.6 at 3 months)		 		      

## Periodontal treatment studies where no effect was seen on glycemic control:		1. Fair to well controlled diabetics, &/or	2. No antimicrobials used during dental tx.						Aldridge et al, JCP 1995				Smith et al, J Perio 1996				Grossi et al, J Perio 97				Christgau et al JCP 1998						 		      

## Slide 31

## Oral Disease and Systemic Disorders

- Periodontitis has an association with:
- Diabetes
- Infective Endocarditis
- Cardiovascular Disease
-  Pre-Term, Low Birth Weight Infants
-  Pulmonary Disease

## Periodontal bacteria increase risk for CVD thru several possible mechanisms:

- Bacteria or viruses from the mouth directly infect blood vessel walls and contribute to development of plaques and atherosclerosis.
- Bacteria or viruses interact with wbc’s or platelets and trigger release of proinflammatory cytokines, prostaglandins, and TNF-α           CV plaques
- Bacterial products in the blood may stimulate liver production of proinflammatory or pro-coagulant molecules such as C-reactive protein and fibrinogen.

## Oral Disease and Systemic Disorders

- Periodontitis

- Bacteria
- Byproducts
- Enter the
- bloodstream

- Liver
- Releases
- CRP

- Arteries
- Inflamed;
- Promoting
- Clot formation

- MI
- Or
- Stroke

- Atherosclerotic Risk in the Community

- Over 7000 participants followed for over 9 years:
- The more severe the periodontitis at baseline,
- the greater the likelihood of heart disease.
- Patients with the greatest degree of attachment loss had the highest asso with stroke/TIA.			Elter 2003

## 	C- Reactive Protein levels have a strong linear relationship with the incidence of CV events
							Ridker 1997
							Ridker NEJM 2002
      Patients with periodontitis had sig greater serum elevations in systemic markers of inflammation                ( CRP, IL-6) compared with healthy controls.
							Loos J Perio 2000
      Periodontal disease progression is associated with significant increases in serum CRP.
							Craig, J Perio 2003
	Perio treatment decreases CRP and TNF- α .				                        		Genco 1998
							Brown 2002
							Iwamoto 2003

**	****	****	****	****	****	****	**Ridker 1997
**	****	****	****	****	****	****	**Ridker NEJM 2002
**      ****Patients with periodontitis had sig greater serum elevations in systemic markers of inflammation                ( CRP, IL-6) compared with healthy controls.**
**	****	****	****	****	****	****	**Loos J Perio 2000
**      ****Periodontal disease progression is associated with significant increases in serum CRP.**
**	****	****	****	****	****	****	**Craig, J Perio 2003
**	****Perio treatment decreases CRP and TNF- ****α**** .****	****	****	****	****                        ****	****	**Genco 1998
**	****	****	****	****	****	****	**Brown 2002
**	****	****	****	****	****	****	**Iwamoto 2003

## Slide 36

## Oral Disease and Systemic Disorders

- Periodontitis has an association with:
- Diabetes
- Infective Endocarditis
- Cardiovascular Disease
-  Pre-Term, Low Birth Weight Infants
-  Pulmonary Disease

## Oral Disease and Systemic Disorders

- PTLBW infant treatment in hospitals for respiratory distress, jaundice, malnutrition, anemia, CP, etc. costs over $5 billion annually.

## Oral Disease and Systemic Disorders

- Pre-Term, Low Birth Weight Infants:
-  < 37 weeks, < 5lbs 8oz
- Related to 60% of infant deaths
- 25%  can’t be explained by accepted risk factors such as smoking, alcohol, nutrition, UTI, and level of education or prenatal care.

## Oral Disease and Systemic DisordersPeriodontitis and pregnancy

## Oral Disease and Systemic DisordersPeriodontitis and pregnancy

## Pregnancy and Risk for Periodontitis

**Increased**:
-  Vascular permeability
-  GCF flow
-  GI scores
-  PMNs in the sulcus
-  PgE2
-  Bacteroides species
- 		Kaulkwarf 78, Kornman 80
- Pregnant women had sig greater:
- 	-gingivitis during pregnancy vs. after delivery.
- 	-Existing gingival problems were aggravated.
- 				Stilness and Loe 1966
-   	- % of moderately deep pockets
- 	- % increased with the month of pregnancy
- 				Miyazaki 1991

##  Pregnancy and Risk for Periodontitis

- Pregnant women given dental exams <26 weeks and w/i 48 hrs delivery:
- Overall, no sig change in mean attachment loss, GI, or BOP           during pregnancy.  Plaque scores improved, % scored healthy improved.
- Those with moderate to severe perio at < 26 weeks were more likely to have periodontitis progress (51%) vs those initially perio healthy (9%).
- Conclusion:   **Pregnancy may accelerate attachment loss.**
- 				Lieff 2004

## Oral Disease and Systemic DisordersPeriodontitis and risk to pregnancy/fetus

- Pregnancy can increase risk for gingivitis and periodontitis.
- Is the relationship 2-Way, like with diabetes?
- Can periodontitis increase risk for adverse pregnancy outcomes?

## Biologic Mechanisms for PTLBW Infants

- Entry of inflammatory products (PgE2, Il-6, TNF- α), endotoxin, and/or
- periodontal bacteria into the bloodstream and their translocation
- to the fetus and decidual tissues

## 	Biologic Mechanisms

- Associations between infections and adverse pregnancy outcomes:
- Chorioamnionic membrane infiltration by neutrophils.
- Incidence of clinically evident infections in preterm neonates (sepsis, meningitis).
- Positive bacterial cultures of amniotic fluid and membranes.
- Markers of infection (cytokines IL-6 and TNF- α, PgE2) in amniotic fluid and maternal serum.
- Bacteria or their products induce PTB in animal models.

- Gibbs 2001

## 	Biologic Mechanisms
The maternal immune response to periodontal infection, with increased inflammation from inflammatory cytokines and PgE2, may interfere with fetal growth and trigger preterm labor.     				Hillier 1988

Infection with P. gingivalis increased PgE2 and TNF-α and appeared to be asso. with decreased fetal birth weight in the hamster.
						Collins, Infec Immun 1994	
PgE2 levels in gingival crevicular fluid was sig higher in mothers of LBW infants than in controls.  The lower the birth weight, the higher the PgE2.									Offenbacher 1998

- The maternal immune response to periodontal infection, with increased inflammation from inflammatory cytokines and PgE2, may interfere with fetal growth and trigger preterm labor.     				Hillier 1988
- Infection with P. gingivalis increased PgE2 and TNF-α and appeared to be asso. with decreased fetal birth weight in the hamster.
**	****	****	****	****	****	**Collins, Infec Immun 1994**	**
- PgE2 levels in gingival crevicular fluid was sig higher in mothers of LBW infants than in controls.  The lower the birth weight, the higher the PgE2.									Offenbacher 1998

## 	Biologic Mechanisms

- Maternal periodontal infection in the absence of a protective maternal antibody response is asso with systemic dissemination of oral organisms that translocate to the fetus resulting in prematurity.
- Highest rate of prematurity of 67%:
- 	Maternal periodontal infection
- 	Decreased IgG response to some periopathogens
- 	Strong IgM fetal response to other periopathogens
- (fetal cord serum samples)
- 						Offenbacher 2001

## 	Women with severe perio during pregnancy had increased risk of developing preeclampsia compared to those with gingival health:

Perio healthy at delivery- 3% developed preeclampsia 
Mild periodontitis at delivery- 5% 
Severe periodontitis at delivery- 10%  (OR 2.4)

Women with periodontal disease progression during pregnancy had an increased risk for developing preeclampsia (OR2.1).				
					Boggess, 2003 Obstet Gynecol
					n= 763 births

**   **
**Perio healthy at delivery- 3% developed preeclampsia **
**Mild periodontitis at delivery- 5% **
**Severe periodontitis at delivery- 10%  (OR 2.4)**
**Women with periodontal disease progression during pregnancy had an increased risk for developing preeclampsia (OR2.1).**
- 					Boggess, 2003 Obstet Gynecol
- 					n= 763 births

- Periodontitis, Pregnancy and Hypertension

## 	Clinical Studies
    Periodontal Infection as a Possible Risk Factor for Preterm Low Birth Weight.     n=93 PTLBW, 31 normal

	The risk for preterm labor requiring medical intervention or premature rupture of membranes (<36 weeks), or low birth wt. Infants (<2500 grams), was greater if the mother had periodontitis:
PTB-   OR 7.9
LBW- OR 7.5
(after controlling for smoking, race, alcohol use, age, nutrition, and genitourinary infection.)
	If the periodontitis got worse during the pregnancy, the percentage of PTLBW births rose from 6% to 43%.
							Offenbacher 1996

**    ****Periodontal Infection as a Possible Risk Factor for Preterm Low Birth Weight.     ****n=93 PTLBW, 31 normal**
**	**
**	****The risk for preterm labor requiring medical intervention or premature rupture of membranes (<36 weeks), or low birth wt. Infants (<2500 grams), was greater if the mother had periodontitis:**
**PTB-   OR 7.9**
**LBW- OR 7.5**
**(after controlling for smoking, race, alcohol use, age, nutrition, and genitourinary infection.)**
**	****If the periodontitis got worse during the pregnancy, the percentage of PTLBW births rose from 6% to 43%.**
**	****	****	****	****	****	****	**Offenbacher 1996

## 	Maternal periodontitis is an independent risk factor for PTB, LBW,  and fetal growth restriction. 5 Year prospective study. n= 814

Perio exams <26 weeks and w/i 48 hrs postpartum.

Prevalence of births for gestational age <28 weeks:
Perio healthy -         1.1%
Mild periodontitis-  3.5%
Mod-severe perio- 11.1%
Prevalence of LBW deliveries at < 1000 grams
Perio healthy-           0%
Mild periodontitis-  6.1%
Mod-severe perio- 11.4%
Periodontitis incidence/progression during pregnancy was asso with sig smaller births for gestational age
								Offenbacher 2001	

- Perio exams <26 weeks and w/i 48 hrs postpartum.
- Prevalence of births for gestational age <28 weeks:
- Perio healthy -         1.1%
- Mild periodontitis-  3.5%
- Mod-severe perio- 11.1%
- Prevalence of LBW deliveries at < 1000 grams
- Perio healthy-           0%
- Mild periodontitis-  6.1%
- Mod-severe perio- 11.4%
- Periodontitis incidence/progression during pregnancy was asso with sig smaller births for gestational age
- 								Offenbacher 2001

## 		                 Oral Disease and Systemic Disorders

	The risk of PTB increases when severe periodontitis exists in the mother. 
	Those with the most severe class of prematurity were more likely to have severe periodontitis during the 2nd trimester (21-24 weeks).

Adjusted OR 4.45 at 37 weeks
Adjusted OR 5.28 < 35 weeks
Adjusted OR 7.07 < 32 weeks

							Jeffcoat 2001

**	**
**	****The risk of PTB increases when severe periodontitis exists in the mother. **
**	****Those with the most severe class of prematurity were more likely to have severe periodontitis during the 2****nd**** trimester (21-24 weeks).**
- Adjusted OR 4.45 at 37 weeks
- Adjusted OR 5.28 < 35 weeks
- Adjusted OR 7.07 < 32 weeks
- 							Jeffcoat 2001

## 	The Relationship Between Periodontal Disease in Pregnant Women and the Nutritional condition of their Newborns.

The more severe the mother’s periodontitis:
 the lower the birth weight. 					(Most sig in those with the severest periodontitis)
the less the gestational age.
		(After controlling for traditional risk factors. N=82)

Conclusion: Periodontal disease in pregnant women could be a clinically significant risk factor for preterm delivery and low birth weight.

 							Romero JP 2002	

- The more severe the mother’s periodontitis:
-  the lower the birth weight. 					(Most sig in those with the severest periodontitis)
- the less the gestational age.
- 		(After controlling for traditional risk factors. N=82)
**Conclusion: Periodontal disease in pregnant women could be a clinically significant risk factor for preterm delivery and low birth weight.**
-  							Romero JP 2002

## Contradictory Clinical Study

	Case control study with 236 cases of PTLBW and 507 controls.  Multi-ethnic population in the UK.

	Results:  No asso. found between maternal perio disease and increased risk for PTLBW infants. (OR 0.78)
		PTLBW asso. with: 
			HTN 	(3.25)
			Previous LBW infant (2.53)
			Smoker (2.15)
	(Adjusted for maternal age, ethnicity, maternal education, smoking, alcohol consumption, infections, and hypertension.)

**    **
**	****Case control study with 236 cases of PTLBW and 507 controls.  Multi-ethnic population in the UK.**
**	****Results:  No asso. found between maternal perio disease and increased risk for PTLBW infants. (OR 0.78)**
**	****	****PTLBW asso. with: **
**	****	****	****HTN ****	****(3.25)**
**	****	****	****Previous LBW infant (2.53)**
**	****	****	****Smoker (2.15)**
**	****(Adjusted for maternal age, ethnicity, maternal education, smoking, alcohol consumption, infections, and hypertension.)**

- Davenport 2002

## Periodontal infection and inflammation Needs deep cleaning- Lower anterior teeth

## 2 months after the 2nd trimester cleaning, infection and inflammation resolved.

## Intervention Studies-PTLBW Infants

- Young pregnant minority women in NYC.
- PTLBW mothers had sig higher levels of periopathogens than women with normal birth outcomes.
- Nonsurgical perio therapy during pregnancy reduced the rate of PTLBW infants from 18.9% to 13.5%.                 (N= 74 received periodontal  tx;  90 no tx till after delivery.)
**	****Subgingival infection with biofilm rich in Gram negative, LPS producing species may play an etiologic role in the pathogenesis of PTLBW infants**
- 							Mitchell-Lewis 2001

## Intervention Studies-PTLBW Infants

**In ****pregnant mothers with periodontitis, perio therapy reduces the risk of PTLBW infants**:
- Control (no perio therapy)- 		 Incidence 10.11%
- Therapy before 28 weeks gestation- Incidence  1.84%
- Periodontitis was the strongest risk factor for PTLBW (OR 4.70), compared to previous PTLBWI (OR 3.98),                                    <6 prenatal visits (OR 3.70),                                                                       and maternal low wt.gain (OR 3.42).
**Periodontitis is an independent risk factor for PTLBWI, and perio therapy reduces the rates of PTLBW.**										      Lopez 2002, n=351

## Intervention Studies-PTLBW Infants

- 	Perio therapy at 21-25 weeks gestation reduced the rate of spontaneous PTB at < 35 weeks:
- 	No perio		rate 6.3%
- 	Perio therapy
- 		 Prophy		rate 4.9%
- 		SRP + Met		rate 3.3%
- 		SRP			rate 0.8% 											Jeffcoat 2003
- 							n=366, w 723 controls

## Antepartum Dental Radiography and Infant LBW

- Case control study, 1117 cases, 4500 controls.
- Women with dental xrays during pregnancy were more likely to have a term LBW baby compared with women with no known dental radiography.  (OR 2.27 which increased to 3.6 when exposure was > 0.4mGy) .
- There was no link between xrays and PTB.
- There was no link between xrays and very low BW.
- All women with LBWIs had xrays in the first trimester.
- Radiation may cause changes in the functioning of the mother’s thyroid gland (not tested).

- Hujoel, JAMA, 2004

## ADA Position on Antepartum Dental Radiography 2004

- In pregnant women, postpone elective dental xrays until after delivery.
- Xrays may be required during pregnancy to help dentists diagnose and treat oral disease.
- Pregnant women should continue to see a dentist regularly for oral exams and professional teeth cleanings.
- In addition to abdominal shielding, dentists should use thyroid collars on all patients, including pregnant women.

## AAP Report 2004

- Preventive oral care services should be provided as early in pregnancy as possible.
- If exam indicates a need for periodontal therapy, these procedures should be scheduled early in the 2nd trimester.
- The presence of acute infection, abscess, or other potentially disseminating sources of sepsis may warrant prompt intervention, irrespective of the stage of pregnancy.

## Conclusions- Periodontitis and PTLBW Infants

- Periodontitis appears to be an independent risk factor for pre-term delivery.
- There is a clear need for more well designed observational and intervention studies to confirm observations.
**Expectant mothers should be counseled in the importance of oral health.**
**And eat less tuna....**

- Systematic ROL, Scannapieco Annals of Perio 2003

## Slide 64

## Oral Disease and Systemic Disorders

- Periodontitis has an association with:
- Diabetes
- Infective Endocarditis
- Cardiovascular Disease
-  Pre-Term, Low Birth Weight Infants
-  Pulmonary Disease

## Biologic Mechanisms-Pulmonary Disease

- Many oral bacteria can be aspirated into lower airways and are strongly associated with bacterial pneumonia.
- Saliva enzyme activity increases in periodontitis, promoting adhesion and colonization of pathologic bacteria in the oropharynx.
- Cytokine release in periodontitis can promote perio pathogen and H. influenza adhesion and colonization of mucosal surfaces, with additional cytokine release from epithelial cells, with neutrophil recruitment, epithelial damage and infection.

## Oral Disease and Systemic Disorders

***Other Explanations for Systemic Disease Susceptibility are Common Risk Factors:***
-    Age
-    Smoking
-    Alcohol use
-    Health behaviors/habits
-    Genetic makeup
-    Stress
-    SES

## In Summary

-    Oral health is important to general health (Surgeon General’s Report), and is not less important and separate from general health.
-    Not only are patients with dm more susceptible to periodontitis, but the presence of periodontitis may negatively affect glycemic control.  Without oral health, it may be difficult to control Type 2 DM.
-     Periodontitis can’t be considered a cause of CVD or stroke yet, but can be considered an additional risk factor, with consistent findings of increased odds ratios and significant probability values.

## In Summary

-   Periodontal intervention may prevent the onset or progression of atherosclerosis-induced diseases.
-   Periodontitis is a strong, independent risk factor for pre-term birth, and periodontal treatment prior to the 3rd trimester can decrease the risk.
-   Poor oral hygiene and periodontal bone loss can increase the risk of chronic and acute respiratory illnesses, particularly bacterial pneumonia.

## Questions?