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Disease-a-Month

journal homepage: www.elsevier.com/locate/disamonth

Effects of periodontal disease on systemic

health
R. Hegde, K.H. Awan∗
College of Dental Medicine, Roseman University of Health Sciences, South Jordan, Utah 84095, United States

a r t i c l e i n f o a b s t r a c t

About one in two adults in the United States has periodon-

Article history: tal disease. Chronic periodontitis is an oral disease affecting
Available online xxx the supporting structures of the teeth leading to progressive
loss of the attachment apparatus and bone around teeth. It
Keywords:
is characterized by gingival pocket formation and/or gingi-
Gingiva
val recession. The disease is initiated by bacteria and their
Inflammatory response
Oral cavity components like lipopolysaccharide and causes a heightened
Periodontal disease host inflammatory response. This cascade of inflammatory
Systemic health response ultimately leads to an increased osteoclastic activ-
ity and bone loss. Individuals with periodontitis have in-
creased systemic levels of acute phase proteins, plasma an-
tibody levels, coagulation factor, total white blood cell count,
neutrophils, C reactive protein (CRP), and cytokines such as
INF- gamma (Interferon gamma), TNF-α (Tumor necrosis
Factor- Alpha), IL (Interleukin)-1β , IL-2 and IL-6. As peri-
odontitis works on the same chronic inflammation model
seen in systemic diseases, there is sufficient evidence to
suggest a bi-directional link between the two. This article
summarizes the established associations between periodon-
tal disease and systemic health.
© 2018 Elsevier Inc. All rights reserved.

Introduction

Periodontitis is a chronic inflammatory disease that affects the gums and the bone surround-
ing teeth caused by an organized community of bacteria called dental plaque. The bacteria

∗
Corresponding author.
E-mail address: kamranhabibawan@gmail.com (K.H. Awan).

https://doi.org/10.1016/j.disamonth.2018.09.011
0011-5029/© 2018 Elsevier Inc. All rights reserved.

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trigger an immune-inflammatory response that ultimately leads to a non-reversible loss of bone

supporting the tooth and leads to tooth loss. According to a recent report by Centers for Disease
Control and Prevention (CDC) about one out of every two American adult or 64.7 million Ameri-
can adults, aged 30 and have mild, moderate or severe periodontitis. Moreover, in adults 65 and
older, prevalence rates increased to 70.1 percent.1
Bacteria and their products in the plaque can affect periodontium either directly or indirectly.
The direct pathological effects of bacteria and their products on periodontium include induction
of inflammatory response resulting in edema and increase in gingival bleeding. The indirect ef-
fects of bacteria predominantly involve host-mediated destructive processes. The bulk of tissue
destruction in periodontitis is a result of the mobilization of the host tissues via activation of
monocytes, lymphocytes, fibroblasts, and other host cells. Furthermore, bacterial lipopolysaccha-
rides (LPS), is thought to stimulate production of both catabolic cytokines and inflammatory me-
diators including arachidonic acid metabolites such as prostaglandin E2 (PGE2).These cytokines
and inflammatory mediators then result in release of tissue-derived enzymes, the matrix metal-
loproteinases, that are destructive to the extracellular matrix and bone.
The strong association of periodontitis with several systemic diseases has been attributed
to a number of factors, including systemic distribution of periodontal pathogens and systemic
leakage of local inflammatory mediators. These mechanisms of the perio-systemic connection
have been actively studied and established. The relation between periodontal disease and sys-
temic disease is bi-directional, i.e. periodontal disease can cause adverse systemic outcomes and
certain systemic diseases pre-dispose a person to have periodontal disease. This paper will sum-
marize the systemic adverse outcomes that have epidemiological evidence of being associated
with periodontal disease.

Cardiovascular disease

Pathogenesis

The most biologic plausible pathogenesis that links cardiovascular disease (CVD) and peri-
odontal disease is that of a chronic, low-level inflammation model.2 As described earlier, peri-
odontal disease is initiated by an organized community of aerobic and anaerobic bacteria called
dental plaque that accumulates on the tooth surface as a result of poor oral hygiene.3 Over
time, this bacterial community multiplies in size and leads to deepening of the periodontal sul-
cus which is the part of the gingiva that attaches to the tooth. This deepening of the periodontal
sulcus or periodontal pocket formation creates an anaerobic environment where the pathogenic
bacteria thrive. LPS, matrix metalloproteinases (MMPs) and other bacterial antigens challenge
the host’s local and systemic immune response. Increased circulating levels of pro-inflammatory
cytokines are seen during the course of disease progression which includes interleukins (IL-1
beta, IL-2, IL-6 and IL-8) and C-reactive protein (CRP).4,5 In addition, the transient bacteremia
that results from periodontal pathogens leaking into the blood vessels initiates the host’s im-
mune response that favors atheroma formation, maturation and exacerbation.6,7

Epidemiologic evidence

Most studies, both cellular and molecular level as well as clinical trials confirm that the cellu-
lar changes that occur in the atherosclerotic changes are that of a chronic inflammatory- fibro-
proliferative disease model.2,8 The pro-inflammatory cytokines previously described have been
found to increase systemically with periodontal disease progression and diminsh after therapy.
The same cytokines have also been found in atheromatous lesions.9–11 CRP, an inflammatory
marker known to be associated with CVD is also found to consistently be elevated in people
with periodontal disease. Wu et al. analyzed the NHANES 1 data and found statistical significant
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increased levels of CRP, high density lipoprotein cholesterol and plasma fibrinogen in patients
with poor oral hygiene. Several other studies confirm these results.12 In the VA Normative Ag-
ing and Dental Longitudinal studies, Dietrich and co-workers evaluated the association between
periodontitis and incidence of coronary heart disease (CHD). In the 1203 men they studied, they
found a significant dose dependent increased incidence of CHD among men <60 years indepen-
dent of other established cardiovascular risk factors.
In addition to the indirect effects caused by the inflammatory models, several studies also
found a direct association between the bacteria that cause periodontal disease and CVD. P
gingivalis, T. forsythia and A. actinomycetemcomitans and Pr. Intermedia, the known periodontal
pathogens have been found in atheromatous plaque.13–15 The Oral Infection and Vascular Dis-
ease Epidemiology Study (INVEST), a prospective cohort study data showed that there was a
dose dependent relation between carotid plaque thickness and periodontal bone loss.16
In summary, there are multiple studies that strongly suggest a biologically plausible asso-
ciation between periodontal disease and CVD through various mechanisms, These results have
been re-validated in experimental cellular and molecular studies, cohort and intervention clinical
studies. According to the consensus report by the Joint European Federation of Periodontology
(EFP) and American Academy of Periodontology (AAP) workshop, statistically significant excess
risk was found for atherosclerotic cardiovascular disease in patients with periodontitis, indepen-
dent of other co-morbidities.17 This risk was found to be greater in males and younger patients
and less in individuals over age 65 years. Hence, periodontal disease in patients who have no
have other risk factor may contribute to cardiovascular risk prediction over the currently estab-
lished prediction models.

Adverse pregnancy outcomes

Infants born before the completion of 37 weeks of gestation are referred to as preterm in-
fants. Preterm infants usually weigh lower at birth (<2500 gm) and prematurity is associated
with increased perinatal mortality.

Pathogenesis

The most significant factor for preterm delivery is maternal infections attributing to about
half of the preterm births.18 Bacteria from the maternal genital tract infections elicit a pro in-
flammatory response in the mother, which ultimately results in release of prostaglandins and
matrix metalloproteinases.19 This in turn causes smooth muscle contraction and membrane
weakening respectively and triggers premature cervical ripening.20 This bacterial- host inflam-
matory response is considered to be the association between maternal periodontal disease and
adverse pregnancy outcomes. In addition to the above pathway, bacteremia associated with pe-
riodontal disease may reach the uterus thus exposing the maternal-fetal unit to the bacteria and
their products. This may elicit the above mentioned inflammatory response leading to preterm
delivery.21

Epidemiologic evidence

The first animal studies that led to the hypotheses linking periodontal disease and adverse
pregnancy outcomes is the one by Collins and co-workers on pregnant hamsters. Injection of
periodontal pathogen P gingivalis resulted in intrauterine growth retardation, increased pro-
inflammatory cytokines in the amniotic fluid and smaller fetuses22,23 . Subsequent studies using
mice and rabbit confirmed these findings.24,25
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Table 1
Effect of periodontal disease on diabetes: observational human studies.

Authors Country sample Study type Results

size

Taylor et al. USA 88 Longitudinal patients with severe periodontitis were associated
(1996)39 cohort with significant elevated amounts of HbA1c >9% at
follow-up after adjustment for confounding factors
Saito et al. Japan 961 Retrospective Increases in pocket depth corresponded to a 0.13%
(2004)40 cohort HbA1c increase (p = 0.007). Increased severity of
periodontitis was associated with development of
glucose intolerance.
Norma et al. Japan 73 Cross-sectional Severity of periodontitis was associated with
(2004)41 severity of diabetic retinopathy
Saremi et al. USA 628 Longitudinal patients with periodontitis had significant
(2005)42 cohort increased death rate ratio (4.5 95% CI 2.0–10.0)
from cardio renal disease
Shultis et al. USA 529 Longitudinal severe periodontitis at baseline was associated
(2007)43 cohort with 2.1 fold increase in incidence of
microalbuminuria and 3.5 increase in incidence of
end stage renal disease when compared with
no/mild periodontitis disease
Demmer et al. USA (NHANES 9269 Longitudinal Increased incidence of diabetes 2.08 (95% CI 1.51-
(2008)44 1 data and its cohort 2.87) was seen in patients with periodontitis
follow-up compared to healthy periodontium
study)
Morita et al. Japan 1023 Longitudinal Development of periodontal disease is associated in
(2010)45 cohort a dose response manner with development of >1
components of metabolic syndrome over 4 years
Demmer et al. Germany 2793 Longitudinal 5 year increase in severity of periodontal disease
(2010)46 cohort was associated with an increase in HbA1
Albrao et al. Brazil 122 Cross-sectional Poorer periodontal status was associated with risk
(2010)47 for neuropathic foot ulceration
Southerland USA 6048 Cross-sectional severe periodontitis was associated with subclinical
et al. 201248 heart disease and CHD in patients with diabetes

Several observational human studies support an association between periodontal disease and
pregnancy: A case-control study by Offecnbacher and co-workers (1996) of 124 pregnant or post-
partum mothers which defined preterm low birth weight (PLBW) as a baby with a birth weight
less than 2500 g and one or more of the following - gestational age <37 weeks, preterm labor
(PTL), or premature rupture of membranes (PROM).26 Controls were normal birth weight infants
(NBW). Assessments included a broad range of known obstetric risk factors, such as tobacco
use, drug use, alcohol consumption, level of prenatal care, parity, genitourinary infections, and
nutrition. Clinical examination was performed to record the severity of periodontal disease (clin-
ical attachment loss) PLBW cases and primiparous PLBW cases (n = 93) had significantly worse
periodontal disease than the respective NBW controls. Multivariate logistic regression models,
controlling for other risk factors and covariates, demonstrated that periodontal disease is a sta-
tistically significant risk factor for PLBW with adjusted odds ratios of 7.9 and 7.5 for all PLBW
cases and primiparous PLBW cases, respectively. Several other case-control studies found positive
associations between adverse pregnancy outcomes and periodontitis27–31 While the preponder-
ance of data supports a connection between periodontitis and pregnancy, two studies found no
association between the two.32–34

Diabetes

The role of diabetes in periodontal disease is bi-directional, that is diabetes is a known risk
factor for periodontitis and periodontitis in turn affects the glycemic control in individuals with
diabetes.
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Table 2
Effects of periodontal therapy on systemic glycemic control in patients with Type 2 diabetes.

Authors Country sample Study type Results

size

Stewart et al. USA 72 controlled clinical trial Intervention group had significant decrease in
(2001)49 HbA1c levels (1.9% vs 0.8%) (p = 0.02) at 18
months
Calbacho et Chile 24 randomized controlled
(2004)50 clinical trial
Promsudthi Thailand 52 controlled clinical trial intervention group had decrease in HbA1c level
et al. (2005)51 (−0.19%) and control had increase (+0.12%)-
however the difference was non-significant
Kiran et al. Turkey 22 randomized controlled intervention group: −0.86% control group:
(2005)52 clinical trial +0.31%, significant difference
Yun et al. China 46 randomized controlled intervention group: −0.77% control group:
(2007)52 clinical trial −0.58%%, Non-significant difference
Jones et al. USA 165 randomized controlled intervention group: −0.65% control group:
(2007)53 clinical trial −0.51%, Non-significant difference
Al-Zahrani Saudi 43 randomized controlled Reduction in the mean HbA1c level after
et al. (2009)54 Arabia clinical trial treatment was observed in all groups but was
only significant for the mechanical
debridement and doxycycline group.
Katagiri et al. Japan 49 randomized controlled intervention group: −0.14% control group:
(2009)55 clinical trial −0.09%, Non-significant difference
Koromantzos Greece 60 randomized controlled intervention group: −0.72% control group:
et al. (2011)56 clinical trial −0.13%, Significant difference
Chen et al. Guangzhou 126 randomized controlled The intergroup difference for HbA1c, FPG,
(2012)57 clinical trial TNF-α , and lipid profiles was not statistically
significant after therapy (P > 0.05).
Engebretson USA 514 randomized controlled intervention group: +0.17% control group:
et al. (2013)58 clinical trial +0.11%, Non-significant difference
Gay et al. USA 126 randomized controlled Non-significant difference in HbA1c reductions
(2014)59 clinical trial (0.6 ± 2.1% and 0.3 ± 1.7%) was found between
test and control groups at 4 months.
Gilowski et al. Poland 34 randomized controlled There were no changes in HbA1c levels after
(2012)60 clinical trial therapy.
Haerian Iran 30 randomized controlled No significant difference was observed between
Ardakani et al. clinical trial the two groups in regard with HbA1c
(2014)61

Pathogenesis

Periodontal infections result in an elevation of serum pro-inflammatory markers. These may

adversely affect metabolic control, may result insulin resistance which in turn over time can lead
to hyperglycemia and type 2 diabetes. Chronic gram negative periodontal infections in individual
with diabetes may also worsen glycemic control.35 Patients that harbor periodontal pathogens
have significantly higher markers of systemic inflammation like C-reactive protein (CRP), IL-6
and fibrinogen than patients without these pathogens.36–38 Systemic dissemination of these or-
ganisms or their products may induce a bacteremia or endotoxemia, inducing an elevated in-
flammatory state and stimulating increased levels of serum inflammatory markers.

Epidemiologic evidence

Table 1 summarizes studies that examined the effects of incidence or increase in severity
of periodontal disease on diabetic outcomes. Current evidence suggests that periodontal disease
both promotes development of type 2 diabetes and adversely affects glycemic control and dia-
betic complications
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Table 2 summarizes numerous interventional studies evaluating the effect of periodontal

therapy on glycemic control in patients with type 2 diabetes. The Cochran database systematic
review concluded that there is evidence to suggest that treatment of periodontal disease helps
improve glycemic control, noting a mean percentage reduction of 0.29% in HbA1c at 3–4 months
of treatment.

Conclusions

There is sufficient evidence to suggest that periodontal disease and systemic health have a
two- way relationship, in that, the periodontal disease can cause adverse systemic conditions
and that certain systemic diseases cause periodontal disease. It is vital that the physicians and
other health care providers educate the patients about this association and to recommend den-
tal care facilitate restoration of oral health in these individuals. The evidence suggests that treat-
ment of one disease could lead to better outcomes for the other. This knowledge should be used
to attain better patient outcomes in future.

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Please cite this article as: R. Hegde, K.H. Awan, Oral health special issue, Disease-a-Month (2018),
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