Systemic Effects of Periodontal Diseases
Frank A. Scannapieco, DMD, PhD
Department of Oral Biology, School of Dental Medicine, University at Buffalo,
State University of New York, 109 Foster Hall, Buffalo, NY 14214, USA
The possibility that a localized oral condition such as periodontal disease
(PD) may have systemic effects seems to be of interest to the average person.
The notion that a condition that is often ignored (or dealt with only when
causing pain) may have long-term systemic consequences gets people’s
attention. To some constituencies of the dental profession, this attention is
a good thing; perhaps some of those who have ignored their oral health will
now pay attention to their mouth and seek regular dental care. This notion
has considerable public health significance because if it is true, then
treatment of periodontal inflammation would contribute to reduction in the
risk of many prevalent, often fatal chronic diseases.
To what extent are the putative associations between PD and systemic
conditions such as atherosclerosis, myocardial infarction, stroke, pneumo-
nia, diabetes mellitus, and adverse pregnancy outcomes based on proven
fact? To what extent can these potential associations be explained by
a plausible pathogenic mechanism? Will provision of periodontal therapy
reduce the risk of these systemic diseases? The goal of this article is to briefly
review the history of this concept, describe the biologically plausible
circumstances that may underlie these potential associations, and provide
a summary of the published literature that supports or refutes them.
History of the focal infection hypothesis
is not new. Indeed, the possibility that a localized, or focal, infection such as
PD could have systemic effects was a popular idea at the turn of the twentieth
century [1,2]. A focal infection is a chronic, localized infection that can
disseminate microorganisms or toxic microbial products to contiguous or
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Dent Clin N Am 49 (2005) 533–550
distant tissues. In addition to the teeth and jaws, other common sites of focal
infection were considered to be tonsils, sinuses, fingers and toes, bronchi, the
gastrointestinal tract including appendicitis and ulcers, the urinary tract, and
lymph nodes. It was thought that many focal infections led to indolent
systemic diseases such as arthritis, nephritis, conjunctivitis and iritis, otitis
media, endocarditis, and anemia. As a result of this theory, many physicians
of the era often recommended preventive full-mouth extractions in subjects
suspected of having a focal infection causing systemic diseases.
Over time, a variety of arguments developed against the focal infection
theory. In many patients, extraction of the teeth did not reverse the course
of the systemic disease. Most of these early ideas were based on anecdotal
evidence, not on evidence obtained from carefully designed epidemiologic
studies or controlled trials (to be fair, such studies were rarely if ever
performed in those days). Thus, by the 1950s, the focal infection hypothesis
fell from favor.
In recent years, evidence has come forth supporting the notion that
localized infectious diseases such as PD may indeed influence a number of
systemic diseases (Fig. 1). This view holds that bacteria from dental plaque
enter the blood stream through discontinuities of the oral tissues (ulcerated
sulcular epithelium; infected root canals) and travel through the blood to
cause infection at a distant site. It may also be possible that PD bacteria
Fig. 1. Recent evidence suggests the possibility that poor oral health, particularly PD, may
influence the initiation or the progression of several important and prevalent systemic diseases
stimulate the release of pro-inflammatory cytokines or acute-phase proteins
at a distant site (eg, liver, pancreas, skeleton, arteries). These products may
initiate or intensify a disease process (eg, atherosclerosis, diabetes). Bacteria
may also travel from oral sites to other mucosal surfaces (lung, gut) to cause
inflammation and infection (pneumonia, gastric ulcers). This article reviews
recent studies that address the association of oral infection with systemic
conditions such as atherosclerosis, pulmonary disease, and pregnancy
Association of periodontal disease with atherosclerosis, cardiovascular
disease, and stroke
Most cases of coronary heart disease and cerebrovascular disease (stroke)
result from atherosclerosis, an aberrant biologic process that causes
narrowing of arteries due to deposition of cholesterol and cholesterol esters
on the surface of blood vessel walls. The cholesterol-rich plaques also con-
tain cells, including fibroblasts and immune cells . Not all individuals
suffer atherosclerosis equally; some individuals have higher risk for this
disease process than others. Well-recognized risk factors for atherosclerosis
include chronically elevated blood levels of cholesterol and triglyceride,
hypertension, diabetes mellitus, and cigarette smoking.
Cholesterol, a lipid necessary for normal cell function, is synthesized in the
receptor-mediated endocytosis. Cholesterol uptake is reduced in some people
and excess cholesterol accumulates in the blood to eventually form athero-
sclerotic plaques. If these plaques occlude blood flow in brain arteries, the
result can be stroke; if they occur in coronary arteries, it can lead to myo-
A recent and growing literature implicates chronic inflammation, in-
fection, and possibly autoimmunity in the pathogenesis of atherosclerosis
. Arterial inflammation may be locally increased by lipid imbalances,
hemodynamic stress, and immune reactions directed against the vascular
wall, eventually leading to the formation of complicated atherosclerotic
lesions . This inflammation-mediated damage may initiate or contribute to
the progression of the atherosclerotic plaque. A number of infectious agents
appear to be associated with atherosclerosis, and alterations in the immune
response may compromise clearance of such agents from these plaques. One
of the best studied of these association’s involves Chlamydia pneumoniae, an
intracellular bacterium that commonly causes pneumonia and milder re-
spiratory tract infections. C pneumoniae DNA and proteins have been de-
tected in arteries of patients with giant cell arteritis  and in endarterectomy
samples . Elevated levels of antibody against C pneumoniae are found in
patients with coronary heart disease compared with controls .
Other chronic infections such as PD have also been implicated as inciting
agents for cardiovascular inflammation and disease. The first article of the
recent era to report a relationship between PD and cardiovascular disease
was a case-control study published by Simonka et al  in 1988. These
researchers age matched 211 men with previous heart attack to 336 patients
without heart attack. They found significantly more evidence of PD and
need for periodontal surgery in patients over 50 years old with heart attack
compared with those without heart attack. Since then, several additional
case-control studies on this subject have been published [10–13]. Of these, all
except one  reported a positive association between indicators of poor
dental health and outcomes of atherosclerosis (cerebrovascular disease). The
one study reporting the absence of a positive association was of very elderly
subjects. It is possible that the cumulative effects of various disease processes
that contribute to atherosclerosis in the elderly could have obscured the
effect of oral disease on these processes. Another recent study determined
whether a combination of clinical variables in a functional risk diagram
enhanced the ability to differentiate between subjects with or without an
immediate history of acute myocardial infarction . Eighty-eight subjects
with recent acute myocardial infarction and 80 matched control subjects
with no history of acute myocardial infarction were compared. It was found
that alveolar bone loss R4.0 mm was significantly greater in subjects with
acute myocardial infarction. Taken together, these studies support a positive
association between PD and the prevalence of cardiovascular events.
Stimulated by the early case-control studies, a number of cross-sectional
studies provided further evidence in support of the association between PD
with cerebrovascular disease, after controlling for other cardiovascular risk
factors, particularly smoking [15–23]. As an example, Table 1 demonstrates
the moderate risk for a history of heart attack in subjects with periodontal
attachment loss . In addition, several other studies have shown a positive
association between PD and stroke [18,24–26], and one study associated PD
with peripheral vascular disease, another sequela of atherosclerosis .
It has been suggested that the association observed between atheroscle-
rosis-induced disease and PD may be the result of etiologic factors common
Risk of heart attack in subjects with various levels of periodontal attachment loss
Sites with periodontal
attachment loss R3 mm (%)
Odds ratio (95% confidence interval) for yes versus no:
‘‘Has your doctor ever told you that you had a heart attack?’’
Data from Arbes SJ Jr, Slade GD, Beck JD. Association between extent of periodontal
attachment loss and self-reported history of heart attack: an analysis of NHANES III data.
J Dent Res 1999;78(12):1779.
to both disease processes, such as lifestyle practices like cigarette smoking,
and therefore coincidental [28–31]. Determining the role of lifestyle factors
independent from the effect of PD on atherosclerosis requires the conduct of
large prospective longitudinal epidemiologic studies of never smokers in
addition to large randomized controlled clinical trials to determine whether
periodontal intervention prevents the initiation or progression of athero-
Because of the great heterogeneity in methodologies used between studies
in assessment of oral disease, it is difficult to directly compare the results of
one study to others. Nevertheless, the available data suggest that PD is
modestly associated with atherosclerosis-induced diseases such as cardio-
vascular disease, stroke, and peripheral vascular disease.
Association of periodontal disease with pneumonia
Pneumonia is defined as an inflammation of the lungs caused by fungal,
cavity and pharyngeal mucosa by potential respiratory pathogens, aspiration
of the colonized pathogens into the lower airway, and failure of defense
of oral secretions, a somewhat frequent event even in normal, healthy in-
frequent in patients with altered consciousness . Other conditions
predisposing to aberrant aspiration include stroke, Parkinson’s disease,
alcohol abuse, and sedative use . Multiple defense mechanisms operate
within the healthy respiratory tract to eliminate aspirated material from the
such as malnutrition, smoking, chronic obstructive pulmonary disease
(COPD), diabetes, corticosteroid use, and endotracheal or nasogastric
Bacterial pneumonia can be classified as either community-acquired
pneumonia or hospital-acquired (nosocomial) pneumonia. Up to 5.6 million
cases of community-acquired pneumonia occur annually in the United States
 and the overall mortality rate is !5%. Among the community-acquired
as 40% in those admitted to ICUs. Community-acquired pneumonia is
typically caused by aspiration of bacteria that normally reside in the
oropharynx, such as Streptococcus pneumoniae, Haemophilus influenzae, and
Nosocomial pneumonia occurs in institutionalized subjects such as
hospitalized patients admitted to ICUs and nursing home patients.
Nosocomial pneumonia accounts for 10% to 15% of all hospital-acquired
infections, with a mortality rate as high as 25%. In contrast to community-
including species such as Staphylococcus aureus and gram-negative bacteria
Escherichia coli, and Enterobacter spp.
Several studies have demonstrated that the oral cavity may serve as
a reservoir for respiratory pathogen colonization and infection. One of the
first studies to document this finding  compared oral hygiene and the rate
of dental plaque or buccal mucosal colonization by potential respiratory
pathogens in ICU subjects with age- and gender-matched outpatients at
their initial visit to a dental school clinic. The ICU patients demonstrated
significantly more plaque than the control subjects. Colonization of dental
plaque or oral mucosa by potential respiratory pathogens was found in 65%
of the ICU patients but in only 16% of the preventive dentistry clinic
patients. The potential respiratory pathogens identified in the ICU patients
included Staphylococcus aureus, Pseudomonas aeruginosa, and a number of
different enteric gram-negative bacteria. Several patients had oropharyngeal
colonization by two or more potential pathogens. Oral colonization by
respiratory pathogens was associated with antibiotic usage.
This observation was also noted in a subsequent study  in which an
association was noted between poor oral health status (including dental
caries, dental plaque, and colonization of dental plaque by respiratory
pathogens) and onset on pneumonia in 57 ICU patients. The relative risk for
pneumonia was increased 9.6-fold when the dental plaque was colonized by
a pathogen between days 0 and 5 followingICU admission. Furthermore, the
pathogen causing pneumonia was noted to first colonize the dental plaque.
Recent studies have also assessed the relationship between oral health,
respiratory pathogen oral colonization, and pneumonia in nursing home
populations. For example, 134 geriatric patients (34 inpatients, 53 long-term
care patients, and 47 outpatients) were assessed for oral conditions such as
xerostomia, caries, PD, and salivary IgA levels . These subjects were also
assessed for a diagnosis of aspiration pneumonia based on body temperature
O2?C above baseline, clinical deterioration, elevated white blood cell count,
and19%ofdentatelong-term carepatients developed aspiration pneumonia,
whereas only 5% edentulous patients developed pneumonia, suggesting that
teeth may serve as a reservoir of respiratory pathogen colonization in these
subjects. A study of the relationship of oral health status and lung infection
in 302 nursing home residents was reported by Mojon et al  who found an
increased risk of respiratory tract infection in subjects with teeth in
comparison to edentulous subjects. Another study  of 189 elderly male
outpatients, hospital inpatients, and nursing-home patients over 60 years of
age found significant associations between pneumonia and the number of
decayed teeth, the frequency of brushing teeth, and being dependent for oral
care. A subsequent study found the dental plaque of 12 of 28 (43%) elderly
patients recently admitted to a hospital were colonized by gram-negative
a reservoir for lung infections . When 28 chronic-care nursing home
matched for gender and race, it was found that the dental plaque scores were
significantly higher in the nursing home residents than in the outpatient
controls (Fig. 2). In addition, 14.3% of chronic-care subjects showed dental
plaque colonization with respiratory pathogens compared with 0% of the
control dental outpatients .
Finally, 358 veterans aged 55 years and older were found to have an
elevated risk of aspiration pneumonia if they had teeth and (1) if their teeth
were carious, (2) when the periodontopathogen Porphyromonas gingivalis
was detected in dental plaque, and (3) when the respiratory pathogen
Staphylococcus aureus was detected in saliva .
Oral intervention trials to prevent pneumonia
The findings reviewed in the previous section suggest that the oral cavity
may serve as a reservoir for lower airway infection, especially in in-
stitutionalized subjects. This observation further suggests that improved
oral hygiene could reduce or eliminate respiratory pathogens from the mouth
Fig. 2. (Upper panel) Example of oral hygiene status of elderly subject presenting for the first
time to a dental school clinic. (Lower panel) Example of oral hygiene status of elderly nursing
home resident. Subjects enrolled in the study are described in Russell et al . (Courtesy of
S. Russell, DDS, MPH, New York, NY.)
and thus prevent the onset of serious respiratory infection in vulnerable
subjects. Although oral hygiene measures are a component of nursing care,
implementation of such measures is difficult in some patients such as those
who are orally intubated. Several intervention studies show, however, that
improved oral hygiene measures can reduce the incidence of ventilator-
associated pneumonia (VAP).
Several approaches have been taken to reduce the numbers of bacterial
pathogens in the oral cavity of subjects with high risk of pneumonia. One
approach uses topical nonabsorbable antibiotics (eg, 150 mg polymyxin B
sulfate, 1 g neomycin sulfate, 1 g vancomycin hydrochloride in 60 mL of 5%
dextrose) . The 25 ICU test patients had the antibiotic mixture applied to
the retropharynx every 24 hours and then swallowed. These patients were
compared with 27 in a placebo group who received topical 5% dextrose.
Application of the antibiotic paste reduced tracheobronchial colonization
by gram-negative respiratory pathogens and Staphylococcus aureus and
reduced the rate of pneumonia fivefold compared with the control
The effectiveness of oral topical chlorhexidine gluconate to reduce
pneumonia was examined in mechanically ventilated patients following
cardiac surgery . Patients were randomly assigned to two groups: one
received the vehicle alone (placebo) applied in a similar fashion. Patients in
bothgroups alsoreceived standardoralcareaccordingtotheICU’sprotocol.
The topical chlorhexidine gluconate treatment reduced the incidence of total
respiratory tract infections by 69% (P ! 0.05) compared with placebo
(Table 2). This intervention also significantly reduced total mortality (1.16%
versus 5.56%) and the need for systemic antibiotics.
In another study, a test group of 30 patients received 0.2% chlorhexidine
gel three times a day , whereas a similar-sized control group received an
oral rinse with bicarbonate isotonic serum and oropharyngeal aspiration
four times a day. The results showed that oral antiseptic decontamination
Reduction of nosocomial respiratory infection by the use of oral 0.12% chlorhexidine gluconate
Experimental groupPlacebo control group
No. of patients
No. of respiratory infections
No. of cases in which gram-negative
bacteria was cause of pneumonia
*P ! 0.05.
Data from DeRiso AJ II, Ladowski JS, Dillon TA, et al. Chlorhexidine gluconate 0.12%
oral rinse reduces the incidence of total nosocomial respiratory infection and nonprophylactic
systemic antibiotic use in patients undergoing heart surgery. Chest 1996;109(6):1558.
with 0.2% chlorhexidine gel significantly reduced the incidence of nos-
A subsequent prospective study  provides additional evidence that
oral topical antimicrobial agents reduce the risk of pneumonia. Three
groups of patients admitted to three ICUs over a 2-year period were enrolled
in this study. The test group of 87 patients received a 2% gentamycin/
colostin/vancomycin paste every 6 hours. A placebo group of 78 patients
received Orabase without antibiotics. A control group of 61 patients
received no treatment. The topical antibiotic treatment prevented acquired
oropharyngeal colonization (10% versus 59% in the placebo group and
63% in the control group, P!0.0001 and P!0.00001, respectively) and the
incidence of VAP (10% versus 31% in the placebo group and 23% in the
control group, P ¼ 0.001 and P ¼ 0.04, respectively).
There have also been several preliminary trials testing oral hygiene
interventions to reduce the incidence of pneumonia in nursing home subjects
[48,49]. For example, 366 elderly residents from 11 nursing homes were
studied; a test group of 184 subjects received supervised toothbrushing after
each meal, and topical povidone iodine 1% once a day; the control group of
182 subjects received no intervention. A 2-year follow-up found that the
relative risk of pneumonia in the group with no active oral care was 67%
greater compared with the oral care group (P ¼ 0.04).
Association of periodontal disease with chronic obstructive pulmonary
Poor oral hygiene and PD also may be associated with other respiratory
diseases such as COPD, a very prevalent chronic disease . COPD is
defined as a spectrum of conditions characterized by chronic obstruction to
airflow due to emphysema and/or chronic bronchitis. Although no study has
established that PD influences the pathophysiology of COPD, several
studies have demonstrated a statistical association between the two con-
ditions. For example, an analysis of 23,808 community-dwelling individuals
enrolled in the First National Health and Nutrition Examination Survey
data  found 365 individuals reporting a respiratory condition confirmed
by a study physician. These subjects were categorized as having a confirmed
chronic respiratory disease (chronic bronchitis or emphysema), acute
respiratory disease (influenza, pneumonia, acute bronchitis), or not having
a respiratory disease. Logistic regression analysis revealed that poor oral
hygiene and smoking status were statistically associated with chronic
respiratory disease. Additional data in support of this concept found that
PD (measured as alveolar bone loss assessed from periapical radiographs)
was an independent risk factor for COPD in adult men enrolled in the VA
Normative Aging study .
To verify these results, a cross-sectional, retrospective analysis of data
from the Third National Health and Nutrition Examination Survey
(NHANES III) was performed. The NHANES III documented the general
health and nutritional status of randomly selected United States subjects
from 1988 to 1994 . Of 13,792 subjects R20 years of age having at least
six natural teeth, those with a history of bronchitis or emphysema were
considered together as having COPD. Subjects with COPD had, on average,
more periodontal attachment loss (mean clinical attachment level [CAL]
1.48 G 1.35) than those without COPD (mean CAL 1.17 G 1.09). Taking
into account a variety of risk factors common to COPD and PD (eg, gender,
age, race, education, income, dental treatment history, alcohol consump-
tion, diabetes status, smoking status), logistic regression analysis found
risk of COPD to be significantly elevated when the mean attachment loss
was R2.0 mm compared with periodontally healthy individuals (mean
attachment loss !2.0 mm; odds ratio 1.35; 95% confidence interval [CI]:
1.07–1.71). In addition, the trend was noted that lung function appeared to
diminish as the amount of attachment loss increased. No such trend was
apparent when gingival bleeding was considered.
A more recent study evaluated the role of smoking in a possible
relationship between PD and COPD . The authors re-evaluated 7625
NHANES III participants R30 years of age who received a spirometric
examination. After adjustment for potential confounders, no statistically
significant association between PD and COPD was found among former
smokers or nonsmokers. Current smokers with R4 mm mean loss of
attachment, however, had an odds ratio of 3.71 (95% CI: 1.74, 7.89) for
relationship between PD and COPD. Because smoking is important in the
etiology of PD and COPD, it is difficult to separate the contribution of PD
and smoking to the etiology of COPD. It is likely that smoking is the major
by way of several pathways .
In summary, oral colonization by respiratory pathogens appears to be
a risk factor for lung infection in high-risk subjects. Oral interventions that
improve oral hygiene and possibly reduce oral inflammation may prove to
be a simple, inexpensive, and effective means to lower risk of pneumonia in
institutionalized populations. Further studies are required to verify the
apparent association between PD and COPD.
Adverse pregnancy outcomes and periodontal disease
Preterm low birth weight (PTLBW) continues to be a significant cause of
infant morbidity and mortality. PTLBW is associated with elevated risk for
mortality in the first year of life, for developmental problems in childhood,
and for several diseases in adulthood. Most perinatal deaths occur in infants
born prematurely, especially in infants delivered before 32 weeks’ gestation
. The prevalence of preterm birth varies from 6% to 15% of all deliveries
depending on the population studied in developed countries, and the
prevalence has risen in recent years. Risk factors that appear to contribute
to adverse pregnancy outcomes include low socioeconomic status, race,
multiple births, the mother’s age, history of a preterm birth or delivery of
a low birth weight infant, parity, past reproductive history, drug and alcohol
abuse, and systemic maternal infection. Bacterial vaginosis is a clinical
condition caused by overgrowth of the vaginal mucosa by certain aerobic
and anaerobic bacteria. Several studies have shown that the onset of bacte-
rial vaginosis during pregnancy is associated with spontaneous abortion,
preterm labor, premature birth, premature rupture of the membranes, am-
niotic fluid infection, postpartum endometriosis, and postcesarean wound
It is also possible that infectious processes occurring elsewhere in the body
may contribute to neonatal morbidity and mortality. It has been suggested
that PD may be one such infection. The first report of a possible association
between PTLBW and PD examined 93 mothers who gave birth to preterm or
low birth weight children . These mothers were matched with 31 control
motherswho gavebirthto children ofnormal term andbirthweight. PTLBW
was defined as birth weight less than 2500 g, spontaneous abortion before 12
weeks gestation, preterm labor requiring medical intervention, or premature
rupture of the membranes before 36 weeks of gestational age of birth, with
gestational age less than 36 weeks. It was found that the risk of PTLBW was
attachment loss) compared with mothers without evidence of PD. Several
the contention that women with PD have a greater risk of having preterm or
low birth weight children [56–60].
In contrast, a case-control study of 236 mothers with PTLBW and 507
normal-birth controls  found no association between maternal PD and
increased risk of PTLBW. In fact, these investigators found that increasing
mean pocket depth at the time of delivery was associated with a reduction in
the risk of PTLBW. Other studies since published have not supported this
These conflicting results demonstrate the need for large-scale, multicenter
randomized trials of PD treatment to establish causal relationships between
periodontal status and PTLBW. Recently, several studies have been
published that have tested the effect of periodontal intervention to reduce
adverse pregnancy outcomes [65,66]. One study examined 200 pregnant
women who received periodontal treatment before 28 weeks of gestation.
These women were compared with 200 mothers who received periodontal
treatment after delivery (Table 3). Although this trial was randomized, it was
not double blinded. Oral intervention included plaque control instruction,
scaling, and root planing, with oral rinsing once a day. It was found that
periodontal therapy before 28 weeks’ gestation significantly reduced the rate
of PTLBW in women with PD. Another study  compared 74 subjects who
received mechanical dental plaque control instructions and scaling and root
planing of all teeth compared with 90 control subjects who did not receive
periodontal intervention. Significant reduction in the incidence of PTLBW
was found in women who received periodontal therapy during pregnancy.
These preliminary intervention studies provide provocative evidence that
periodontal therapy before 28 weeks of gestation may significantly reduce the
incidence of PTLBW children.
Diabetes mellitus (diabetes) is a metabolic derangement characterized by
impairment in glucose use. Diabetes occurs in two major forms: type 1
diabetes is the result of a reduction in or the elimination of insulin
production by beta cells in the pancreas. Insulin functions through
interaction with muscle and liver cells to regulate glucose metabolism.
Reduced insulin production is most often the result of destruction of the
beta cells, probably due to autoimmune or viral disease. Individuals with
type 1 diabetes require daily insulin supplementation to properly regulate
glucose use. Insulin delivery is usually by injection, although progress has
been made with the use of insulin pumps and pancreatic transplantation that
provides an endogenous source of insulin.
Type 2 diabetes is characterized by a deficient response to insulin by
target cells, although insulin production is typically normal or even
enhanced in these individuals. This impairment may be due to changes in
the structure or number of the cell receptors for insulin. This form of
diabetes is by far the most common (estimated to be 85%–90% of all
diabetes). Taken together, type 1 and 2 diabetes now appear to occur in
epidemic proportions, with 5% to 10% of all Americans having some form
of the disease. Recent studies suggest that the number of cases of diabetes is
increasing each year, probably related to the concomitant increase in obesity
in the population.
Incidence of preterm births, low birth weight, and preterm/low birth weight in treatment and
Treatment group (N ¼ 163)
Control group (N ¼ 188)
Low birth weight
Preterm/low birth weight
Treatment consisted of plaque control instructions, rinse once a day with 0.12%
chlorhexidine, scaling, and root planing performed under local anesthesia. The control group
subjects received no intervention.
Modified from Lopez NJ, Smith PC, Gutierrez J. Periodontal therapy may reduce the risk of
preterm low birth weight in women with periodontal disease: a randomized controlled trial.
J Periodontol 2002;73(8):916.
Diabetes is a serious medical condition, with numerous acute and chronic
complications. The complications of diabetes are related to chronic
elevation of blood glucose levels in peripheral blood (hyperglycemia). One
effect of hyperglycemia is the formation of advanced glycation end products
(AGEs), the products of nonenzymatic glycation/oxidation of proteins/
lipids that accumulate in the blood vessel wall . These AGEs are
monitored as the concentration of glycated hemoglobin (HbA1c) in the
blood. These molecules bind to the receptor for AGE (RAGE). This in-
teraction leads to recruitment of inflammatory cells and their activation to
stimulate inflammatory pathways that exacerbate atherosclerosis and other
Over time, several serious side effects can occur as the result of AGE–
RAGE interactions, including so-called ‘‘macrovascular’’ complications
such as coronary artery disease, cerebrovascular disease (stroke), and
peripheral vascular disease. Microvascular complications include retinopa-
thy, nephropathy, and neuropathy. Detailed descriptions of the clinical signs
and symptoms, complications, and treatment are beyond the scope of the
Diabetes also seems to impact fibroblast and collagen metabolism.
Hyperglycemia has been associated with reduced cellular proliferation and re-
duced collagen synthesis [69,70]. Hyperglycemia could have untoward effects
on wound healing, which is essential in the response to periodontal therapy.
It has been known for several decades that persons with diabetes tend
to have more serious PD than nondiabetics. Numerous studies have
documented that diabetics show more severe pocket depths, alveolar
bone loss, frequent abscess formation, and poor healing following therapy
than nondiabetics . Studies of Pima Native Americans, who have
a very high rate of diabetes , show a higher prevalence and incidence of
periodontal attachment loss and alveolar bone loss than control popu-
A recent study found a relationship between periodontitis and glucose
tolerance status . Patients with deep periodontal pockets (defined as
having a mean pocket depth O2.0 mm) were significantly associated with
having impaired glucose tolerance and diabetes compared with subjects with
shallow pockets (!1.3 mm). Subjects with normal glucose tolerance at
baseline and who subsequently developed impaired glucose tolerance were
significantly more likely to have deep pockets.
The mechanisms responsible for more aggressive periodontitis in diabetics
may involve the same mechanisms involved in chronic complications of
diabetes. For example, diabetic mice infected with the human periodontal
pathogen Porphyromonas gingivalis were treated with soluble RAGE .
Soluble RAGE binds ligand and blocks interaction with and activation of
cell-surface RAGE. Blockade of RAGE diminished alveolar bone loss, with
decreased generation of tumor necrosis factor a and interleukin 6 in gingival
tissue and decreased levels of matrix metalloproteinases.
In addition to the finding that individuals with diabetes have a greater
risk of PD, recent studies have also suggested that subjects with PD are
more likely to have poor glycemic control than diabetics without PD.
Infections such as periodontitis may stimulate proinflammatory cytokine
synthesis to amplify the production of AGEs in diabetics . Thus, control
of chronic periodontal infection may contribute to long-term glycemic
control. For example, in one study, 113 Native Americans (81 female and 32
male subjects) with PD and type 2 diabetes were randomized into five
treatment groups . Periodontal treatment included ultrasonic scaling and
curettage combined with one of the following antimicrobial regimens: (1)
topical water and systemic doxycycline, 100 mg, for 2 weeks; (2) topical
0.12% chlorhexidine and systemic doxycycline, 100 mg, for 2 weeks; (3)
topical povidone-iodine and systemic doxycycline, 100 mg, for 2 weeks; (4)
topical 0.12% chlorhexidine and placebo; and (5) topical water and placebo
(control group). The doxycycline-treated groups showed the greatest
reduction in probing depth and subgingival Porphyromonas gingivalis
compared with the control group. In addition, all three groups receiving
systemic doxycycline showed significant reductions (P%0.04) in mean
HbA1c at 3 months, reaching nearly 10% from the pretreatment value. It
was unclear from this study what role scaling alone would play in reducing
HbA1c in diabetics. In a more recent study, subjects with type 2 diabetes
with periodontitis were randomly divided into two groups . Group 1 (15
subjects) received full-mouth scaling and root planing plus amoxicillin/
clavulanic acid, 875 mg. The second group (15 patients) received only full-
mouth scaling and root planing. Following therapy, both groups showed
reduction in probing depths and reduced levels of HbA1c values after the 3
months; however, the reduction in HbA1c values was statistically significant
only for group 2.
A number of studies suggest that PD is associated with diseases resulting
from atherosclerosis, lung diseases such as pneumonia and COPD, and
adverse pregnancy outcomes. Presently, the data must be regarded as pre-
liminary. Additional large-scale longitudinal epidemiologic and interven-
tional studies are necessary to validate these associations and to determine
whether the associations are causal.
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