Periodontology 2000, Vol.

25, 2001, 2136

Printed in Denmark All rights reserved

Copyright C Munksgaard 2001

PERIODONTOLOGY 2000
ISSN 0906-6713

Relationship between periodontal

disease and systemic health
R AUL I . G ARCIA, M ICHELLE M . H ENSHAW & E LIZ ABETH A . K RALL
Extraordinary progress is being made in understanding the relationship between periodontal disease
and systemic health. Periodontitis, one of the oldest
and most common diseases of humans, was once
generally believed to be an inevitable consequence
of aging. However, we have learned over time that
not all people, nor all populations, are at equal risk
of developing periodontitis. An increasing body of
epidemiological and experimental work has helped
to identify specific risk factors and risk indicators,
permitting better understanding of what makes an
individual more susceptible to periodontal disease
(20). This new knowledge gives increasing emphasis
to the important role that systemic factors, diseases,
and conditions may play in the causation and progression of periodontal disease. Dentistry has also
become more cognizant of the extent to which behavioral factors play a role in risk. One goal of such
investigations is that they may enable us to better
identify individuals susceptible to periodontal disease in order to more effectively prevent and treat
the disease.
It is now becoming widely recognized that certain
systemic diseases, such as osteoporosis, diabetes
and immune disorders, may increase the risk for
periodontal disease. However, until relatively recently, less attention has been devoted to exploring
the role that chronic oral diseases may have on systemic health. The hypothesis that oral conditions,
such as periodontal infections, may be risk factors
or indicators for important medical outcomes represents a paradigm shift in thinking about causality
and the directionality of oral and systemic associations (64).
This paradigm shift is encapsulated by the new
term periodontal medicine, which refers to the perspective that periodontal disease is interrelated with
systemic health in important ways. The possibility
that morbidity and mortality from systemic diseases
may be reduced by improving periodontal health
makes it imperative that this relationship be exam-

ined more closely. When one considers that periodontal disease is a chronic infection that produces
a local and systemic host response, as well as a
source of bacteremia, it is not surprising that there
is increasing evidence to support this hypothesis. To
date, evidence has appeared indicating that periodontal disease may adversely increase risk of arteriosclerosis, myocardial infarction, stroke, premature births and other systemic health outcomes.

Historical overview
The concept that oral infections, such as in periodontitis, can adversely affect systemic health is not
new. At the turn of the last century, a theory of focal
infection developed that proposed that local foci
of infection were responsible for the initiation and
progression of various inflammatory conditions,
such as arthritis, appendicitis and peptic ulcers (32).
The essence of this theory was that the products of
a local infection in one part of the body could adversely affect distant target organs. During the early
twentieth century, many extreme treatments were
developed based on the focal infection theory. For
example, there was a widespread practice of socalled preventive or therapeutic edentulation, including extraction of otherwise healthy teeth, in
attempts to treat or prevent various systemic diseases (71). However, the underlying rationale of the
focal infection theory was not implausible, the supposition being that microorganisms or their products can enter the systemic circulation and thereby
affect other sites. For example, the accepted mechanism of the causation of subacute bacterial endocarditis may be considered an example of a focal
infection having dire systemic consequences. During an episode of bacteremia, circulating pathogens
may adhere to and colonize damaged or otherwise
receptive endocardial surfaces, leading to subacute
bacterial endocarditis. In the case of oral sources of

21

Garcia et al.

infection, such types of transient bacteremia are well

documented and may be triggered by dental procedures, toothbrushing and even routine mastication. While streptococci are most commonly associated with subacute bacterial endocarditis, a number
of gram-negative periodontal flora have also been
isolated from infected heart valves. As various dental
procedures are associated with bacteremia, it has become the standard of care to administer antibiotics
prophylactically to individuals susceptible to subacute bacterial endocarditis to prevent potential
colonization of vulnerable cardiac tissue by oral
pathogens and subsequent development of subacute
bacterial endocarditis. However, it is important to
note that the role of oral infection in subacute bacterial endocarditis remains controversial, as does the
effectiveness of antibiotic prophylaxis (79).

An evidence-based approach to
oral-systemic relationships
A significant recent advance in health care has been
the movement toward a model of evidence-based
practice, which is also gaining attention in dentistry
(51). An important component of the evidencebased approach is risk assessment, involving the
classification of an individuals probability of acquiring a disease based on scientifically determined risk
factors. Such an assessment of risk could provide important information to guide clinical decisions regarding prevention and treatment of disease in individual patients. The concept of universal susceptibility to periodontal disease has been discarded, as it
has become clear that susceptibility differs widely
among people and that the disease is not evenly distributed throughout populations. Increasing attention is now aimed at identifying the specific attributes and exposures associated with increased risk
of developing periodontal disease and, in turn, with
the systemic consequences of periodontitis.
The multi-factorial causation of periodontal disease, coupled with the large number of risk factors
and risk indicators that may impact the severity and
extent of disease, makes the determination of pathogenesis difficult. A risk factor is commonly defined
as a particular characteristic, behavioral aspect or
environmental exposure that is associated with disease occurrence. In the case of periodontal disease,
risk factors may involve the host response and
pathogenic flora and include characteristics such as
age, gender, education, and frequency of dental

22

visits. To complicate further the quest to elucidate a

comprehensive causal model for periodontal disease, certain important indicators of disease may not
be causally related. For example, increasing age does
not in itself cause disease, but older individuals may
have more attachment loss due to multiple periods
of disease throughout their lives.
Currently, the most commonly used methods of assessing periodontal disease in populations typically
involve measures of clinical attachment loss or radiographic alveolar bone loss. However, due to the
chronic and episodic nature of periodontal disease,
such assessments necessarily measure the cumulative effects of the disease process over time, rather
than the current disease activity. Since there is currently no generally accepted assessment tool to reliably measure active periodontal disease, the value of
longitudinal studies become apparent as they permit
assessments of change over time. Such longitudinal
studies are of particular value in evaluating potential
causal relationships, in large part as they allow examination of the temporal sequence of the appearance of
risk factors and the subsequent occurrence of disease
and its progression. However, the strongest evidence
for evaluating the role of potential risk factors most
often comes from experimental studies, such as a randomized controlled trial in which modification of the
risk factor is randomly assigned to a test group as
compared to a control group that receives a placebo
intervention, for example.

Health-related quality of life

In understanding the potential effects of periodontal
disease on systemic health, it is also important to consider a broader construct of health beyond that defined by just biomedical status. Of importance is also
the patients functional status and their ability to carry
out the activities of daily life. The concept of healthrelated quality of life is intended to encompass a multi-dimensional view of health that includes both traditional clinician-based assessments of health status
as well as an individuals own subjective assessment
of its impact on his or her well-being and daily functioning (78). The value of health-related quality of life
measures is that they may provide a more comprehensive assessment of an individuals overall wellbeing and also aid in more fully determining the effectiveness of various interventions.
This is an emerging area of research in dentistry,
with growing literature on oral health-related quality
of life. Several measures of the impact of oral con-

Relationship between periodontal disease and systemic health

ditions on daily functioning have already been developed and tested. For example, the Geriatric Oral
Health Assessment Index was specifically designed
to assess the effect of oral diseases in elderly people
(2), the Oral Health Impact Profile was designed to
comprehensively assess the social and physiological
effects of multiple oral conditions (75), and although
not designed as a specific assessment tool, the selfperceived impact of dental disease was measured as
part of the Rand Health Insurance Experiment.
Using Health Insurance Experiment data, Gooch et
al. (23) showed that self-reported oral health-related
quality of life was lower for participants that reported toothaches, greater numbers of decayed teeth
and more periodontal disease. Work in elderly populations has shown that having more missing teeth
was related to poor oral health-related quality of life
as measured by questionnaire assessments (2, 43).
Such findings are similar to earlier results (67, 75)
showing that periodontal status and dental symptoms were associated with perceived functional impact of oral conditions, and the latter was significantly associated with overall assessments of quality
of life, along with medical functional status and perceived physical and dental health. Such findings suggest that oral conditions, and specifically periodontal disease, are important determinants of social, psychological and physical health and
functioning. Work in this area highlights the interplay between oral and general health conditions and
underscores the impact that oral conditions may
have on an individuals quality of life.

Effects of systemic disease on the

periodontium
It has been well known for many years that various
systemic diseases such as neutropenia and other
blood dyscrasias have a profound effect on the periodontal tissues (see Pihlstrom, the next chapter in
this volume). However in recent years, other systemic diseases and conditions also have been shown
to result in increased risk for periodontal disease.
Examples include osteoporosis, renal dysfunction,
immunodeficiency diseases, environmental immunosuppression, pregnancy and diabetes.

Osteoporosis: a model systemic disease

with periodontal sequelae
Osteoporosis is a common metabolic bone disorder,
associated with aging, that results in a reduction in

bone mass and may lead to skeletal fragility and

fracture. Bone loss is also a hallmark of periodontitis,
an inflammatory disease characterized by loss of
connective tissue and alveolar bone, and is one of
the major reasons for the loss of teeth in adults.
While the pathogenesis of periodontitis and osteoporosis differ, these diseases have several risk factors
in common. These include an increased prevalence
with increasing age, smoking, and deleterious influences of diseases or medications that may interfere
with healing. Osteoporosis may, in turn, increase the
risk of periodontal disease. It has been hypothesized
that osteoporosis may cause decreased alveolar bone
density, which may in turn be more susceptible to
resorption by the effect of coexisting or subsequent
periodontal infection and inflammation. This hypothesis is borne out in experimental animal models,
which show that, although osteoporosis does not initiate periodontal disease, it may affect the course of
the disease by reducing trabecular bone mass and
bone mineral density. Several human studies have
assessed the relation between skeletal bone mineral
density and radiographic measurements of alveolar
bone height in dentate individuals. Most have reported only moderate correlations between alveolar
bone height and bone density at the forearm, spine
or femoral neck. However, in the largest study to
date (16), no significant correlations were found between loss of alveolar bone height (around molars
and premolars) and spine bone mineral density. Surrogate measures of alveolar bone loss, such as probing pocket depth and clinical attachment loss, have
also been associated with bone mineral density in
some (86, 87) but not all studies (16). It is clear that
additional longer-term studies are needed to determine the nature of the association between skeletal
bone mineral density and alveolar bone loss.
However, this association may be further elucidated in part by examining recent work carried out
on the relationship between skeletal bone mineral
density and tooth loss. There is a growing body of
evidence to suggest that the status of the extracranial
skeleton is associated with risk of tooth loss, and this
relationship is hypothesized to be based on extent of
periodontal bone loss. Cross-sectional studies have
yielded inconsistent results when investigating the
relation of tooth loss to bone mineral density. However, since cross-sectional studies essentially look
retrospectively at the reason for extraction, such a
study design is not the best suited for this purpose.
A more appropriate design is a longitudinal study,
which would follow subjects over a period of time,
measure changes in bone density prospectively and

23

Garcia et al.

accurately identify reasons for tooth loss. The results

from one such long-term study show a clear relationship between systemic bone loss and tooth
loss. In a 7-year longitudinal study of 189 women
who were not taking hormone replacement therapy,
rapid loss of bone mineral density was significantly
associated with an increased risk of additional tooth
loss (39) while controlling for a large number of
other risk factors.
Another approach to examining the possible association between tooth loss and systemic bone loss
is to study tooth retention among individuals who
undergo strategies that reduce or prevent systemic
bone loss. Several studies of postmenopausal hormone replacement therapy provide data to support
the association as clinically relevant (24, 40, 62). Additional support for this hypothesis was obtained
from the Framingham Heart Study, where an association was found between hormone replacement
therapy and increased tooth retention (40). This
study was also noteworthy, as it demonstrated a
dose-response relationship between tooth retention
and increased duration of hormone replacement
therapy. The odds of being edentulous were found
to be reduced by 6% for each 1-year increase in duration of hormone replacement therapy. Collectively,
these results suggest that postmenopausal women
who take hormone replacement therapy for the prevention or treatment of osteoporosis may have an
additional benefit of increased tooth retention, and
the findings lend support to an association between
osteoporosis and periodontal bone loss.

Renal dysfunction and periodontal health

Renal osteodystrophy and the related skeletal bone
changes are consequences of renal failure. Clinically,
children with this disorder may experience growth
retardation and frequent bone fractures. In adults,
the clinical presentation includes bending and fracture of the long bones due to a gradual softening of
bones over time. The underlying mechanism of renal
osteodystrophy is a defect in the hydroxylation of the
vitamin D precursor 25-dihydroxyvitamin D (calcidiol or hydrocholecalciferol) to 1,25-dihydroxyvitamin
D (calcitriol or dihydrocholecalciferol), a process
that normally occurs in the kidney. Since a primary
function of 1,25-dihydroxyvitamin D is to stimulate
calcium absorption from the intestine, individuals
with this disorder often experience hypocalcemia.
The hypocalcemic state results in secretion of parathyroid hormone. The increased parathyroid hormone is secondary to the imbalance in calcium and

24

phosphorous levels, and is therefore termed secondary hyperparathyroidism. The net effect of this imbalance is bone resorption, as the body tries to
maintain homeostatic balance.
The alveolar bone changes associated with renal
osteodystrophy are consistent with those seen in primary hyperparathyroidism and include generalized
loss of bone density, thinning of bone cortices and
total or partial loss of lamina dura. Individuals with
osteodystrophy may also demonstrate decreased trabeculation with a concomitant increase in medullary
space. This loss of trabeculation may continue until
the bone gives a homogeneous appearance, often
described as ground glass or chalky in appearance. Other areas may exhibit an increase in bone
density termed osteosclerosis. Although osteosclerotic lesions are well documented in the literature
(35), there is currently no demonstrated biological
mechanism to explain this finding.
The physiological imbalances and resultant osseous changes caused by chronic renal failure are
often reduced or reversed when the individuals
underlying renal disease is treated, by either dialysis
or renal transplant (34, 68). It is not known if the
same is true for reversibility of oral bone changes.
Patients on renal dialysis have been found to have
higher prevalence of periodontitis (57). It appears
likely that the decreased bone mineral density in
such patients would increase risk for progressive alveolar bone loss from subsequent periodontal infections, similar to what has been hypothesized to occur in individuals with osteoporosis. In addition,
when such individuals are being prepared for organ
transplant, it is important that they undergo a thorough dental screening and that all sources of dental
infection be removed prior to transplantation since
complications from infections can be severe and
lead to significant morbidity, including failure of the
transplanted organ (76).

Immunodeficiency and periodontal

health
The advent of human immunodeficiency virus (HIV)
infection and the improved success of organ transplantation have led to an increased number of
people living with suppressed immune systems. Oral
problems commonly occur in these patients, many
of which develop as a direct result of immunosuppression. These problems include oral infections,
hairy leukoplakia and malignant changes, drug induced gingival overgrowth, and periodontal disease.
In addition, physical and psycho-emotional stress,

Relationship between periodontal disease and systemic health

which produce well characterized neuroendocrine

and biochemical changes in experimental animals,
can also cause imbalances in the immune system.
The physiological consequences of these stress-mediated changes have been shown to have significant
adverse effects on the proper functioning of the human immune system (8).
Organ transplant patients are iatrogenically immunosuppressed by the administration of drugs such
as cyclosporin in order to reduce the chance of organ
rejection. One recognized side effect of the long-term
administration of such immunosuppressive drugs is
accumulation of excess connective tissue intraorally.
This may involve severe gingival overgrowth, most
commonly on the labial gingiva of anterior teeth, although all areas of the mouth may be affected. Although the increasing popularity of multi-drug therapy makes it difficult to categorize prevalence of druginduced gingival overgrowth, studies have shown that
approximately 30% of dentate patients medicated
with cyclosporin alone and 50% of patients medicated
with both cyclosporin and nifedipine experience clinically significant gingival overgrowth that requires
treatment (73). Such findings have been confirmed by
other clinical studies (77).
The multifactorial pathogenesis of drug-induced
gingival overgrowth is not well understood. However,
it is believed that a combination of duration of drug
therapy, level of plaque-induced inflammation, susceptibility of gingival fibroblasts and related genetic
factors may all play a pivotal role in the development
of this condition. One prospective study that examined the relationship between pre-transplant periodontitis and post-transplant gingival overgrowth
showed that there was no difference in serum drug
level or Plaque Index between individuals who experience drug-induced gingival overgrowth and
those who maintained a healthy gingival state. Moreover, all individuals who experienced severe gingival
overgrowth had evidence of hyperplasia before the
transplant. These results suggest that a hyperplastic
gingival inflammatory response is a key factor in the
post-transplant gingival overgrowth (85). Although
the exact mechanism for drug-induced gingival overgrowth is not elucidated, it is hypothesized that the
immunosuppressive drug reduces collagenase activity and connective tissue catabolism by lowering
cytosolic free calcium ions and systemic and local
folic acid concentrations. This effect, combined with
a plaque-induced inflammatory host response that
increases connective tissue production in the periodontium, is thought to produce drug-induced gingival overgrowth. However, the clinical importance

of the latter mechanism is unclear since many other

drugs administered to immunosuppress these patients also result in suppression of the host inflammatory response (91), and other studies have not
found an association between plaque level and druginduced gingival overgrowth (73). Since improving
oral hygiene alone does not appear to prevent the
development or recurrence of gingival overgrowth in
the susceptible patient, prevention and treatment of
this unwanted side effect remains challenging. Although alternative immunosuppressive drugs are
currently available that do not produce drug-induced gingival overgrowth, their cost is often prohibitive (73). It is unclear if these newer drugs will
replace existing immunosuppressive drugs. Therefore, recent work (89) that demonstrated a protective
effect against drug-induced gingival overgrowth by
use of prednisolone and azathioprine administration
along with cyclosporin and nifedipine is of great interest.

Immunodeficiency diseases
Acquired immunodeficiency syndrome (AIDS) is the
end stage of infection with HIV. This disease is characterized by a reduction in the cell-mediated immune response. A consequence of this systemic immunosuppression is an increased propensity to develop fungal, viral and bacterial infections, as well as
specific malignancies that can dramatically affect
the health of the infected individual. First described
in the 1980s, periodontal manifestations of HIV infection include linear gingival erythema (formerly
known as HIV-associated gingivitis), necrotizing ulcerative gingivitis, and necrotizing ulcerative periodontitis (formerly known as HIV-associated periodontitis). Recent work suggests these conditions
may not be as prevalent as originally reported. One
possible explanation for the variance is that selection bias occurred in the earlier studies that used
samples of individuals who were seeking treatment
for oral problems (65). More recent studies have reported that necrotizing ulcerative gingivitis occurs in
less than 10% of HIV-infected individuals, while necrotizing ulcerative periodontitis occurs in less than
5% of infected individuals and usually occurred in
individuals with severe immunosuppression (22).
When clinical attachment loss or radiographic alveolar bone loss measures have been utilized, in
either cross-sectional or longitudinal studies, there
typically have been associations noted between HIV
infection and risk of periodontal disease. For example, Yeung et al. (92) reported that, over an 18-

25

Garcia et al.

month period, the progression of periodontal disease was more pronounced in HIV-infected individuals. However, some work has also noted that HIVinfected individuals who are non-symptomatic or
mildly symptomatic may have no increased prevalence of periodontal disease (14). Such results suggest that there may be an important association between the level of immunosuppression and subsequent risk of periodontal disease (80).
Much work on the pathogenesis of HIV periodontitis has focused on components of subgingival
plaque. Most studies have found that, in general, the
subgingival species are similar to those found in
non-HIV-infected individuals with periodontal disease. However, several interesting differences have
emerged in recent work. Zambon et al. (93) found
that occasionally the subgingival plaque of HIV-infected individuals contained organisms not generally
associated with adult periodontitis, including Enterococcus faecalis, Clostridium species and Klebsiella
pneumoniae. In addition, they detected Candida albicans in 62% of the patients studied, which was a
much higher prevalence than what was found in the
non-HIV-infected individuals. Lamster et al. (41) also
found an increased sub-gingival colonization by
Candida albicans, an apparent association of Candida and linear gingival erythema, and a diminished
local host response to microbial challenge associated
with HIV infection.

Environmental immunosuppression
As many biological and behavioral risk factors in the
pathogenesis of periodontal disease have been identified, there is increasing interest being focused on
the important role of psychosocial factors. Most human studies have found significant associations between certain psychosocial factors and chronic inflammatory periodontal disease (12). In fact, the
concept that psychoemotional stress may contribute
to the development of periodontal pathology is well
established and accepted in the case of acute necrotizing ulcerative gingivitis. More recently, the role of
emotional/psychological stress in the causation of
more common forms of periodontal disease has
been investigated by Genco et al. (21).
Recent work has suggested an interesting association between occupational stress and periodontal
disease. A small prospective study of employed
adults found that a large proportion of the variance
in periodontal pocket depth could be accounted for
by occupational stress, together with smoking habits
and toothbrushing frequency (18). A controlled clin-

26

ical study that compared self-reported indicators of

stress and daily depression in 71 individuals with
periodontal disease and 77 controls without disease
found that people with high scores on the depression scale were almost three times more likely to
have periodontal disease (56). A 1-year follow-up of
this sample demonstrated that among individuals
rating themselves high on a depression scale at baseline, elevated serum antibodies against Bacteroides
forsythus and baseline smoking status were associated with an increased proportion of sites showing
further loss of attachment.
Recently, a case-control study matched 100 dental
patients with periodontal disease with 100 genderand age-matched periodontally healthy controls.
The results showed that periodontal disease was significantly associated with the impact of negative life
events, the number of negative life events, high level
of dental plaque, tobacco use and unemployment.
These associations remained statistically significant
after adjusting for oral health behavior and sociodemographic variables, but not tobacco smoking (9).
The authors suggested, and other studies agree, that
psychosocial factors and oral health risk behaviors
appear to cluster together as important determinants of periodontal disease.
There are several biologically plausible models to
explain the role of stress in the pathogenesis of periodontal disease. One model of chronic inflammatory
periodontal disease that includes stress as a risk factor suggests that disease occurs when the host response to infection is affected by stress-related depression of immune responsiveness. Stress activates
the central nervous system and the resultant release
of cortisol may cause a depression in the immune
response, including secretory immunoglobulin A
(IgA), IgG and neutrophil functions. This may provide the periodontal bacteria an opportunity to proliferate and possibly invade the tissues, eventually
causing a more extensive inflammatory response.
Mental and psychosocial stress can also result in activation of the autonomic nervous system and a resultant secretion of epinephrine and norepinephrine. These catecholamines then affect prostaglandins and proteases, which in turn could enhance
periodontal destruction. Unfortunately, there is no
conclusive evidence to explain the mechanism by
which stress affects periodontal disease. In order to
assess this model, longitudinal studies could be designed that will provide information on immune status, cortisol levels and periodontal status.
A plausible alternative model to explain how stress
may affect periodontal disease emphasizes the be-

Relationship between periodontal disease and systemic health

havioral changes that can accompany stress which,

in turn, may increase certain recognized periodontal
risk behaviors such as smoking, poor oral hygiene,
and poor compliance with dental care (21). Such behavior changes can occur simultaneously to the
physiological changes described previously. Therefore, when future investigations attempt to more
clearly elucidate the association between stress and
periodontal disease, these at-risk behaviors must be
evaluated to determine the extent to which they contribute to the interplay of periodontal disease and
stress.

Pregnancy and risk of periodontal disease

Although there is considerable debate about the incidence and causation of gingival changes during
pregnancy, it is generally accepted that increases in
gingival inflammation typically begin in the second
month and reach a maximal level during the eighth
month of pregnancy (28). These inflammatory
changes may lead to gingiva that appear edematous,
hyperplastic and erythematous; the changes may be
localized or generalized and are usually noted on the
marginal, gingival and interdental papilla. The anterior teeth usually show the greatest relative increase in inflammation, but the molar teeth typically
show the most severe inflammation. One-month
post partum, the gingival state may return to the
condition of the second month of pregnancy. One
proposed explanation of the causation of pregnancy
gingivitis is that changing hormonal levels cause
the gingival inflammation. The course and timing of
pregnancy gingivitis in relation to fluctuating hormone levels gives credence to this hypothesis. In the
second month of pregnancy, estrogen and progesterone levels rise coinciding with the onset of gingival
inflammation. The hormonal levels continue to rise
until the eighth month of pregnancy, when the gingival inflammation also reaches its peak. Finally, after
the eighth month of pregnancy the hormone levels
rapidly decrease, which also coincides with the reduction in gingival inflammation. One of the effects
of hormones is to increase capillary dilation, which
provides a biologically plausible mechanism by
which increased hormone levels can cause gingival
inflammation. Another area of investigation has focused on the type and amount of subgingival flora
present during pregnancy. The classic work of Kornman & Loesche (37) showed that the ratio of anaerobic to aerobic bacteria increased significantly during the thirteenth through sixteenth weeks of pregnancy and remained high until the third trimester.

They also showed that Bacteroides intermedius was

the sole bacterial species whose subgingival concentration significantly increased. At the peak of gingival
bleeding, there was a five-fold increase in this organism. Laboratory studies of B. intermedius have demonstrated a possible clinical explanation for this substantial increase. In pure culture studies, estrogen
and progesterone can substitute for menadione as
an essential growth factor for B. intermedius (38),
allowing for increased growth.
Since one role of maternal hormones during normal pregnancy is to slightly immunosuppress the
mother in order to prevent rejection of the fetus, it has
also been suggested that immune mechanisms may
play a part in the initiation of pregnancy gingivitis. Although the mechanism underlying this pregnancy
immunosuppression is not completely understood,
Matthiesen et al. reported systemic suppression of
maternal immune systems, specifically an altered Tcell response, and impaired lymphocyte proliferation
was found (46). Based on the results of an in vitro
study that showed progesterone, at concentrations
found in the placenta, blocks K channels, Ehring et
al. (15) suggested that this is the mechanism by which
progesterone contributes to maternal immunosuppression. Additionally, it has been shown that cellmediated immunity is depressed during pregnancy,
which may contribute to the gingivas altered response to plaque (61). ONeil (61) also showed that
during the thirteenth and fourteenth weeks of pregnancy, gingival inflammation increased despite the
absence of changes in plaque level. He attributed this
increased inflammation to the bodys depressed immune response to the same bacterial challenge.

Diabetes
Diabetes mellitus is the most common of all endocrine disorders. There are two forms of diabetes mellitus: type 1 or insulin dependent and type 2, or noninsulin dependent. The hallmark of type 1 is the destruction of the beta cells of the pancreas, which
leads to hypoproduction of insulin. This type of diabetes is usually diagnosed before age 30 and the
treatment requires insulin administration. In type 2,
the most common type of diabetes, the hallmark is
insulin resistance, whereby target tissues do not respond to the insulin that is present and there is often
a corresponding hyperinsulinemia. This form of diabetes commonly occurs later in life and can often be
managed by diet modification and oral hypoglycemic drugs, although insulin may also be necessary to
treat more advanced cases.

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Garcia et al.

Epidemiological studies have demonstrated an association between both types of diabetes and periodontal disease (17, 54). Individuals with diabetes
typically are found to have more periodontal attachment loss than non-diabetic subjects, even after correcting for possible confounding factors. However,
increased periodontal risk is often related to duration and adequacy of control of the diabetic state.
For example, it has been noted that individuals with
non-insulin-dependent diabetes mellitus have a
three-fold increased risk of developing periodontal
disease that can not otherwise be explained on the
basis of age, sex or oral hygiene (17). Furthermore, in
a case-control study of insulin-dependent diabetes
mellitus and periodontal disease, Thorstensson &
Hugoson (83) demonstrated that the duration of diabetes measured by the age of onset was found to be
an important risk factor for future periodontal destruction. The metabolic control of diabetes has also
been shown to be associated with periodontal disease in a longitudinal study (69) that showed that
individuals with poor metabolic control had increased attachment loss compared to well-controlled subjects, despite similar oral hygiene levels.
Taken together, these and other results strongly
suggest that diabetes mellitus is an important risk
factor for periodontal disease. It is also well documented that diabetic patients have a compromised
ability to respond to bacterial infections, and it has
been proposed that it is this compromised host response that in part may increase diabetics risk of
periodontal disease. Interestingly, the reverse possibility that the periodontal infection may exacerbate
the diabetic condition is now beginning to receive
increasing attention (26).
The presence of glycated hemoglobin in the circulation and in tissues, resulting from the hyperglycemia of diabetes, is believed to be a contributing factor to the degenerative microvascular and arterial
changes that are common sequelae of diabetes. A
longitudinal study of the Gila River Indian Community, a population having a prevalence of non-insulin-dependent diabetes mellitus of about 50%, has
recently tested the hypothesis that severe periodontitis in individuals with non-insulin-dependent
diabetes mellitus increases the concentration of glycated hemoglobin (81). The results showed that severe periodontitis at baseline was associated with increased risk of having poor glycemic control at follow-up 2 or more years later. If periodontal disease
does affect diabetic status, we would expect that
treating periodontal disease would reduce the severity of diabetes. A recent systematic review of the

28

literature by Grossi et al. (26) concluded that the effect on diabetic status was dependent upon the
treatment modality. Studies that investigated the effect of only mechanical debridement were unable to
demonstrate any effect on blood glucose level or glycated hemoglobin level regardless of periodontal disease severity or degree of diabetes control (1, 61, 72).
However, all three studies that added systemic antibiotics to mechanical debridement demonstrated
improved metabolic control of diabetes (53, 61, 88).
Results from a randomized clinical trial conducted
on the Pima population indicated that all subjects
that were treated with doxycycline experienced a reduction in glycated hemoglobin (25). These results
suggest that periodontal antimicrobial treatment
may reduce the level of glycated hemoglobin in diabetic subjects and may ultimately hold the potential
to reduce diabetic sequelae. However, this has yet to
be conclusively demonstrated and is an active area
of current investigation (27, 82).

Periodontal disease as a risk factor

for systemic disease
There is increasing evidence that individuals with
periodontal disease may be at increased risk for adverse medical outcomes. A number of studies to date
indicate that this increased risk appears to be independent of other known behavioral and medical risk
factors and also appears related to the severity of
periodontal disease. One way of examining the overall effect of periodontal disease on systemic health
is to consider its effect on risk of mortality from all
causes. This relationship has been investigated by
DeStefano et al. (13), using a large United States national sample survey population (NHANES I) and its
follow-up data. They found that men and women, 25
to 74 years old, with periodontitis had a 46% increased risk for mortality from all causes. The increased risk of mortality due to periodontitis remained significant even after controlling for multiple
biomedical, behavioral, and sociodemographic variables including age, gender, race, education, poverty
index, marital state, body mass index, physical activity, diabetes, systolic blood pressure, cholesterol, alcohol consumption and cigarette smoking. These results were confirmed using data from men enrolled
in the VA Normative Aging Study and Dental Longitudinal Study, which also showed an increased risk
of death associated with periodontal status at the
study baseline, independent of smoking status and

Relationship between periodontal disease and systemic health

other risk factors (19). Subjects with the deepest average probing pocket depths were found to be at
74% higher risk of death, controlling for all relevant
co-variates. There was also noted a significant doseresponse effect in the relationship between periodontal status and mortality. The risk of death was
increased in relation to increasing average alveolar
bone loss, whereby for each 20% increment in average alveolar bone loss the risk of death increased by
51%.

Cardiovascular diseases
The potential effect of periodontal disease on risk of
coronary heart disease and stroke continues to be
an area of active investigation (55). Atherosclerosis,
ischemic heart disease and stroke are the major
causes of death in the United States; coronary
thrombosis and myocardial infarction represent
about half of these outcomes. Atherosclerosis is a
progressive, degenerative disease process, whose advanced lesion is an atheroma, a plaque consisting
of lysed cells, cholesterol-ester crystals, lipid-laden
foam cells, and plasma proteins such as fibrin and
fibrinogen. The central core of the plaque is associated with a cellular infiltrate with hypertrophic
smooth muscle cells, macrophages and sparse T
lymphocytes. The presence of an atheroma increases
the risk for thrombosis, as these plaques enhance
platelet aggregation and are the source of thrombi
that can either occlude the artery or result in infarction at distant sites.
The recognized risk factors for cardiovascular disease, such as hypertension, hypercholesterolinemia,
and cigarette smoking, do not account for all the
variation in the incidence of cardiovascular disease,
and other as yet unrecognized risk factors for cardiovascular disease may play a role including several
common chronic infections (10). There is also increasing evidence that one of these potential risk
factors may be periodontal disease (71). Cardiovascular disease and periodontal disease have a
number of characteristics in common. For example,
both diseases are more likely to occur in persons
who are older, male, of lower educational status,
have fewer financial resources, who smoke and are
hypertensive, stressed and socially isolated. These
commonalities suggest that periodontal disease and
heart disease may also share a similar causative
pathway. For example, a number of case control
studies have shown an association between cardiovascular disease and indicators of poor oral health
(47, 48).

The Nutrition Epidemiologic Follow-up Study, a

prospective study of United States adults, was designed to investigate the association between baseline risk factor measures in persons (as obtained
by the NHANES I study) with their subsequent development of various specific diseases and conditions (13). They followed a total of 20,749 original participants and the main outcome measures
in addition to mortality were hospital admissions
and diagnoses for coronary heart disease. They
found that adults (men and women) with periodontitis had a 25% increased incidence of coronary heart disease over a median follow-up period
of 14 years, after controlling for the recognized risk
factors known to affect periodontal disease and
cardiovascular disease. Men younger than 50 years
of age at baseline who had periodontitis were 70%
more likely to have coronary heart disease than
men who did not have periodontal disease. Such
associations have been confirmed by prospective
data from the Normative Aging Study and the
Dental Longitudinal Study of the Department of
Veterans Affairs that were analyzed to evaluate the
association between periodontal disease and cardiovascular disease and stroke (19). The findings of
this study were similar to those of DeStefano et al.
(13), which showed increases in risk of 50% to
100%, also using a longitudinal design that allowed
investigators to confirm that oral conditions preceded in time the occurrence of heart disease.
Peripheral vascular disease and coronary heart
disease share atherosclerosis as a common pathophysiological mechanism and it has been hypothesized that periodontal disease may also be an independent risk factor for development of peripheral
vascular disease (50). Using longitudinal data, Mendez et al. (50) found that persons with clinically significant periodontal disease at baseline were over
twice as likely to develop peripheral vascular disease
over time, even after adjusting for other recognized
vascular diseases risk factors.
However, other longitudinal studies do not show
such a clear association between periodontal disease
and cardiovascular diseases. Joshipura et al. (33)
analyzed longitudinal data collected over a six year
period from 44,119 men in the Health Professionals
Follow-up Study, who had not reported coronary
heart disease symptoms at baseline. The authors reported no significant association between periodontal disease and coronary heart disease, with a
relative risk increase of only 4%. However, men who
had less than ten teeth had a 40% increased relative
risk, as compared with men who had 25 or more

29

Garcia et al.

teeth. Further analysis showed that this association

was limited to men who had both periodontal disease and extensive tooth loss, with a 67% increased
relative risk of coronary heart disease for men who
had ten or fewer teeth and a positive history of periodontal disease.

Hypothetical mechanisms:
atherosclerosis, inflammation
and infection
The biological basis for the observed association between periodontal disease and atherosclerosis, coronary heart disease and stroke is not yet known (5).
However, infection is a recognized risk factor for
atheroma formation and thromboembolic events. In
animal models, gram-negative bacteremia can induce inflammatory cell infiltration into major blood
vessels, vascular smooth muscle proliferation, vascular fatty degeneration and intravascular coagulation.
The similarities between such pathogenic processes
and the natural history of atherosclerosis have led to
the hypothesis that, in addition to recognized risk
factors such as genetic and dietary influences, infections of unknown origin may contribute to the increased risk of atherosclerosis and cardiovascular
diseases.
It is becoming recognized that there is marked
variability in the individual host response to microbial infection. Such differences have been attributed to individual differences in T-cell and monocyte function, with such differences in part having a
genetic basis. It has been hypothesized that certain
individuals may respond to a microbial challenge
with an over-exuberant or hyperreactive inflammatory response. For example, this may be demonstrated by an increased release of pro-inflammatory
mediators (such as prostaglandin E2, interleukin-1b
and tumor necrosis factor-a) when challenged by
bacterial lipopolysaccharide. In laboratory tests, peripheral blood monocytes from such individuals secrete 310 times more inflammatory mediators in response to bacterial lipopolysaccharide than those
from normal individuals. Such observations have led
to the hypothesis that the variation in inflammatory
response may be a direct consequence of at least two
factors: those genes that regulate the T-cell monocyte response, and the host-microbial environment,
which can trigger and modulate the response (5).
Interestingly, there is growing evidence that individuals who have severe forms of periodontal disease
may possess such hyperreactive inflammatory response traits. The types of periodontitis associated

30

with increased incidence of this trait include earlyonset periodontitis, refractory periodontitis and
those with insulin-dependent diabetes mellitus.
There are several observed similarities between
periodontitis and cardiovascular diseases that led
Beck & Offenbacher (5) to propose that the natural
history of both diseases may be related to such
hyperreactive inflammatory response traits. They
note that these shared characteristics include:
O Monocytic cells and the resultant cytokines play a
crucial role in the initiation and propagation of
both atherosclerosis and periodontitis. The recent
discovery that many individuals with severe types
of periodontal disease have a systemic hyperinflammatory phenotype, which secretes abnormally
high levels of inflammatory cytokines, raised the
possibility that this phenotype might be a risk factor for atherosclerosis and emboli formation.
O The hyper-inflammatory phenotype appears to be
under both genetic and environmental influence.
For example, dietary-induced elevation of serum
low-density lipoprotein has been shown to upregulate monocytic response to lipopolysaccharide, thereby producing an environmental response on the hyper-inflammatory phenotype.
Thus, known risk factors for coronary heart disease such as dietary fat intake may enhance
monocyte secretion of inflammatory and tissue
destructive cytokines, and via this common mechanism may contribute to the severity of the expression of coronary heart disease and periodontal disease.
O In a recent study, most individuals tested with insulin-dependent diabetes mellitus appear to possess the hyper-inflammatory phenotype, regardless of their periodontal status. The presence of
a lipopolysaccharide-specific serum antibody for
Porphyromonas gingivalis was the discriminating
factor between individuals who had periodontal
disease and those who did not.
O Periodontal disease results in a chronic, systemic
vascular challenge with bacterial lipopolysaccharides and host-derived inflammatory cytokines
that are theoretically capable of initiating and promoting vasculitis and atheroma formation.
The effect of environmental and behavioral factors
such as dietary intake can affect the expression of
the hyperinflammatory phenotype, which can influence the severity of atherosclerosis or periodontitis. Finally, in this model, periodontitis may
directly contribute to the pathogenesis of athero-

Relationship between periodontal disease and systemic health

sclerosis by providing a microbial source of repeated

systemic vascular challenges with lipopolysaccharide and inflammatory cytokines (5).
There is now extensive evidence suggesting that
risk of cardiovascular disease may be related to several specific microbial infections (10). Of particular
note is the link to cytomegalovirus, which has an affinity for vascular endothelia and in particular,
atheromas. Similarly, herpesvirus has been detected
in atheromatous plaques. More recently, is the finding that periodontal pathogens can also be identified
in atheromas.
Thrombogenesis is related to atherogenesis, and
hypercoagulable states are also considered to predispose to ischemic disease. In this hypercoagulable
state, high levels of fibrinogen are produced. In localized responses to microbial infection, plasma fibrinogen levels are known to increase in many infectious diseases, including Chlamydia pneumoniae
and Helicobacter pylori infections.
When the epithelial integrity of the periodontal
pocket is breached, oral streptococci may enter
tissues and be introduced into the circulation. While
these commensal streptococci are relatively harmless in the oral cavity, they may behave as opportunistic pathogens outside of their normal environment.
Streptococcus sanguis is an example of a common
component of dental plaque that once released into
the bloodstream may behave as a thrombogenic
agent (30). In vitro and animal studies have demonstrated that S. sanguis increased thrombus-like
platelet aggregation. It is possible that during episodes of dental bacteremias, it might act as a thrombogenic trigger to promote thrombi formation and
resultant cardiovascular disease. In addition, P. gingivalis has also been shown to induce human platelet
aggregation in vitro. Both bacteria express a similar
surface antigen that is implicated in the mechanism
of platelet aggregation.
While the weight of current evidence supports an
association between periodontal disease and cardiovascular diseases, the exact nature of this association
remains undefined and no causal relationship has yet
been established. An important step in determining
causality would be to show that elimination of this
risk factor reduces the increased risk of cardiovascular
disease. In other words, will periodontal treatment,
and prevention lead to decreased risk of cardiovascular disease? To date, no studies have directly investigated this hypothesis, although such types of clinical
intervention studies have been conducted on the relationship of periodontitis to diabetic glycemic control. Were one able to demonstrate a beneficial effect

of periodontal treatment on diabetes or cardiovascular disease risk reduction, then this would argue for
the existence of an important causal relationship. A
current research challenge is to determine whether
there are beneficial effects of periodontal treatment
on these important medical conditions.

Periodontal disease and risk of

pulmonary disease
Bacterial pneumonia is a common infection of the
pulmonary parenchyma that may be caused by a
wide spectrum of bacterial species. Although there
are several mechanisms by which microorganisms
can enter the lower airways, it has been reported
that the most common route of infection is aspiration of oropharyngeal contents (6). Studies have
demonstrated that 50% of healthy subjects aspirate
oropharyngeal contents during normal sleep, and
this percentage is higher in individuals who have
chronic swallowing disorders, impaired consciousness, and endotracheal or nasogastric tubes (49).
Normally, host defense mechanisms eliminate the
bacteria. If the body fails to clear the contaminating
bacteria, bacterial pneumonia can ensue. Oral bacteria have also been implicated in the pathogenesis
of bacterial pneumonia, and it has been hypothesized that dental plaque may be an important
reservoir of these potential respiratory pathogens.
Support for this has been reviewed by Limeback (42)
and comes in part from many case reports that have
identified various oral bacteria, such as A. actinomycetemcomitans, Actinomyces israelii, Capnocytophaga species, Eikenella corrodens and others, in
infected sputum and lung abscesses. It has also been
hypothesized that individuals with periodontal
infection may be at increased risk for bacterial
pneumonia (71). Interestingly, potential respiratory
pathogens
such
as
Staphylococcus
aureus,
Pseudomonas and Enterobacteriaceae usually comprise less than 1% of bacterial plaque in individuals
who have periodontal disease; however, following
antibiotic treatment, the prevalence of these pathogens increases. These bacteria can then be aspirated
and cause respiratory disease in individuals with
compromised immune defenses, as is common in
hospitalized patients. It has also been suggested that
the greater infectious burden in people with chronic
periodontitis and with poor oral hygiene also is related to increased risk.
Scannapieco et al. (70) have recently carried out a
detailed epidemiological analysis of the relationship
between oral conditions and risk of pulmonary dis-

31

Garcia et al.

ease (using data from the NHANES I study described

earlier). They also investigated whether there was an
association between poor oral hygiene and chronic
respiratory disease (defined as chronic bronchitis or
emphysema; that is, chronic obstructive pulmonary
disease). They found that persons with chronic
respiratory disease had significantly worse oral hygiene index scores than subjects without respiratory
disease. After controlling for age, race, gender, and
smoking status, those persons with the worst oral
hygiene index scores were still 4.5 times more likely
to have chronic respiratory disease than those persons with the best oral hygiene. However, in this
study, there was no significant association found between the gingivitis or periodontal index scores and
chronic respiratory disease.
Chronic obstructive pulmonary disease is characterized by chronic obstruction to airflow due to
chronic bronchitis and/or emphysema. Chronic
bronchitis is an inflammatory condition associated
with excessive mucus production sufficient to cause
cough with expectoration for at least 3 months of the
year for 2 or 3 years. Emphysema is the destruction
of the air spaces distal to terminal bronchioles.
Travis et al. (84) described a biologically plausible
mechanism to explain a theoretical association between periodontal disease and chronic obstructive
pulmonary disease. They noted that both emphysema and periodontal disease have similar pathophysiological processes, in particular, both diseases
involve recruitment of neutrophils to inflammatory
sites resulting in tissue destruction. Both diseases
also may exhibit the effects of a process termed
frustrated phagocytosis which results in the release
of oxidative and hydrolytic enzymes and the stimulation of neutrophils. This in turn results in increased
phagocytosis, connective tissue damage, and complement inactivation of regulating inhibitors.
Recently, Hayes et al. (29) examined the possible association between periodontal disease and the risk of
developing chronic obstructive pulmonary disease
over a 25-year follow-up time period. In this study,
periodontal disease was assessed using radiographic
alveolar bone loss. After adjusting for known chronic
obstructive pulmonary disease risk factors including
smoking, it was found that alveolar bone loss at baseline was an independent predictor of chronic obstructive pulmonary disease incidence. The relationship
was most pronounced in individuals who demonstrated the greatest extent of alveolar bone loss, with
persons who had average bone loss greater than 20%
per site being two times more likely to develop
chronic obstructive pulmonary disease over the

32

studys 25-year duration. While the results of this

longitudinal study point to an association between
periodontal disease and chronic obstructive pulmonary disease, there is no evidence that the relationship
is causal. Rather, periodontal status may be serving as
an indicator of risk, and the two conditions may share
a common host susceptibility factor related to an
underlying inflammatory response trait. The nature
of the association is under investigation in prospective studies in other populations.

Adverse pregnancy outcomes

Although infant mortality rates have declined in the
United States, the prevalence of low birth weight (defined as less than 2500 g) preterm infants remains a
significant cause of perinatal morbidity and mortality, representing 10% of all preterm births in the
United States. There are many recognized risk factors for preterm low birth weight, including maternal
age (younger than 17 or older than 34); AfricanAmerican ancestry; low socioeconomic status; inadequate prenatal care; drug, alcohol and/or tobacco
use; hypertension; genitourinary tract infection; diabetes; and multiple pregnancies (60). However, the
recognized risk factors alone do not wholly explain
the high prevalence of preterm low birth weight infants. Given the importance of this problem, there is
great effort being given to identifying other risk factors. It has been proposed that one important factor
contributing to the continuing prevalence of infants
with preterm low birth weight is the effect of maternal burden of infection. In this context, periodontal infection may be of importance. Studies
have shown that conditions such as bacterial infection of the genitourinary tract, bacterial vaginosis
and a high prevalence of maternal lower genitourinary tract infections are associated with adverse
pregnancy outcomes. For example, colonization of
the vagina and cervix with Bacteroides species has
been shown to cause inflammation of the placental
membrane, even in the absence of any clinically apparent infection (58, 59). The fact that the inflammation of the placental membranes may occur without clinical signs of infection and that such inflammation is associated with poor pregnancy outcomes,
lends credence to the potential of an indirect effect
of periodontal pathogens on pregnancy outcomes
(11). Currently, evidence is lacking to directly link
specific periodontal pathogens to infants with preterm low birth weight. However, Offenbacher et al.
(5860) have hypothesized that gram-negative anaerobic pathogens from the periodontium initiate a

Relationship between periodontal disease and systemic health

host inflammatory response that has systemic

consequences. Bacterial endotoxins from the periodontal infection trigger release of a variety of biologically active mediators such as prostaglandin E2 and
tumor necrosis factor, which may trigger premature
labor. Experimental evidence to support this hypothesis has been obtained in rodents where maternal
exposure to periodontal infection, or bacterial products such as lipopolysaccharides, is associated with
a reduction in fetal weight by up to 25% (7). The results of the animal model now have support from
several human case-control studies, which have
shown that having periodontal disease significantly
increases the likelihood of an outcome with preterm
low birth weight (11). For example, the work of Offenbacher et al. (60) has shown that women with severe periodontal disease were 7.5 times more likely
than women without periodontal disease to have an
infant with preterm low birth weight.

Conclusions
It is well documented that many systemic conditions
may affect the oral cavity. In contrast, the current
theories that oral conditions may negatively affect
systemic health are largely unproven and remain
speculative. Nevertheless, they represent a new and
exciting area of research that has far-reaching clinical and public health implications. The strongest
evidence for the role of periodontal disease as a risk
factor for systemic health outcomes is likely to come
from well-controlled intervention studies. For example, if resolution of periodontal infection can be
shown to lead to better glycemic control in diabetics,
this would lend credence to the hypothesis that periodontitis is a true risk factor and is causally linked
to important systemic health outcomes.
Still, it has become clear that oral health is intimately inter-related with systemic health. The mouth
truly is connected to the rest of the body. Much recent
work has been devoted to clarifying the directionality
of specific relationships. Often, the associations are
bidirectional, and the model of diabetes and periodontal disease we have earlier discussed is a good example of the complex interplay between oral and systemic conditions. It is recognized that diabetics are at
increased risk of infection (including periodontal infection), but also that unresolved infections in diabetics (potentially including periodontal infection)
place them at risk of poor glycemic control.
The advent of periodontal medicine may also
change the traditional objectives of periodontal

treatment. The evaluation of success may shift from

one focused on preventing attachment loss to one
focused more on measurable reductions in the bacterial infection burden or reducing the levels of inflammatory mediators at involved sites. The preventive recall intervals currently in routine use may be
inappropriate for such new treatment endpoints.
New recall regimens may be developed that focus on
reducing the risk of systemic bacteremia or reducing
levels of endotoxin or host cytokines.
Over the coming decade the focus on evidencebased practice of dentistry is likely to grow. As the
multiple risk factors for periodontal disease become
more clearly elucidated, the practitioner will be able
to more accurately determine an individuals risk for
present and future periodontal disease, based on a
systematic assessment of their individual risk
characteristics. We already recognize that a number
of important patient characteristics need to be considered when developing periodontal treatment
plans, including age, smoking status, level of oral hygiene, and systemic health status. Given the current
knowledge base, for identification of high-risk individuals microbial sampling and even genetic testing
(36) may become standard practice. It has been estimated (65) that patients demographic characteristics, smoking habits, certain components of the
microbial/antibody profile, and particular gene
polymorphisms, could account for 79% of the variance in mean attachment loss and 90% of the variance in mean probing depth. Earlier studies of periodontal disease in twins (52) produced heritability
estimates that indicated that between 38% to 82% of
the population variance in such measures of periodontal disease could be attributed to genetic factors. As the creation of specific risk profiles become
more accurate as predictors of periodontal disease
incidence and progression, this may provide a more
scientific basis for individualized patient recall
schedules and treatment plans.
The future of dental practice will be dramatically altered if subsequent research confirms that periodontal disease is a true risk factor for systemic disease and that the initiation or progression of these
medical conditions can be reduced by periodontal
treatment. Most obviously, there will be further integration of dental and general medicine that will bring
new opportunities for diagnosis and collaboration
across specialties. For example, endocrinologists may
refer poorly controlled diabetics for periodontal treatment as one means of aiding in controlling their diabetes. Dental practitioners may also contribute their
expertise in assessing risk for several systemic con-

33

Garcia et al.

ditions. For example, the fact that elevated levels of

prostaglandin E2 may be found in the gingival crevicular fluid of preterm mothers may serve as a useful diagnostic tool when assessing risk for preterm birth
and low-birthweight outcomes. The fact that oral diagnostic samples can be readily obtained non-invasively, and at potentially lower costs, may offer important advantages to some traditional medical testing. A
greater integration of medicine and dentistry will
likely require that dentists take more responsibility for
the management of their patients systemic health
and conversely that physicians assume a more active
role in their patients oral health.

Postscript
Hujoel et al. (reference below) have analyzed the
most recent NHANES-I follow-up data, through
1992, extending by 5 years the observation period
first studied by DeStefano et al. (13). Using multivariate models, and after adjusting for relevant covariates, they found no significant association between
periodontal status and the risk of coronary heart disease. They suggest that other reports showing a significant association may be the result of residual
confounding. Mattila et al. (reference below), in a
case-control study in Finland, found no significant
association between various dental disease index
measures and the risk of coronary heart disease after
adjusting for relevant covariates.
When taken in the context of reports from other
observational studies, such findings indicate that a
causal association between periodontal status and
the risk of coronary heart disease, although biologically plausible, remains speculative. However, there is
sufficient evidence for an association to justify the
need for randomized controlled trials to definitively
address the question of causality.

References
Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA. Periodontal disease and coronary heart disease risk. JAMA 2000:
284: 14061410.
Mattila KJ, Asikainen S, Wolf J, Jousimies-Somer H, Valtonen V,
Nieminen M. Age, dental infections and coronary heart disease.
J Dent Res 2000: 79: 756760.

Acknowledgments
The VA Dental Longitudinal Study is a component of
the Massachusetts Veterans Epidemiology Re-

34

search & Information Center, supported by the Cooperative Studies Program of the U.S. Dept. of Veterans Affairs. Dr. Garcia is the recipient of an Advanced Research Career Development Award in
Health Services Research from the VA HSR&D Service. Supported by NIH grants K24 DE-00419 and
K23 DE-00454.

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