Acquired immune suppression

and other risk factors/indicators

for periodontal disease
progression
Thomas W. Stanford & Terry D. Rees
As has been discussed in other chapters of this text,
the response to the presence of dental plaque may be
inuenced by a variety of external and internal risk
factors or indicators that may or may not be suf-
cient to predispose an individual to periodontal dis-
eases. The periodontal health of the host appears to
be dependent upon the intricate interaction of
extrinsic risk factors/indicators with systemic neu-
roendocrineimmunologic mechanisms. This dis-
cussion will review several putative risk factors/
indicators that may be involved in periodontal dis-
ease progression with emphasis on those associated
with altered immune mechanisms.
Acquired immune suppression
Immune suppression may occur as a result of the
various blood dyscrasias and hormonal inuences
described earlier in this text. It may also be associated
with a variety of systemic diseases such as lupus
erythematosus, Sjogrens syndrome, progressive sys-
temic sclerosis, Crohns disease/inammatory bowel
disease and the acquired immunodeciency syn-
drome (AIDS) (39, 77, 121, 136, 163, 172, 198, 228,
234). Long-term use of immunosuppressant drugs to
prevent organ transplant rejection has been reported
to increase the incidence of oral infections, to include
candidiasis, oral hairy leukoplakia, Kaposis sarcoma,
herpes simplex and cytomegalovirus associated oral
ulcerations (8, 10, 69, 124, 198). There is also evidence
to suggest that viral infections may play an etiologic
role in occurrence of periodontal diseases in immu-
nosuppressed individuals (6, 49, 146, 173). However,
there is surprisingly little information in the period-
ontal literature to afrm an increased incidence in
chronic or aggressive periodontitis in conjunction
with long term use of immunosuppressive drugs (89,
121, 162). Cyclosporin A is an immune suppressant
often prescribed to prevent rejection of bone marrow
or solid organ transplants. Although the drug is asso-
ciated with susceptibility to gingival overgrowth in
animals and humans in the presence of bacterial pla-
que, there are no reports indicating that periodontal
destruction is enhanced. Additionally, other immuno-
suppressant drugs used in prevention of organ trans-
plant rejection are not associated with gingival
overgrowth in humans (233). In fact, substitution of
immunosuppressive drugs such as sirolimus, tacroli-
mus, or aziathiaprine has been reported to reduce or
eliminate cyclosporine-induced gingival enlargement
(45, 110, 117, 174, 213).
Some studies have described an increased inci-
dence and severity of periodontal diseases in humans
suffering from rheumatoid arthritis (RA) (89, 151, 152,
224). To date, however, no cause/effect relationship
has been established. Both conditions are potentiated
by an exaggerated inammatory response featuring
an increase in localized and perhaps circulating cyto-
kines, tissue necrosis factor and platelet-derived
growth factor (29, 222). Patients suffering from RA
are often treated with immune suppressant corticos-
teroids, and it is possible that the anti-inammatory
function of these drugs reduce clinical evidence of
periodontal disease (205). To date, no large studies
have evaluated individuals with RA for presence of
more subtle evidence of periodontal disease such as
gingival recession or clinical attachment loss.
118
Periodontology 2000, Vol. 32, 2003, 118135 Copyright
#
Blackwell Munksgaard 2003
Printed in Denmark. All rights reserved
PERIODONTOLOGY 2000
ISSN 0906-6713
The relationship between HIV infection, AIDS, and
periodontal diseases has been reviewed recently by
several authors (90, 178, 188, 193, 198). The reader is
referred to these papers for detailed information.
These reviews conrm an increase in certain period-
ontal conditions among individuals infected with the
human immunodeciency virus (HIV). These include
linear gingival erythema (LGE), necrotizing ulcerative
gingivitis (NUG) and necrotizing ulcerative period-
ontitis (NUP). Necrotizing ulcerative stomatitis (NUS)
may occur as an aftermath of NUP (188, 195). None
of these conditions is unique to HIV-infected indivi-
duals, however, and they have all been reported in
patients believed to be otherwise healthy (111, 171).
The incidence of these conditions does appear to
increase in association with diminishing immune
competency but most individuals with AIDS are
not aficted even in the later stages of the disease.
The evidence is less clear regarding the incidence
and severity of gingivitis and chronic periodontitis in
individuals with AIDS. Linear gingival erythema may
occur more frequently in HIV-infected children and
young adults, but there is no strong evidence to sug-
gest that it is more harmful than plaque-related gin-
givitis in the general population (90, 91, 125, 126, 144,
193).
Some studies have suggested that chronic period-
ontitis is increased among adults with AIDS in direct
relation to the degree of immune suppression, and
accelerated periodontal pocket formation and clini-
cal attachment loss have been reported (18, 72, 91,
149, 150, 164, 194). Others have found no difference
in periodontal diseases in adult AIDS patients when
compared to HIV-negative controls (84, 190, 202).
The bulk of evidence, however, indicates that gingi-
val recession and loss of clinical attachment occurs
more frequently in individuals with AIDS, with or
without the signs and symptoms of chronic period-
ontitis. Although a slight increase in susceptibility to
periodontal destruction may occur when bacterial
plaque is present (149, 150, 193, 195, 235), most indi-
viduals with AIDS who practice effective home care
and seek appropriate professional dental care, can
anticipate a lifetime of periodontal health (65, 84,
125, 126, 190, 220).
Medical management of patients with AIDS has
entered a new era in which highly active antiretro-
viral therapy (HAART) has resulted in marked
increases in T4 lymphocyte counts and diminished
viral bioload in many HIV-positive individuals. The
incidence of oral manifestations of HIV infection
including chronic periodontitis appears to diminish
when this therapy is successful (17, 38, 221).
Conclusions
Acquired immunodeciency may adversely affect
host resistance to the presence of bacterial plaque
and predispose some individuals to an increase in
incidence and/or severity of periodontal diseases.
The presence of severe immunodeciency, however,
does not prevent most aficted individuals from
maintaining periodontal health consistent with that
of the general population.
Psychosomatic, psychosocial and
stress factors
Stress has been dened as the psychophysiological
response of an organism to perceived threat or chal-
lenge (32). In a physiologic response to stress, the
hypothalamus-pituitary-adrenal cortex (HPA) axis is
stimulated. The anterior hypothalamus secretes cor-
ticotropin-releasing factor and arginine vasopressin,
which act on the hypophysis. The pituitary gland, in
turn, releases adrenocorticotrophic hormone, which
acts on the adrenal cortex and increases production
and release of glucocorticoid hormones, which in
turn stimulate the immune response. Meanwhile,
corticotropin-releasing factor, adrenocorticotrophic
hormone and other neuroendocrine hormones con-
tribute to mediation of the immune mechanism. The
autonomic nervous system is also activated to induce
release of adrenalin from the adrenal medulla, while
various neuropeptides such as substance P are
released from sensory nerve bers (19, 103). Under
ideal circumstances these factors function in har-
mony to enable the organism to ward off the stressful
event and maintain homeostasis. In contrast,
increased levels of cortisol and epinephrine may dis-
rupt homeostasis and lead to increased susceptibility
to disease (41, 52).
A relationship between a sound mind and a
sound body has been proposed for centuries (133).
However, little was known about this association
until Selyes classic work in the 1930s and 1940s
(203, 204). He proposed that the initial HPA axis
response to stress was benecial but that prolonged
mental or physical stress can be detrimental to the
human body by exhausting or diminishing the ability
to respond to a perceived threat or challenge. Selye
dened this as the General Adaptation Syndrome
(GAS) (204) and his work has been at least partially
substantiated by more recent studies that suggest
that prolonged stress can be harmful and often man-
ifests as depression (16, 32, 41, 50, 87). In general,
Acquired immune suppression for periodontal disease progression
119
individual variations in the way one perceives and
copes with a stressful event may be more important
to health than the event itself (32, 87, 104).
Poor coping skills may manifest as anxiety or
depression (87, 137, 159). Although an individuals
emotional status may directly affect host resistance
factors, it may also lead to negligence in performing
oral hygiene procedures, failure to seek dental care,
increased smoking and use of alcohol, altered food
intake and bruxing (56, 85, 158, 159). Anxiety and
depression may also cause salivary ow rates to
decrease, making the individual more susceptible
to oral diseases and disorders.
An association between stress and periodontal dis-
ease was suggested over 50 years ago (54) and has
subsequently been supported by several studies (59,
87, 100, 101, 201). For example, Sakki et al. (201)
evaluated 780 individuals from a Finnish community
and reported that lifestyle characteristics were asso-
ciated with periodontal health status. Individuals
who smoked, had inadequate dietary habits, used
alcohol or were physically inactive tended to be more
irregular toothbrushers. It is reasonable to assume
that some of these individuals were affected by anxi-
ety or depression and poor coping skills. Numerous
studies have reported an increased susceptibility to
systemic diseases and delayed wound healing in both
animals and humans who are subjected to prolonged
physical or emotional stress (15, 16, 30, 31, 47, 48, 83,
109, 127, 191, 209). It is very difcult, however, to
assay the signicance of the role that stress plays due
to the multifactorial nature of many diseases and the
altered behavioral responses that stress may induce.
Additionally, personality types, mental stability, psy-
chologic disorders, lifestyle, variations in locus of
control and coping style may alter the effects of stress
(78, 85, 87, 109, 132, 145, 155, 157, 230). Harmful
effects of stress in humans have been associated with
unwelcome life events such as nancial and occupa-
tional strain, perceived ill health, loss of a spouse or
loved one, academic strain, low socioeconomic sta-
tus, low level of education, military combat, exces-
sive noise, and marital difculties (50, 5559, 61, 87,
112). Animal studies have consistently found a
depressed immune response in association with
noise, isolation, increased population density,
malefemale proximity, handling by animal keepers,
exposure to cold temperatures and deliberate physi-
cal trauma (47, 102, 186, 209, 212, 215). In most
instances the stressful event was prolonged. How-
ever, Riley (191) demonstrated that in a low stress
environment, plasma cortisol levels were signi-
cantly increased by single, mildly stressful stimuli
and that the immune response of the animals was
adversely affected. Breivik et al. (31) studied two
genetic strains of Wistar rats, one of which responded
to stress by high corticosteroid production while the
other expressed low corticosteroid secretion. Those
that produced high levels of corticosteroids were
more sensitive to periodontitis, suggesting that
genetic factors may determine periodontal disease
susceptibility.
Other animal studies have evaluated the effects of
prolonged stress on periodontal structures. Osteo-
porosis, loss of alveolar bone height, degeneration
of the periodontal ligament, apical migration of the
epithelial attachment, increased probing depths,
destruction of C type sensory bers and delayed
wound healing have been reported (47, 102, 103,
118, 127, 186, 212). These studies do not conrm,
however, that stress induces a similar effect in
humans. Of interest is the observation that use of
immunosuppressive drugs such as corticosteroids
or azathioprine in humans has not been associated
with increased incidence or severity of periodontal
disease. This may, however, be due to the anti-
inammatory properties of these drugs (89, 109,
121, 206).
Human studies have related stressful life events to
increased incidence and severity of periodontal dis-
ease and to behavioral modications (13, 23, 41, 50,
56, 82, 85, 87, 94, 112, 137, 138, 157160, 209). It is
difcult, however, to separate the physiological com-
ponent from the adversely altered behavioral
changes noted above. Freeman & Goss (82) longitu-
dinally evaluated the effect of occupational stressors
on periodontal health status and reported signicant
increases in mean plaque score, subgingival calculus,
bleeding on probing and pocket depth. They also
reported that these effects may have been related
to the personality traits of study participants. Deinzer
and associates (5559) conducted a series of studies
regarding the oral effects of academic stress. They
reported that bacterial plaque accumulation and gin-
gival inammation were signicantly increased in
medical students undergoing academic examina-
tions when compared to control students who were
not being tested. They also identied increased levels
of interleukin-1 beta (IL-1b) in crevicular uid of
stressed individuals and reduced salivary immuno-
globulin A. These studies suggest that psychosocial
stress induces adverse behavioral changes in con-
junction with alterations in host resistance. Monteiro
da Silva et al. (157) reported psychosocial factors
(depression and loneliness) were more prevalent in
patients with aggressive periodontitis than in to
120
Stanford & Rees
those with chronic periodontitis or periodontal
health. In another study, Monteiro da Silva et al.
reported that depression had little direct effect on
plaque accumulation between groups of individuals
with aggressive or chronic periodontitis (158). Becker
et al. (23) studied personality traits of periodontal
patients who did or did not adhere to a periodontal
maintenance program following therapy. They
reported that the maintained group displayed a more
positive image of themselves and a lower incidence
of stressful life events than those who did not adhere
to the maintenance protocol (23).
Hugoson et al. (112) evaluated 298 dentate Swedes
between the ages of 50 and 80. They reported that
traumatic life events were associated with increased
risk for periodontal disease, especially in those indi-
viduals with poor coping skills as expressed in their
locus of control perception. Those individuals who
believed they had no control over their disease
(external locus) did not fare as well as those who
maintained a positive attitude and a belief that they
could inuence the progression of their disease
(internal locus). Galgut et al. found a similar effect
of locus of control in patient participation in a pre-
ventive periodontal program (85).
Genco et al. (87) conducted a cross-sectional study
of 1,426 subjects to evaluate the association of
stress, distress and coping behaviors to the pre-
sence or absence of periodontal disease. Regression
analysis indicated that nancial strain was asso-
ciated with greater attachment and alveolar bone
loss among individuals who demonstrated inade-
quate coping skills (high emotion-focused coping)
while those with nancial strain and good coping
skills (problem-based coping) had no more period-
ontal disease than those without nancial strain.
Studies of this nature offer signicant support to
the concept that properly coping with stressful life
events may be more important than the events them-
selves.
Axtelius et al. (13) investigated psychosocial strain
in a small group of patients in relation to their
response to periodontal therapy. They reported that
response to therapy was less in those individuals with
more psychosocial stress and a more passive-depen-
dent personality.
Necrotizing ulcerative gingivitis appears to be
diminishing in frequency among immunocompetent
individuals and its diagnosis indicates the need for
evaluation of the patients immune system, including
testing for HIV (119, 188, 196, 197). NUG is also, how-
ever, the periodontal condition most frequently asso-
ciated with psychosocial stress (48, 157). The disease
has been reported to be more common among
college students at examination time, among in-
dividuals adjusting to military life, soldiers in combat
or those undergoing other stressful events (53, 88, 99,
179, 181). It has been associated with anxiety and
depression(48, 160) and several authors have reported
signicantly elevated cortisol levels in individuals with
NUG that returned to normal after recovery (48, 148,
208). This suggests involvement of the neuroendocrine
systemleadingtolymphocytopenia, alterations inche-
motaxis, phagocytosis and killing by polymorphonuc-
lear leukocytes, and macrophage dysfunction (46, 48,
196). These immune complex changes have also been
associated with blood dyscrasias, malnutrition, malig-
nancy and other debilitating diseases andthese condi-
tions have all been associated with in increased
incidence of NUG (46, 199, 233). Smoking is very
common in this patient population (161). Increased
smoking may be stress related and may induce vaso-
consriction and localized ischemia (109, 114, 141).
NUG is associated with a specic periodontal micro-
ora and it is possible that increased cortisol levels
predispose to overgrowth of selective microorganisms
(109, 141).
Successful treatment of NUG is dependent upon
control of the bacterial microora even if the stress-
ful situation or smoking continues (48, 196). This
provides insight into the limited role of stress and
related conditions to periodontal health and strongly
suggests that stress has a limited role as an etiologic
factor for periodontal disease.
Conclusions
Available evidence indicates that psychosocial and
physiological stress may play a role in contributing
to periodontal destruction in the presence of patho-
genic dental plaque organisms. It appears, however,
that the inability of some individuals to apply effec-
tive coping measures may be of more importance
that the stress itself. The signicance of these factors,
however, remains to be established and further study
is indicated.
Nutrition
The potential mediating role of nutrition in the oral
healthsystemic disease relationship has increased
interest in the effect of nutrition on oral health and
periodontal disease. This relationship has been the
subject of many studies and the majority of opinions
and research ndings concerning the effects of
121
Acquired immune suppression for periodontal disease progression
nutrition on oral and periodontal tissues indicate the
folllowing:
there are nutritional deciencies that produce
changes in the oral cavity.
there are no nutritional deciencies that by them-
selves can cause gingivitis or periodontal pockets
(128, 183).
There are few studies, however, which have add-
ressed the risk associated with the effects of nutri-
tional deciencies on periodontal disease or tooth
loss (66, 131, 165, 166, 183). Since nutritional require-
ments change as one progresses from birth, through
childhood, puberty, adulthood, and into old age,
experimental design to achieve statistically signi-
cant data is quite difcult (5).
The effects of specic nutritional deciencies have
been the subject of recent reviews (128, 189). Efforts to
associateperiodontal diseasewithnutritional decien-
cies have yieldedconicting results, oftendemonstrat-
ing dissimilar results in animals and humans (66, 176).
Vitamins
Vitamins are coenzymes essential for metabolism
and health, and have been classied as fat-soluble
(A, D, E, and K) and water-soluble (B and C).
Vitamin A is involved in the production and main-
tenance of epithelial cells of the skin and mucous
membranes and a deciency may produce dermato-
logic, mucosal, and ocular changes. Vitamin A de-
ciency states, induced in animal models, have
demonstrated detrimental effects on the periodontal
tissues, including hyperkeratosis of the gingival
epithelium, pocket formation, cementum resorption
and osseous changes (28, 64, 79, 153). In a case report
of hypervitaminosis A in the human, De Menezes
et al. (62) described gingival erosions and ulcera-
tions, bleeding, swelling, loss of keratinization and
color changes, desquamation and loss of hair in a 20-
year-old patient who had been taking 200,000 IU of
vitamin A daily for 6 months to treat acne. After
discontinuing the vitamin A, the patient demon-
strated improvement within 1 week, and a return
to normal after about 2 months.
The B-Complex includes thiamin (B
1
), riboavin
(B
2
), niacin, pyridoxine (B
6
), biotin, folic acid, and
cobalamin (B
12
). A deciency resulting in oral disease
usually involves more than one component of the B-
Complex. Thiamin (B
1
) deciency may result in
degeneration of the myelin sheath of peripheral
nerve bers and manifest clinically as beriberi. Oral
changes associated with thiamin deciency include
hypersensitivity of the teeth and oral mucosa and
enlargement of the fungiform papillae of the tongue.
Small vesicles or cracks may appear on the vermi-
lion border of the lips and commissures of the
mouth. Riboavin (B
2
) deciency affects the oral
cavity by causing angular chelitis, atrophy of the li-
form papillae producing glossitis, and oral ulcera-
tions. Niacin is involved in oxidation and reduction
reactions, and a deciency manifests in the oral cav-
ity as generalized oral erosions, hyperemia of the
buccal mucosa and an inamed and erythematous
tongue, with papillary atrophy. Pyridoxine (B
6
) is
involved in amino acid metabolism and the clinical
deciency states are most frequently associated with
malnutrition secondary to alcoholism. Oral changes
are non-specic. Biotin deciency presents as atro-
phy of the lingual papillae, but deciencies seldom
occur. Folic acid deciency is common in alcoholics,
the elderly, and the malnourished, and manifests
clinically as severe oral ulcerations. Folic acid as a
supplement has been reported to reduce gingivitis or
phenytoin-induced gingival enlargement; however,
these nding have not been duplicated in all studies
(34, 107, 184, 226). Cobalamin (B12) is a cobalt-con-
taining vitamins and the deciency state most com-
monly seen is pernicious anemia. Glossitis is the
most frequent oral manifestation, occurring in 50
60% of the patients. Other oral lesions include sto-
matitis and mucosal ulcerations. The oral manifesta-
tions may occur in the absence of symptomatic
anemia. Epithelial cell abnormalities have also been
reported, and these tissues may be more susceptible
to epithelial dysplasia or malignant transformation.
Symmetrical neuropathy, affecting the limbs, spinal
cord, and optic nerves, has been reported (75, 107,
156, 189, 223). The standard treatment for cobalamin
(B12) deciency involves regular intramuscular co-
balamin injections. For patients with food-cobalamin
malabsorption resulting in a deciency state, oral
cobalamin therapy has shown promising results (9).
Vitamin C (ascorbic acid) is a water-soluble vita-
min found in citrus fruits and fresh vegetables. Its
primary function is in the hydroxylation of proline. It
is essential to collagen biosynthesis. In the extreme
deciency state, known as scurvy, the collagen in
connective tissue, osteoid, and dentin is adversely
affected (107). The periodontal changes have been
related to increased permeability of gingival sulcular
epithelium, increased levels of glycosaminoglycans,
and retention of extracellular uid associated with
altered capillary permeability (214). The mild de-
ciency state manifests as gingivitis, attributed to
altered host response, and perhaps related to effects
on polymorphonuclear leukocytes (227). As the de-
122
Stanford & Rees
ciency becomes more acute, the gingiva becomes
grossly inamed and bleeds easily. Eventually, severe
periodontal destruction occurs, with increased tooth
mobility, destruction of the periodontal ligament and
loss of teeth (107, 135, 227). Scurvy is the result of
months of severe vitamin C deciency, and there has
been no evidence to indicate that mild vitamin C
deciency causes periodontitis (115). Groups of
patients at risk for a vitamin C deciency include
food faddists, alcoholics, isolated elderly and the
mentally ill (40, 74, 207, 219). Recently, Nishida
and co-workers (165) evaluated the role of dietary
vitamin C as a risk factor for periodontal disease.
Using information from the Third National Health
and Nutrition Examination Survey, they found a rela-
tionship between reduced dietary vitamin C and a
minor increased risk for periodontal disease for the
overall population (odds ratio [OR] 1.19; 95% CL:
1.051.33). Current and former smokers showed an
increased risk of periodontal disease with an OR of
1.28 (95% CL: 1.041.59) for former smokers and an
OR of 1.21 (95% CL: 1.021.43) for current tobacco
users. They also reported a doseresponse relation-
ship between the levels of dietary vitamin C and
periodontal disease. They concluded that dietary
intake of vitamin C showed a weak, but statistically
signicant, relationship to periodontal disease in
current and former smokers.
Vitamin D is a fat-soluble vitamin associated with
the absorption of calcium and phosphorous from the
intestinal tract. The primary compound, cholecalci-
ferol (vitamin D3), forms in the skin after exposure to
UV rays of the sun. It is converted to the active hor-
mone, 1,25-dihydroxycholcalciferol, which promotes
calciumabsorptionintheintestine, reabsorptioninthe
kidney, andalsoeffects alkalinephosphataseactivityin
bone. Vitamin D and parathyroid hormone work
together to control calcium levels in plasma by their
effects on bone (107, 156). Vitamin D deciency inter-
fereswithmineralizationof organicbonematrix, witha
resulting replacement of normal bone with osteoid.
The condition is called rickets in children and osteo-
malacia in adults. The effects of this deciency on the
oral tissues in children may include delayed develop-
ment of permanent teeth, enamel hypoplasia, cemen-
tal resorption, enlarged pulp chambers, and frequent
pulp stones. In adults, osteomalacia may result in
destruction of the periodontal ligament, a decrease in
thewidthof theperiodontal ligament space, resorption
of alveolar bone, and replacement brous dysplasia
(26, 134). Dietary calcium intake as a contributing risk
factor for periodontal disease was recently studied
using NHANES III data by Nishida and co-workers
(166). The relationship between calcium intake and
periodontal disease showed an odds ratio (OR) of
1.84 (95% CL: 1.362.48) for young males, 1.99 (95%
CL: 1.342.97) for young females, and 1.90 (95% CL:
1.412.55) for older males. A dose response was also
seeninfemales, where54%demonstratedagreater risk
of periodontal disease at the lowest level of dietary
calcium intake (2499 mg), and a 27% greater risk in
females who took moderate levels of dietary calcium
(500799 mg) as compared to those who took 800 mg
or more dietary calciumper day. They alsofounda sta-
tistically signicant association between total serum
calcium and periodontal disease in younger females
aged 2039 with OR 6.11 (95% CL: 2.3615.84) but
not in males and older females. Pitiphat et al. (183)
evaluated dietary calcium intake and periodontal dis-
easeinmale healthprofessionals age4575years. They
reported men taking the recommended daily allow-
ance of calcium (>1,000 mg) had a 13% lower risk for
periodontitis (RR 0.87; 95% CL: 0.780.97) as com-
pared with men consuming less than the daily recom-
mended daily allowance. Their results suggest an
inverse association between total calcium intake
greater than 1,000 mg/day and risk for periodontitis
in the study population. Ostoporosis is a systemic ske-
letal disease characterized by low bone mass and has
been associated with calcium deciency. It is a bone
resorptive disease and may be a risk factor for period-
ontal disease (this relationship is discussed in detail
earlier intheissueinthearticlebyGeurs et al). Calcium
and vitamin D supplements to reduce skeletal bone
loss have demonstrated a benecial effect on tooth
retention. Krall and co-workers (131) conducted a 3-
year randomized, placebo-controlled trial on healthy
subjects aged 65 and older. They reported calcium
intake to be signicantly associated with the odds of
tooth loss (OR 0.5; 95% CL: 0.20.9; P 0.03) and
suggest that intake levels of calcium and vitamin D
aimed at preventing osteoporosis have a benecial
effect on tooth retention.
Vitamin K is a water-soluble vitamin required for
hepatic synthesis of coagulation factors II, VII, IX and
X. Deciency of this vitamin leads to inadequate
production of coagulant factors with an adverse
effect on clotting. The oral manifestations of vitamin
K deciency include gingival bleeding and postex-
traction hemorrhage (107). Anticoagulants such as
coumarin inhibit vitamin K metabolism and create
an articial vitamin K deciency state for the patient.
Some studies indicated an association between vita-
min K and osteoporosis; however, the relationship
between vitamin K and bone health remains unclear
(25).
123
Acquired immune suppression for periodontal disease progression
Trace metals
Trace metals such as zinc, manganese, molybdenum,
cobalt, copper, and selenium are needed in small
amounts by the body. A balanced diet usually sup-
plies an adequate amount of trace metals. Little is
known about the requirements and deciency states
associated with these metals (107). An impaired
immunologic and inammatory response as well as
delayed wound healing have been attributed to de-
ciencies of these metals (2, 105).
Zinc participates in cellular proliferation and is an
important part of many enzymes (214). Zinc de-
ciencies have been evaluated in animal models,
and have been shown to increase susceptibility to
plaque-induced disease and delayed wound healing;
however, they have not directly induced periodontal
destruction (120, 231).
Selenium has structural and enzymatic roles, and is
needed for proper function of the immune system.
Findings linking selenium to cardiovascular disease
have been equivocal. An elevated selenium intake
has been associated with reduced cancer risk (187).
In an animal model, selenium has been shown to
participate in the initiation of leukocyte adherence
to endothelium, and plays a role in the cellular
response in inammation (142).
Copper, along with calcium, iron, magnesium,
manganese, and zinc, were evaluated in a group of
80 dental patients with periodontal disease. Serum
levels of copper were linearly related to the period-
ontal index used in this study. There were no corre-
lations with the other trace metals. The authors
suggested a role for copper in the inammatory
response (81).
Antioxidants
Free oxygen radicals are toxic molecular fragments
capable of producing DNA mutations, changes in
enzymatic activities, peroxidation of lipid mem-
branes and cell death. The role of nutrients either
as antioxidants or as key components of antioxidant
enzymes has been a major area of research. Among
the antioxidant nutrients are zinc, alpha-tocopherol
(vitamin E), beta carotene (provitamin A), and ascor-
bic acid (vitamin C) (71). Studies have been directed
toward the use of antioxidant agents in the preven-
tion of cancer and cardiovascular disease, but the
results have been inconclusive (71, 86, 108). There
is evidence that free oxygen radicals are associated
with periodontal tissue destruction (20). Proteases
with free oxygen radicals are released by polymor-
phonuclear leukocytes and may produce changes in
periodontal tissues (6, 11). Antioxidant nutritional
deciencies and resulting peroxidative damage at
the tissue level have been reported and could con-
stitute an indirect risk for periodontal breakdown
(69, 214). Studies assessing the effect of antioxidant
supplements are in progress (12).
Protein deficiency
Protein is a vital constituent of the human diet, and
serves as the source of essential amino acids (those
not produced by the body). The other amino acids
found in protein can be synthesized by the body.
Humans have no storage capacity for the essential
amino acids, other than the protein of their own
body. Therefore, a deciency of any of the amino
acids can reduce the level of endogenous protein
synthesis. This becomes especially critical during
periods of growth and development (107). Severe
protein deciency will retard growth and alter phy-
siologic function, including host defense mechan-
isms and wound healing. This deciency will also
adversely affect polymorphonuclear neutrophil leu-
kocyte (PMN) chemotaxis, complement activation
and both humoral and cell-mediated immune res-
ponses (223). Protein deciency has been associated
withoral changes suchas glossitis, angular chelitis, and
xerostomia. Periodontal effects include an increased
incidence of gingival inammation and periodontal
bone loss (182). Severe protein deciency (kwashior-
kor) is associated with an increased incidence and
severity of acute necrotizing gingivitis, periodontitis
and cancrum oris (noma) (70, 182). Protein deciency
in animal models has demonstrated osteoporosis in
alveolar bone, degeneration of the periodontal liga-
ment, decreased cementum deposition and delayed
wound healing; however, periodontal pocketing does
not occur intheabsenceof plaque(37, 42, 80, 217219).
Analterationinresistancetoperiodontal diseasedueto
mild protein deciency has not been supported in the
literature (43, 44).
Hyperlipidemia
Several studies have addressed the possible relation-
ship between hyperlipidemia and periodontitis (51,
63, 76, 113, 122, 123, 140, 168, 229). Iacopino has
noted a mechanistic link involving the broad axis
of inammation, immune cell phenotype, serum
lipid levels, and tissue homeostasis (113).
At this time, it is unclear whether hyperlipidemia
contributes to periodontal disease, or if periodontal
124
Stanford & Rees
disease contributes to hyperlipidemia. Hyperlipide-
mia has been shown to impair PMN function and
increase superoxide production and has also been
shown to modulate the release of pro-inammatory
cytokines and growth factors (51, 63, 141, 229). Con-
versely, bacterial lipopolysaccharides associated with
periodontal disease, have been shown to induce the
release of inammatory cytokines such as IL-1b and
tumor necrosis factor -alpha (TNF-a, which, in turn,
alter fat metabolism and promote hyperlipidemia
(51, 76).
Cutler and co-workers reported a signicant rela-
tionship between the presence of periodontitis and
elevated cholesterol (OR 7, P 0.004) and ele-
vated triglycerides (OR 8.6, P 0.0009), in a group
of adult periodontitis patients, when compared with
age-matched controls (51). Loesche and co-workers
(141) found total cholesterol, low density lipoprotein
cholesterol and triglycerides to be signicantly
higher in periodontally diseased patients, compared
with controls. The predisposition for diabetes melli-
tus (in the absence of diagnosed diabetic disease) or
hyperlipidemia to serve as risk indicators for period-
ontitis was evaluated by Noack et al. (168). They
reported a small but statistically signicant correla-
tion between probing depth and lipid levels in test
patients compared with controls. They also reported
no correlation for predisposition for diabetes melli-
tus, and concluded that impaired lipid metabolism
does seem to be a risk indicator for periodontitis. A
signicant relationship between CPITN score of 4
(pockets > 6 mm) and hypercholesterolemia was re-
ported by Katz (122) in 1,094 males aged 2653 years.
No association was found with regard to triglycerides.
Thesameauthors foundsimilar resultsinalarger study
(10,590), which included both men and women. They
reported CPITN scores of 4 to be strongly associated
with total and low density lipoprotein (LDL) choles-
terol, andstronglynegativelyassociatedwithhighden-
sity lipoprotein (HDL) in men. They reported no
signicant association in women (123).
The reports noted above provide support for
hyperlipidemia as a risk indicator for periodontal
disease. Further studies are necessary to establish
the true relationship between periodontal disease
and hyperlipidemia.
Malnutrition
Primary malnutrition may be dened as undernutri-
tion because of an environmental lack of essential
foodstuffs. It may occur in underdeveloped countries
for a variety of reasons. Secondary malnutrition
occurs when adequate food is available, but the indi-
vidual is unable to make full use of the nutrients for
whatever reason (107).
Starvation is the result of a long-continued depri-
val of food, and can be considered the ultimate form
of malnutrition. Anorexia is the lack or loss of appe-
tite for food and bulimia is an abnormal increase in
the sensation of hunger. Anorexia nervosa and buli-
mia nervosa are two psychosomatic, socially driven
eating disorders with oral manifestations. Altered
eating behaviors may be the result of medical pro-
blems such as infections, malignant disease, depres-
sion, or the result of religious, ethnic, or cultural
practices (27, 154, 192).
Anorexia nervosa is characterized by self-imposed
starvation, intense fear of gaining weight, refusal to
maintain body weight, a distorted perception of body
image, neuroendocrine abnormalities, and depres-
sion (27). Bulimia nervosa, more common than anor-
exia nervosa, is characterized by uncontrolled
ingestion of large quantities of food, often followed
by either voluntary or involuntary vomiting. In gen-
eral, anorexics are more than 15% below ideal body
weight, whereas bulimics are within 10% of ideal
weight or may be overweight (154). Oral conditions
associated with these disorders include erosion of the
enamel and dentin of the teeth, dental caries, gingi-
vitis, and parotid gland enlargement (192). Several
studies have assessed the incidence of these oral
conditions and found erosion of the teeth only in
those patients who reported vomiting as part of their
disease. Oral hygiene, gingivitis, and caries incidence
were similar for both conditions, and loss of connec-
tive tissue was not reported (95, 118, 192).
Obesity
Obesity may be considered a unique form of malnu-
trition, in the sense that there is disorder in the indi-
viduals nutrition. The prevalence of obesity is
increasing in the U.S. and is considered a signicant
risk factor for various adult diseases such as type 2
diabetes, hyperlipidemia, hypertension, arterio-
sclerosis, and cardiovascular and cerebrovascular
disease (129). Recent publications have associated
obesity with periodontal disease (68, 97, 167, 180,
200).
Perlstein & Bissada introduced gingival irritation
into an animal model, and found that obesity contrib-
uted signicantly to the severity of the periodontal
response (180). Elter et al. (68) studied the relation-
ship between obesity and periodontitis in the Ather-
osclerotic Risk in Communities Study (ARIC) cohort.
125
Acquired immune suppression for periodontal disease progression
They dened obesity as body mass index (BMI) >28.
BMI was calculated as weight in kilograms/height in
meters
2
. They reported the unadjusted odds of per-
iodontitis were signicantly higher among those with
obesity as compared to those without obesity (OR
1.41, CL 1.191.66). In their multivariate logistic
model, obesity was again associated with periodontal
disease (OR 1.44, CL 1.201.72) when adjusting for
other variables. Saito et al. (200) studied the relation-
ship between upper body obesity and periodontitis
in 643 apparently healthy dentulous Japanese adults.
They measured the waisthip ratio (to determine
upper body obesity), BMI and percent body fat and
reported a signicantly increased adjusted risk of
periodontitis in subjects with high waisthip ratios
and higher categories of BMI, when compared with
subjects with low waisthip ratios and the lowest
category of BMI.
Grossi & Ho (97) analyzed data from the Third
National Health and Nutrition Examination
(NHANES III) to study the relationship between obe-
sity and periodontal disease and the nature of this
association. In the study, BMI was the independent
variable, periodontal disease was the dependent vari-
able, and age, gender, race, education, income, smok-
ing, and the index of insulin resistance (IR) (fasting
insulin fasting glucose) were covariates. They
reported BMI to be positively and signicantly related
to the severity of attachment loss (P < 0.0001). Over-
weight individuals with insulin resistance in the
upper 25 percentile exhibited an odds ratio of 1.48
(CL 1.131.93) for severe attachment loss, whereas
for subjects with high BMI and low insulin resistance,
the association was not signicant. The authors con-
cludedthat obesity is signicantly associatedwithper-
iodontal disease and insulin resistance mediates this
relationship. Nishimura & Murayama (167) suggest a
role for the pro-inammatory cytokine, TNF-, pro-
duced from adipose tissues in obese individuals, in
the development of insulin resistance and, in turn, its
inuence on chronic inammation, such as that seen
in periodontal disease.
While obesity has not been shown to be a risk
factor for periodontal disease, a positive association
has been clearly demonstrated. This adds periodon-
tal disease to the many other negative health effects
of obesity.
Summary
Validation of nutrition as a risk factor for periodontal
disease, necessitates longitudinal study designs,
which will clarify the timing between the deciency
state and the onset of the disease. Isolating the
effects of individual nutrients in a longitudinal study
design has proven to be extremely difcult. Hence,
there have been few studies that have demonstrated
a nutritional risk factor for periodontal disease. At
this time, only vitamin C, calcium, and hyperlipide-
mia have demonstrated statistically signicant
increased risk of periodontal disease (76, 122, 123,
131, 139, 165, 166, 168, 183).
Alcohol
Alcohol consumption in the United States has been
estimated to involve 90% of the population, and has
been associated with detrimental changes in the oral
tissues, including a higher incidence and severity of
periodontal disease (142, 170). Alcohol may affect the
periodontal tissues and constitute a risk, through a
number of different mechanisms. These may include
adverse effects on host defense, toxic effects on the
liver, interference with protein metabolism and tis-
sue healing, stimulation of bone resorption and
nally, direct toxic effects on periodontal tissue
(236).
In the past, the relationship of alcohol consump-
tion to periodontal disease has been attributed to
lifestyle or behavior factors. Most often noted are
those related to poor oral hygiene and dietary habits,
as well as the liver effects associated with chronic
alcohol abuse (142, 201, 211, 137). Recently, the rela-
tionship of alcohol consumption and the risk for an
increase in severity of periodontal disease, indepen-
dent of lifestyle factors, has been examined (211,
236).
Lifestyle effects
Sakki and co-workers (201) evaluated alcohol con-
sumption along with other lifestyle characteristics
such as toothbrushing frequency, dietary and smok-
ing habits, and physical activity in 55-year-old
Finnish citizens. Controlling for smoking and tooth-
brushing frequency, they found that the mean per-
centages of probing depths greater than 3 mm were
signicantly related to alcohol consumption of
greater than seven drinks in a 2-week period. They
reported an odds ratio of 2.52 (95% CL: 1.404.54),
and considered the alcohol effect to be related to the
individuals lifestyle. Alcohol consumption was also
one of several lifestyle factors evaluated by
Shizukuishi et al. in workers in a manufacturing com-
pany in Japan. They utilized Millers modication of
126
Stanford & Rees
the Community Periodontal Index to assess period-
ontal health, and found the Community Periodontal
Index score increased with age, but varied with life-
style. These authors reported an odds ratio of 1.8
(95% CL 1.13.1) for workers who consumed
alcohol every day when compared with workers
who did not. They suggested the excessive use of
alcohol may contribute to the development of peri-
odontal disease and recommended further studies
(211). Conversely, Yoshida and co-workers (236)
studied the relationship between tooth loss and
lifestyle factors in adult men aged 2059 years.
They performed clinical examinations, followed by
the administration of a lifestyle survey. Yoshida
reported more tooth loss for patients who did not
drink, compared with those who did. The quantity
of alcohol consumed was not included in the
survey.
Biological effects
Tezal et al. (225) assessed the relationship between
alcohol consumption and the severity of periodontal
disease as part of the Erie County Study. Alcohol
intake was obtained from validated questionnaires,
and the outcome variables included gingival bleed-
ing, clinical attachment loss, alveolar bone loss, and
presence of subgingival microorganisms. Their sta-
tistical model adjusted for age, gender, race, educa-
tion, income, smoking, diabetes mellitus, dental
plaque, and the presence of eight subgingival micro-
organisms. They found that individuals consuming
5 drinks/week had an odds ratio (OR) of 1.65 (95%
CL: 1.222.23) of having higher gingival bleeding, and
OR of 1.36 (95% CL: 1.021.80) of having more severe
clinical attachment loss compared to those consum-
ing <5 drinks/week. Those consuming 10 drinks/
week had an OR of 1.62 (95% CL: 1.122.33) of having
higher gingival bleeding and an OR of 1.44 (95%
CL: 1.042.00) of having more severe clinical attach-
ment loss compared to those consuming <10 drinks/
week. They also found alcohol consumption was
not signicantly related to alveolar bone loss or to
any of the subgingival microorganisms. There was,
however, a trend in the odds of more alveolar bone
loss with increasing levels of alcohol consumption.
These results suggest that alcohol may affect soft and
hard tissues differently, with the strongest effect
being on the gingiva. The authors evaluated the effect
of each type of alcohol (wine, beer, hard liquor)
separately, but found no differences in their effect
on the periodontium, and concluded total intake
was more important than alcohol type. The authors
stated that alcohol intake may be a mild risk indica-
tor for periodontal disease.
At this time, there is insufcient evidence to con-
sider alcohol consumption a risk factor for period-
ontal disease. Future studies should be longitudinal,
and more specic as to alcohol consumption, includ-
ing past as well as current history, and include quan-
tity, frequency, and pattern of intake.
Aging(asariskfactorforperiodontal
disease)
The current trend towards an increase in life expec-
tancy has resulted in a simultaneous increase in the
number of dentate older individuals. Thus, there are
a continually increasing number of patients (and
teeth) susceptible to periodontal disease. It has been
widely claimed that aging is a risk factor for period-
ontitis, and that elderly individuals are more suscep-
tible to periodontal disease than younger individuals.
Early studies support a close association between
age, periodontal disease and tooth loss (24, 67, 147,
185). Contemporary studies using more sophisti-
cated data analysis have reported new and, in some
cases, conicting ndings regarding this association
(21, 35, 138, 176). The basic issue is whether the
increase in prevalence and severity of periodontitis
observed in older persons is a function of time (life-
time accumulation) or a truly enhanced susceptibil-
ity (risk) of aging.
Cross-sectional studies
A number of cross-sectional studies have reported a
direct relationship between age and the prevalence
and severity of clinical attachment loss, alveolar bone
loss, and pocket depth (96, 98, 116, 137). Grossi et al.
(98) studied risk indicators for attachment loss in a
population aged 2574 years, and reported age as
the most strongly associated factor, with odds ratios
for subjects 3544 years old being 1.72 (95% CL:
1.182.49) compared to 9.01 (5.8613.89) for subjects
6574 years old. In a companion study, the same
authors found a stronger association between age
and alveolar bone loss, with odds ratios for subjects
3544 years being 2.6 (95% CL: 1.753.83) increasing
to 24.08 (95% CL: 15.9336.29) for subjects 6574
years old (96). Locker & Leake (137) examined risk
indicators and risk markers in older Canadian adults,
using mean attachment loss, with both bivariate and
multivariate analysis of the data. In both analyses,
age was among the risk indicators for periodontal
127
Acquired immune suppression for periodontal disease progression
disease. A recent review noted that cross-sectional
studies measuring disease experience should demon-
strate more attachment loss among older groups,
since clinical attachment level and bone loss are
(effectively) irreversible measures of prior disease
experience (35). Longitudinal studies that assess dis-
ease progression (or regression) have been recom-
mended as a better model to assess aging is a risk
factor for periodontal disease (137).
Longitudinal studies
Several longitudinal studies implicate age as a risk
factor for periodontal disease (4, 73, 93, 104, 116, 169,
177). Papapanu et al., using both bi- and multivariate
analysis, found age to be a signicant risk factor for
alveolar bone loss over a 10-year period, in Swedish
patients aged 2570 years (177). Ismail and co-
workers (116) reported age as a signicant risk factor
for clinical attachment loss in patients observed over
a 28-year period. They found a mean difference in
attachment level of 1.34 ( 0.78) over this time per-
iod, and reported an odds ratio of 10.38 (CL not
reported). While the reported odds ratio is highly
signicant, the mean attachment loss was less than
2 mm and is unlikely to cause tooth loss. In a short-
term study, Haffajee et al., after controlling for other
variables, found age to be a signicant risk factor for
clinical attachment loss in patients aged 2079 years
(104). Norderyd and co-workers (169) evaluated risk
factors for severe periodontal disease in a Swedish
adult population aged 2060 years, over a period of
1518 years. In the multivariate logistic regression
model, age was signicantly associated with severe
disease progression at an odds ratio of 1.13 (95% CL:
1.061.19).
An almost equal number of longitudinal studies
have failed to establish age as a risk factor for period-
ontal disease (3, 14, 22, 33, 210). Brown and co-work-
ers evaluated the effects of age on clinical attachment
levels over an 18-month period in individuals 65
years of age, and using multivariate analysis of the
data, reported no effect of age (33). Beck & Koch
reported no effects of age on clinical attachment
levels in a 3-year study of 338 people aged 65 years
(22). Ship & Beck (210) reported on 95 healthy men
and women (aged 2976 years at initial visit) from the
Baltimore Longitudinal Study of Aging over a 10-year
period. Changes in attachment levels and attach-
ment loss were assessed as a longitudinal measure
of disease progression. They reported periodontal
disease destruction (as measured by attachment
loss) occurred over time but was not related to age
or gender. The authors suggested that periodontal
diseases are not a natural consequence of the aging
process, and that advanced age is not an accurate
predictor of attachment loss. Ajwani & Ainamo (3)
studied participants in the Helsinki Aging Study,
which included 57 dentate elderly persons, in groups
aged 81, 86, and 91 years. The authors described the
study subjects as representative of the healthy old
elderly of Helsinki. Based on changes in CPITN over
time, the authors reported minor changes in the
periodontal health status. CPITN scores increased
in the code 2 (calculus, bleeds on probing) and
decreased in code 3 (45 mm pockets). They con-
cluded that periodontal disease in the relatively
healthy elderly is not caused by the aging process.
Baelum and co-workers (14) studied the progression
of periodontal disease in an adult and elderly Chi-
nese population aged 2080 years. Over a 10-year
period of observation, they found an increase in
the progression of disease with age, but not at a
statistically signicant level. They concluded that
the inuence of age was minimal. Faddy and co-
workers (73) used the CPITN to assess periodontal
disease patterns in 504 individuals, aged 1865, over
a 3-year period. They employed a data analysis
model (Markov chain model), which describes tem-
poral changes in patients levels of disease in terms of
transition probabilities, and which accounts for both
regression and progression of the disease. They
reported increasing age had no effect on disease pro-
gression in this population, but did have a signicant
effect in reducing the regression of the disease, i.e.
the relationship between age and periodontal disease
represents both the cumulative effect of the non-
reversible component of tissue destruction and the
effect of a reduced rate of repair. They also found that
the effect becomes stronger with increasing age.
Other studies
The severity of periodontal breakdown at baseline,
has been reported as a risk for future periodontal
deterioration (93, 104, 116). The association between
aging and the progression of periodontal breakdown,
controlling for baseline periodontal status, has also
been studied (15, 25). Grbic & Lamster (92) devel-
oped a hazard rate based on risk for clinical attach-
ment loss at different attachment levels and probing
depths. They reported a progressive increase in the
hazard rate with increasing initial clinical attachment
loss and probing depths. They found signicantly
higher hazard rates for individuals 6069, with initial
clinical attachment loss of 6 mm and probing depths
128
Stanford & Rees
greater than 4 mm, compared to those less than age
60 with similar initial clinical attachment levels. They
concluded that age remained a signicant risk for
clinical attachment loss after adjusting for baseline
levels of attachment. Haffajee et al. (104) evaluated
the association of baseline clinical parameters with
disease progression after 1 year in a Japanese popu-
lation. They used a logistic regression analysis of
their data, and reported that subsequent attachment
loss was strongly associated with increased levels of
attachment loss at baseline. The authors reported an
association between age and additional attachment
loss, with older subjects having an increased risk for
disease progression. However, their analysis attribu-
ted the increased risk to prior attachment loss, not to
increased age.
The effect of oral hygiene on the association
between age and risk for periodontal disease progres-
sion introduces another variable. Abdellatif & Burt
evaluated this relationship, using data from the rst
National Health and Nutrition Examination Survey
(NHANES I, 1971-1974). They found the increase in
periodontitis with age, across all age groups, to be
much higher in individuals with poor oral hygiene.
They reported the odds ratio for the association
between oral hygiene status and periodontitis as
20.52 (95% CL: 17.7523.72), while that for the asso-
ciation between increasing age and disease was only
1.24 (95% CL: 1.211.28). Their conclusion was that
the effects of age on periodontal disease progression
could be considered negligible when good oral
hygiene is maintained (1).
Cohort effect
Kornman (130) has suggested that what previously
has been thought of as an age effect, may actually
constitute a cohort effect. He explains that differ-
ence between age groups probably results from the
fact that each successive generation of adults is more
attentive to dental care and, in turn, is experiencing
better oral health. The greater number of teeth at risk
to periodontal disease is increasing as the number of
teeth per person is increasing. Consequently, there is
an increase in periodontal disease in older adults not
because age is a risk factor, but because there are
many more older adults with more teeth susceptible
to periodontal disease.
Summary
Some of the evidence reviewed here supports the
observation that the prevalence and severity of
periodontitis increases with increasing age; however,
most of the evidence, controlled for other factors,
indicates that the relationship between age and per-
iodontal disease, is age-associated, rather than a con-
sequence of aging. In risk assessment for periodontal
diseases, agingis most likelyabackgroundfactor (7).
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Acquired immune suppression for periodontal disease progression