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State of the Art Review
Pathophysiological Relationships Between Periodontitis
and Systemic Disease: Recent Concepts Involving Serum
Lipids
Anthony M. Iacopino* and Christopher W. Cutler
Periodontitis has been traditionally regarded as a
chronic inflammatory oral infection. However, recent
studies indicate that this oral disease may have pro-
found effects on systemic health. The search for cel-
lular/molecular mechanisms linking periodontitis to
changes in systemic health and systemic physiology
has resulted in the evolution of a new area of lipid
research establishing linkages between existing mul-
tidisciplinary biomedical literature, recent observa-
tions concerning the effects of serum lipids on immune
cell phenotype/function, and a heightened interest
in systemic responses to chronic localized infections.
There appears to be more than a casual relationship
between serum lipid levels and systemic health (par-
ticularly cardiovascular disease, diabetes, tissue repair
capacity, and immune cell function), susceptibility to
periodontitis, and serum levels of pro-inflammatory
cytokines. In terms of the potential relationship
between periodontitis and systemic disease, it is pos-
sible that periodontitis-induced changes in immune
cell function cause metabolic dysregulation of lipid
metabolism through mechanisms involving pro-
inflammatory cytokines. Sustained elevations of
serum lipids and/or pro-inflammatory cytokines may
have a serious negative impact on systemic health.
The purpose of this paper is to present the back-
ground, supporting data, and hypotheses related to
this concept. As active participants in this emerging
and exciting area of investigation, we hope to stimu-
late interest and awareness among biomedical sci-
entists and practitioners. J Periodontol 2000;71:1375-
1384.
KEY WORDS
Cells, immune; cytokines; lipid metabolism;
systemic health; periodontitis; diabetes mellitus;
cardiovascular diseases.
* Division of Prosthodontics, Marquette University School of Dentistry,
Milwaukee, WI.
Department of Periodontics, Baylor College of DentistryTexas A&M
Health Science Center, Dallas, TX.
J Periodontol August 2000
Chronic inflammatory periodontal disease (peri-
odontitis) represents a primarily anaerobic Gram-neg-
ative oral infection that leads to gingival inflamma-
tion, destruction of periodontal tissues, loss of alveolar
bone, and eventual exfoliation of teeth in severe
cases.1,2 It is generally accepted that certain organ-
isms within the microbial flora of dental plaque are
the major etiologic agents of periodontitis.2 These
microorganisms, particularly Porphyromonas gingi-
valis (P. gingivalis), produce endotoxins in the form
of lipopolysaccharides (LPS) that are instrumental in
generating a host-mediated tissue destructive immune
response.1,3 Traditional thinking/paradigms have
maintained that periodontitis is an oral disease and
that the tissue destructive response remains local-
ized within the periodontium, limiting effects of the
disease to oral tissues supporting the teeth. Recent
studies have indicated that periodontitis may produce
any number of alterations in systemic health. Inves-
tigators have demonstrated significant associations
between periodontitis and acute cerebral infarc-
tion/stroke,4,5 failure of joint/organ replacements and
kidney dialysis,6,7 coronary heart disease,5,8,9 pre-
term low birth weight,10-12 aspiration pneumonia,13
and diabetes.14 The notion that oral infection has the
ability to cause systemic disease is not a novel con-
cept. The theory of focal infection (seeding of path-
ogenic microorganisms as well as their virulent com-
ponents and metabolites from local foci of infection
to distant body sites) was first suggested by Hip-
pocrates and became a popular concept in terms of
the oral cavity in the 1920s.15 Resistance to this con-
cept began to build in the 1930s as convincing sci-
entific evidence failed to confirm the validity of the
theory. However, many health professionals have
remained faithful to the general principles of the oral
focal infection hypothesis.
The recent studies demonstrating relationships/
associations between periodontitis and systemic dis-
ease have been epidemiological and retrospective in
nature. This type of research can reliably identify
associations, but cannot demonstrate causation. It is
possible that periodontitis may merely be an oral
component of certain systemic disorders, may have
1375
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State of the Art Review
common etiological features of systemic disorders,
or may simply occur together with some medical
problems.15 Thus, one must exercise caution when
implicating periodontitis as the cause of major med-
ical disorders. Additional mechanistic research must
form the basis for establishing that periodontitis
causes negative changes in overall systemic health,
elucidating changes in metabolism and/or physiol-
ogy potentially responsible for observed associations.
PATHOPHYSIOLOGICAL RELATIONSHIPS
Periodontitis, Pro-Inflammatory Cytokines, and
Systemic Health
It is generally accepted that much of the periodontal
tissue destruction observed in periodontitis is host-
mediated through release of pro-inflammatory
cytokines by local tissues and immune cells in
response to the bacterial flora and its products/
metabolites, especially LPS.1,16 There have been sev-
eral pro-inflammatory cytokines implicated in the
immunopathology of periodontitis; however, some of
the most convincing evidence for destruction of the
periodontium involves interleukin-1 beta (IL-1) and
tumor necrosis factor alpha (TNF-).17-19 These
cytokines are significantly elevated in diseased peri-
odontal sites demonstrating inflammation and during
periods of active disease/tissue destruction.17,20 Addi-
tionally, they are significantly reduced after peri-
odontal therapy and return of the tissues to a healthy
state.19,20 In terms of tissue destructive effects, it is
believed that IL-1 recruits inflammatory cells, facil-
itates polymorphonuclear leukocyte (PMN) priming/
degranulation, increases synthesis of inflammatory
mediators (prostaglandins)/matrix metalloproteinases
(MMPs), inhibits collagen synthesis, and activates
both T and B lymphocytes.21-23 TNF- is a major
signal for cellular apoptosis, bone resorption, MMP
secretion, intercellular adhesion molecule (ICAM)
expression, and interleukin-6 (IL-6) production.24-26
IL-6, once produced, stimulates formation of osteo-
clasts, promotes osteoclastic bone resorption, and
facilitates T cell differentiation.26,27
Recently, there has been great interest in the sys-
temic effects of serum pro-inflammatory cytokine lev-
els potentially elevated by periodontitis. Investigators
have hypothesized that periodontitis-induced eleva-
tions of pro-inflammatory cytokines such as IL-1 and
TNF- may have a detrimental effect on the fetus and
play a major role in development of a variety of sys-
temic diseases (cardiovascular, circulatory, pulmonary,
metabolic).4-14 In fact, recent studies have suggested
that in advanced periodontitis, levels of IL-1 and TNF-
1376 Periodontitis and Systemic Disease
are sufficiently elevated in gingival crevicular fluid
(GCF) to be dumped systemically, falling within the
detectable range of biological serum assays.12,28,29
Thus, patients with advanced periodontitis could be
considered to be systemically compromised even in
the absence of overt clinical symptoms of disease.
However, these studies only measured GCF IL-1/
TNF- levels and only evaluated the cytokine release
response of LPS-stimulated peripheral blood mono-
cytes in culture. Thus, there has still been no pub-
lished documentation of periodontitis-induced eleva-
tions of serum pro-inflammatory cytokines. In addition,
there have been no hypotheses put forward that
include mechanistic details concerning how these ele-
vated serum cytokines would mediate systemic
changes in metabolism/physiology.
Diabetes, Periodontitis, Lipid Metabolism, and
Pro-Inflammatory Cytokines/Growth Factors
Diabetes mellitus is a major health problem in the
United States affecting close to 17 million people.30
Approximately 15% of diabetics are classified as type
I (insulin-dependent), a condition characterized by
abrupt onset at any age, destruction of pancreatic
islet cells, and dependence on exogenous insulin. The
more prevalent form of diabetes is type II (non-insulin
dependent or adult-onset), a condition which often
develops over a period of time, involves reduced
responsiveness of tissues to circulating insulin, and
is often controlled by diet or oral hypoglycemic
agents. Both types are characterized by hyper-
glycemia, hyperlipidemia, and associated complica-
tions.30 The 5 classic major complications of dia-
betes include microangiopathy, nephropathy,
neuropathy, macrovascular disease, and delayed
wound healing. Periodontitis has been recognized as
the sixth major complication of diabetes.31 Despite
some conflicting studies,32-34 the majority of clinical
and epidemiological evidence demonstrates that indi-
viduals with diabetes (type I and type II) tend to
have a higher prevalence and more severe/rapidly
progressing forms of periodontitis than non-diabet-
ics.35-40 Additionally, patients with poor control of
diabetes experience more periodontitis than well-con-
trolled diabetics.41-43
In both type I and type II diabetes, hyperglycemia
is often accompanied by hyperlipidemia.44-47 The
hyperlipidemia often manifests marked elevations of
low density lipoprotein cholesterol (LDL), triglycerides
(TRG), and omega-6 free fatty acids.48-50 These
serum lipid abnormalities are caused by disruption in
fatty acid metabolism and accumulation of omega-
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6 polyunsaturated fatty acids that contribute to for-
mation of LDL and TRG. Specifically, conversion of
omega-6 polyunsaturated essential fatty acids to
active metabolites is impaired because insulin defi-
ciency inhibits 6-desaturase enzyme activity. These
6-desaturated metabolites function as key compo-
nents of cell membrane structure. Increasing evi-
dence suggests that lipid composition of membranes
is a critical factor influencing cellular function.51 The
physical/chemical properties of membranes are
largely determined by the nature of fatty acids within
the phospholipid bilayer affecting receptor re-
sponses51-54 and operation of membrane-bound
enzyme systems.55-57 It has been demonstrated that
diabetes-induced changes in membrane fluidity mod-
ulate function of membrane proteins potentially
impairing cellular function/homeostasis.46,47,50 Thus,
in contrast to previous dogma concerning hyper-
glycemia, abnormal fatty acid metabolism and hyper-
lipidemia are now thought to be largely responsible
for impairments in a variety of cell types and devel-
opment of many diabetic complications.58 This is sig-
nificant because, even though effective management
of hyperglycemia results in amelioration of serum
lipid abnormalities for many type I diabetics, hyper-
lipidemia often persists in type II diabetics despite
glycemic control.46,59
Several studies have indicated that circulating
monocytes from diabetic patients exhibit an exag-
gerated inflammatory response to Gram-negative
bacterial LPS (particularly P. gingivalis LPS) releas-
ing large amounts of inflammatory mediators and
pro-inflammatory cytokines such as IL-1 and
TNF-.60-65 This hyper-responsive monocytic phe-
notype is not associated with hyperglycemia,64,65 can
exist independently of periodontitis,65 and may be
related to hyperlipidemia.66-68 Others postulate a
genetic basis in the HLA-DR and HLA-DQ gene
regions and/or polymorphisms in the promoter
regions of cytokine genes.69-71 Additionally, there is
a class of non-enzymatically glycated proteins/lipids
formed as a result of chronically elevated serum glu-
cose and lipids in the diabetic state called advanced
glycation end products (AGEs).72 It has been sug-
gested that the interaction of AGEs with monocytic
receptors also contributes to this hyper-responsive
phenotype through activation of the transcription fac-
tor NF-B increasing gene transcription for pro-
inflammatory cytokines.73-77 This systemic mono-
cytic hyper-response trait is significant in that it may
cause diabetic patients or patients with high serum
lipids to maintain continually high levels of serum
J Periodontol August 2000
State of the Art Review
pro-inflammatory cytokines predisposing them to tis-
sue breakdown and/or certain systemic diseases.
We have published findings concerning the rela-
tionship of diabetes/serum lipids and mononuclear
cell cytokine production, in which we demonstrated
that PMNs exposed to TRG exhibit a significantly
increased production of IL-1/superoxide78-80 and
that PMNs isolated from diabetic and normal patients
with high serum LDL/TRG demonstrate impaired
chemotaxis, phagocytosis, and killing.78,79 Thus, the
effects of diabetes/hyperlipidemia on PMNs appear to
be similar to those observed for peripheral blood
monocytes relative to a hyper-inflammatory response
and potential predisposition to tissue breakdown. We
performed similar studies in monocyte-derived
macrophages from rats and humans both in vitro and
in vivo demonstrating that high serum lipid levels,
whether induced by diabetes or diet, alter the phe-
notype of these cells as evidenced by specific changes
in surface marker antigens.81-83 Production of essen-
tial polypeptide growth factors such as platelet-
derived growth factor (PDGF), transforming growth
factor beta 1 (TGF-1), and basic fibroblast growth
factor (bFGF) was significantly inhibited by exposure
to LDL/TRG levels above the normal physiologic
range.82,83 This macrophage phenotype was found
to be associated with non-healing wounds and peri-
odontitis.81,84-86 Interestingly, reduction of serum lipid
levels within the physiologic range utilizing lipid-low-
ering drugs in vivo actually caused significant
increases in macrophage growth factor production.82
The existence of the diabetes and/or lipid-induced
macrophage hypo-response trait is significant in com-
bination with the observed monocyte and PMN hyper-
response traits. Reduced growth factor production at
local tissue sites may diminish repair capacity and
ability of tissues to resist pro-inflammatory cytokine
mediated breakdown.
Hyperlipidemia and Infection
Some studies have found no relationship or even an
inverse relationship between infection and hyperlipi-
demia.87 However, many recent studies have docu-
mented a relationship between infection and hyper-
lipidemia. Chronic local and acute systemic infections
have been demonstrated to induce profound changes
in the plasma concentrations of cytokines and hor-
mones leading to a catabolic state characterized by
altered lipid metabolism.88-90 The main features of
this altered metabolism are hypertriglyceridemia and
lipid oxidation. Most of the published studies concern
severe sepsis or endotoxemia;91,92 however, there is
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State of the Art Review
evidence to suggest that even low-level chronic expo-
sure to Gram-negative microorganisms and/or their
LPS can manifest a similar response.88,92 This pos-
sibility is especially interesting relative to periodon-
titis and P. gingivalis/P. gingivalis LPS as recent stud-
ies have shown that this organism can invade deep
connective tissues/vascular endothelium associated
with the periodontium,93-95 can be found within vas-
cular pathological plaques,96-98 and can elicit a cir-
culating antibody response.99-101 This suggests that
even in a localized oral infection, such as periodon-
titis, the potential exists for chronic low-level sys-
temic exposure to microorganisms/LPS leading to
generalized alterations in lipid metabolism. Indeed,
the ability of periodontitis to produce an asympto-
matic bacteremia has already been established.96,98
Studies in humans/baboons have shown a number
of cytokines are produced in response to systemic
Gram-negative LPS exposure.102-104 Two principal
cytokines involved in this response are TNF- and IL-
1. Their appearance in the plasma has a well-defined
temporal relationship indicative of a cytokine cas-
cade. TNF- is the first factor in this cascade fol-
lowed by IL-1.92,105,106 It is believed that these
cytokines exert effects on lipid metabolism by influ-
encing production of other cytokines,107,108 altering
hemodynamics/amino acid utilization of various tis-
sues involved in lipid metabolism,108,109 or modify-
ing the hypothalamic-pituitary-adrenal axis increas-
ing plasma concentrations of adrenocorticotropic
hormone, cortisol, adrenaline, noradrenaline, and
glucagon.110-113 Thus, through action of TNF- and
IL-1, exposure to microorganisms/endotoxin results
in elevated levels of free fatty acids (FFA), LDL, and
TRG. These elevations in serum lipids are thought to
arise from enhanced hepatic lipogenesis,114 increased
Figure 1.
Linkage between infection and hyperlipidemia. Infection (chronic localized or acute systemic) causes bacteremia and/or endotoxemia producing a
cytokine cascade that leads to increased levels of serum pro-inflammatory cytokines.These biological signaling molecules have myriad physiological
effects promoting enhanced lipogenesis, increased lipolysis, and reduced lipid clearance.The end result is hyperlipidemia or an accumulation of
serum FFA, LDL, and TRG.
1378 Periodontitis and Systemic Disease
adipose tissue lipolysis/blood flow,115-117 increased
synthesis or reduced clearance of TRG,90,118 and
reduced clearance of LDL due to reductions in
lipoprotein lipase activity.119,120 Thus, any condition
producing elevations in serum IL-1/TNF- has
potential to cause hyperlipidemia. In the case of peri-
odontitis, elevations of these cytokines may be medi-
ated by systemic dumping of locally produced IL-
1/TNF-12,28,29 and/or low-level asymptomatic
bacteremia/endotoxemia.96,98 This would be espe-
cially problematic in diabetic patients who may
already exhibit elevated serum lipids and a systemic
monocytic hyper-response trait.60-65 Figure 1 repre-
sents a summary of the linkage between infection
and hyperlipidemia.
Relationship Between Periodontitis and Serum
Lipid Levels
Our most recent studies80,86 involve clinical evalua-
tion/laboratory assessment of healthy and diabetic
patients (with and without periodontitis). Data from
these studies justify further investigation into the
potential linkage between periodontitis, elevated
serum lipids, and level of diabetic control. Analysis
of sera from random healthy clinic patients demon-
strated significant elevations of serum lipids and P. gin-
givalis antibody titers in patients with periodontitis
compared to patients without periodontitis. Addi-
tionally, logistic regression analysis of disease status
with serum lipids and P. gingivalis antibody titers
(odds ratios) demonstrated significant association of
the presence of disease with total serum cholesterol,
triglycerides, and P. gingivalis antibodies. A similar fol-
low-up analysis of sera from healthy clinic patients
demonstrated significant elevations of serum LDL and
TRG in patients with periodontitis compared to
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9214_IPC_AAP_553270 8/10/00 9:45 AM Page 1379
patients without periodontitis. However, the existence
of an association does not establish whether peri-
odontitis causes elevations in serum lipid levels or
whether elevations in serum lipid levels predispose to
periodontitis. Future studies are currently being
designed to answer this important question.
We have conducted human studies80,86 using gin-
gival crevicular fluid (GCF) and gingival samples
involving controls and diabetics (well controlled/
poorly controlled) without periodontitis. These data
demonstrate that even in clinically healthy gingiva, as
diabetic control decreases, there is an increase in
TRG levels, GCF/tissue IL-1 levels, and gingival
inflammation. Additional similar human studies
involved controls and diabetics (well controlled, poorly
controlled) with periodontitis. These studies demon-
strated that in diseased tissues, as diabetic control
decreases, there is an increase in TRG levels, GCF
IL-1 levels, and gingival inflammation.
HYPOTHESES AND MODELS
Our previously published studies80,82-86 have indi-
cated many potential interactions involving peri-
odontitis, diabetes, elevated serum lipid levels, tis-
sue repair, and immune cell function.
Consideration of the literature demonstrating rela-
tionships between pro-inflammatory cytokines/lipid
metabolism and observed associations between peri-
odontitis/systemic disease provides the opportunity
to develop creative and innovative hypotheses con-
cerning mechanisms by which periodontitis may
cause systemic diseases. Figure 2 outlines our basic
hypotheses and models addressing the relationship
between periodontitis and systemic disease.
Our proposed model may provide an explanation
for the severe and rapidly progressive periodontitis
observed in many diabetic patients. Exaggerated pro-
inflammatory monocytic responses to LPS, enhanced
PMN production of pro-inflammatory cytokines, and
inhibited macrophage growth factor production may
be related to diabetes-induced elevations in serum
lipid levels resulting in extremely high levels of serum
pro-inflammatory cytokines, further elevation of
serum lipids, and an even greater reduction of tissue
repair capacity. Our initial studies80,86 demonstrat-
ing that periodontitis itself elevates serum lipid lev-
els and recent studies by others demonstrating that
within diabetics,65 the degree of monocytic hyper-
responsiveness is directly related to the severity of
periodontitis certainly support this view. Synergistic
elevations in serum lipid levels produced by peri-
odontitis superimposed on diabetes may exceed the
J Periodontol August 2000
State of the Art Review
lipid threshold value necessary for exponential impair-
ment of tissue response.
Of even greater interest is a 1998 study demon-
strating that circulating monocytes may acquire this
hyper-responsive phenotype solely from long-stand-
ing severe periodontitis.29 The investigators specu-
late that the increased monocytic systemic respon-
siveness may be due to hyperlipidemia but serum
lipid levels were not evaluated. Our initial data indi-
cating that periodontitis itself can elevate serum lipid
levels provide a potential explanation for their obser-
vations. According to our model, elevated pro-inflam-
matory cytokines produced by chronic severe peri-
odontitis cause elevated serum lipid levels. This alters
immune cell function resulting in: 1) increased pro-
duction of pro-inflammatory cytokines by PMNs and
decreased production of growth factors from tissue
macrophages reducing tissue repair capacity and
leading to further tissue breakdown; and 2) a hyper-
responsive monocytic state resulting in further ele-
vations of serum pro-inflammatory cytokines and
lipids. Thus, in otherwise healthy individuals, the
potential linkage of the monocytic hyper-response
trait and systemic disease can actually begin with
periodontitis. Our previously published studies80,86
indicating that periodontitis itself elevates serum lipid
levels and P. gingivalis antibody titers also support
the literature concerning the general relationship of
infection, pro-inflammatory cytokines, and hyper-
lipidemia.87-92 When these relationships are consid-
ered within the context of the hyper-responsive
monocytic phenotype,60-65 there is additional support
for the hypotheses and models we have proposed to
explain the relationship between periodontitis and
systemic disease. Indeed, the only published study
in which hyperlipidemia was induced by exposure
to endotoxin in humans demonstrated that the sys-
temic inflammatory response was potentiated.67
Additionally, our laboratory and others have pub-
lished studies demonstrating that elevated serum
lipids, whether induced by diabetes, periodontitis, or
diet increase PMN production of pro-inflammatory
cytokines such as IL-1 and inhibit macrophage pro-
duction of essential polypeptide growth factors such
as PDGF, TGF-1, and bFGF both in vitro and at
sites of injury reducing the tissue capacity for
repair.80,82-86,121 Thus, the proposed cyclical rela-
tionship between chronic oral infection, diabetes,
serum pro-inflammatory cytokine/lipid levels, exac-
erbated tissue destruction, and systemic dis-
eases/metabolic disturbances appears to be a likely
scenario. Future studies will need to address this
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State of the Art Review

Figure 2.
Serum lipids, tissue response,
periodontitis, and systemic health: A
working model A. In an ideal situation,
an individual demonstrates a certain
serum lipid profile within the normal
physiologic range.This level is highly
variable within the upper and lower
limits at a certain set point. The set
point is influenced by diet (fat content),
inherited physiology/metabolism or
presence of systemic disease
(diabetes), and periodontal status
(periodontitis).Thus, the set point
represents a serum lipid level that is
determined by multiple factors within
each individual and approaches the
upper limits of the normal range when
conditions that elevate serum lipids are
present. In cases where periodontitis is
superimposed on any of the other
factors, the set point is shifted to the
right in a synergistic manner.The
synergism is due to the fact that
different lipid elevating mechanisms are
operative for periodontitis (increases in
serum TNF-/IL-1 levels) and other
factors such as diabetes (inhibition of
6-desaturase enzyme activity) and
inheritance/diet (genetic or behavior-
induced hyperlipidemia).The upper
limit of the physiologic range
corresponds to a threshold serum
lipid value.This threshold represents a
point at which there is a significant
change in the relationship between
serum lipid levels and tissue response.
Serum lipid levels below threshold are
related to degree of tissue response
impairment in a linear fashion; however,
once threshold is crossed, the
relationship is exponential (further
elevations in serum lipid levels cause severe impairments in tissue response). B. A cyclic relationship exists between serum lipid levels, tissue
response, periodontitis, and systemic health.The cycle may begin if serum lipid levels (LDL/TRG) rise toward the upper limit of the normal
physiologic range (diet, genetics) or beyond this threshold (diabetes). Elevated serum lipids cause altered immune cell function resulting in impaired
tissue response mainly due to increased production of pro-inflammatory cytokines such as TNF- and IL-1 by PMNs and decreased production of
essential polypeptide growth factors such as PDGF,TGF-1, and bFGF by tissue macrophages. Additionally, elevated serum lipids may cause a
systemic monocytic hyper-response trait leading to maintained elevations of serum TNF-/IL-1. Compromised tissue response may predispose to
periodontitis. Periodontitis results in further elevation of serum lipid levels through systemic actions of pro-inflammatory cytokines (IL-1/TNF-).This
leads to further impairment of tissue response and more severe periodontitis. Over time, chronic advanced periodontitis may cause and/or
contribute to systemic diseases through continual high serum levels of pro-inflammatory cytokines. Alternatively, in some patients, the cycle may
actually begin with periodontitis which serves to elevate serum lipid levels toward the upper limit of the normal physiologic range (dashed line).This
is a very provocative possibility as it outlines a potential causal relationship between periodontitis and systemic diseases.

1380 Periodontitis and Systemic Disease Volume 71 Number 8

9214_IPC_AAP_553270 8/10/00 9:45 AM Page 1381
important clinical issue through an evidence-based
approach.
ACKNOWLEDGMENT
This work was supported by NIH-NIDCR grant R29
DE11553.
REFERENCES
1. Socransky SS, Haffajee AD. The bacterial etiology
and progression of destructive periodontal disease:
current concepts. J Periodontol 1992;63:322-331.
2. Liljenberg B, Lindhe J, Dahlen G, Jonsson R. Micro-
biological, histopathological, and immunohistochem-
ical characteristics of progressive periodontal disease.
J Clin Periodontol 1994;21:720-727.
3. Offenbacher S. Periodontal diseases: pathogenesis.
Ann Periodontol 1996;1:821-878.
4. Syrjanen J, Peltola J, Valtonen V, Kaste M, Huttunen
JK. Dental infections in association with certain infarc-
tion in young and middle-aged men. J Intern Med
1989;225:179-184.
5. DeStefano F, Anda RF, Khan HS, Williamson DF, Rus-
sell CM. Dental disease and risk of coronary heart
disease and mortality. Br Dent J 1993;306:688-691.
6. Page RC. The pathobiology of periodontal diseases
may affect systemic diseases: inversion of a para-
digm. Ann Periodontol 1998;3:108-120.
7. Lowe GD. Etiopathogenesis of hemostasis, thrombo-
sis, and vascular disease. Ann Periodontol 1998;3:121-
126.
8. Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, Syr-
jala SL. Association between dental health and acute
myocardial infarction. Br Med J 1989;298:779-781.
9. Genco RJ. Periodontal disease and risk for myocar-
dial infarction and cardiovascular disease. Cardio Rev
Rep 1998;19:34-40.
10. Offenbacher S, Katz VL, Fertik GS, Collins JG, Maynor
GB. Periodontal infection as a risk factor for pre-term
low birth weight. J Periodontol 1996;67:1103-1113.
11. Dasanyake AP. Poor periodontal health of the preg-
nant woman as a risk factor for low birth weight. Ann
Periodontol 1998;3:206-211.
12. Offenbacher S, Jared HL, Wells SR, et al. Potential
pathogenic mechanisms of periodontitis associated
pregnancy complications. Ann Periodontol 1998;3:
233-250.
13. Loesche W, Lopatin DE. Interaction between peri-
odontal disease, medical diseases, and immunity in
the older individual. Periodontol 2000 1998;16:80-
105.
14. Grossi SG, Genco RJ. Periodontal disease and dia-
betes mellitus: a two-way relationship. Ann Periodontol
1998;3:20-29.
15. Slots J. Casual or causal relationship between peri-
odontal infection and non-oral disease. J Dent Res
1998;77:1764-1765.
16. Page RC. The role of inflammatory mediators in the
pathogenesis of periodontal disease. J Periodont Res
1991;26:230-242.
17. Stashenko P, Obernesser MS, Prostak L, Haffajee AD,
J Periodontol August 2000
State of the Art Review
Socransky SS. Levels of interleukin-1 in tissue sites
of active periodontal disease. J Clin Periodontol 1991;
18:548-554.
18. Heasman PA, Collins JG, Offenbacher S. Changes in
crevicular fluid levels of interleukin-1, leukotriene
B4, prostaglandin E2, thromboxane B2, and tumor
necrosis factor in experimental gingivitis in humans.
J Periodont Res 1993;28:241-247.
19. Gemmell E, Marshall RI, Seymour GJ. Cytokines and
prostaglandins in immune homeostasis and tissue
destruction in periodontal disease. Periodontol 2000
1997;14:112-143.
20. Offenbacher S, Collins JG, Heasman PA. Diagnostic
potential of host response mediators. Adv Dent Res
1993;7:175-181.
21. Butler LD, Layman NK, Sharp J, Bedate AM. Inter-
leukin-1 induced pathophysiology. Clin Immunol
Immunopathol 1989;53:400-406.
22. Fujihashi K, Kono Y, Beagley KW. Cytokines and
periodontal disease: immunopathological role of
interleukins in B cell responses within chronically
inflamed gingival tissues. J Periodontol 1993;64:400-
406.
23. Hayashi J, Saito I, Ishikawa I, Miyasaka N. Effects of
cytokines and periodontopathic bacteria on gingival
fibroblasts in adult periodontitis. Infect Immun 1994;
62:5205-5212.
24. Birkedal-Hansen H. Role of cytokines and inflamma-
tory mediators in tissue destruction. J Periodont Res
1993;28:500-510.
25. Wiebe SH, Hafezi M, Sandhu HS, Sims SM, Dixon SJ.
Osteoclast activation in inflammatory periodontal dis-
eases. Oral Dis 1996;2:167-180.
26. Yamamoto M, Fujihashi K, McGhee JR, Van Dyke TE,
Kiyono H. Molecular and cellular mechanisms for peri-
odontal diseases: role of cytokines in induction of
mucosal inflammation. J Periodont Res 1997;32:115-
119.
27. Neta R, Sayers TJ, Oppenheim JJ. Relationship of
TNF to interleukins. Immunol Series 1992;56:499-
566.
28. Prabhu A, Michalowicz BS, Mathur A. Detection of
local and systemic cytokines in adult periodontitis. J
Periodontol 1996;67:515-522.
29. Salvi GE, Brown CE, Fujihashi K, Kiyono H, Beck JD,
Offenbacher S. Inflammatory mediators of the termi-
nal dentition in adult and early onset periodontitis. J
Periodont Res 1998;4:212-225.
30. Cowie CC, Eberhardt MS. American Diabetes Associ-
ation Vital Statistics. Washington, DC: American Dia-
betes Association; 1996:13-20.
31. Le H. Periodontal disease: the sixth complication of
diabetes mellitus. Diabetes Care 1993;16:329-334.
32. Beneviste R, Conneally PM. Periodontal disease in
diabetics. J Periodontol 1967;38:271-279.
33. Hore KA, Stallard RE. Diabetes and the periodontal
patient. J Periodontol 1970;41:713-718.
34. Barnett ML, Baker RL, Yancey JM, MacMillan DR,
Kotoyan M. Absence of periodontitis in a population
of insulin-dependent diabetes mellitus patients. J Peri-
odontol 1984;55:402-405.
35. Cianciola LJ, Park BH, Bruck E, Mosovich L, Genco
Iacopino, Cutler 1381
9214_IPC_AAP_553270 8/10/00 9:45 AM Page 1382
State of the Art Review
RJ. Prevalence of periodontal disease in insulin-
dependent diabetes mellitus. J Am Dent Assoc 1982;
104:653-660.
36. Emrich L, Shlossman M, Genco R. Periodontal dis-
ease in non-insulin-dependent diabetes mellitus. J
Periodontol 1991;62:123-130.
37. Katz PP, Wirthlin MR, Selby JV, Sepe SJ, Showstack
JA. Epidemiology and prevention of periodontal dis-
ease in individuals with diabetes. Diabetes Care 1991;
14:375-385.
38. Saftkan-Seppala B, Ainamo J. Periodontal conditions
in insulin-dependent diabetes mellitus. J Clin Peri-
odontol 1992;19:24-29.
39. Haber J, Wattles J, Crowley R, Mandell R, Joshipura
K, Kent R. Assessment of diabetes as a risk factor for
periodontitis. J Dent Res 1991;70:414-415.
40. Grossi SG, Zambon JJ, Machtei EE, Norderyd OM,
Genco RJ. Assessment of risk for periodontal disease.
J Periodontol 1994;65:260-267.
41. Ervasti T, Knuuttila M, Pohyamo L, Haukipuro K. Rela-
tionship between control of diabetes and gingival
bleeding. J Periodontol 1985;56:154-157.
42. Tervonen T, Knuuttila M. Relation of diabetes con-
trol to periodontal pocketing and alveolar bone level.
Oral Surg Oral Med Oral Pathol 1986;61:346- 349.
43. Seppala B, Ainamo J. A site-by-site follow-up study
on the effect of controlled versus poorly controlled
insulin-dependent diabetes mellitus. J Clin Periodon-
tol 1994;21:161-165.
44. Howard BVL. Lipoprotein metabolism in diabetes. J
Lipid Res 1987;28:613-628.
45. Merrin PK, Elkeles RS. Treatment of diabetes: the
effect on serum lipids and lipoproteins. Postgrad Med
J 1991;67:931-937.
46. Gary A. Lipid lowering therapy and macrovascular
disease in diabetes. Diabetes 1992;41:111-115.
47. Kim DK, Escalante DA, Garber AJ. Prevention of ath-
erosclerosis in diabetes: emphasis on treatment for
the abnormal lipoprotein metabolism of diabetes. Clin
Ther 1993;15:766-778.
48. Tilvis RS, Miettinan TA. Fatty acid composition of
serum lipids, erythrocytes, and platelets in insulin-
dependent diabetics. J Clin Endocrinol Metab 1985;61:
741-745.
49. Horrobin DF. The roles of essential fatty acids in the
development of diabetic neuropathy and other com-
plications of diabetes mellitus. Prostaglandins Leukot
Essent Fatty Acids 1988;31:181-197.
50. Arisaka M, Arisaka O, Yamashiro Y. Fatty acid and
prostaglandin metabolism in diabetes mellitus: the
effect of evening primrose oil supplementation on
serum fatty acid and plasma prostaglandin levels.
Prostagland Leukotr Essential Fatty Acids 1991;43:
197-201.
51. Dutta-Roy AK. Lipid metabolism. Curr Opin Lipidol
1993;4:8-9.
52. Hagve TA. Effects of unsaturated fatty acids on cell
membrane functions. Scand J Clin Lab Invest 1988;
48:381-388.
53. Poisson JP. Animal models of abnormalities in essen-
tial fatty acid metabolism in diabetes mellitus. Adv
Fatty Acid Res 1993;34:1-14.
1382 Periodontitis and Systemic Disease
54. Clarke SD, Jump DB. Regulation of gene expression
by polyunsaturated fatty acids. Prog Lipid Res 1993;
32:139-149.
55. Stubbs CD, Smith AD. The modification of mam-
malian membrane polyunsaturated fatty acid com-
position in relation to membrane fluidity and function.
Biochim Biophys Acta 1998;779:89-137.
56. Wahle KWJ. Dietary regulation of essential fatty acid
metabolism and membrane phospholipid composi-
tion. Biochem Soc Trans 1990;18:775-778.
57. Clandinin MT, Cheema S, Field CJ. Dietary fat: exoge-
nous determination of membrane structure and cell
function. FASEB J 1991;5:2761-2769.
58. Dutta-Roy AK. Insulin-mediated processes in platelets,
erythrocytes, and monocyte/macrophages: effects of
essential fatty acid metabolism. Prostaglandins Leukot
Essent Fatty Acids 1994;51:385-399.
59. Howard BV, Schniederman N, Falkner B, Laws A.
Insulin, health behaviors, and lipid metabolism. Metab-
olism 1993;42:25-35.
60. Molvig J. A model of the pathogenesis of insulin-
dependent diabetes mellitus. Dan Med Bull 1992;39:
509-541.
61. Pociot F, Briant L, Molvig J, Nerup J, Cambon-Thom-
sen A. Association of tumor necrosis factor (TNF)
and class II major histocompatibility complex alleles
with the secretion of TNF by human mononuclear
cells: a possible link to insulin-dependent diabetes
mellitus. Eur J Immunol 1993;23:224-231.
62. Yalda B, Offenbacher S, Collins JG. Diabetes as a
modifier of periodontal disease expression. Periodon-
tol 2000 1994;6:37-49.
63. Salvi GE, Yalda B, Collins JG, Arnold RR, Offenbacher
S. Inflammatory mediator response as a potential risk
marker for periodontal diseases in IDDM patients. J
Periodontol 1997;68:127-135.
64. Salvi GE, Collins JG, Yalda B, Arnold RR, Lang NP,
Offenbacher S. Monocytic TNF- secretion patterns
in IDDM patients with periodontal diseases. J Clin Peri-
odontol 1997;24:8-16.
65. Salvi GE, Beck JD, Offenbacher S. PGE2, IL-1, and
TNF- responses in diabetics as modifiers of peri-
odontal disease expression. Ann Periodontol 1998;
3:40-50.
66. Craig TE, Jackson RL, Ohlweiler DF, Ku G. Multiple
lipid oxidation products in low density lipoproteins
induce interleukin-1 beta release from human blood
mononuclear cells. J Lipid Res 1994;35:417-427.
67. Van der Poll T, Braxton CC, Coyle SM, Calvano SE,
Hack CE, Lowry SF. Effect of hypertriglyceridemia
on endotoxin response in humans. Infect Immun 1995;
63:3396-4000.
68. Jovinge S, Ares M, Kallin B, Nilsson J. Human
monocytes/macrophages release TNF- in response
to ox-LDL. Arterioscler Thromb Biol 1996;16:1573-
1579.
69. Pociot F, Molvig J, Baek L, Nerup J. A tumor necro-
sis factor gene polymorphism in relation to monokine
secretion and insulin-dependent diabetes mellitus. J
Immunol 1991;33:37-49.
70. Reinhardt RA, Maze CA, Seagren-Alley CD, Dubois
LM. HLA-D types associated with type I diabetes and
Volume 71 Number 8
9214_IPC_AAP_553270 8/10/00 9:45 AM Page 1383
periodontitis. J Dent Res 1991;70:414-415.
71. Takashiba S, Van Dyke TE, Shapira L, Amar S.
Lipopolysaccharide-inducible and salicylate-sensitive
nuclear factors of the human tumor necrosis factor
alpha promoter. Infect Immun 1995;63:1529-1534.
72. Schmidt AM, Yan SD, Brett J. Regulation of human
mononuclear phagocyte migration by surface binding
protein for advanced glycation end products. J Clin
Invest 1993;92:2155-2168.
73. Vlassara H, Brownlee M, Manogue K, Dinarello CA,
Pasagian A. Cachectin/TNF and IL-1 induced by glu-
cose-modified proteins: role in normal tissue remod-
eling. Science 1988;240:1546-1548.
74. Neeper M, Schmidt AM, Stern D. Cloning and expres-
sion of RAGE: a cell surface receptor for advanced
glycation end products. J Biol Chem 1992;267:14998-
15004.
75. Collins T. Endothelial nuclear factor KB and the ini-
tiation of the atherosclerotic lesion. Lab Invest 1993;
68:499-508.
76. Schmidt AM, Hori O, Brett J. Cellular receptors
for advanced glycation end products: implications
for induction of oxidant stress and cellular dysfunc-
tion. Arterioscler Thromb Biol 1994;14:1521-1528.
77. Morohoshi M, Fujisawa K, Uchimura I. The effect of
glucose and advanced glycosylation end products on
IL-6 production by human monocytes. Ann New York
Acad Sci 1995;748:562-570.
78. Uhlinger DJ, Cutler CW, Arnold RR, Lambeth JD, Mer-
rill AH. Functional differences in human neutrophils
isolated pre and post-prandially. Fed Eur Biochem Soc
1991;286:28-32.
79. Cutler CW, Eke P, Arnold RR, Van Dyke TE. Defec-
tive neutrophil function in insulin-dependent diabetes
mellitus: a case report. J Periodontol 1991;62:394-
401.
80. Cutler CW, Shinedling EA, Nunn M, et al. Association
between periodontitis and hyperlipidemia: cause or
effect? J Periodontol 1999;70:1429-1434.
81. Doxey DL, Nares S, Park B, Trieu C, Cutler CW,
Iacopino AM. Diabetes-induced impairment of macro-
phage cytokine release: role of serum lipids. Life Sci
1998;63:1127-1136.
82. Doxey DL, Cutler CW, Iacopino AM. Diabetes pre-
vents periodontitis-induced increases in gingival
PDGF-B and IL-1 in a rat model. J Periodontol 1998;
69:113-119.
83. Chu X, Newman J, Park B, Nares S, Ordonez G,
Iacopino AM. In vitro alteration of macrophage phe-
notype and function by serum lipids. Cell Tiss Res
1999;296:331-337.
84. Iacopino AM. Diabetic periodontitis: possible lipid-
induced defect in tissue repair through alteration of
macrophage phenotype and function. Oral Dis 1995;1:
214-229.
85. Doxey DL, Dill RE, Iacopino AM. Platelet-derived
growth factor levels in wounds of diabetic rats. Life Sci
1995;57:1111-1123.
86. Cutler CW, Machen RL, Jotwani R, Iacopino AM.
Heightened gingival inflammation and attachment loss
in type II diabetics with hyperlipidemia. J Periodontol
1999;70:1313-1321.
J Periodontol August 2000
State of the Art Review
87. Lopes-Virella MF. Interactions between bacterial
lipopolysaccharides and serum lipoproteins and their
possible role in coronary heart disease. Eur Heart J
1993;14:118-124.
88. Gallin JI, Kaye D, OLeary WM. Serum lipids in infec-
tion. N Engl J Med 1969;281:1081-1086.
89. Alvarez C, Ramos A. Lipids, lipoproteins, and apopro-
teins in serum during infection. Clin Chem 1986;32:
142-145.
90. Samra JS, Summers LKM, Frayn KN. Sepsis and fat
metabolism. Br J Surg 1996;83:1186-1196.
91. Kaufmann RL, Matson CF, Beisel WR. Hypertriglyc-
eridemia produced by endotoxin: role of impaired
triglyceride disposal mechanisms. J Infect Dis 1976;
133:548-555.
92. Casey LC, Balk RA, Bone RC. Plasma cytokine and
endotoxin levels in patients with sepsis syndrome.
Ann Intern Med 1993;119:771-778.
93. Meyer DH, Mintz KP, Fives-Taylor PM. Models of inva-
sion of enteric and periodontal pathogens: a com-
parative analysis. Crit Rev Oral Biol Med 1997;8:389-
409.
94. Njoroge T, Genco RJ, Sojar HT, Hamada N, Genco
CA. A role for fimbriae in Porphyromonas gingivalis
invasion of oral epithelium. Infect Immun 1997;65:
1980-1984.
95. Deshpande RG, Khan MB, Genco CA. Invasion of aor-
tic and heart endothelial cells by Porphyromonas gin-
givalis. Infect Immun 1998;66:5337-5343.
96. Loesche WJ. Association of the oral flora with impor-
tant medical diseases. Curr Opin Periodontol 1997;
4:21-28.
97. Herzberg MC, Weyer MW. Dental plaque, platelets,
and cardiovascular diseases. Ann Periodontol 1998;3:
151-160.
98. The American Academy of Periodontology: Peri-
odontal disease as a potential risk factor for systemic
diseases (Position Paper). J Periodontol 1998;69:841-
850.
99. Colombo AP, Sakellari D, Haffajee AD, Tanner A, Cug-
ini MA, Socransky SS. Serum antibodies reacting with
subgingival species in refractory periodontitis sub-
jects. J Clin Periodontol 1998;25:596-604.
100. Lamster IB, Kaluszhner-Shapira I, Herrera-Abreu M,
Sinha R, Grbic JT. Serum IgG antibody response to
Actinobacillus actinomycetemcomitans and Porphy-
romonas gingivalis: implications for periodontal diag-
nosis. J Clin Periodontol 1998;25:510-516.
101. Pietrzak ER, Polak B, Walsh LJ, Savage NW, Sey-
mour GJ. Characterization of serum antibodies to Por-
phyromonas gingivalis in individuals with and with-
out periodontitis. Oral Microbiol Immunol 1998;13:
65-72.
102. Hesse DG, Tracey KJ, Fong Y. Cytokine appearance
in human endotoxemia and primate bacteremia. Surg
Gynecol Obstet 1988;166:147-153.
103. Michie HR, Manogue KR, Spriggs DR. Detection
of circulating tumor necrosis factor after endo-
toxin administration. N Engl J Med 1988;318:
1481-1486.
104. Koopmans R, Hoek FJ, van Deventer SJH, van der
Poll T. Model for whole body production of tumor
Iacopino, Cutler 1383
9214_IPC_AAP_553270 8/10/00 9:45 AM Page 1384

State of the Art Review

necrosis factor-alpha in experimental endotoxemia in 118. Feingold KR, Staprans I, Memon RA. Endotoxin
healthy subjects. Clin Sci 1994;87:459-465. rapidly induces changes in lipid metabolism that pro-
105. Dinarello CA, Wolff SM. The role of interleukin-1 in duce hypertriglyceridemia: low doses stimulate
disease. N Engl J Med 1993;328:106-113. hepatic triglyceride production and inhibit clearance.
106. Van der Poll T, Saurwein HP. Tumor necrosis factor- J Lipid Res 1992;33:1765-1776.
alpha: its role in the metabolic response to sepsis. 119. Fried SK, Zechner R. Tumor necrosis factor decreases
Clin Sci 1993;84:247-256. human adipose tissue lipoprotein lipase mRNA lev-
107. Van der Poll T, Romijn JA, Endert E, Borm JJJ, Buller els, synthesis, and activity. J Lipid Res 1989;30:1917-
HR, Sauerwein HP. Tumor necrosis factor mimics the 1923.
metabolic response to infection in healthy humans. 120. Lanza-Jacoby S, Tabares A. Triglyceride kinetics, tis-
Am J Physiol 1991;261:457-465. sue lipoprotein lipase, and liver lipogenesis in septic
108. Moldawer LL. Biology of pro-inflammatory cytokines rats. Am J Physiol 1990;258:678-685.
and their antagonists. Crit Care Med 1994;22:3-7. 121. Malden LT, Chait A, Raines EW, Ross R. The influ-
109. Fukushima R, Saito H, Taniwaka K. Different roles of ence of oxidatively modified LDL on expression of
IL-1 and TNF on hemodynamics, amino acid metab- platelet-derived growth factor by human monocyte-
olism in dogs. Am J Physiol 1992;262:275-281. derived macrophages. J Biol Chem 1991;262:6046-
110. Gwosdow AR, Kumar MSA, Bode HH. Interleukin-1 6049.
stimulation of the hypothalamic-pituitary-adrenal axis.
Am J Physiol 1990;258:65-70. Send reprint requests to: Dr. Anthony M. Iacopino, Divi-
111. Imura H, Fukata J, Mori T. Cytokines and endocrine sion of Prosthodontics, Marquette University School of Den-
function: an interaction between the immune and neu- tistry, P.O. Box 1881, Milwaukee, WI 53201-1881. Fax:
roendocrine systems. Clin Endocrinol 1991;35:107- 414/288-3586; e-mail: Anthony.Iacopino@Marquette.edu
115.
112. Chrousos GP. The hypothalamic-pituitary-adrenal axis Accepted for publication February 10, 2000.
and immune-mediated inflammation. N Engl J Med
1995;332:1351-1362.
113. Hauner H, Petruschke T, Russ M, Rohrig K, Eckel J.
Effects of tumor necrosis factor alpha on glucose
transport and lipid metabolism of human fat cells in
culture. Diabetologia 1995;38:764-771.
114. Feingold KR, Grunfeld C. Tumor necrosis factor alpha
stimulates hepatic lipogenesis in the rat in vivo. J
Clin Invest 1987;80:184-190.
115. Divertie GD, Jensen MD, Miles JM. Stimulation of
lipolysis in humans by physiological hypercorti-
solemia. Diabetes 1991;40:1228-1232.
116. Simonsen L, Bulow J, Madsen J, Christensen NJ.
Response to epinephrine in the forearm and abdom-
inal subcutaneous adipose tissue. Am J Physiol 1992;
263:850-855.
117. Kurpad A, Khan K, Calder AG. Effect of noradrena-
line on glycerol turnover and lipolysis in the whole
body and subcutaneous adipose tissue. Am J Phys-
iol 1992;263:850-855.

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