Periodontal Diseaseand Overall Health

ii
Periodontal Disease and Overall Health: A Clinician’s Guide

Second Edition
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iii
CONTRIBUTORS
Silvana P. Barros, DDS, MS, PhD William V. Giannobile, DDS, DMedSc
Associate Professor Najjar Endowed Professor of Dentistry
Department of Periodontology Chair, Department of Periodontics and
School of Dentistry, University of North Carolina Oral Medicine
Chapel Hill, NC, USA University of Michigan School of Dentistry
Professor of Biomedical Engineering
P. Mark Bartold, BDS, DDSc, PhD, College of Engineering
FRACDS (Perio) Ann Arbor, MI, USA
Professor of Periodontology
Director, Colgate Australian Clinical Dental Ricardo A. Gómez, MD
Research Centre Director
University of Adelaide Centro de Diagnóstico, Investigaciones Perinatales
Department of Dentistry e Innovación Docente (CEDIP),
Adelaide, South Australia Hospital Padre Hurtado
Professor, Universidad del Desarrollo
Yiorgos A. Bobetsis, DDS, PhD Chief of Unidad de Medicina Materno-Fetal y
Lecturer, Department of Periodontology Ultrasonido de Clínica Santa María
National and Kapodistrian University of Athens Santiago, Chile
School of Dentistry
Athens, Greece
Ying Gu, DDS, PhD
Wenche Sylling Borgnakke, DDS, MPH, PhD Assistant Professor
Department of Periodontics and Oral Medicine Department of General Dentistry
University of Michigan School of Dentistry Stony Brook University
Ann Arbor, MI, USA School of Dental Medicine
Stony Brook, NY, USA
Dawn Caster, MD
Assistant Professor Casey Hein, BSDH, MBA
Division of Nephrology Assistant Professor, Division of Periodontics
Department of Internal Medicine Faculty of Dentistry
University of Louisville School of Medicine Director of Education, International Centre
Louisville, KY, USA for Oral-Systemic Health
Assistant Professor, Division of Continuing
Noel Claffey, BDS, MDent Sc, FDS, FFD, FTCD Professional Development
Professor of Periodontology Faculty of Medicine
Dental School and Hospital Director of Interprofessional
Trinity College Dublin Continuing Development
Dublin, Ireland University of Manitoba
Manitoba, Canada
Robert J. Genco, DDS, PhD
SUNY Distinguished Professor of Oral Biology
and Microbiology William C. Hsu, MD
Vice Provost Senior Physician
University at Buffalo Medical Director, Asian Clinic
Office of Science, Technology Transfer and Joslin Diabetes Center
Economic Outreach Assistant Professor of Medicine
Baird Research Park Harvard Medical School
Amherst, NY, USA Boston, MA, USA
iv CONTRIBUTORS
Srividya Kidambi, MD, MS Angelo Mariotti, DDS, PhD

Assistant Professor of Medicine Professor and Chair
Medical College of Wisconsin Division of Periodontology
Milwaukee, WI, USA The Ohio State University
College of Dentistry
Denis F. Kinane, BDS, PhD, FDSRCS, Columbus, OH, USA
FDSRCPS
Dean, University of Pennsylvania School of Joseph M. Mylotte, MD
Dental Medicine Professor of Medicine Emeritus
Philadelphia, PA, USA Department of Medicine
University at Buffalo
James A. Kinane, MBChB School of Medicine and Biomedical Sciences
Buffalo, NY, USA
Junior House Officer, Ninewells Hospital
University of Dundee
Timothy C. Nichols, MD
Dundee, Scotland, UK Professor of Medicine, Pathology, and
Laboratory Medicine
Evanthia Lalla, DDS, MS Director, Francis Owen Blood Research Laboratory
Professor of Dental Medicine University of North Carolina at Chapel Hill
Columbia University College of Dental Medicine Chapel, Hill, NC, USA
New York, NY, USA
Steven Offenbacher, DDS, PhD, MMSc
Ira B. Lamster, DDS, MMSc WR Kenan Jr., Distinguished Professor
Professor of Health Policy & Management Chair, Department of Periodontology
Mailman School of Public Health Director, Center for Oral and Systemic Diseases
Dean Emeritus North Carolina Oral Health Institute
Columbia University College of Dental Medicine UNC School of Dentistry
Chapel Hill, NC, USA
Bruno G. Loos, DDS, MSc, PhD
Professor and Chair David Paquette, DMD, MPH, DMSc
Department Periodontology and Professor and Associate Dean for Education
Oral Biochemistry Stony Brook University School of Dental Medicine
ACTA (Academic Centre for Stony Brook, NY, USA
Dentistry Amsterdam)
University of Amsterdam and VU University Shailendra B. Patel, BM, ChB, DPhil, FRCP
Amsterdam Staff Attending, Clement J. Zablocki VAMC
Amsterdam, The Netherlands Professor of Medicine, Division of Endocrinology,
Metabolism and Clinical Nutrition
Néstor J. López, DDS Medical College of Wisconsin
Professor of Periodontology Milwaukee, WI, USA
University of Chile School of Dentistry
Santiago, Chile Ioannis Polyzois, DMD, PhD, MDentCh,
MMedSci
Phoebus N. Madianos, DDS, PhD Associate Professor, Department of Restorative
Professor, Department of Periodontology Dentistry and Periodontology
National and Kapodistrian University of Athens Dublin Dental School & Hospital
School of Dentistry Trinity College Dublin
Athens, Greece Dublin, Ireland
CONTRIBUTORS v
Hector F. Rios, DDS, PhD Thomas E. Van Dyke, DDS, PhD

Assistant Professor, Department of Periodontics Vice President for Clinical and
and Oral Medicine Translational Research
University of Michigan School of Dentistry Chair, Department of Applied Oral Sciences
Ann Arbor, MI, USA Center for Periodontology
Senior Member of the Staff
Maria Emanuel Ryan, DDS, PhD The Forsyth Institute
Professor and Chair Cambridge, MA, USA
Oral Biology and Pathology
Medical Staff University Hospital Ray C. Williams, DMD
Stony Brook University School of Dental Medicine Professor, Department of Periodontology
Stony Brook, NY, USA School of Dental Medicine
Stony Brook University
Frank A. Scannapieco, DMD, PhD Stony Brook, NY, USA
Professor and Chair
Department of Oral Biology
University at Buffalo
School of Dental Medicine
Buffalo, NY, USA
From the Editors
Dear Colleagues:
We are very pleased to have had the privilege of assembling and editing the 2nd Edition of the textbook,
Periodontal Disease and Overall Health: A Clinician’s Guide.
The relationship of oral disease to overall disease is certainly not a new concept. For centuries, the role of
oral infection and inflammation in contributing to diseases elsewhere in the body has been studied and
reported. Going back to ancient times in Greece, we learn that Hippocrates treated two patients suffering
from joint pain by removal of teeth. Clearly, this was an early example of oral disease being associated with
afflictions elsewhere in the body. Then, moving forward in time from 1912 to around 1950, the era of “focal
infection” dominated our thinking. Reports by individuals such as WD Miller, William Hunter, and Frank
Billings noted that in their opinion many of the diseases of humans could be traced to infections elsewhere
in the body, such as the teeth and gums, the tonsils, or the sinuses. While these observations were not
supported by sound scientific evidence, and in fact led to largely incorrect practices, they nonetheless
brought attention to the effect of the mouth on the rest of the body.
Then in 1989, with a series of intriguing reports from Finland, the current interest in the role of oral health
and disease on contributing to general health and systemic conditions was launched. Kimmo Mattila and
his coworkers reported that individuals presenting to the emergency room with a myocardial infarction were
overwhelmingly likely to have periodontal disease. Might periodontal disease be a risk factor for
cardiovascular disease? Since then, a phenomenal body of work has been directed at understanding how
periodontal disease might affect distant sites and organs, and thus have an effect on overall health.
Recent studies of the human microbiome using DNA sequencing technologies have revealed new insights
into the possible mechanisms that help explain how oral infections can occur in distinct sites such as
atheromas, the colon, and reproductive tissues. These findings, pointing to a “mobile microbiome,” and
other new research findings are included in this revision.
Renowned clinicians and scientists worldwide have studied the relationship of periodontal disease to overall
health and disease, and along the way several conferences and workshops have been convened to examine
the evidence to date for the relationship between periodontal disease and the risk for systemic conditions. At
one of those conferences, in January 2008, we discussed the need for a textbook that would summarize and
put into context the current information on periodontal disease and systemic disease together for students
of dentistry and medicine. Happily for us, Foti Panagakos and his team at the Colgate-Palmolive Company
agreed to support, through an educational grant to the publisher, the undertaking of this textbook. We were
fortunate to have assembled a group of respected and scholarly clinicians and scientists who, in 18 chapters,
provide a current and thoughtful perspective on the relationship of periodontal disease to systemic
conditions.
It is a pleasure to present the second edition of this textbook. We hope you find it useful and that you enjoy it.
Sincerely,
Robert J. Genco, DDS, PhD Ray C. Williams, DMD

Dear Reader:
I am delighted to be presenting the Second Edition of the textbook Periodontal Disease and Overall Health:
A Clinician’s Guide. And how appropriate that we launch this new edition at a time when we commemorate
the 100th anniversary of the American Academy of Periodontology, an organization dedicated to
improving the overall health of patients.
The dynamic nature of the science behind the oral-systemic relationship demanded an update based on new
learnings since the textbook was first published in 2010. It is noteworthy that nearly all of our contributing
authors in the first edition concurred with this assessment and are on board for the second edition.
This edition is the result of a 15-month updating process based on the most contemporary thinking behind
what the dental and medical literature suggest is an association between oral and systemic diseases. As
before, the book delves into the sciences behind diabetes mellitus, atherosclerosis, adverse pregnancy events,
respiratory diseases, osteoporosis, rheumatoid arthritis, and cancer; looks at risk factors in common with
periodontal disease, such as inflammatory processes; then, logically, follows with a discussion of the steps
needed for comprehensive comanagement of the diseases by both dental and medical caregivers.
This Second Edition of Periodontal Disease and Overall Health: A Clinician’s Guide has been developed to
serve as a resource for dental students, dental hygiene students, medical students, faculty members of dental
schools, dental hygiene programs, and medical schools, and for practicing dental and medical professionals.
As alliances between the dental and medical professions grow, we believe this textbook will provide
important information to facilitate a more effective collaboration relative to the patients they treat.
We would like to again express our deep appreciation to the book’s Editors, Dr. Robert J. Genco and Dr.
Ray C. Williams. It was through their knowledge of this vitally important subject, their professional
relationships with the key opinion leaders doing research in this field, their backgrounds as highly regarded
researchers and educators in dentistry, and their encouragement to publish an update to our 2010 edition
that we are able to bring you this significant work.
Since the launch of its first toothpaste in 1873, the Colgate-Palmolive Company has been a world leader in
oral care, both through cutting-edge therapeutics, as well as important educational services to the dental
professions. The Second Edition of Periodontal Disease and Overall Health: A Clinician’s Guide, which has
been produced and distributed through an educational grant from the company (by which the company
provided funding to the publisher), is a prime example of our continuing commitment to ensuring the
dental professions’ education.
Sincerely,
Fotinos S. Panagakos, DMD, PhD

Global Director, Scientific Affairs
The views expressed in this textbook are those of the authors, not necessarily those of the
Colgate-Palmolive Company.
viii
CONTENTS
CHAPTER 1 1
Overview
Robert J. Genco, Ray C. Williams
CHAPTER 2 6
Periodontal Diseases: Classification,
Epidemiology, Pathogenesis, and Management
Ying Gu, Maria Emanuel Ryan, Bruno G. Loos
CHAPTER 3 30
Infection and Inflammation
Phoebus Madianos, Yiorgos A. Bobetsis, Thomas Van Dyke
CHAPTER 4 49
History of the Oral-Systemic Relationship
Noel M. Claffey, Ioannis N. Polyzois, Ray C. Williams
CHAPTER 5 63
Diabetes Mellitus: A Medical Overview
Srividya Kidambi, Shailendra B. Patel
CHAPTER 6 99
Hyperglycemia/Diabetes Mellitus and Periodontal Infection
Adversely Affect Each Other
Wenche S. Borgnakke
CHAPTER 7 123
Atherosclerosis: A Pervasive Disease Affecting Global Populations
Timothy C. Nichols
CHAPTER 8 131
Association Between Periodontal Disease and Atheromatous Diseases
David W. Paquette, Robert J. Genco
CHAPTER 9 152
Adverse Pregnancy Effects
Silvana P. Barros, Steven Offenbacher
CHAPTER 10 176
Oral Health and Diseases of the Respiratory Tract
Frank A. Scannapieco, Joseph M. Mylotte
CONTENTS ix
CHAPTER 11 193
Osteoporosis
Hector F. Rios, William V. Giannobile
CHAPTER 12 214
Periodontitis and Rheumatoid Arthritis
P. Mark Bartold, Angelo J. Mariotti
CHAPTER 13 231
Periodontal Diseases and Cancer
CHAPTER 14 252
Dental and Medical Comanagement of Patients with Diabetes
Evanthia Lalla, William Hsu, Ira B. Lamster
CHAPTER 15 275
Dental and Medical Comanagement of Cardiovascular Disease
Timothy C. Nichols, David W. Paquette
CHAPTER 16 287
Dental and Medical Comanagement of Pregnancy
Néstor J. López, Ricardo A. Gómez
CHAPTER 17 308
Dental and Medical Comanagement of Osteoporosis,
Kidney Disease, and Cancer
Dawn J. Caster, James A. Kinane, Denis F. Kinane
CHAPTER 18 327
Role of the Professional in Educating the Public
About the Importance of Oral Health
Casey Hein
INDEX 345
“A person can’t have good general health without good oral health.”
—Former U.S. Surgeon General C. Everett Koop

CHAPTER 1
Overview
Robert J. Genco, Ray C. Williams
“A person can’t have good general health without good oral health.”
—Former U.S. Surgeon General C. Everett Koop
INTRODUCTION Alzheimer’s disease (83,494), and diabetes

We welcome you to the Second Edition of (69,071). Five of these, including heart
Periodontal Disease and Overall Health: A disease, cancer, respiratory disease, stroke,
Clinician’s Guide. Research into the relation- and diabetes, are chronic diseases related to
ship between periodontal disease and general periodontal disease.1 By successfully meeting
health continues to emerge at a rapid pace. the challenge to improve oral health through
Thus, an update to our 2010 edition seems the management of periodontal disease,
appropriate and necessary. general health will also be advanced through
Periodontal disease is one of the most shared approaches targeting common risk
common diseases of man and is responsible factors. To best address the common risk
for most of the tooth loss in adults. This factors and interactions between oral and
oral disease has received considerable atten- systemic disease, it is important to under-
tion in the last several decades, and a new stand the extent to which periodontal disease
understanding of it is emerging. The micro- is related to certain systemic diseases, the his-
bial causes of periodontal disease, the mech- torical foundations of current therapeutic
anisms through which periodontal tissues are approaches, the role of inflammation, and
destroyed, the effect of the host on peri- the possibilities for intervention.
odontal disease expression, and the impact
periodontal disease has on overall health THREE HISTORICAL ERAS OF
have been subjects of intense study. Under- PERIODONTAL DISEASE
standing the complex interaction between In the last 50 years, considerable progress
chronic infections such as periodontal has been made in understanding the etiology
disease and systemic conditions such as car- and pathogenesis of periodontal disease and
diovascular disease has led to a new way of its interactions with the host. The studies
thinking about the importance of periodon- and concepts can be described as having
tal disease in overall health. occurred in three phases or eras: the
etiopathologic (or host-parasite) era, the risk
Periodontal Disease as an Integral Link to factor era, and, most recently, the periodon-
Systemic Disease tal disease-systemic disease era.
According to the National Center for Health
Statistics of the Centers for Disease Control Etiopathologic Era
and Prevention, the seven leading causes of The etiopathologic era included landmark
death in the United States in 2010 were investigations into the microbial etiology and
heart disease (597,689), cancer (574,743), pathogenesis of periodontal disease. The role
chronic lower respiratory disease (130,080), of bacteria as a cause of periodontal disease
stroke/cerebrovascular diseases (129,476), was demonstrated by a series of seminal
unintentional accidental injuries (120,859), studies conducted from the 1960s to the
2 Periodontal Disease and Overall Health: A Clinician’s Guide
1980s. Classic studies by Löe and col- Other investigators began to explain the
leagues2,3 clearly demonstrated that microbial pathogenesis of periodontal disease, describ-
plaque buildup on the teeth was associated ing how the host in fact was responsible for
with the onset of gingivitis and that the tissue destruction. We came to understand
removal of microbial plaque resulted in the that the initial response to the bacteria on
resolution of gingivitis. These studies pro- the tooth and subgingivally is a series of
vided unarguable evidence that microbial immunopathologic actions. Antibodies to
dental plaque buildup, rather than other sus- these bacteria are formed, which in combi-
pected agents such as calculus, was responsi- nation with neutrophils, provide important
ble for gingivitis. protection.7,8 It was seen that when neu-
In the 1970s and 1980s, Socransky and trophils are suppressed, more severe peri-
coworkers4 conducted studies showing that odontal disease occurs. Soon thereafter, the
specific organisms were associated with peri- role of the macrophage was understood.
odontal disease (for review see Socransky and This important cell invades the gingival
Haffajee, 2005). These studies identified several tissue and, on triggering by bacterial prod-
categories of organisms, ranging from early ucts such as endotoxin, produces proinflam-
colonizers, which are commensal and relatively matory cytokines and matrix metallopro-
nonvirulent, to moderately virulent organisms, teinases that destroy the connective tissues of
which bridged the early colonizers and inter- the periodontium. Inflammatory mediators
connected them to specific pathogens such as such as prostaglandin E2 and interleukin 1
Porphyromonas gingivalis, Tannerella forsythen- induce alveolar bone resorption. As the role
sis, and Treponema denticola. Research from of the host becomes more understood,
many investigators found that the specific inflammation and the inflammatory
pathogens, in combination with the early colo- response can explain much of the tissue
nizers and moderately virulent organisms, destruction caused by periodontal disease.9,10
form a complex microflora that exists as a
biofilm within the periodontal pocket. More Risk Factor Era
recent studies using 16S rRNA sequencing The second era of discovery brought the
techniques, which reveal most if not all of the identification of risk factors that influence or
organisms at a site (i.e., the microbiome), have modulate the expression of periodontal
revealed a set of new potential pathogens.5 disease. Epidemiologic studies reported that
These new studies support the shift from a the risk factors in and of themselves were
gram-positive community in health to a gram- not etiologic, but rather modified or exagger-
negative–dominated community in periodontal ated the etiopathologic processes set into
disease. Several new genera and species—some motion by the causative bacteria. The fol-
not able to be cultivated and others newly lowing risk factors were identified in the late
described—emerge as potential periodontal 1980s and early 1990s: genetic elements,
pathogens. behaviors such as smoking, and acquired
Microbiome analysis by 16S rRNA disorders such as diabetes mellitus.11–13 The
sequencing has opened a new and fruitful concept of modifying risk factors as part of
approach to studying the migration of organ- the management of periodontal disease is
isms from the oral community to distant sites, now well established.
a phenomenon that may help explain the
many associations of periodontal disease with Periodontal Disease-Systemic Disease Era
systemic diseases such as heart disease, colon The understanding of periodontal disease is
cancer, and fatal prenatal septicemia.6 currently focused on the relation of peri-
CHAPTER 1 Overview 3
odontal disease as a risk for certain systemic also contribute to a systemic inflammatory
diseases. Robust studies have shown that response such as rheumatoid arthritis, psori-
periodontal disease is independently associ- asis, and obesity. This chronic systemic
ated with certain systemic diseases such as inflammatory response in turn increases the
cardiovascular disease,14–16 diabetes and com- risk for cardiovascular disease, diabetes and
plications of diabetes,17–20 adverse pregnancy complications of diabetes, adverse pregnancy
outcomes,21,22 and respiratory infections.23 outcomes, and possibly some cancers. The
Evidence supporting the association of research supporting these associations is dis-
periodontal disease with systemic disease cussed in detail in the following chapters.
was reviewed by a panel of experts from the
United States and throughout Europe.24 The THE ROLE OF DENTISTRY IN
authors concluded that scientific evidence RISK FACTOR MODIFICATION
shows a strong association between peri- Common Risk Factors
odontal disease and several systemic disor- A theme throughout this text is that peri-
ders. Periodontal disease likely contributes to odontal disease and several diseases associ-
the bacterial burden that causes a destructive ated with periodontal disease are chronic dis-
systemic inflammatory response, thus con- eases, often associated with aging. Those
tributing to these diseases. Treatment of peri- individuals with cardiovascular disease, dia-
odontal disease reduces this burden. It is betes, and cancer often share common risk
clear that periodontal disease, especially factors with those with periodontal disease,
severe periodontitis, may also initiate general such as smoking and obesity. These
health issues.25 common risk factors may account for some
The periodontal disease-systemic disease of the associations. But at least for cardio-
concept has amassed enough evidence and vascular disease, diabetes, respiratory dis-
support that it is now believed that findings eases, and some forms of cancer associated
about this interrelationship should be incor- with periodontal disease, they are not
porated into the curriculum in schools for entirely accounted for because periodontal
health professionals and should also be disease is also an independent risk factor for
made available to enhance the knowledge these diseases in nonsmokers. Aside from the
base of practicing healthcare professionals. issue of causation; the clinical implication is
The association of periodontal disease that management of these common risk
with several systemic conditions, such as dia- factors will likely reduce the risk for peri-
betes and cardiovascular disease, is likely odontal disease as well as for cardiovascular
related to the inflammatory response associ- disease, diabetes, cancer, and respiratory dis-
ated with periodontal disease. C-reactive eases. This is a compelling argument for
protein is an important marker of the proactive common risk factor management
inflammatory response and is elevated in by dental professionals, since it can result in
subjects with periodontal disease; its levels in better general health as well as in better oral
peripheral blood are reduced when peri- health.
odontal disease is treated. Another indica-
tion of the systemic inflammatory response GOALS FOR THIS TEXTBOOK
associated with periodontal disease is the Much research is focused on understanding
presence of cytokines, including tumor how periodontal disease increases the risk
necrosis factor alpha and interleukins 1 and for systemic diseases. It is not yet clear what
6, often found in the circulation of patients impact the biofilm in the oral cavity might
with periodontal disease. Other conditions have on distant sites and organs; likewise the
role of the inflammatory response is not the role of dental professionals in the educa-
fully understood. Some chapters review the tion of the public and other health profes-
biologic plausibility of periodontal disease as sionals about the oral health-general health
a risk for systemic conditions. Mechanisms interrelationship.
through which periodontal disease can
confer this risk are also presented. Our Hope for This Textbook
The overall goal of this second edition The hope of the authors and editors is that
of the textbook is to present the latest this textbook will provide an up-to-date
emerging and compelling evidence that peri- understanding of the information that
odontal disease is a risk for several systemic details the relation of periodontal disease to
conditions and to look at the role of oral systemic disease, with each chapter outlining
health in contributing to overall health. As a state-of-the-art understanding of the
before, this book also seeks to provide the optimal management of patients. This text-
reader with a guide to patient management book has been prepared as a resource for
in which dentistry and medicine work dental students, dental hygiene students,
together. faculty members of dental educational insti-
tutions, and dental professionals in general.
Textbook Organization We also believe this resource will prove valu-
The chapters in this book are organized in a able to students as well as practicing
manner that is consistent with the first edition. members of other health professionals in the
The initial chapters outline the basics of medical community. The integration of med-
understanding periodontal disease and its icine and dentistry grows daily, and a
interrelationship with systemic disease: common resource such as this textbook can
Chapter 2 discusses the causes and pathogen- serve as a constructive tool to help the two
esis of periodontal disease; the role of infec- disciplines work collaboratively.
tion and inflammation in periodontal disease The editors would like to thank the
is examined in Chapter 3; and the history of authors and coauthors of this textbook for
the oral disease-systemic disease relationship their role in preparing and updating infor-
is explained in Chapter 4. mation in a complete, yet concise and read-
An overview of diabetes (Chapter 5) and able manner in this revision. We are hopeful
atherosclerotic diseases (Chapter 7) are fol- that this textbook will find broad readership
lowed by chapters that describe the relation of and will be useful to the dental and medical
periodontal disease to these conditions communities and—most important—that it
(Chapters 6 and 8, respectively). will result in better general health as well as
The next chapters examine the evidence oral health.
for periodontal disease being a risk for
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odontal disease. Periodontol 2000 2013;62:59-94. sclerotic cardiovascular disease: consensus report of
14. Mattila K, Nieminen M, Valtonen V, Rasi VP, the Joint EFP/AAP Workshop on Periodontitis and
Kesäniemi YA, Syrjälä SL, Jungell PS, Isoluoma Systemic Diseases. J Periodontol 2013;84(4
M, Hietaniemi K, Jokinen MJ. Association Suppl):S24–9. doi: 10.1902/jop.2013.1340019.
between dental health and acute myocardial infarc- 25. Borgnakke WS, Glick M, Genco RJ. Periodontitis:
tion. Brit Med J 1989;298:779–81. the canary in the coal mine. J Am Dent Assoc
15. DeStefano F, Anda RF, Kahn HS, Williamson 2013;144:764–6.
CHAPTER 2
Epidemiology, Pathogenesis,
and Management
Ying Gu, Maria Emanuel Ryan, Bruno G. Loos
INTRODUCTION form of the disease and generally involves

Periodontal diseases are serious chronic inflammation of the gingival tissues
infections that involve destruction of the without loss of connective tissue attach-
tooth-supporting apparatus, including the ment.1 Periodontitis has been defined as
gingiva, periodontal ligament, and alveolar gingival inflammation at sites of pathologic
bone. These diseases are initiated by a local detachment of collagen fibers from cemen-
accumulation of bacteria (dental plaque) tum, apical migration of the junctional
adjacent to the tooth in susceptible persons. epithelium, and radiographic evidence of
Periodontal diseases, including gingivitis alveolar bone loss. The inflammatory
and periodontitis, can affect one tooth or events associated with connective tissue
many teeth and, if left untreated, can lead attachment loss lead to the resorption of
to tooth loss, particularly in adults. It is the tooth-supporting alveolar bone.2 The
most common dental condition in adults concept of periodontal disease is continu-
and also one of the most common chronic ally changing as new research evidence
inflammatory diseases, possibly affecting a emerges. Therefore, the classification of
majority of the population in the world. periodontal disease has changed since the
Moreover, it has been indicated as a con- system was developed at the 1989 World
tributing factor to other systemic diseases Workshop in Clinical Periodontics. The
such as diabetes and cardiovascular diseases. classification from the most recent 1999
Although plaque is essential for the initia- International Workshop organized by the
tion of periodontal diseases, most destruc- American Academy of Periodontology
tive processes associated with these diseases (AAP) is presented in this chapter.
are due to an excessive host response to the The classification of periodontal dis-
bacterial challenge. Therefore, periodontal eases now includes eight general types3:
disease is a multifactorial, complex disease. 1. Gingivitis
The purpose of this chapter is to provide a 2. Chronic periodontitis
general overview of the types of periodon- 3. Aggressive periodontitis
tal disease, the risk factors associated with 4. Periodontitis as a manifestation of
the disease, and the etiology, pathogenesis, systemic diseases
and management of periodontal diseases. 5. Necrotizing periodontal diseases
6. Abscesses of the periodontium
TYPES OF PERIODONTAL DISEASE 7. Periodontitis associated with
For many years, periodontal diseases have endodontic lesions
been described as being divided into two 8. Developmental or acquired deformi-
general categories based on whether there is ties and conditions
loss of connective tissue attachment and The overall classification system is pre-
alveolar bone loss: gingivitis and periodon- sented in Table 1.3 In addition, this classifica-
titis. Gingivitis is considered a reversible tion is different from that of case types pre-
CHAPTER 2 Epidemiology, Pathogenesis, and Management 7
viously developed by the AAP.4,5 The current and alveolar bone loss will develop. Gingivi-
case types for periodontal diseases are: tis can occur on teeth with no attachment
• Gingivitis (Case Type I) loss and also occurs in the gingiva of the
• Mild periodontitis (Case Type II) teeth previously treated for periodontitis with
• Moderate periodontitis (Case Type III) no further attachment loss.
• Advanced periodontitis (Case Type IV)
• Refractory periodontitis (Case Type V) Dental Plaque Only: Gingivitis is initiated by
Each of the eight general types of peri- local accumulation of bacteria (i.e., dental
odontal disease are discussed briefly in the plaque organized in a biofilm) adjacent to the
following text. tooth.6 The bacterial antigens and their meta-
Table 1. Periodontal Diseases bolic products (e.g., endotoxin) stimulate epithe-
lial and connective tissue cells to produce
I. Gingival diseases
Dental plaque-induced gingival diseases inflammatory mediators that result in a local-
Non-plaque-induced gingival lesions ized inflammatory response recruiting polymor-
phonuclear leukocytes (PMNs or neutrophils) to
II. Chronic periodontitis
Localized the site. An antibody response to bacterial anti-
Generalized gens is also mounted. Inflammatory cells and
III. Aggressive periodontitis their products, such as cytokines and enzymes,
Localized are present at the site of inflammation. Thus, a
Generalized host immunoinflammatory response is estab-
IV. Periodontitis as a manifestation of lished in the gingival tissues, and the clinical
systemic diseases signs of gingivitis develop, including redness,
V. Necrotizing periodontal diseases swelling, and bleeding. The plaque-host interac-
Necrotizing ulcerative gingivitis (NUG) tion can be altered by the effects of local factors,
Necrotizing ulcerative periodontitis (NUP) systemic factors, or both.
VI. Abscesses of the periodontium
Gingival abscess Systemic Factors: Systemic hormonal change
Periodontal abscess associated with puberty, menstrual cycle, and
Pericoronal abscess
pregnancy, as well as chronic diseases such as
VII. Periodontitis associated with diabetes, can alter the host response to dental
endodontic lesions plaque.1,7 Hormonal changes and certain dis-
VIII. Developmental or acquired deformities eases can upregulate systemic cellular and
and conditions immunologic function, resulting in local severe
gingival inflammation even in the presence of
Adapted from: Ann Periodontol 1999;4:1–6.
minimal plaque. Significant gingivitis is com-
Gingival Diseases monly seen in pregnant women who have not
Gingival disease is further characterized into had adequate oral hygiene before becoming
plaque-induced and non-plaque-induced cat- pregnant. Blood dyscrasias such as leukemia
egories.3 may also alter immune function by decreasing
normal immunologic function. Patients
Plaque-Induced Gingival Diseases usually present with gingival enlargement and
Gingivitis is gingival inflammation associated bleeding, which is associated with edematous
with dental plaque and calculus accumula- and erythematous gingival tissues.
tion. It is the most common form of gingival
disease. Gingivitis may or may not progress Medications: Medications such as anticonvul-
to periodontitis, in which clinical attachment sant drugs (e.g., dilantin), immunosuppressive
drugs (e.g., cyclosporin A), and calcium gival tissues appear red and swollen, followed
channel blockers (e.g., diltiazem) can cause by the formation of small blisters, which
severe gingival enlargement and pseudo-peri- eventually break down to form shallow,
odontal pocketing (i.e., increased probing painful ulcers. These lesions are usually self-
depths with no associated attachment or limiting and heal within 1 to 2 weeks. After a
bone loss).8 Medication-associated gingival primary infection, the herpes virus becomes
conditions are often reversed after discontinu- latent and is preserved in the ganglion of the
ation of the offending medications. trigeminal nerve. The virus may be reactivated
later in life by reduced immune function or
Malnutrition: The host immune system can be stress, resulting in recurrent herpes labialis,
diminished when malnutrition develops, result- gingivitis, and stomatitis.
ing in excessive gingival inflammation. Severe Gingival lesions of fungal origin usually
ascorbic acid (vitamin C) deficiencies (scurvy) occur in people with diabetes or other
can produce bright red, swollen, and bleeding immunocompromised states. A shift in the
gingival tissues.1 In vitamin C deficiency, gin- normal oral flora related to the long-term use
givitis is associated with a suppressed synthesis of systemically administered antibiotics can
of both connective tissue collagens (e.g., types also lead to lesions of fungal origin.11 The
I and III) and basement membrane collagen most common fungal infection is candidiasis,
(type IV), because vitamin C is one of the ele- caused by Candida albicans, often seen in
ments required for collagen synthesis. patients wearing removable prosthetic devices
Improved dietary intake and/or vitamin C sup- such as dentures, and in patients with dry
plements can reverse this condition. mouth due to multiple medications or sali-
vary gland dysfunction. Clinical manifesta-
Non-Plaque-Induced Gingival Lesions tions include white patches on the gingiva,
Non–plaque-induced gingival lesions usually tongue, or oral mucous membranes, which
are rare and are mainly due to systemic con- can be removed with a cotton swab or with
ditions. In addition, bacteria, viruses, and gauze, leaving behind a bright red, bleeding
fungi that are not normally part of the dental surface. Treatment with antifungal agents is
biofilm can cause these types of gingival often necessary to resolve these conditions.
lesions. Sexually transmitted diseases such as Gingival lesions can also be caused by
gonorrhea (Neisseria gonorrhoeae) and genetic, systemic mucocutaneous disorders,
syphilis (Treponema pallidum) can cause allergic reactions, trauma, and foreign body
lesions in the tissues of the periodontium.9 In reactions. One of the most common genetic
addition, primary streptococcal gingivitis is an conditions associated with gingival lesions is
acute inflammation of the oral mucosa asso- autosomal dominant, hereditary gingival
ciated with pain, fever, edematous and erythe- fibromatosis—a benign condition affecting
matous gingival tissues, with bleeding or both dental arches. 12 In this condition, the
abscess formation. These lesions can be gingival tissues are enlarged and asympto-
managed with routine periodontal scaling matic. This may be an isolated finding or
and root planing and targeted antibiotic associated with other syndromes. Treatment is
therapy. Herpes simplex virus type I is a gingivectomy; recurrence is possible. Systemic
common virus that can cause gingival conditions, such as pemphigoid, pemphigus
lesions.10 In children and young adults, herpes vulgaris, erythema multiforme, and lupus ery-
infections can be primary and usually thematosus, can cause desquamative lesions
without symptoms, but in some cases pain and ulceration.10,13 Gingival changes due to
and fever are reported. In these cases, the gin- allergic reactions to certain restorative materi-
als, toothpastes, or mouth rinses are rare, but inflammation results in the degradation of
have been observed.10 Traumatic lesions are the gingival connective tissues.
usually produced unintentionally.10 Aggressive Figure 1.
tooth brushing and flossing can cause gingi-
val damage. Traumatic lesions can also be
iatrogenically induced by healthcare profes-
sionals during oral examinations or dental Microbiological Genetic
care. Eating crunchy foods or foods with risk factors risk factors
small particles that can be lodged in the inter-
proximal areas and directly into the gingival
tissues can cause these types of lesions as
well. Hot foods and drinks can cause minor Lifestyle
burns of the gingival tissues. Localized risk factors
inflammation can also develop when gingival
tissue is exposed to foreign materials. The
Development and progression of periodontitis
most common example is the amalgam
remaining in gingival tissues during restora- Periodontitis is a complex disease; multiple causal risk
tions or surgical procedures, eventually pro- factors act simultaneously in its onset and progression.
Three main causal risk factors always play a role: micro-
ducing amalgam tattoos.10
biologic, genetic, and lifestyle. When the patient has a
systemic disease, such as diabetes, which could affect the
PERIODONTITIS onset and/or progression of periodontitis, another over-
Periodontitis is a chronic inflammatory lapping circle needs to be added. Note that the relative
contribution of each of the causal factors may vary
disease of the supporting tissues around the
from patient to patient (see Figure 2).
teeth that results in irreversible periodontal
attachment loss, alveolar bone destruction, Notably, the junctional epithelium pro-
and ultimately, if left untreated, tooth loss.14 liferates and also produces cytokines and
The current concept of the cause of peri- other immune mediators and tissue-destruc-
odontitis is that it is a complex disease in tive proteinases. These participate in the
which multiple causal factors simultaneously degradation of the basement membrane and
play a role.15 There are three main causal risk allow for the apical migration of the junc-
factors: microbiology (subgingival bacterial tional epithelium along the root surface, con-
biofilm), genetics, and lifestyle (Figure 1). tributing to the deepening of the gingival
Subgingival bacteria in the biofilm and their crevice and producing periodontal pockets
metabolic products (e.g., endotoxin) as well as and associated attachment loss—the hall-
other antigens, initiate the periodontal inflam- mark of periodontitis. Osteoclasts are then
matory reactions, which lead to the recruit- stimulated to resorb the underlying alveolar
ment of neutrophils and other inflammatory bone. Some of the clinical signs include
cells into the gingival tissues. Subsequently, bleeding on probing, deep pockets, attach-
the recruited immune cells, particularly neu- ment loss and recession, radiographic evi-
trophils, release proinflammatory mediators, dence of alveolar bone loss, and tooth
including cytokines, prostanoids, and mobility. Often, this destructive process is
enzymes. The type and severity of the peri- silent and painless and continues for years
odontal inflammatory reaction to the dental without being identified. Eventually, teeth
biofilm is determined by genetic risk factors can become loose and may be lost on their
and lifestyle risk factors such as smoking, own or deemed hopeless and require extrac-
stress, and micronutrients. The periodontal tion. There are many forms of periodontitis.
Chronic Periodontitis and HIV infection can decrease host defenses

Chronic periodontitis is the most common to bacterial infection. Lifestyle risk factors
form of periodontitis and is characterized by such as smoking and stress can also decrease
pockets with associated attachment and bone host immune function, resulting in increased
loss and/or recession of the gingival tissues. It susceptibility to disease. Chronic periodontitis
is common in adults, but can occur at any can occur as a localized form, in which less
age. Progression of attachment loss usually than 30% of sites are involved, or as a more
occurs slowly, but periods of rapid progres- generalized form, in which more than 30% of
sion or periods of remission can occur. existing sites demonstrate increased pocket
Several studies have addressed the “episodic” depth, attachment, and bone loss.4 As previ-
nature of periodontitis.16 The rate of disease ously mentioned, the severity of disease can
progression may be influenced by local or be described as slight, moderate, or severe,
systemic conditions; the latter can alter the based on the level of destruction.
immune response to the biofilm. Local
factors such as large accumulations of dental Aggressive Periodontitis
plaque and calculus due to poor oral hygiene Aggressive periodontitis was previously cate-
and lack of preventive measures (lifestyle gorized as early-onset periodontitis, as in juve-
factors) or, less commonly, to subgingivally nile periodontitis. Common features are rapid
placed fillings or crowns, can promote gingi- attachment loss and bone destruction in the
val inflammation and clinical attachment loss. absence of large accumulations of plaque and
Other lifestyle risk factors such as smoking, calculus.18 These forms of periodontitis usually
lack of proper micronutrients and vitamins, affect young persons (juveniles, adolescents,
and stress, reduce in general the host resist- post-adolescents), often during puberty from
ance to the dental biofilm.17 Genetic factors 10 years to 30 years of age, with a strong
play a less important role in chronic peri- genetic predisposition (see Figure 2). The
odontitis than in aggressive periodontitis microbiologic risk factor most often associ-
(Figure 2). Systemic factors such as diabetes ated with aggressive periodontitis is Aggregati-
Figure 2. Genetic and Microbiologic Risk Factors Associated with Periodontitis
Case 1: aggressive Case 2: aggressive Case 3: aggressive Case 4: chronic
periodontitis periodontitis periodontitis periodontitis
(11 years old) (16 years old) (35 years old) (54 years old)
Genetic risk factors
Microbiological and lifestyle risk factors
Genetics contribute more in relatively younger patients with aggressive periodontitis than in adults with chronic peri-
odontitis. Conversely, in relatively older patients, the microbiologic risk factors and lifestyle factors contribute the
most to onset and/or progression, whereas genetics plays a smaller role.
bacter actinomycetemcomitans (previously sion can increase the risk. Necrotizing peri-
Actinobacillus actinomycetemcomitans). Indi- odontal diseases are further divided into two
viduals present with hyperactive inflammatory forms: necrotizing ulcerative gingivitis
cells producing high levels of cytokines and (NUG) and necrotizing ulcerative periodon-
enzymes causing rapid, aggressive destruction titis (NUP). These two diseases have the
of periodontal tissues. Aggressive periodontitis same etiology and clinical signs, except that
can be further characterized as localized or NUP involves clinical attachment and alveo-
generalized. The localized form usually affects lar bone loss.20
first molars and incisors. The generalized form
usually involves at least three teeth other than Abscesses of the Periodontium
first molars and incisors. Periodontal abscess is a localized purulent
infection of the periodontal tissues.21 Iatro-
Periodontitis as a Manifestation of genic abscess formation can be precipitated
Systemic Diseases after inadequate scaling and root planing,
Systemic conditions such as diabetes are associ- leading to a tightening of the coronal epithe-
ated with this form of periodontitis.19 Diabetes, lial cuff with continued subgingival calculus
and any other chronic condition that lowers driving inflammation. Abscesses can also
the host resistance to bacterial infections, occur in healthy periodontal tissues owing to
increases the susceptibility and progression of the presence of foreign objects lodged in the
periodontitis. Several hematologic and genetic gingival crevice such as a toothbrush bristle
disorders have also been associated with the or a popcorn kernel being tightly packed
development of periodontitis, such as acquired, into the interproximal spaces or between the
familial, and cyclic neutropenias; constitutive tooth and the tissues.
neutropenia (Kostman syndrome [case 1 in A pericoronal abscess is an infection of
Figure 2]); leukemias; Down syndrome; certain the gingiva around a partially erupted tooth,
types of Ehlers-Danlos syndrome, such as leading to pericoronitis. A small flap of tissue
types IV and VIII; Papillon-Lefevre syndrome; may cover a partially erupted tooth surface,
Cohen syndrome; and hypophosphatasia. The serving as a nidus for food and debris to accu-
mechanisms by which all these disorders affect mulate and become trapped beneath the tissue
the health of the periodontium are not fully flap. Patients usually find it very difficult to
understood and continue to be investigated by keep these areas clean and can develop
many basic and clinical researchers. However, inflammation and infection. In addition,
the strong genetic component is clear for most trauma due to constant contact between the
of these syndromes. Genetic mutations affect tissue flap and a tooth in the opposing arch
host defense mechanisms in various ways and can also lead to a pericoronal abscess. The
cause hypo- or hyperinflammatory responses, areas most commonly affected are associated
resulting in fast progressive and aggressive peri- with mandibular third molars. Pain, swelling,
odontal destruction. redness, and suppuration are associated with
periodontal abscesses. Treatment may include
Necrotizing Periodontal Diseases incision and drainage, use of antibiotics, and
Necrotizing lesions are most commonly removal of the offending source.
observed in persons with a poor state of
health and systemic condition and strongly EPIDEMIOLOGY AND RISK FACTORS
associated with smoking, stress, and poor Epidemiology of Gingivitis
nutrition. Certain systemic conditions, such Gingivitis can occur in early childhood,
as HIV infection, but also immunosuppres- becomes more prevalent during teenage
years, and decreases in older persons.22 In tive chairside tool to measure active peri-
1986–1987, the National Institute of Dental odontitis. The development of these markers
Research (NIDR) conducted a national will also help to facilitate screening for peri-
survey of oral health in US school children23 odontal diseases by medical professionals or
and reported that approximately 60% of even help patients in self-assessment of oral
children 14–17 years of age were found to inflammation, prompting referrals to the
have gingivitis. A 2005 AAP position paper dental office for clinical assessment. Moni-
reported that over 50% of adults had gin- toring levels of these markers may also help
givitis on an average of three to four teeth, in assessing patient response to various peri-
whereas 63% of 13- to 17-year-old teenagers odontal therapeutic options.
had gingival bleeding according to the The national data suggest that the
National Health and Nutrition Examination milder forms of periodontitis are close to
Survey (NHANES III) conducted from universal.25 The more severe forms are less
1988 to 1994.24,25 Both surveys assessed gingi- prevalent. According to a review of the liter-
val bleeding by a gingival sweep method. ature by Brown and Löe28 focused on a
number of epidemiologic studies resulting
Epidemiology of Periodontitis from a 1981 national probability survey, the
Basic clinical measurements for periodontitis prevalence of chronic periodontitis was
are gingival bleeding on probing (BOP), clin- about 36% for the adult US population as
ical attachment loss (CAL), and pocket assessed by pocket depth measurements. The
depths accompanied by radiographic bone prevalence of periodontitis increased with
loss. These types of clinical measurements age; 29% in those age 19 to 44 years of age
may be somewhat subjective. As our knowl- had chronic periodontitis, which increased to
edge of the pathogenesis of periodontitis 50% for people 45 years or older. In general,
improves, new diagnostic markers for peri- moderate periodontitis occurred in 28% of
odontitis may emerge to better screen for, all people, and 8% had advanced disease.
diagnose, and manage periodontitis. Inflam- However, the prevalence of moderate and
matory cytokines, enzymes, and bone break- severe periodontitis increased to 44% in the
down products released into the gingival population greater than 45 years of age.
crevicular fluid reflect the host response to Based on the presence of periodontal
the bacterial challenge. These biochemical pockets ≥ 4 mm, it was determined that 30%
markers may be good candidates for new of the population had periodontitis on an
diagnostic or prognostic markers of disease. average of three to four teeth. Severe pockets
A number of cytokines have been associated of ≥ 6 mm were found in less than 5% of
with active disease, including prostaglandin the population.24 The prevalence of aggres-
E2 (PGE2), tumor necrosis factor-alpha sive periodontitis was low with less than 1%
(TNF-a), interleukin-1 beta (IL-1b), and in this 1991 survey.29
others.26,27 Enzymes such as matrix metallo- Following this report, the NHANES III
proteinases (MMPs) and breakdown prod- reported the prevalence of periodontitis for
ucts, such as the collagen telopeptide (ICTP), adults ages 30 to 90 years old.30 Attachment
have been studied as well. loss and probing depths were assessed at two
To date, these biochemical markers in sites per tooth. Attachment loss of ≥ 3 mm
gingival crevicular fluid are still being investi- was found in 53% of the population. The
gated. It will be helpful to both clinicians prevalence of attachment loss increased with
and researchers if one or more of these age, from approximately 35% for the 30-
markers can be developed as a more objec- year-old participants to 89% for the 80-year-
old participants. Probing depths of ≥ 3 mm paradigm shift in our understanding of the

were found in approximately 64% of the etiology of periodontal disease: namely, that
population. The prevalence of periodontitis periodontal destruction is not caused by
increases with age and was found to be more dental plaque in a biofilm per se, but rather
prevalent in males than females, and in by the host’s inflammatory response.41 Both
African and Mexican Americans than Cau- hyper- and hyporesponsiveness of the
casians. Most recently, it was reported that immune system toward the microbial chal-
periodontal disease may have significantly lenge in periodontitis has been described.42
decreased between NHANES III and Host susceptibility is essentially the aggregate
NHANES 1999–2004.31 However, on further of unfavorable genetic and lifestyle factors,
evaluation, it was recognized that partial- which in turn determines disease expression
mouth periodontal examination protocols and/or progression of an existing disease.15,43
used in NHANES underestimated the The complexity of these interrelated factors
prevalence of periodontitis by approximately explains the variation in phenotypes between
50% when compared with a full-mouth individuals and among populations.
“gold standard” periodontal examination in Summarized below are risk factors
a convenience sample of 454 adults ≥ 35 within the three main clusters of causal
years of age.32 These findings prompted a factors for periodontitis.
full mouth assessment of pocket depth and The microbiologic cluster is the subgin-
clinical attachment loss in NHANES 2009– gival biofilm containing the known and as-
2010 revealing periodontitis in over 47% of yet unknown periodontal pathogenic bacte-
the population aged 30 years and older, with ria. The risk bacteria include A. actino-
8.7% mild, 30% moderate, and 8.5% severe.33 mycetemcomitans, Porphyromonas gingivalis,
Fusobacterium nucleatum, Tannerella for-
Risk Factors sythia, and Treponema denticola. The cluster
As previously explained, periodontitis is a of life-style risk factors for periodontitis
complex disease, with three main causal includes smoking, stress, and shortage of
factors simultaneously playing a role— micronutrients such as vitamin C.44 The level
microbiologic, genetic, and lifestyle (see of oral hygiene, motivation for oral health,
Figure 1). Within these clusters, various risk and regular check-ups by a dental profes-
factors have been identified.34–39 Estimating sional also are considered part of lifestyle
and/or determining risk is helpful in develop- factors.
ing recommendations for prevention and in The specific genetic risk factors for peri-
determining strategies for the overall man- odontitis are largely unknown. The initial
agement of periodontitis. It has been recog- candidate gene studies that examined the
nized that the severity and progression of association of genetic polymorphisms with
periodontal disease varies from individual to periodontitis focused on genes that are
individual. Within the microbiologic cluster involved in the innate and adaptive immu-
of risk factors, the known periodontal nity and thus have the potential to determine
pathogens and other still unknown bacteria disease susceptibility and severity, e.g., genes
are essential for the initiation of the disease. of the interleukin [IL] and Toll-like receptor
However, it is the host response to the bacte- families, MMPs, or various metabolic path-
rial challenge that determines the severity ways.15 Recently, 23 genes, which were repeat-
and progression of the disease. The original edly proposed to be associated with
concept of host susceptibility by Page and increased disease risk in white populations,
Schroeder in 197640 has recently led to a new were replicated in a comprehensive associa-
tion study using a large population of north- account lifestyle effects such as smoking, age,
ern European patients with aggressive peri- and the presence of other diseases.50
odontitis.45 The potential relevance of the Within the cluster of specific genetic
observed association was subsequently tested risk factors, the IL-1 composite genotype ad
in chronic periodontitis subjects. It was con- modum, Kornman and colleagues51 deserve
cluded that all analyzed putative susceptibility special attention because of the large
genes, except for IL-10, do not carry common number of studies that have been carried out
risk variants and that previous positive reports on the relation between this composite geno-
were probably caused by false-positive results type and the two main forms of periodonti-
(type 1 errors). For complex diseases, large tis in a variety of ethnic populations. The
case-control populations are the indispensable IL-1 genes, comprising IL-1A, IL-1B, and
prerequisite for any association study to over- IL-1RN, are located in close proximity to
come the inherent heterogeneity within popu- each other on the long arm of chromosome
lations. It is currently believed that in complex 2. IL-1A –889 (rs1800587, in linkage with
diseases, common markers or causative +4845), IL-1B –511 (in linkage with –31),
genetic variants usually do not exceed an odds IL-1B +3954 (rs1143634, also mentioned in
ratio (OR) of 1.3, with many having even the literature as +3953) and IL-1RN VNTR
much smaller ORs.46–49 To identify such a (in linkage with +2018 [rs419598]) have been
variant in the population (OR 1.3 and with studied extensively in relation to chronic
a variant allele frequency of 20%, for periodontitis.15 Kornman and colleagues51
example), a minimum of 1,000 well-defined were the first to report that the combined
cases is necessary to reach the required statis- presence of the minor allele of the IL-1A
tical power of 0.8, and at least the same gene at position –889 and the minor allele of
amount of healthy controls.50 None of the the IL-1B gene at position +3954 was associ-
early candidate gene studies reached this ated with severity of chronic periodontitis, in
sample size and were underpowered. Hence, particular in nonsmoking whites; these
most associations of the past seem arbitrary authors proposed this combination to be the
and suffer from a lack of successful replica- “IL-1 composite genotype.” Carriage rates
tion, the gold standard of any association of the IL-1 composite genotype vary across
study. populations; for example, a low minor allele
In addition to power and sample size frequency ([MAF] < 5%) was seen in Asian
issues, another important limitation of can- populations compared with white popula-
didate gene studies in the field of periodonti- tions. The IL-1 composite genotype and the
tis is that initial studies did not capture the other IL-1 candidate single-nucleotide poly-
complete genetic information of a particular morphisms (SNPs) are not associated with
region of interest. In almost all studies, only European patients with aggressive periodon-
one or a few variants rather than the com- titis.45,52 A recent systematic review on IL-1
plete set of all haplotypes of a gene were gene polymorphisms in chronic periodontitis
genotyped.50 However, information about the patients and controls in whites suggested evi-
complete haplotypes must be assessed to dence for the minor alleles in IL-1A, in IL-
ensure that all potentially relevant polymor- 1B and the composite genotype to be risk
phisms are analyzed. Further limitations of factors.53 However, the latter results also
most previous studies on genetics in peri- demonstrated significant heterogeneity
odontitis often include inadequate pheno- among the included studies, indicating that
type classification for disease and control some of the included studies may suffer
subjects, as well as that of failing to take into from a type 1 error. In that respect, a recent
letter is useful for the evaluation of system- prostaglandin H2, which is the precur-
atic reviews on genetic risk factors.54 sor of PGE2). PGE2, which mediates
Taking into consideration the limita- proinflammatory and anti-inflamma-
tions just mentioned, the following genes are tory reactions in many tissues, is also
currently considered to carry validated sus- partly responsible for the resorption of
ceptibility variants for periodontitis; these the alveolar bone during the pathogene-
genes were successfully replicated in a large sis of periodontitis.
sample population: • DEFB1: Genetic markers within
• GLT6D1: In 2010, in the first genome- DEFB1 coding for beta defensin B1
wide association study on periodontitis, were also validated for periodontitis.67
GLT6D1 was found to be associated In a fine mapping approach, SNP
with AgP.55 GLT6D1 encodes a protein rs1047031 was best associated with
belonging to a family of proteins that is both aggressive and chronic periodonti-
characterized by a glycosyltransferase tis, and the rare allele was predicted to
domain-1. It was shown that the rare impair a microRNA binding site at the
allele of SNP rs1537415 resulted in 3’-untranslated region (UTR) of
impaired binding of the transcription DEFB1. The antimicrobial peptide that
factor GATA-3. is encoded by DEFB1 was suggested to
• ANRIL: This gene was identified as the be responsible for maintaining a healthy
first genetic risk factor of coronary status in the mucosal epithelia prior to
artery disease.56–59 In 2009, ANRIL was infection with pathogenic bacteria.68
identified to be a shared genetic risk To conclude this section on genetic risk
factor of coronary artery disease and factors for periodontitis, note that common
aggressive periodontitis.60 This associa- genetic risk variants for complex diseases are
tion was further replicated in several generally not located within the protein
independent aggressive and chronic coding sequences of the classic candidate
periodontitis case-control samples of genes, but rather lie within the regulatory ele-
Northern European descent,61 a comments of unforeseen genes and chromoso-
bined group of aggressive periodontitis mal regions.69 Most common human
patients in a German and Northern genomic variants that are genome-wide asso-
Irish population,62 and in a Turkish ciated with over 400 complex diseases and
aggressive periodontitis case-control traits are located within regulatory and
population.45 Functional characteriza- intronic regions and not within coding
tion of the molecular function of regions. This was also demonstrated for the
ANRIL showed, apart from others, a risk variants for periodontitis, which are
long-distance regulatory effect on the located within introns (ANRIL and
activity of the CAMTA1/VAMP3 GLT6D1), 5’ to the promoter region (COX-
region.63 This region was previously 2) and within the 3’-UTR (DEFB1).
shown to be associated with increased Certain risk factors (Table 2) and risk
periodontal pathogen colonization. reduction strategies (Table 3) should be con-
• COX-2: Associations of COX-2 with sidered when assessing each patient.70 Some
periodontitis were first identified in Tai- risk factors can be modified to reduce a
wanese and Chinese case-control popu- patient’s susceptibility. Lifestyle factors such
lations and subsequently validated in a as tobacco use and stress can be managed
Northwest-European population.64–66 with smoking cessation and stress manage-
COX-2 converts arachidonic acid into ment; for acquired factors such as systemic
Table 2. Risk Assessment for Periodontitis

1. Estimate the relative contribution of genetic factors by the age of the patient and by family history
2. Smoking, including frequency, current use, and history
3. Hormonal variations such as those seen in:
a. Pregnancy, in which increased levels of estradiol and progesterone may change the environment and
permit the virulent organisms to become more destructive
b. Menopause, in which the reduction in estrogen levels leads to osteopenia and eventually osteoporosis
4. Systemic diseases such as:
a. Diabetes (duration and level of control are important)
b. Osteoporosis
c. Immune system disorders such as HIV
d. Hematologic disorders such as neutropenias
e. Connective tissue disorders such as Marfan’s and Ehlers-Danlos syndromes
f. Metabolic syndrome and obesity
5. Stress as reported by the patient
6. Nutritional deficiencies that may require a dietary analysis
7. Medications such as
a. Calcium channel blockers
b. Immunomodulatory agents
c. Anticonvulsants
d. Those known to cause dry mouth or xerostomia
8. Faulty dentistry such as overhangs and subgingival margins
9. Poor oral hygiene resulting in excessive plaque and calculus
10. History of periodontal disease
Sources: J Dent Res 2012;91:914–20; Periodontol 1994;65:260–7; J Periodontol 1995;66:23–9; J Periodontol 1999;70:711–
23; J Periodontol 2000;71:1057–66; J Periodontol 2000;71:1215–23; J Periodontol 2000;71:1492–8. (Refs. 33–39).
diseases, medications usually prescribed by important to update and assess risk factors
the physician help in the management and for each patient on a regular basis because
control of these chronic disorders and some of these factors are subject to change
should therefore reduce susceptibility to throughout life.
infectious processes such as periodontitis (see
Table 3). Chemotherapeutic agents specifi- ETIOLOGY AND PATHOGENESIS OF
cally designed to improve upon the clinical PERIODONTAL DISEASE
outcomes of mechanical treatments for peri- Initially, periodontal disease was thought to
odontal diseases may be particularly useful be related to aging and was therefore uni-
in the management of those with single or formly distributed in the population, with
multiple risk factors. Risk assessment can disease severity being directly correlated with
help the practitioner to establish an accurate plaque levels. Now, as a result of extensive
diagnosis, provide an optimal treatment research, it has been shown that periodontal
plan, and determine appropriate mainte- disease is initiated by the microorganisms in
nance programs. In patients with multiple the subgingival biofilm (dental plaque), but
risk factors, the practitioner may aggressively the severity and progression of the disease
use pharmacologic adjuncts such as antimi- are determined by the host response (aggre-
crobials and host modulatory therapy in gate of genetic risk factors and lifestyle risk
addition to mechanical therapy. It is also factors) to the bacterial biofilm. Thus, some
Table 3. Risk Reduction Strategies

1. More frequent visits for those with a high estimated genetic predisposition; use of pharmacotherapeutics for
the management of periodontitis
2. Smoking cessation, using one or more of the six approved regimens; these regimens rarely are successful as
sole therapies (multiple forms of therapy often are used in combination with counseling to achieve success)
3. Hormonal variations such as those seen in:
a. Pregnancy, which requires good oral care before pregnancy to prevent complications during pregnancy;
treatment of women during pregnancy may be necessary to prevent adverse pregnancy outcomes
b. Menopause, which may require hormonal supplements, calcium, and other medications and
supplements prescribed by the physician to prevent osteopenia
4. Systemic diseases that require consultation with the physician and pharmacotherapies include:
a. Diabetes (for improved glycemic control)
b. Osteoporosis (requiring calcium supplements, bisphosphonates)
c. Immune system and hematologic disorders
d. Connective tissue disorders
e. Weight loss for obesity and metabolic syndrome
5. Stress management; possible referral to a psychologist or psychiatrist
6. Nutritional supplementation; referral to a nutritionist
7. Medications can be changed in consultation with the physician
8. Corrective dentistry
9. Occlusal adjustments
10. Improved oral hygiene
Source: Dent Clin N Am 2005;49:611–36.

people with severe plaque and calculus accu- bial products also chemotactically attract a
mulation may have gingivitis, but not neces- constant flux of proinflammatory cells migrat-
sarily periodontitis. On the other hand, ing from the circulation to the gingival crevice.
certain individuals, despite maintaining ade- Neutrophils, or PMNs, are predominant in
quate oral hygiene, find themselves suscepti- the early stages of gingival inflammation.
ble to aggressive forms of periodontitis, with Thus, an immune response is generated in the
deep pocketing, tooth mobility, and early periodontal tissues, and proinflammatory
tooth loss. cytokines such as IL-1b, TNF-a, and MMPs
To better treat and manage periodontal are produced by inflammatory cells recruited
diseases, we need a more detailed understand- to the lesion site. The functions of PMNs
ing of periodontal pathogenesis (Figure 3).70–72 include phagocytosis and destruction of bac-
The bacteria and their metabolic products teria. Initially, the clinical signs of gingivitis
(e.g., endotoxin) stimulate the junctional are evident. This response is essentially protec-
epithelium to proliferate and to produce tive in nature to control the bacterial infection.
tissue-destructive proteinases. This infection In persons who are not susceptible to peri-
also increases the permeability of the junc- odontitis, the primary defense mechanisms
tional epithelium, which allows microbes and control the infection, and chronic inflamma-
their products to gain access to the subepithe- tion (i.e., chronic gingivitis) may persist.
lial connective tissue. Epithelial and connective However, in persons susceptible to periodonti-
tissue cells are thus stimulated to produce tis, the latter inflammatory process persists
inflammatory mediators that result in an and eventually extends apically and laterally to
inflammatory response in the tissues. Micro- involve deeper connective tissues and alveolar
Figure 3. Schematic Illustration of the Pathogenesis of Periodontitis
Genetic risk factors
Antibody Cytokines
PMNs
Antigens Host Prostanoids Connective Clinical

Microbial immune- tissue and signs of
challenge LPS inflammatory bone disease
response metabolism
MMPs
Other
virulence
factors
Environmental and acquired

risk factors
Tissue breakdown products and ecological changes
Copyright © 2006 by Saunders, an imprint of Elsevier Inc.
Source: Carranza’s Clinical Periodontology, 10th ed. WB Saunders Company; 2006:275–82. With permission.
bone, recruiting monocytes and lymphocytes Under normal healthy conditions, the anti-
to the site of infection at later stages. These inflammatory mediators are balanced with
monocytes and macrophages are activated by inflammatory mediators, thereby controlling
the bacterial endotoxins such as LPS, leading tissue destruction. If an imbalance occurs,
to the production of high levels of with excessive levels of the proinflammatory
prostaglandins (e.g., PGE2), interleukins (e.g., mediators, upregulated MMP expression, and
IL-1a, IL-1b, IL-6), TNF-a, and MMPs by insufficient levels of protective anti-inflamma-
the host cells. The MMPs break down colla- tory mediators, the loss of periodontal con-
gen fibers, disrupting the normal anatomy of nective tissue and bone will occur.
the gingival tissues, resulting in destruction of Thus, plaque bacteria initiate the disease,
the periodontal apparatus. If left untreated, followed by an inflammatory response
the inflammation continues to extend apically, mounted by the host producing excessive
and osteoclasts are stimulated to resorb alveo- levels of proinflammatory mediators
lar bone triggered by the high levels of (prostaglandins, interleukins) and enzymes
prostaglandins, interleukins, and TNF-a in (MMPs) and resulting in the destruction of
the tissues. The elevated levels of proinflam- periodontal tissue. If this inflammation con-
matory mediators and MMPs are counterbal- tinues and extends farther apically, more bone
anced by a protective response in the host is resorbed, and more periodontal tissue is
with elevations in anti-inflammatory media- broken down. This leads to deeper and deeper
tors such as the cytokines IL-4 and IL-10, as pockets and associated attachment and bone
well as other mediators such as IL-1ra (recep- loss revealed as the clinical and radiographic
tor antagonist) and tissue inhibitors of matrix signs of periodontitis. In people with peri-
metalloproteinases (TIMPs) (Figure 4).71,72 odontitis, these inflammatory mediators (e.g.,
Figure 4. The Periodontal Balance
Risk factors (e.g., genetics, Reduction of

smoking, diabetes) risk factors
Overproduction of proinflammatory or Expression of host-derived anti-inflammatory

destructive mediators and enzymes (e.g., or protective mediators
IL-1, IL-6, PGE2, TNF-a, MMPs) (e.g., IL-4, IL-10, IL-1ra, TIMPs)
Underactivity or overactivity Host modulatory Resolution of

of aspects of host response therapy inflammation
Poor compliance Subgingival OHI, SRP, surgery, antiseptics, antibiotics

Poor plaque control bioburden to reduce bacterial challenge
DISEASE HEALTH
prostanoids and cytokines) and local oral bac- shared common risk factors and plausible
teria eventually enter into the circulation, stim- mechanistic pathways. Despite our gap in
ulating the liver to produce acute-phase pro- research, it is clear that periodontitis can be
teins (notably C-reactive protein [CRP]), but considered a contributing factor to many sys-
also fibrinogen, haptoglobin, etc.), which are temic conditions and diseases. The details are
biomarkers of a systemic inflammatory presented in other chapters of this book.
response. Emerging evidence supports the fact
that this chronic systemic inflammatory MANAGEMENT OF PERIODONTAL
response driven by the chronic infection and DISEASES
inflammation associated with periodontitis Periodontal management includes a com-
eventually increases a person’s risk for devel- plete assessment of each patient. Medical
oping a number of systemic diseases, includ- and dental history, clinical and radiographic
ing cardiovascular diseases, adverse pregnancy examination, and assessment of risk factors
outcomes, and diabetic complications. In a all are important in making an accurate
recent workshop jointly held by the European diagnosis and prognosis and in developing
Federation of Periodontology and the Ameri- an optimal treatment plan. Many treatment
can Academy of Periodontology, potential options are available for the management of
mechanisms linking periodontitis to systemic periodontal diseases, and review of treatment
conditions were discussed. Metastatic infec- outcomes or re-evaluation is key to success-
tions, innate inflammatory responses, and ful management and long-term maintenance.
adaptive immunity were proposed as three In the past, treatments that focused on
basic mechanisms for this association.73 reduction of the microbial load were basi-
Although the causative relation between peri- cally the sole consideration for all periodon-
odontitis and systemic diseases cannot be tal therapy. Currently, because of increased
established, current studies have identified knowledge of the host response, host modu-
lation therapies have been used as adjunctive traditional scaling and root planing
approaches to both nonsurgical and surgical • Intensive periodontal treatment with
treatments to aid in reducing probing depths, local antimicrobial administration or
increasing clinical attachment levels, and general antimicrobial therapy with oral
regenerating the lost attachment apparatus. administration of antibiotics
In the future, more effective therapeutic • Host modulation therapy
approaches are likely to include multiple syn- • Periodontal surgery
ergistic host modulation therapies combined It is the responsibility of the dentist to
with treatments that target the microbial eti- provide appropriate treatments on an indi-
ology. vidual basis. A combination of treatment
In addition to reducing the bacterial approaches for each patient provides optimal
challenge and modulating the host response, periodontal treatment and results in a better
reduction of risk is also a key treatment prognosis (Figure 5).77
strategy when managing periodontitis. For Figure 5. Complementary Treatment
example, it is known that smoking can con- Strategies in Periodontitis
tribute to periodontal disease and can make
the management of the disease more diffi-
cult.74,75 Therefore, smoking cessation would Reduction of Risk factor
benefit all patients with periodontitis. bacterial burden:
SRP, local antimicrobials,
modification:
Smoking cessation therapy
Surgical pocket
Smoking cessation can be undertaken in the reduction
Best chance
Diabetes control
dental office (if the staff is appropriately for clinical

improvement
trained) or in a medical setting. A variety of
medications aid in smoking cessation, coun-
seling is important, and alternative medicine
such as acupuncture may be used. When Host-modification therapy:
subantimicrobial dose doxycycline,
Enamel matrix proteins, rhPDGF, BMP-2l
poorly controlled, systemic diseases such as
diabetes increase a patient’s risk for peri-
odontitis.76 When treating people with dia-
betes, knowing the patient’s level of diabetic Adapted from: Carranza’s Clinical Periodontology, 10th
ed. WB Saunders Company; 2006:275–82.
control is important in assessing risk. Collab-
oration with medical colleagues to improve The Antimicrobial Approach
control of diabetes is essential to ensure suc- Traditional periodontal therapy based on the
cessful periodontal treatment. Periodontitis is antimicrobial approach consists of mechanical
also prevalent in patients with cardiovascular nonsurgical and surgical therapies, which may
disease. Periodontal therapy may have a pos- or may not be supplemented by local antisep-
itive impact on the overall health status of tics and/or local or systemic antibiotics.
these individuals.
The treatment of patients with peri- Mechanical Therapy
odontitis can therefore involve the following Preventive and maintenance strategies for the
complementary treatment strategies: patient include adequate home care. Brush-
• Patient education, including oral hygiene ing and flossing make up the most basic
instruction and explanation of the approach to microbial reduction and control
rationale for any adjunctive treatments for the patient. Good oral hygiene can effec-
• Risk factor modification and risk reduc- tively reduce bacterial loads to prevent gin-
tion strategies givitis and aid in the treatment and manage-
• Reduction of the bacterial burden by ment of periodontitis. This simple approach
relies on an individual’s knowledge of the motivation and do not spend a sufficient

correct techniques and compliance with amount of time brushing or flossing on a
home care instructions. The Bass technique daily basis.80 For this reason, oral antiseptic
of brushing for 2 minutes twice daily, along rinses have been developed. Antiseptic
with flossing once daily, is the current recom- mouthrinses have been found to improve on
mendation. The use of end tuft and proxy- plaque reduction as well as reductions in gin-
brushes as well as powered toothbrushes can gival inflammation seen with brushing and
improve home care in certain patients. flossing alone. Therefore, antiseptic rinses
Routine scaling of teeth every 6 months have been accepted as adjuncts to the
by the dental care provider is also a key com- mechanical approach of brushing and floss-
ponent in treating and preventing gingivitis. ing. Two clinically proven American Dental
Scaling and root planing is the traditional Association (ADA)-accepted antiseptic
nonsurgical treatment of periodontitis, with mouthrinses are Peridex® (chlorhexidine glu-
many clinical studies demonstrating that it conate) and the four essential oils in Lister-
effectively reduces the microbial load and ine®. An association between oral conditions
leads to reductions in bleeding on probing, such as periodontal disease and several respi-
reduces probing depths, and allows for gains ratory conditions such as pneumonia and
in clinical attachment.78 However, this proce- chronic obstructive pulmonary disease has
dure can be very time-consuming and is oper- been noted. The plaque surrounding the teeth
ator-dependent.79 Surgical procedures can be is an excellent harbor for respiratory
used to visualize remaining subgingival calcu- pathogens. Studies have shown that using a
lus, and through resective or regenerative pro- chlorhexidine oral rinse can reduce the risk of
cedures will also lead to decreased probing pneumonia in institutionalized patients with
depths that are more manageable for long- poor oral hygiene.81
term maintenance of patients with periodonti-
tis. Although nonsurgical and surgical proce- Locally Applied Antiseptics
dures aimed at reducing the bacterial load, Periochip® contains the active ingredient of
reducing probing depths, and restoring the chlorhexidine gluconate (2.5 mg) that is
attachment apparatus continue to be the most released into the pocket over a period of 7
widely used methods of treating periodontitis, to 10 days. It has been found to suppress the
these strategies alone may be insufficient at bacteria in the pocket for up to 11 weeks
reducing the bacterial load adequately. It has after application.82 Periochip is the only
been recognized that significant numbers of ADA-approved locally applied antiseptic
microorganisms may be left behind, requiring used as an adjunct to scaling and root
additional therapeutic approaches. Many planing procedures to aid in the reduction of
putative pathogens remain within the oral pocket depths.
cavity at distant sites, allowing for repopula-
tion in the future. Therefore, the need for the Dentifrices
development of chemotherapeutic agents as Major improvements in the oral health of
adjuncts to mechanical debridement was populations in developed countries have
deemed necessary. been seen over the last 50 years. Most of this
has resulted from reduction in the caries rate
Antiseptics and Toothpastes of about 50%. The principle reason for this
Antiseptic Mouthrinses is thought to be the addition of fluoride to
Unfortunately, many patients are not compli- dentifrices. Modern commercial dentifrices,
ant with brushing and flossing. They lose in addition to providing the anticaries effects
of fluoride, also contribute to reduction of a tooth brushing regimen are mainly on the
plaque, gingivitis, calculus formation, and occlusal and smooth surfaces of the teeth
tooth stain. They reduce halitosis and result and that interproximal plaque and gingivitis
in a clean, fresh mouth feel. Two dentifrices control is not optimally achieved with tooth
available in the United States that are brushing alone with or without a dentifrice.
approved by the ADA for their effects on Interproximal aids such as flossing, interprox-
the reduction of gingivitis include a stannous imal brushing, and, to some extent, flushing
fluoride/sodium hexametaphosphate denti- with effective mouth rinses, are often needed
frice and a sodium fluoride/triclosan/copoly- for full plaque control on interproximal sur-
mer dentifrice. faces of the teeth. Since periodontal disease is
There is a large amount of literature on often initiated and progresses more rapidly in
the latter dentifrices and other dentifrices interproximal spaces, it is clear that interprox-
containing chlorhexidine and other agents in imal cleansing is an important adjunct to
the control of gingivitis. A review of the role tooth brushing with dentifrices.
of triclosan/copolymer toothpaste in the
management of periodontal disease was Antibiotics
carried out by Blinkhorn and colleagues.83 Locally Applied Antimicrobials
They found approximately 200 articles Atridox: An FDA-approved locally delivered
dating from 1998 to 2008 relating to tri- tetracycline system, Atridox® is a 10% for-
closan/copolymer dentifrice and concluded mulation of doxycycline in a bioabsorbable,
that twice daily use of this dentifrice will ‘‘flowable’’ poly(DL-lactide) and N-methyl-2-
result in clinically significant improvements pyrrolidone mixture delivery system that
in plaque control and gingivitis with slowed allows for controlled release over 7 days. This
progression of periodontal disease. Further system is applied subgingivally to the base of
long-term studies extending over several the pocket through a cannula. Atridox is a
years with these dentifrices are needed to resorbable, site-specific, locally applied antibi-
establish whether the short-term effects will otic proven to promote clinical attachment
be sustained over the long term and indeed gains and reduce pocket depths, bleeding on
result in preventing the initiation of peri- probing, and levels of pathogenic bacteria
odontitis and slowing the progression of for up to 6 months after placement.70 Peri-
already existing periodontitis. odontal disease has been linked to systemic
Furthermore, the Cochrane Oral Health diseases such as diabetes. Research has
Group has recently published a review of 30 shown that periodontal treatment with topi-
clinical trials that included 14,835 partici- cally delivered doxycycline (10 mg) in peri-
pants and examined the effect of odontal pockets produces favorable clinical
triclosan/copolymer as compared to an ordi- results in diabetic patients.85
nary fluoride toothpaste on various end-
points and concluded that there was “mod- Arestin: An FDA-approved minocycline
erate-quality evidence” supporting the fact microsphere system, Arestin® is bioadhesive
that toothpaste containing triclosan/copoly- and bioresorbable, allowing for sustained
mer reduced plaque and gingivitis, including release of 1 mg of minocycline. Arestin can
gingival inflammation and gingival bleeding, be used as an adjunct to scaling and root
as compared to a regular fluoride tooth- planing procedures for reduction of pocket
paste.84 depth in patients with adult periodontitis.
It should be noted that the antiplaque Arestin is delivered to sites of 5 mm or
and antigingivitis effects of dentifrices during greater. Periodontitis has been associated
with increased systemic inflammation, which to incision and drainage. For patients with
is directly linked to diabetes and cardiovascu- allergies to beta-lactam drugs, azithromycin
lar diseases. Recent research has shown that or clindamycin would be the drug of choice.
periodontal therapy with local Arestin Researchers have shown that periodon-
administration resulted in decreased HbA1c tal treatment can improve on systemic dis-
levels in diabetic subjects86 and significant eases known to be associated with periodon-
reductions in systemic inflammatory bio- titis, such as diabetes. Periodontal therapy,
markers, which are risk factors for cardiovas- including the use of antibiotics and extrac-
cular disease.87,88 tion of hopeless teeth, reduced the number
of insulin injections required daily in young
Systemic Antimicrobials patients with diabetes.94 Grossi and col-
Systemic antimicrobial therapy is usually leagues95 reported that diabetic patients
reserved for advanced cases of periodontitis undergoing scaling and root planing with
(1) for patients with sites that have not systemic doxycycline showed significant
responded to treatment, as so-called “refrac- reductions in mean HbA1c.95 Effective treat-
tory periodontitis,” and (2) for patients ment of periodontal infection and reduction
demonstrating progressive periodontal of periodontal inflammation are associated
destruction.70 Systemic antibiotics can be with a reduction in levels of glycated hemo-
used as adjuncts to conventional mechanical globin.
therapy, but strong evidence for their use as
a monotherapy has not been developed. For Host Modulation Therapy
these special situations, randomized double- Bacteria and the host response are two
blind clinical trials and longitudinal assess- essential components in the development of
ments of patients indicate that systemic periodontitis. Reduction of bacterial loads is
antimicrobials may be useful in slowing the conventional approach for the manage-
disease progression.89 Metronidazole can be ment of periodontal diseases. More recently,
used to cure acute necrotizing ulcerative gin- periodontal treatment strategies have
givitis,90 and metronidazole amoxicillin com- included host modulatory therapy as an
bination therapy can be used to treat aggres- adjunctive treatment option. It addresses the
sive adolescent periodontitis associated with host response to either reduce the excess pro-
A. actinomycetemcomitans.91 duction of cytokines and destructive
Systemic antibiotic therapy has the enzymes so that there is less damage to the
advantage of simple, easy administration of periodontal tissues or to stimulate the regen-
drugs to multiple periodontal sites. However, erative process, allowing for the restoration
patient compliance needs to be considered, of connective tissue attachment and bone
inability to achieve adequate concentrations formation.
at the site of infection, adverse drug reac- Host modulation was first introduced to
tions, and the development of antibiotic dentistry by Williams96 and Golub and col-
resistance are possible issues.92 Common leagues.97 Williams stated: “There are com-
antibiotic therapies for the treatment of peri- pelling data from studies in animals and
odontitis are metronidazole, clindamycin, human trials indicating that pharmacologic
doxycycline or minocycline, ciprofloxacin, agents that modulate the host responses
azithromycin, metronidazole and amoxicillin, believed to be involved in the pathogenesis of
and metronidazole and ciprofloxacin.93 For periodontal destruction may be efficacious in
adult patients with acute periodontal slowing the progression of periodontitis.”96
abscesses, amoxicillin is used as an adjunct Golub and colleagues discussed “host mod-
Figure 6. Potential Adjunctive Therapeutic Approaches
Bisphosphonates
NSAIDs Periostat
Periostat
Antimicrobials Osteoclasts
Pockets
Prostaglandins and
Bone
CAL
Bacterial Host Cytokines resorption
products cells (IL-1, IL-6, TNF)
Connective
Tooth
MMPs tissue
mobility
breakdown
and
loss
Periostat
Bacterial + Host response component = Clinical

component sequelae
ulation with tetracyclines and their chemi- disease, researchers have investigated the
cally modified analogues.“97 A variety of effect of SDD on these systemic conditions.
drug classes have been evaluated as host Studies have shown that SDD
modulation agents, including the non- 1. Can effectively reduce the levels of
steroidal anti-inflammatory drugs localized and systemic inflammatory
(NSAIDs), bisphosphonates, tetracyclines mediators (hsCRP) in osteopenic
(Figure 6), enamel matrix proteins, growth patients in addition to improving on the
factors, and bone morphogenetic proteins. clinical measurements of periodonti-
tis98,99
Systemically Administered Agents 2. Has been shown to reduce systemic
Subantimicrobial-Dose Doxycycline inflammatory biomarkers (hsCRP) in
Subantimicrobial-dose doxycycline (SDD) is patients with cardiovascular disease100
the only FDA-approved MMP inhibitor and 3. Decreases HbA1c in patients who are
systemic host modulatory therapy for the taking normally prescribed hypo-
management of periodontitis. SDD is a 20- glycemic agents101
mg dose of doxycycline (Periostat®) taken The impact of SDD therapy has been
twice daily for at least 3 months, and used in shown in many studies to go beyond the
multicenter clinical trials for up to 24 clinical benefits to periodontitis.
months of continuous dosing. SDD is used
as an adjunct to scaling and root planing in Locally Administered Agents
the treatment of chronic periodontitis. Its Enamel Matrix Proteins, Growth Factors, and
host modulatory effects include enzyme inhi- Bone Morphogenetic Proteins
bition, cytokine reductions, and effects on A number of local host modulation agents
osteoclast function. Since periodontitis is have been investigated for potential use as
associated with many systemic diseases, such adjuncts to surgical procedures to improve
as osteoporosis, diabetes, and cardiovascular periodontal health. These have included
enamel matrix proteins (Emdogain®), bone Acknowledgments

morphogenetic proteins (BMP-2), and The authors would like to acknowledge Dr. Hsi-ming
growth factors (PDGF). The initial local Lee, Rene Martin, and Laura Bertolotti for their assis-
host modulatory agent approved by the tance in the organization of this manuscript.
FDA for adjunctive use during surgery to
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CHAPTER 3
Infection and Inflammation
Phoebus Madianos, Yiorgos A. Bobetsis, Thomas Van Dyke
INTRODUCTION cancer5,6 are associated with oral organisms

Periodontal diseases (gingivitis and peri- entering the circulation and elevated systemic
odontitis) are destructive inflammatory dis- inflammation. The coexpression of inflam-
eases of the gingiva and the supporting matory periodontitis with other inflamma-
structures of the teeth induced by a micro- tory diseases suggests a common pathway in
bial biofilm commonly called dental plaque. pathogenesis.
The fundamental principle of the bacterial Depending on the effectiveness of the
etiology of gingivitis was first established in a innate immune response, bacterial infection
landmark study by Löe et al.1 in 1965. Using may persist and lead to perpetuation of
a novel—now classic—experimental design, inflammation, which may become chronic
it was demonstrated that when students with with the development of acquired immunity.
healthy gingiva abstained from oral hygiene However, if the infection is cleared, then res-
practices for 10 to 21 days, marginal inflam- olution of inflammation occurs with the
mation of the gingiva (gingivitis) developed return of tissue homeostasis without perma-
as a result of plaque accumulation. When nent damage. Recent discoveries have altered
oral hygiene was reinstated, gingival health our understanding of inflammation resolu-
returned. Today, in vitro and in vivo experi- tion and return of tissue homeostasis. We
ments, along with histologic assessments of now understand that resolution of inflam-
inflamed and healthy gingiva, have provided mation is an active process, not the passive
a clearer understanding of the nature of the decay of proinflammatory signals as once
interactions between bacteria and host cells. thought. The ability to manipulate these
However, current understanding of the etiol- processes may provide a new treatment para-
ogy and pathogenesis of the periodontal dis- digm for both local and systemic inflamma-
eases is far from complete. tory diseases.7
Periodontal bacteria possess a plethora
of virulence factors that, upon interaction Chapter Goals
with host cells, induce production of inflam- This chapter is structured to (1) provide
matory mediators at the gingival level. These background information regarding the initi-
mediators are thought to be important for ation and orchestration of inflammation at
the initiation and progression of an inflam- the gingival level after the interaction of the
matory response, which though intended to biofilm with host cells; (2) examine the evi-
eliminate the bacterial challenge, inevitably dence for periodontal disease influencing
results in tissue damage when the bacterial systemic inflammation and describe the
challenge persists. It is also important to possible biologic pathways, as well as the
note that inflammation is not confined solely cellular and molecular events that may
to periodontal tissues. Bacteria and inflam- occur; (3) explore the idea that systemic
matory mediators may enter blood circula- inflammation may be the link that associ-
tion to induce systemic inflammation. Evi- ates periodontal disease with other systemic
dence is increasing that cardiovascular diseases, focusing on the potential mecha-
disease (CVD),2 adverse pregnancy out- nisms of action; (4) address the role of reso-
comes,3 diabetes mellitus,4 and possibly lution of inflammation in the pathogenesis
CHAPTER 3 Infection and Inflammation 31
of inflammatory diseases; and (5) introduce cell receptors called pattern recognition recep-
new strategies directed at mechanisms of tors (PRRs). These highly conserved innate
inflammation resolution that may be used immune receptors evolved for detection of
in treating inflammatory diseases. invading bacteria. Binding of PAMPs by
PRRs activates specific signaling pathways in
PART I: INFLAMMATION AT THE host cells that are important for the initiation
GINGIVAL LEVEL of an inflammatory response. Although this
Periodontal disease is an inflammatory dis- response is intended to eliminate the micro-
order of the supporting tissues of the teeth bial challenge, the inflammatory mediators
in a susceptible host. Bacteria in the oral that are secreted may lead to further tissue
cavity colonize the teeth, the gingival sulcus, damage if bacterial clearance is not
and eventually the periodontal pocket, achieved. Today, the most studied bacterial
forming an organized biofilm. Depending on factors are LPS, PGN, lipoteichoic acids
the stage of maturation, the biofilm may (LTAs), fimbriae, proteases, heat-shock pro-
consist of several hundred bacterial species, teins (HSPs), formyl-methionyl peptides, and
many of which have yet to be identified.8 toxins. Host PRRs include the Toll-like
Some of these species are associated with receptors (TLRs) and other G-protein–
health, whereas others are associated with coupled receptors (GPCRs). Table 1 presents
pathology.9 However, the identity of the a summary of the results by actions of
organisms that actually initiate disease various bacterial factors after interaction
remains unknown. with specific host cells.10
Bacterial Components Bacteria and Gastrointestinal Equilibrium

The formation of organized biofilms The oral cavity, as part of the gastrointesti-
enhances the ability of bacteria to survive. nal tract, is naturally colonized by a wide
Bacteria have also evolved a variety of viru- variety of bacteria. This physiologic situation
lence factors to further enhance their sur- does not always result in pathology. The
vival, such as toxins, proteases, and glycosi- tooth-gingival interface is the site of a variety
dases. Virulence factors are presumably of natural, innate host defense mechanisms,
intended to hide the bacteria from host including the regular shedding of epithelial
detection as well as to provide essential mol- cells, the washing effect of the saliva and the
ecules for nourishment. Conversely, the host gingival crevicular fluid (GCF), and, most
has evolved mechanisms for detection of important, the phagocytic action of neu-
bacteria through the recognition of struc- trophils that migrate continuously through
tural components of the bacterial surface, the junctional epithelium into the gingival
such as lipopolysaccharide (LPS), peptido- sulcus. These mechanisms preserve an equi-
glycan (PGN), and other cell surface compo- librium in the number of bacteria around
nents such as fimbriae, which perform essen- the teeth. However, excess inflammation may
tial physiologic functions for the bacteria. disturb this equilibrium and pathogenic bac-
Variations of these bacterial components teria may overgrow, initiating the pathogene-
may be seen among various species, or even sis of gingivitis and possibly periodontitis.
among different strains of the same species. Current understanding of the steps
Despite their structural heterogeneity, most leading to periodontal disease includes peri-
of these molecules have conserved motifs odontal bacteria attaching to epithelial cells
known as pathogen-associated molecular pat- using their fimbriae and PRR recognition of
terns (PAMPs), which are recognized by host PAMPs, inducing epithelial cell secretion of
Table 1. Summary of Main Effects of Bacterial Virulence Factors on Host Cells
Responses of Host Cells

Bacterial Epithelial Monocytes/ Endothelial Fibroblast
Factor Cells Macrophages Cells Cells Mast Cells
IL-1b
TNF-a
IFN-g
IL-6 IL-1b
IL-12 MCP-1 TNF-a
IP-10 IL-1b IFN-g
MCP-5 E-, P-selectin IL-6 IL-6
LPS IL-8 IL-8 MCP-1 IL-8 IL-12
MIP-1a, MIP-2 ICAM-1 IP-10
PGE2
NO
L-selectin
CD11a/CD18,
CD11b/CD18
IL-1b Histamine
TNF-a TNF-a
PGN IL-8 IL-6 ICAM-1 IL-8 Prostaglandins
IL-8 IL-8 IL-4
MIP-1a IL-5
NO IL-10
IL-1b
TNF-a
IFN-g IL-6
LTA IL-8 IL-6 IL-8
IL-8 E-selectin
IL-10
NO
IL-1b IL-1b MCP-1
Fimbriae TNF-a TNF-a IL-8 IL-1b
IL-6 IL-6 ICAM-1, TNF-a
IL-8 VCAM-1 IL-6
P-, E-selectin
Proteases IL-6
b-defensins
HSP IL-6 IL-6
IL-8
TNF-a
fMLP CD11a/CD18
CD11b/CD18
IL-1b
IFN-g
Toxins IL-6
IL-8
IL-10
Adapted from J Clin Periodontol 2005;32(Suppl 6):57–71.10
proinflammatory cytokines (TNF-a, IL-1b, reversibly to the vessel wall and causing circu-
IL-6), and the chemokine IL-8 in the con- lating leukocytes to appear to “roll” along
nective tissue. Normally, the intact sulcular the activated endothelium. Then, IL-8 and
and junctional epithelium serves as an effec- other chemokines, bound to proteoglycans
tive natural barrier that keeps the bacteria on the surface of leukocytes, trigger a confor-
from entering host tissues. However, several mational change of integrins (LFA-1,
periodontopathogens (e.g., Porphyromonas. CD11b: CD18). As a result, adhesive proper-
gingivalis, Aggregatibacter [formerly Acti- ties increase dramatically, and leukocytes
nobacillus] actinomycetemcomitans) have been attach firmly to ICAM-1 expressed on
shown to invade and transverse epithelial endothelial cells. Tumor necrosis factor-a
cells to gain access to the connective tissue. (TNF-a), PGE2, and histamine increase vas-
Moreover, bacterial components (e.g., LPS, cular permeability, allowing leukocytes to
PGN) and products (e.g., proteases, toxins) squeeze between the endothelial cells, thereby
that are either shed or secreted can also entering the connective tissue in a process
diffuse through the epithelial junctions to the known as diapedesis. Finally, chemokines,
connective tissue.11 such as IL-8, which are produced at the site
of infection and bind to proteoglycans of the
Bacteria in Connective Tissue extracellular matrix, and along with bacterial
Bacteria and/or their virulence factors found chemoattractants (fMLP, fimbriae), form a
in the periodontal pocket epithelium and the concentration gradient that guides the leuko-
connective tissue directly stimulate host cells cytes to migrate to the focus of infection.
residing in this area, such as leukocytes,
fibroblasts, mast cells, endothelial cells, den- The Inflammatory Cascade
dritic cells, and lymphocytes. Neutrophils, Neutrophils are the first leukocytes to arrive,
macrophages, fibroblasts, and mast cells followed by mononuclear phagocytes, which
release more proinflammatory cytokines subsequently differentiate into macrophages.
(TNF-a, IL-1b, IL-6, IL-12), chemoattrac- The interaction of these cells with bacterial
tants (IL-8, MIP-1-a, MIP-2, MCP-1, virulence factors induces further activation,
MCP-5), and prostaglandin E2 (PGE2) in the which enhances their phagocytic activity by
connective tissue. In addition, degranulation increasing the production of nitric oxide
of mast cells results in the secretion of hista- (NO) and the expression of complement
mine and leukotrienes, further amplifying the receptors (CR3). If the innate immune
inflammatory cascade.12,13 response is successful, the bacteria are elimi-
Mediators that are secreted from acti- nated, and resolution of inflammation
vated host cells (e.g., IL-1b, TNF-a, PGE2, follows. However, persistence of bacteria
and histamine) further assist bacterial viru- leads to a chronic response characterized by
lence factors in the activation of endothelial extracelluar release of neutrophil granule
cells. This leads to secretion of more contents, including degradative enzymes and
chemokines (IL-8, MCP-1) and expression of reactive oxygen species that spill into the
adhesion molecules on the surface of extracellular milieu, leading to local tissue
endothelial cells, which are important for damage and amplification of acute inflam-
leukocyte extravasation (P- and E-selectins as matory signals.15
well as intercellular adhesion molecule 1 Proinflammatory cytokines (TNF-a,
[ICAM-1] and ICAM-2).14 Specifically, P- IL-1b, IL-6) from the site of inflammation
and E-selectins interact with glycoproteins on enter the circulation and reach the liver,
leukocytes, allowing the cells to adhere where they activate hepatocytes. This leads,
among other events, to the synthesis of The Immune Response

plasma proteins known as acute-phase pro- If the infection persists, the acquired
teins, including LPS-binding protein (LBP) immune response is initiated, and the estab-
and CD14, which are important for the lished lesion is created, as described by Page
recognition of bacterial virulence factors. and Schroeder.16 Briefly, dendritic cells within
Complement proteins and C-reactive protein the epithelium take up bacterial antigens and
(CRP) contribute by opsonizing bacteria, migrate to the peripheral lymph nodes. The
thereby aiding in recognition for phagocyto- antigens are processed into a form that is
sis. These products enter the circulation and, recognizable by the immune system; that is,
because of increased vascular permeability, the antigenic peptide binds to a class II
diffuse into the inflamed gingival tissues. major histocompatibility complex (MHC)
Figure 1 illustrates the initiation of inflam- receptor that consequently “presents” the
mation at the gingiva. antigen. As a result, antigen-specific effector
Figure 1. Initiation of Inflammation at the Gingival Level
IL-1"
Hepatocyte
TNF-!
LBP
IL-6
sCD14
CRP
Endothelial cells Complement
Blood vessel lumen
Leukocyte
LFA-1
CD11b:CD18
E-
se IC A
tin le 8
IL- P-1 ICA M -1
ec ct Increased vascular
el in M-
P -s MC 2 permeability
LTB-4 IL-1"
Connective Tissue
TNF-! LBP Histamine

C5a TNF-!
sCD14 TNF-!
Histamine
CRP PGE2
TNF-!
Complement
IL-6
IL-8 Epithelial Cells
Sulcus/pocket
hBDs
Neutrophil
Bacteria and virulence factors
Neutrophils in the gingival crevicular fluid (GCF) and epithelial cells comprise the first line of defense to prevent
bacteria from invading the host. The interaction of the bacterial biofilm with epithelial cells leads to activation and
secretion of proinflammatory cytokines (green). Bacteria and their virulence factors (red) may penetrate the epithelial
lining and enter the connective tissue. In this compartment, they may interact with host cells, such as macrophages,
fibroblasts, and mast cells to stimulate these cells to release more proinflammatory mediators such as TNF-α, IL-1β,
IL-8, LTB-4, and histamine. These mediators, along with bacteria/virulence factors, may activate endothelial cells to
attract circulating leukocytes in the connective tissues. In this compartment, phagocytic cells take up bacteria and
their antigenic molecules. This process, if further enhanced by acute-phase response proteins, such as CRP, which are
produced from activated hepatocytes, enter the connective tissue via circulation as a result of increased vascular per-
meability. If the noxious agents are eliminated, resolution of inflammation follows. However, if the bacterial challenge
persists, the more efficient adaptive immune response takes over.
Adapted from J Clin Periodontol 2005;32(Suppl 6):57–71.10
T cells and antibody-secreting B cells are addition, recent animal studies suggest that
generated by clonal expansion and differenti- the level of host inflammation has a major
ation over the course of several days, during impact on the composition of the biofilm. It
which time the induced responses of innate is interesting that inflammation is a stronger
immunity continue to function. Eventually, predictor of periodontal attachment loss than
antigen-specific T cells, and then antibodies, the composition or quantity of the oral
are released into the blood to target the infec- biofilm.19 Clearly, the etiology and pathogene-
tion site.17 Macrophages that engulf bacteria sis of periodontitis require further study. It is
at the site of infection express costimulatory also apparent that traditional periodontal
molecules (MHC II) and present bacterial pathogens (Socransky’s red complex) con-
antigens on their surface. Antigen-specific T tribute to and accelerate disease when they
cells see the antigens and activate the overgrow in the periodontal environment.
macrophages, enabling them to destroy intra- However, the role of inflammation and the
cellular bacteria more efficiently. host immune response has taken on a new
In addition, secreted antibodies protect perspective, potentially determining suscepti-
the host from infection by (1) inhibiting the bility and providing a novel therapeutic target.
toxic effects or infectivity of pathogens by
binding (neutralization); (2) opsonizing the PART II: SYSTEMIC INFLAMMATION
pathogens and promoting phagocytosis; and DUE TO PERIODONTAL INFECTION
(3) activating the complement system. Despite the localized nature of periodontal
Failure to clear the infection at this point disease, infection of the sulcus/periodontal
leads to further tissue damage. Activated pocket with periodontopathogens may be
macrophages produce oxygen radicals, NO, responsible for inflammatory responses that
and proteases in the gingival tissues, which develop beyond the periodontium. To date,
are toxic to the host cells. Moreover, recent several biologic pathways have been recog-
work on a mouse model revealed that the nized that present reasonable hypotheses for
induction of an adaptive immune response periodontal disease induction of systemic
to colonizing pathogens results in receptor inflammation.
activator of nuclear factor-kappaB ligand-
dependent periodontal bone loss.18 Inflammatory Pathways
In health, the sulcular epithelium, along with
Summary of Part I innate immune molecules, acts as a natural
The trigger that causes the shift from tissue barrier system that prevents bacterial pene-
homeostasis to pathology remains unclear. tration. Hence, only a small number of bac-
The logical extension of Löe’s observation is teria, mostly facultative anaerobes, manage
that this is caused by specific bacteria, and to enter the gingival tissues and the blood-
indeed, a large body of evidence suggests that stream. However, in cases of periodontal
certain bacteria are associated with progres- disease, the inflamed and ulcerated pocket
sive disease. However, studies of the micro- epithelium is vulnerable to bacterial penetra-
biota of the periodontal lesion are cross-section and forms an easy port of entry for the
tional, and definitive cause-effect relationships bacteria. This leads to an increase in the
have not been demonstrated. number of periodontopathogens, mainly
A longitudinal study of periodontal anaerobic gram-negative, in the gingival
disease progression failed to implicate any tissues and consequently in the circulation.
single organism or group of organisms in the Bacteremia can be further aggravated after
initiation of periodontal attachment loss.19 In mechanical irritation of the inflamed gingiva
during tooth brushing, chewing, oral exami- systemic. Proinflammatory cytokines may
nation, and scaling and root planing.20 The induce leukocytosis, which is characterized
microorganisms that gain access to the blood by an increase in circulating neutrophils.
are usually eliminated by the reticuloen- Moreover, IL-1b, TNF-a, and especially IL-
dothelial system within minutes (transient 6 may reach the liver and activate hepato-
bacteremia) and usually without any other cytes to produce acute-phase proteins. The
clinical symptoms except possibly a slight most important acute-phase reactants are
increase in body temperature.21 However, if CRP, serum amyloid A (SAA) protein, fib-
the disseminated bacteria find favorable con- rinogen, plasminogen activator inhibitor 1
ditions, they may colonize distant sites and (PAI-1), complement proteins, LBP, and
form ectopic foci of infection. soluble CD14. These proteins are released in
Similarly, bacterial virulence factors that the plasma and possess a wide variety of
are secreted or shed in the gingival tissues functions, such as proinflammatory activities
may also disseminate via the circulation and and stimulation of tissue repair mechanisms.
stimulate remote tissues.22 Bacteria and bac- The production of these proteins is part of
terial antigens that are systemically dispersed an acute-phase response that is characterized
can trigger significant systemic inflamma- by fever, increased vascular permeability, and
tion. Leukocytes as well as endothelial cells a general elevation of metabolic processes.
and hepatocytes respond to bacteria/viru- An acute-phase response starts within hours
lence factors, producing proinflammatory or days of most forms of acute tissue
immune mediators. Moreover, soluble anti- damage or inflammation and, despite its
gens may react with circulating specific anti- name, persists with chronic inflammation.
bodies, forming macromolecular complexes As acute-phase reactants enter the circula-
that may further amplify inflammatory reaction, they may return to the inflamed gingi-
tions at sites of deposition.23 val tissues. However, since they circulate
throughout the body, they can affect ectopic
Proinflammatory Mediators sites, causing inflammation or exacerbation
A different biologic pathway that may of existing inflammatory processes. This
explain the systemic inflammation induced concept takes on new meaning in light of
by periodontal disease involves proinflam- the recent implication of CRP in the patho-
matory mediators, such as IL-1b, IL-6, genesis of CVD.25
TNF-a, and PGE2, which are produced by Because no consensus exists to date on
host cells in the inflamed gingival tissues. the mechanisms that induce systemic inflam-
These mediators are secreted locally in mation from periodontal disease, any of the
response to bacterial challenge, but may spill above pathways (bacteremia, systemic
into the circulation and exert distant or sys- spilling of cytokines, and activation of the
temic effects. acute-phase response) must be considered a
Specifically, cytokines may reach distant candidate for the generation of systemic
sites and further activate endothelial cells, inflammation. It is also possible that,
leading in some cases to endothelial dysfunc- depending on the severity of periodontal
tion.24 Moreover, the circulating mediators, disease, any of these mechanisms may occur
because of the increased vascular permeabil- alone or in combination, leading to varia-
ity at the sites of inflammation, may enter tions of induced systemic inflammation.
inflamed tissues and exacerbate the inflam-
matory processes. However, the most impor- Acute-Phase Proteins
tant impact of these circulating mediators is CRP is produced mainly by the liver, but it
may also be synthesized locally at sites of XIII to form a clot. Thus, fibrinogen is
inflammation. CRP opsonizes different bac- involved in blood coagulation and platelet
teria by binding to phosphorylcholine found activation.
on the surface, thereby assisting in bacterial
uptake by phagocytes.26 Opsonization and Plasminogen Activator Inhibitor 1
phagocytosis are further enhanced by activa- PAI-1 is produced by the liver and endothe-
tion of the complement system by CRP. lial cells. It inhibits the serine proteases tPA
Other proinflammatory activities of CRP and uPA/urokinase, and therefore is an
include the upregulation of the expression of inhibitor of fibrinolysis, the physiologic
adhesion molecules, such as ICAM-1 and E- process that degrades blood clots.
selectin on endothelial cells and the induc-
tion of IL-6, IL-1b, and TNF-a, and of the Complement Proteins
chemokines IL-8 and MCP-1. Other proper- Complement proteins take part in a trig-
ties of CRP that may not be of obvious gered enzyme cascade that activates the com-
importance in periodontal disease but may plement system. There are three ways by
significantly affect other systemic inflamma- which complement is involved in inflamma-
tory diseases (e.g., atherosclerotic lesions) tory processes. First, activated complement
include thrombosis due to the procoagulant proteins may bind covalently to pathogens as
activity and reduction of fibrinolysis by opsonins for engulfment by phagocytes
inducing an increase in the expression of bearing receptors for complement. Second,
PAI-1, the main inhibitor of fibrinolysis.27 the small fragments of some complement
Finally, CRP mediates proliferation and proteins act as chemoattractants to recruit
activation of smooth muscle cells and more leukocytes to the site of complement
decreases the expression of endothelial nitric activation. Third, terminal complement com-
oxide synthase (eNOS). CRP may also have ponents damage certain bacteria by creating
anti-inflammatory properties, and hence its pores in the bacterial membrane.28
primary role is likely to be the regulation of
acute inflammation. LPS-Binding Protein and Soluble CD14
The proteins LBP and soluble CD14 play
Serum Amyloid A an important role in transferring LPS and
SAA proteins are a family of apolipopro- PGN to the TLRs. Hence, their presence is
teins associated with high-density lipoprotein critical for initiating and organizing an
in plasma. They have several proinflamma- inflammatory immune response after bacter-
tory functions, such as the recruitment of ial challenge.
immune cells to inflammatory sites and the
induction of enzymes that degrade extracel- Systemic Cellular and Molecular Markers
lular matrix. Also, SAA proteins transport of Inflammation
cholesterol to the liver for secretion into the Periodontal infection may induce an inflam-
bile. matory response that is not limited to the
tissues surrounding the teeth, but is also
Fibrinogen extended systemically. The main cellular and
Fibrinogen is a soluble plasma glycoprotein. molecular markers of systemic inflammation
Processes in the coagulation cascade acti- induced by periodontal disease include the
vate prothrombin to thrombin, which is increased number of peripheral leukocytes,
responsible for converting fibrinogen into the higher concentrations of serum antibod-
fibrin. Fibrin is then cross-linked by factor ies against periodontopathogens, and the ele-
vated levels of circulating proinflammatory increase their concentration in the plasma.

cytokines and acute-phase proteins. Of the proinflammatory mediators studied,
With the exception of serum antibodies only IL-6 levels have been consistently shown
against periodontopathogens, these markers to be elevated in the serum. This increase is
are not specific for periodontal disease, but related to the extent and severity of inflam-
can be shared with distant inflammatory mation in periodontal tissues.31 However,
processes that have systemic effects. As such, controversial reports have been published on
these markers can be affected by other inflam- the impact of periodontal therapy on IL-6
matory diseases that can occur concomitantly. levels, suggesting the need for further
The following systemic markers have been research on the topic. Finally, most of the
associated with the presence of periodontal studies looking at the levels of serum IL-1
disease and are usually affected by the severity and TNF-a among healthy and periodonti-
of inflammation in the gingiva. tis patients failed to report any differences,
and in most cases cytokine levels were not
Peripheral Blood Leukocytes measurable.32
In patients with periodontitis, leukocyte
counts have been shown to be slightly ele- Acute-Phase Proteins
vated compared with the counts of healthy The levels of several acute-phase reactants,
subjects, though not always significantly.29 such as CRP, fibrinogen, LBP, and soluble
The elevated level of circulating leukocytes CD14 have been studied and have been
depends largely on the extent and severity of shown to be elevated in patients with peri-
periodontal disease. Periodontal therapy may odontal disease. However, the acute-phase
lead to a reduction in the number of periph- proteins that have received the most attention
eral leukocytes.30 Polymorphonuclear leuko- and are consistent markers of systemic
cytes are the main leukocytes that are inflammation in periodontal disease are CRP
increased; these cells are possibly recruited at and fibrinogen. A large number of studies,
higher levels during episodes of bacteremia both in animal models and in humans, have
and leakage of bacterial virulence factors revealed a positive association between peri-
during periodontal disease. odontal disease and circulating CRP levels,
whereas a recent meta-analysis limited to
Serum Antibodies Against human studies has confirmed that plasma
Periodontopathogens CRP is elevated in patients with periodontitis
In chronic periodontal disease, in which the compared with CRP in healthy persons.33
adaptive immune response has been acti- Moreover, this increase was proportional to
vated, local and systemic exposure to peri- the extent and severity of the disease. Several
odontopathogens leads to an increase in the studies report a decrease of plasma CRP
levels of circulating antibodies against the after periodontal intervention, but there is
pathogenic antigens. Treatment of disease is modest evidence that periodontal therapy
followed by a reduction in antibody levels. lowers the levels of this protein. Finally, in
several studies, the levels of fibrinogen have
Serum Proinflammatory Cytokines also been found to be elevated in patients
In healthy subjects, the levels of circulating with periodontitis compared with fibrinogen
proinflammatory cytokines are very low or levels in healthy individuals.34 However, no
nondetectable. However, in patients with available evidence exists to support that
periodontitis, several proinflammatory theory that periodontal therapy actually
cytokines may spill into the bloodstream and reduces the amount of circulating fibrinogen.
Possible Role of Systemic Inflammation in important because increasing evidence sug-

Various Disorders gests that elevated levels of the markers of
During the late nineteenth and early twenti- systemic inflammation are associated with
eth centuries, the focal infection theory dom- an increased risk for systemic diseases.
inated the medical world.35 This theory held
that foci of sepsis were responsible for the Cardiovascular Disease
initiation and progression of a variety of There is now abundant clinical evidence
inflammatory diseases, such as arthritis, demonstrating that many biomarkers of
peptic ulcers, and appendicitis. As a result, inflammation are elevated years in advance
therapeutic full-mouth extractions became a of first-ever myocardial infarction (MI) or
common dental practice. However, many thrombotic stroke, and that these same bio-
teeth were extracted without evidence of markers are highly predictive of recurrent
infection. When it was finally realized that MI, recurrent stroke, and death due to
there was no therapeutic benefit, the theory CVD.2 Moreover, studies demonstrate that
was discredited and the practice abandoned. serum IL-6 levels were significantly elevated
During the final two decades of the twenti- in subjects who subsequently experienced an
eth century—as our knowledge concerning MI compared with IL-6 levels of age-
the inflammatory component of systemic matched controls.37 Similarly, plasma levels
diseases was enriched and our understanding of soluble P-selectin, soluble CD40L, and
of the relation of periodontal disease to sys- macrophage-inhibitory cytokine-1 all were
temic inflammation increased—the idea that significantly increased in healthy subjects
periodontal infection may affect the progres- who subsequently developed CVD events
sion of systemic disorders such as CVD, compared with those of matched controls.38
adverse pregnancy complications, diabetes Elevated plasma concentrations of TNF-a
mellitus, and other diseases re-emerged. have also been associated with CVD, and
Hence, to date, a large volume of data specifically with recurrent nonfatal MI or
has been gathered evaluating the possible other CVD events. Moreover, TNF-a levels
association of periodontal disease with sys- were persistently higher among post-MI
temic diseases. Observational studies have patients at increased risk for recurrent coro-
primarily used several clinical parameters nary events.
such as probing pocket depth, clinical Besides these proinflammatory
attachment loss, and bleeding on probing to cytokines, several acute-phase reactants have
assess the severity of periodontal disease and also been associated with CVD. One of the
consequently the risk for systemic exposure. factors with the strongest evidence as a bio-
However, the results of these studies are not marker for predicting CVD events is CRP
always consistent, indicating that these (specifically, high-sensitivity CRP, hsCRP).
parameters separately may not be able to When measured in the blood, hsCRP
reflect the inflammatory burden at the gingi- proved to be a strong, independent predictor
val level. Thus recently, Nesse et al.36 intro- of future MI and stroke among apparently
duced a new index that incorporates the healthy asymptomatic men. Also, the relative
latter parameters. This index calculates the risk for first MI and ischemic stroke
surface area of the inflamed periodontal increased significantly with each increasing
tissues (periodontal inflamed surface area, quartile of baseline concentrations of CRP.39
PISA), which may reflect, in a way, the mag- As described already, CRP may contribute
nitude of systemic inflammatory exposure to the initiation and development of
posed by periodontal disease. This may be atherothrombotic lesions not only by upreg-
ulating the expression of proinflammatory were more likely to develop type 2 diabetes
cytokines, but also by mediating proliferation over a period of 20 years compared with
and activation of smooth muscle cells and those in the lowest tertile. Moreover, in two
by activating the procoagulant system. This other studies, healthy persons demonstrating
last property may be further enhanced by serum levels of CRP and IL-6 within the
another acute-phase protein, fibrinogen, highest quartiles were more likely to develop
which is often found to be elevated in type 2 diabetes in the next 4 to 7 years com-
patients with CVD. pared with those in the lowest quartile.4
Similar results were found with increased
Adverse Pregnancy Outcomes levels of PAI-1, another acute-phase protein.
Systemic inflammation has also been impli- Insulin resistance, which is associated with
cated in adverse pregnancy outcomes, since type 2 diabetes and usually precedes the
elevated concentrations of CRP in early development of frank diabetes, may also be
pregnancy are associated with an increased affected by preexisting systemic inflamma-
risk of preterm birth and very-preterm tion, since several proinflammatory and
birth. acute-phase proteins, such as TNF-a, IL-6,
MCP-1, PAI-1, and SAA, are associated
Diabetes Mellitus with the induction of insulin resistance.41
Finally, systemic inflammation has been
associated with both type 1 and type 2 dia- Summary of Part II
betes mellitus. Recent studies suggest that in Based on available evidence, systemic inflam-
type 1 diabetes, the levels of systemic mation may actually be the link that associ-
markers of inflammation, such as CRP, do ates periodontal disease with other systemic
not differ between healthy persons and diseases. Details of the plausible biologic
persons for which type 1 diabetes has been mechanisms that may associate periodontal
just diagnosed. However, the levels of circu- disease with various systemic diseases are
lating CRP are significantly higher in those further analyzed in other chapters of this
with long-term diabetes.40 It is also believed book.
that inflammatory processes may have a
more pronounced effect on the development PART III: RESOLUTION OF
of complications of type 1 diabetes. Thus, INFLAMMATION IN PERIODONTITIS
elevated levels of plasma CRP and of the AND OTHER SYSTEMIC DISEASES
proinflammatory soluble adhesion molecule, Inflammation is thought to play a central
vascular cell adhesion molecule-1 (VCAM-1) role in the progression of periodontal disease
have been found in patients with microvascu- and a number of systemic diseases. Experi-
lar disease compared with those without ments in animal models and in man have
microvascular disease. demonstrated that periodontal destruction is
In those with type 2 diabetes, inflamma- mediated primarily by the inflammatory
tory processes are more strongly associated response, although periodontal pathogens
with the development of the disease. Sys- are a necessary etiologic factor.22,42,43 Genetic
temic markers of inflammation are found to polymorphisms and other factors may also
be increased in healthy persons who develop be responsible for a hyperinflammatory phe-
type 2 diabetes later in life. Among Pima notype, which may further affect the suscep-
Indians, a population in whom type 2 dia- tibility of the host to periodontal disease and
betes is highly prevalent, subjects with white tissue destruction. Currently, it is believed
blood cell counts within the highest tertile that in chronic periodontal disease, destruc-
tion does not follow a linear pattern with Returning to Homeostasis

time, but occurs in random bursts with After inflammation reaches its peak, resolu-
periods of remission and exacerbation. tion of inflammation occurs with the reduc-
However, the reasons behind this random tion or removal of leukocytes and debris
progression are not fully understood. Disease from inflamed sites with a return to home-
progression becomes even more enigmatic ostasis.7 Until recently, resolution of inflam-
considering that it is not always clear why a mation was considered to be a passive
chronic inflammation of the gingiva remains process in which the lack of bacterial stimuli
as gingivitis in some patients and progresses decreased the production of inflammatory
to periodontitis in others. Regardless of the mediators, which in turn reduced the inflam-
nature of periodontal disease progression, matory response, thereby returning to
the perpetuation of the inflammatory normal function. New data suggest that res-
process in the gingiva may lead to a chronic olution of inflammation is an active bio-
low-grade systemic inflammatory response, chemical and metabolic process initiated by
which in turn potentially contributes to the a newly identified class of receptor agonists
progression of systemic diseases. that emerge temporally as the inflammatory
lesion matures.7 Although prostaglandins and
Process of Inflammatory Resolution leukotrienes secreted by neutrophils have
The landmark events during inflammation proinflammatory properties, as inflammation
include the accumulation of leukocytes in proceeds, the same prostaglandins (PGE2
the infected area and phagocytosis of the and PGD2) may promote expression of the
bacteria and/or their virulence factors. As 15-LO gene. This leads to a switch in the
part of the inflammatory process, activation expression of biosynthetic enzymes by infil-
of neutrophil lysosomal phospholipase trating neutrophils (Figure 2). Binding of
releases free arachidonic acid from mem- lipoxin A4 to neutrophils leads to a pheno-
brane phospholipids. Once free arachidonic typic change, stopping all proinflammatory
acid is available, two separate pathways can activity of neutrophils and leading to apop-
be initiated: (1) the cyclooxygenase (COX) tosis. As a result, they stop secreting the
pathway, which leads to the production of chemoattractant LTB4, and several cellular
prostaglandins (e.g., PGE2, prostacyclins, pathways are activated, producing, at a local
and thromboxanes), and (2) the lipoxyge- level, other dual-acting anti-inflammatory
nase (LO) pathways, which lead to the pro- and proresolution lipid mediators, including
duction of a series of hydroxyl acids charac- resolvins and protectins.
terized by the 5-LO products, the
leukotrienes (e.g., LTB4). There are three cell Mechanisms of Inflammation Resolution
type-specific LOs: the 5-LO from myeloid Resolvins and protectins provide potent
cells, the 12-LO from platelets, and the 15- signals that orchestrate and accelerate mecha-
LO of epithelial and endothelial cells. PGE2 nisms that promote resolution of inflamma-
is a potent activator of osteoclast-mediated tion and homeostasis. Specifically, as depicted
bone resorption, and with other eicosanoids in Figure 3, proresolution mediators stop
mediates inflammation and periodontal neutrophil infiltration and drive neutrophils
tissue destruction. LTB4 attracts neutrophils, to apoptosis, while at the same time attract-
stimulates the release of granule associated ing monocytes to the lesion.44 Lipoxin-stimu-
enzymes from neutrophils, and contributes lated monocytes/macrophages obtain a non-
to proinflammatory processes and to further phlogistic phenotype, which results in phago-
tissue damage. cytosis of apoptotic neutrophils and
Figure
F 2. Biosynthesis of Proresolving Lipid Mediators
Injury
Chronic Acute Class switching

Inflammation Inflammation Resolution
Arachidonic EPA DHA

Acid
cell-cell
LO:LO interaction
COX-1&2 Lipoxins Resolvin Es Resolvin Ds
5-LO
(LXs) (RvEs) (RvDs)
[Neuro]Protectins
Prostaglandins Leukotrienes OH (PDs)
HO OH
COOCH3 HO
OH OH COOH
O F
COOH
OH OH
ATLa RvE1 PD1
Resolution agonists
Chemical mediators involved in the initiation of acute inflammation, such as prostaglandins and leukotrienes, induce
"class switching" toward proresolving lipid mediators. The proresolving mediators include arachidonic acid-derived
lipoxins (LXs), aspirin-Triggered LXs (ATLa), eicosapentanoic acid (EPA)-derived resolvins Es (RvEs), docosahexa-
noic acid (DHA)-derived resolvins Ds (RvDs), and protectins (PDs) (or neuroprotectins in neural tissues).
Figure 3. Dual Anti-inflammatory and Proresolution Actions of Specific Lipoxins,

Resolvins, and Protectins
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enhanced mucosal clearance of bacteria Role of Proresolution Mediators

without concomitant secretion of proinflam- Examples of the actions of therapeutic prores-
matory mediators that could contribute to olution mediators in periodontal disease
tissue damage.45 Moreover, proresolution include overexpression of lipoxin A4 in trans-
lipid molecules increase the exit of phago- genic rabbits, protecting against periodontitis
cytes from the inflamed site through the lym- and atherosclerosis.46 In another study, topical
phatics. Finally, some of these molecules may treatment with resolvins (omega 3 fatty acid–
also stimulate the uptake and clearance of derived resolution agonists, vide infra) pre-
local cytokines by apoptotic neutrophils. vented more than 95% of alveolar bone
After neutrophils and debris are removed, destruction in rabbits. Moreover, histologic
homeostasis returns and repair mechanisms analysis revealed few, if any, neutrophils in the
are initiated; lipoxins are antifibrotic and tissue and little tissue damage. At the same
allow for complete tissue healing without time, the numbers of osteoclasts were also
scarring. found to be reduced. In addition, treatment of
Hence, it can be argued that the persist- periodontitis with resolvins systemically
ence of an inflammatory disease, such as reversed the observed increase in CRP and IL-
periodontal disease, may be caused by too 1b levels. Also, in established periodontal
much proinflammatory signal or not disease, resolvins prevented further tissue
enough proresolution signal. In other words, destruction, and both gingival and osseous
a hyperinflammatory phenotype due to a tissues that were lost during disease were
particular genetic background of the host regenerated.47
may result in oversecretion of inflammatory Finally, in in vitro bone cultures, resolvins
mediators in response to bacterial stimuli, significantly enhanced expression of osteopro-
which in turn contributes to periodontal tegerin (OPG) without inducing change in
disease susceptibility, or a failure of resolu- receptor activator of NF-kB ligand levels,
tion pathways. As high levels of inflamma- whereas osteogenic markers alkaline phos-
tory cytokines are maintained, tissue phatase, bone sialoprotein, and Runt-related
destruction continues and inflammation per- transcription factor 2 remained unchanged.48
sists. If proresolution signals are weak, neu- These results indicate that resolvins may mod-
trophils are not removed and monocytes/ ulate osteoclast differentiation and bone
macrophages maintain a phlogistic pheno- remodeling by direct actions on bone, rescuing
type. This results in further production of OPG production and restoring a favorable
inflammatory cytokines and perpetuation of receptor activator of NF-kB ligand/OPG ratio.
the inflamed state. Resolvins, lipoxins, and protectins have
also been shown in animal models to have
New Treatment Paradigms beneficial impact on a variety of other
It is reasonable to suggest that the under- inflammatory diseases. For example, lipoxins
standing and ability to manipulate resolution stopped neutrophil recruitment and pro-
of inflammation may provide a new treat- moted lymphatic removal of phagocytes in
ment paradigm for inflammatory diseases, periotonitis.45 Moreover, in cystic fibrosis,
local and systemic. Although human data lipoxins decreased neutrophil inflammation,
are not yet available, a growing and promis- pulmonary bacterial burden, and disease
ing literature from in vitro work and animal severity.49 Resolvins in a colitis model in mice
models supports the beneficial actions of res- decreased neutrophil recruitment and proin-
olution agonists on both periodontal disease flammatory gene expression, improved sur-
and other systemic diseases.7 vival, and reduced weight loss.50 In addition,
resolvins protected against neovasculariza- Origins of Proresolution Mediators

tion in retinopathy.51 Finally, in an asthma To manipulate resolution of inflammation
model, protectins protected against lung more effectively, it is imperative to under-
damage, airway inflammation, and airway stand the biologic origin of the proresolution
hyperresponsiveness.52 Table 2 lists the mediators. Lipoxins (e.g., lipoxin A4) derive
impact of lipoxins, resolvins, and protectins from arachidonic acid after activation of the
on various inflammatory disease models. 12-/5-LO or the 15-/5-LO pathways.
It is conceivable that the use of proreso- Resolvins and protectins are biosynthesized
lution mediators in managing periodontal from omega-3 essential polyunsaturated fatty
and other inflammatory diseases may prove acids (w-3 PUFAs), such as eicosapentanoic
to be beneficial in humans as well. Mechani- acid (EPA) and docosahexanoic acid
cal debridement, which aims at the reduction (DHA). EPA and DHA can be metabolized
of the bacterial load in the gingival pocket, by aspirin-modified COX-2 pathways to
may help the host/patient to clear the infec- form resolvins, whereas DHA can be con-
tion. In addition, it is possible that the use of verted to protectins via an LO-mediated
locally applied proresolution mediators could pathway (Figure 4).
prevent further tissue damage, enhance the Another aspect of current anti-inflam-
resolution of inflammation (which would matory strategies was the discovery that dis-
lead to healthy gingiva), and ideally result in ruption of biosynthesis of these proresolu-
periodontal tissue regeneration rather than in tion mediators by either COX-2 or LO
scarring and repair. Moreover, resolution of inhibitors may lead to a resolution deficit
inflammation at the gingival level may mini- phenotype, which is characterized by
mize systemic inflammation induced by peri- impaired phagocyte removal, delayed resolu-
odontal disease, thereby attenuating the pos- tion, and prolonged inflammation. This may
sible negative effects of periodontal disease explain why several anti-inflammatory
on systemic diseases. agents, such as selective COX-2 inhibitors
Figure 4. Schematic Illustration of Lipid-Mediated Proinflammatory and
Proresolution Pathways
Table 2. Impact of Lipoxins, Resolvins, and Protectins on Various Inflammatory Disease Models
Disease Model Species Action(s)
Lipoxin A4/ATL
Periodontitis Rabbit –Reduces neutrophil infiltration
–Prevents connective tissue and bone loss
Peritonitis Mouse Stops neutrophil recruitment and lymphatic removal of phagocytes
Dorsal air pouch Mouse Stops neutrophil recruitment
Dermal inflammation Mouse Stops neutrophil recruitment and vascular leakage
Colitis Mouse –Attenuates proinflammatory gene expression
–Reduces severity of colitis
–Inhibits weight loss, inflammation, pulmonary dysfunction
Asthma Mouse Inhibits airway hyperresponsiveness and pulmonary inflammation
Cystic fibrosis Mouse Decreases neutrophilic inflammation, pulmonary bacterial burden, and disease severity
Ischemia-reperfusion injury Mouse –Attenuates hind-limb ischemia-reperfusion lung injury
–Causes detachment of adherent leukocytes in mesenteric ischemia-reperfusion injury
Corneal disorders Mouse –Accelerates cornea re-epithilialization
–Limits sequelae of thermal injury (such as neovascularization and opacity)
–Promotes host defense
Angiogenesis Mouse Reduces angiogenic phenotype: endothelial-cell proliferation and migration
Bone marrow transplant Mouse Protects against bone-marrow-transplant–induced graft-versus-host diseases
Glomerulonephritis Mouse –Reduces leukocyte rolling and adherence
–Decreases neutrophil recruitment
Hyperalgesia Rat –Prolongs paw withdraw latency and reduces hyperalgesic index
–Reduces paw edema
Pleuritis Rat Shortens the duration of pleural exudation
Resolvin E1
Periodontitis Rabbit –Reduces neutrophil infiltration
–Prevents connective tissue and bone loss
–Promotes healing of diseased tissues
–Regenerates lost soft tissue and bone
Peritonitis Mouse –Stops neutrophil recruitment
–Regulates chemokine and/or cytokine production
–Promotes lymphatic removal of phagocytes
Dorsal air pouch Mouse Stops neutrophil recruitment
Retinopathy Mouse Protects against neovascularization
Colitis Mouse –Decreases neutrophil recruitment and proinflammatory gene expression
–Improves survival
–Reduces weight loss
Resolvin D1
Peritonitis Mouse Stops neutrophil recruitment
Dorsal skin air pouch Mouse Stops neutrophil recruitment
Kidney ischemia- Mouse –Protects from ischemia-reperfusion kidney damage and loss of function
reperfusion injury Mouse Regulates macrophage
Protectin D1
Peritonitis Mouse –Inhibits neutrophil recruitment
–Regulates chemokine and/or cytokine production
–Promotes lymphatic removal of phagocytes
–Regulates T-cell migration
Asthma Mouse Protects from lung damage, airway inflammation, and airway hyperresponsiveness
Asthma Human Protectin D1 is generated in humans and appears to be diminished in asthmatics
Kidney ischemia- Mouse Protects from ischemia-reperfusion kidney damage and loss of function
reperfusion injury Regulates macrophages function
Ischemic stroke Rat –Stops leukocyte infiltration
–Inhibits nuclear factor-kB and cyclooxygenase-2 induction
Alzheimer’s disease Human Diminishes protecting D1 production in human Alzheimer’s disease
and certain LO inhibitors, have been shown 5. Rubinstein MR, Wang X, Liu W, Hao Y, Cai G,
to impair resolution of inflammation and Han YW. Fusobacterium nucleatum promotes col-
orectal carcinogenesis by modulating E-cadherin/ -
lead to systemic inflammatory complications. catenin signaling via its FadA adhesion. Cell Host
Microbe 2013;14:195–206.
Summary of Part III 6. Kostic AD, Chun E, Robertson L, Glickman JN,
Theoretically, combining proresolution medi- Gallini CA, Michaud M, Clancy TE, Chung DC,
ators and anti-inflammatory agents such as Lochhead P, Hold GL, El-Omar EM, Brenner D,
Fuchs CS, Meyerson M, Garrett WS. Fusobac-
aspirin and statins—agents that decrease the terium nucleatum potentiates intestinal tumorigene-
extent of inflammation without interfering sis and modulates the tumor-immune microenvi-
with the endogenous proresolution ronment. Cell Host Microbe 2013;14:207–15.
processes—may be a useful strategy to 7. Serhan CN, Chiang N, Van Dyke TE. Resolving
control excessive inflammation and restore inflammation: dual anti-inflammatory and proreso-
lution lipid mediators. Nat Rev Immunol
homeostasis. More research is necessary to 2008;8:349–61.
obtain solid information on the efficacy and 8. Paster BJ, Olsen I, Aas JA, Dewhirst FE. The
safety of these interventions in humans. breadth of bacterial diversity in the human peri-
However, it is possible that in the future we odontal pocket and other oral sites. Periodontol
can expect new treatment strategies to be 2000 2006;42:80–7.
9. Haffajee AD, Cugini MA, Tanner A, Pollack RP,
available for the treatment of periodontal Smith C, Kent RL Jr, Socransky SS. Subgingival
disease and its systemic complications. microbiota in healthy, well-maintained elder and
periodontitis subjects. J Clin Periodontol
Supplemental Readings 1998;25:346–53.
Serhan CN, Chiang N, Van Dyke TE. Resolving 10. Madianos PN, Bobetsis YA, Kinane DF. Genera-
inflammation: dual anti-inflammatory and pro-resolution of inflammatory stimuli: how bacteria set up
tion lipid mediators. Nat Rev Immunol 2008;8(5):349–61. inflammatory responses in the gingiva. J Clin Peri-
odontol 2005;32(Suppl 6):57–71.
Madianos PN, Bobetsis YA, Kinane DF. Generation of 11. Sandros J, Papapanou PN, Nannmark U, Dahlén
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Induction of interleukin-1 and -6 in human gingi-
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protein, and atherothrombosis. J Periodontol responses of mast cell Toll-like receptors 2 and 4 in
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CHAPTER 4
History of the
Oral-Systemic Relationship
Noel M. Claffey, Ioannis N. Polyzois, Ray C. Williams
INTRODUCTION illness. One area of the body that has been

In the last decade, the possible association repeatedly implicated in the origin of human
between oral and systemic health has been diseases is the oral cavity. Writings from as far
highlighted in numerous reports. The focus of back as those of the ancient Egyptians (2100
attention is mainly periodontitis and its impact BC) mention tooth pain associated with
on certain conditions. Periodontitis is an infec- women’s reproductive system diseases.1 In
tious disease associated with a number of pre- Assyria, the physician of King Ashurbanipal
dominantly gram-negative bacteria, and it is (669–626 BC) wrote about the troubles of his
now recognized that for the initiation and pro- king: “The pains in his head, arms, and feet
gression of this disease, a susceptible host is are caused by his teeth and must be
also required. It is also well documented that removed.”2 In ancient Greece, Hippocrates
certain systemic conditions can modify the (400 BC) recorded two cases in which eradica-
host’s susceptibility to periodontitis, but only tion of the infections of the mouth appeared
recently has evidence surfaced about the possi- to relieve patients of rheumatic-like troubles of
bility of a two-way relationship. Specifically, the joints.3 Aristotle, perhaps the first dental
periodontitis has been implicated as a poten- anatomist—especially from the standpoint of
tial risk factor for cardiovascular diseases, res- comparative anatomy—stated, “those persons
piratory diseases, diabetes mellitus, preterm who have the most teeth are the longest
labor, low birth weight, and renal disease. lived.”4 In his book, On Hygiene, the Roman
Interest in the relationship of oral health/ physician Galen (166–201 AD) emphasized the
periodontal disease to general health is not interrelationship between the oral cavity and
new, but is more of a resurgence in the old other illnesses.5
and discredited concept of focal infection. From the end of the Roman Empire
Focal infection theory became popular in the until the Middle Ages, all sciences fell into
beginning of the twentieth century because it abeyance. Had it not been for the Arabs (who
explained a number of conditions for which had access to the learning and science con-
there was no scientific explanation at the time. tained in Greek manuscripts brought to their
It eventually fell into disrepute because of a country by Nestorian exiles from Byzantium
lack of scientific evidence. and Greeks who settled in southern Italy), the
This chapter examines the history of the bulk of science and knowledge accumulated to
hypothesis that microorganisms would localize that date might have been lost.4 The next
from the source focus to the distant, systemic notable advance in dentistry probably occurred
focus, and it follows, step by step, concepts of in Italy in the 1400s when a physician named
the oral-systemic relationship that have evolved Giovanni d’Arcoli began filling decayed teeth
over the years. with gold leaf, an admirably progressive step
for that time. He is further credited with
ANCIENT CIVILIZATIONS stating that for cases of severe dental pain,
AND THE MIDDLE AGES early intervention was advisable because “such
Throughout recorded history, many theories violent pains are followed by syncope or
have been put forward to explain human epilepsy, through injury communicated to the
heart or brain.”6 In 1548, Ryff wrote a mono- scientist Antonie von Leeuwenhoek in 1683.
graph that dealt exclusively with dental afflic- However, it was with the discoveries of the
tions. In his pamphlet, Useful Instructions on late 1800s that the centuries-old debate about
the Way to Keep Healthy, to Strengthen and the influence of the mouth on the rest of the
Re-invigorate the Eyes and the Sight. With body began. One of the main reasons for
Further Instructions of the Way of Keeping the interest in this area was due to strides made
Mouth Fresh, the Teeth Clean and the Gums in the study of microbiology. Major contrib-
Firm, he wrote, “The eyes and teeth have an utors to advances in microbiology included
extraordinary affinity or reciprocal relation to Pasteur, Lister, and Koch. Koch was a physi-
one another, by which they easily communi- cian working as a District Medical Officer in
cate to each other their defects and diseases, so Wöllstein, a small city in what is now
that one cannot be perfectly healthy without Germany. During the Franco-Prussian war,
the other being so too.”5 he began to study the disease anthrax, which
In 1768, Berdmore, in A Treatise on the was prevalent among farm animals in the
Disorders and Deformities of the Teeth and community. Earlier, the anthrax bacillus had
Gums, described the relation between the teeth been discovered by Pollande, Royer, and
and the entire body as one leading to the most Davine. Through a series of experiments,
“excruciating pains and dangerous inflamma- Koch demonstrated that pure cultures of the
tions and sometimes deep seated abscesses anthrax bacillus could cause the anthrax
which destroy neighbouring parts and affect disease. His work was published in 1876 and
the whole system by sympathy, or by infecting the “germ theory of disease causation” was
the blood with corrupted matter.”7 In 1818, introduced to the world. Soon, scientists
one of the most famous physicians in around the globe became interested in bacte-
America, Benjamin Rush, reported the course ria and their role in disease etiology.
of a disease in which a woman who was suf- Miller, an American dentist working at
fering from rheumatism of long standing had Koch’s Institute for Infectious Diseases, was
an aching tooth extracted and “she recovered convinced that the bacteria residing in the
in just a few days.”7 mouth could explain most illnesses. In 1880,
All these statements over the course of to support his theory, Miller published a
history were made without sufficient support- book, The Microorganisms of the Human
ing evidence; yet they were current beliefs at Mouth: The Local and General Diseases
the time. The conclusions were usually drawn Which are Caused by Them. In 1891, Miller
by repeated observation of a number of published a classic article in the Dental
patients with similar symptoms and outcomes. Cosmos journal.8 The title of the article was
Today these ancient theories—especially those “The Human Mouth as a Focus of Infec-
related to oral systemic conditions—cannot be tion.” This article aimed to “call attention to
considered anything more than guesswork the various local and general diseases which
based on simple observation. However, it is of have been found to result from the action of
great interest that historically a suspicion or microorganisms which have collected in the
hunch existed of an interrelationship between mouth and to various channels through
oral disease and systemic conditions. which these microorganisms or their waste
products may obtain entrance to parts of
ORAL SEPSIS AS A the body adjacent to or remote from the
CAUSE OF DISEASE mouth.” It also aimed to “establish the great
The importance of oral hygiene in relation importance of thorough understanding on
to bacteriology was first detailed by Dutch the part of the physician, no less than of the
CHAPTER 4 History of the Oral-Systemic Relationship 51
dentist, of mouth germs as a factor in the oral hygiene, together with iatrogenic conser-
production of disease.” The article was pre- vative dentistry, as causes of the multitude of
sented under three headings or sections: diseases attributed to focal infection. He
• Diseases of the human body that have advocated oral antisepsis measures to dis-
been traced to the action of mouth eased teeth or inflamed gums, the removal of
bacteria “tooth stumps,” the boiling of every “tooth
• The pathogenic mouth bacteria plate” worn, and the avoidance of restora-
• Prophylactic measures tions such as bridges, which can’t be cleanly
The diseases that Miller felt could be maintained.5,9
traced to bacteria colonizing the mouth In 1900, Godlee described how the
included ostitis, osteomyelitis, septicemia, signs and symptoms of other conditions,
pyemia meningitis, disturbance of alimentary such as pleurisy, could be attributed to pyor-
tract, pneumonia, gangrene of the lungs, rhea alveolaris and how all the signs and
Ludwig’s angina, diseases of the maxillary symptoms disappeared after careful removal
sinus, actinomycosis, noma, diphtheria, of all calculus and regular syringing of the
tuberculosis, syphilis, and thrush. He pockets with a hydrogen peroxide solution.5,10
described 149 cases, many of which he In 1902, Colyer described the resolution of
ascribed to a dental origin, such as fistulae irregular heartbeat, gastric effects, and
that opened on the neck, shoulder, arm, and “general debility” after the treatment of any
breast. Thus was developed the concept of oral sepsis. He also suggested a good maxim
focus of infection, with organisms in the oral with which a dentist should work—“better
cavity being implicated in diseases of the no teeth than septic ones.”5,11
body remote from the mouth. Although In an article published by Wilcox in
Miller did not mandate removal of teeth as 1903, antral disease was put forward as an
a method of eradication of foci of infection, important sequela of oral sepsis.12 It was
he sometimes suggested that the “treatment believed that prolonged antral suppuration
and filling of root canals” could serve this could lead to extreme mental depression,
purpose. In Miller’s opinion, local collection often ending in suicidal tendency.5,12 Other
of disease-producing organisms could relationships that were put forward were
produce “a metastatic abscess wherever a those between oral sepsis and migraine
point of diminished resistance existed.” headaches, laryngeal pain and spasm (which
Moreover, he postulated that teeth were not could induce cough, loss of voice, and
the only source of aggregation of such bac- wasting), blindness, and deafness, all of
teria but that foci in other organs, such as which Wilcox hypothesized could be cured
the tonsils and uterus, could be implicated.5,8 by treating the oral sepsis.5 As the concept of
The next important figure in the oral sepsis became more popular, theories
history of oral sepsis as a cause of disease were put forward as to which organs were
was the English physician, Hunter. At the most susceptible to different types of oral
time of Miller’s paper presentation, which sepsis, and how the treatment of oral sepsis
Hunter attended, he was the senior assistant could lead to recovery from tonsillitis, tuber-
physician at the London Fever Hospital, and culosis, and diabetes. It was also believed
his attention was already drawn to the that oral sepsis could be transmitted by the
mouth as a possible source of infection. In licking of envelopes, use of contaminated
1900, he wrote “Oral Sepsis as a Cause of telephone receivers, and men with beards.
Disease,” an article published in the British In 1908, Merritt published an article in
Medical Journal.9 Hunter implicated poor Dental Cosmos titled, “Mouth Infection: the
Cause of Systemic Disease.”13 He stated, rheumatic infections, kidney diseases, all

“there is a general disposition on the part of those which owe their origin to, or are
the medical and dental professions to under- gravely complicated by the oral sepsis pro-
estimate the relations which exist between an duced by these gold traps of sepsis. Time
unclean mouth and many local and systemic and again I have traced the very first onset
disorders of grave nature.” He felt that in of the whole trouble to the period within a
many cases of malnutrition, the sole cause month or two of their insertion.” Hunter’s
was a “filthy mouth” and that “no greater condemnation of conservative dentistry
good could come to humanity than the full appears to be based primarily on its poor
recognition of the dangers from this insidious, standard. It was fashionable in London at
prolific and virulent infection in the human the time to mimic complicated American
mouth.” Merritt also stated, “the adoption of dentistry. However, in many cases the results
proper oral hygiene practices would result in were of substandard quality. Some well-
immediate and marked improvement to respected dentists, such as Edward Cameron
general health and notable increase in the Kirk, the editor of Dental Cosmos, recog-
average duration of human life.” nized the potential systemic effects of oral
On October 3, 1910, Hunter was sepsis, but felt that Hunter’s criticism of den-
invited to McGill University in Montreal, tistry was unfair since Hunter’s observations
Canada, to give the keynote address at the were based primarily on the disastrous
dedication of the Strathcona Medical Build- effects of a very low-standard dentistry.5
ing. The title of his address was “The Role In 1911, Billings, the long-serving Dean
of Sepsis and Antisepsis in Medicine.” In his of Medicine at the University of Chicago
address, he blamed “oral sepsis” as the cause and head of the focal infection research
of a great many diseases, and made an team at Rush Medical College and Presbyte-
attack on conservative dentistry or, as he rian Hospital, replaced the term “oral
called it, “septic dentistry.”5 His address was sepsis” with “focal infection.” Soon after
published in The Lancet, the leading British that, he was honored by being asked to give
medical journal at the time, as well as in the the annual Lane Memorial Lecture at Stan-
Dental Register.14,15 Hunter is best remem- ford University in 1915. There, he defined a
bered for the following statement in The focus of infection as a “circumscribed area
Lancet report: “No one has probably had of tissue infected with pathogenic organ-
more reason than I have had to admire the isms” and said that the term focal infection
sheer ingenuity and mechanical skill con- implied that: (1) such a focus or lesion of
stantly displayed by the dental surgeon. And infection existed, (2) the infection was bacter-
no one has had more reason to appreciate ial in nature, and (3) it was capable of dis-
the ghastly tragedies of oral sepsis which his semination, resulting in systemic infection of
misplaced ingenuity so often carries in its other contiguous or noncontiguous parts.
train. Gold fillings, crowns and bridges, fixed The teeth, tonsils, adenoids, and mastoids
dentures, built on and about diseased tooth were thought to be the usual sources of bac-
roots form a veritable mausoleum of gold teremia, and certain bacteria, such as strep-
over a mass of sepsis to which there is no tococcus and pneumococcus, had special
parallel in the whole realm of medicine.” He affinities for target organs like the heart and
continued with “The worst cases of lungs.5,16 Billings believed that chronic infec-
anaemia, gastritis, obscure fever, nervous dis- tious arthritis was often associated with
turbances of all kinds from mental depres- remote foci of streptococcus, gonococcus, or
sion to actual lesions of the cord, chronic tuberculosis organisms, and suggested the
removal of all foci of infection and the such as Mayo, also advocated the focal infec-
improvement in patients’ immunity by tion theory. He stated that “in children the
absolute rest and improvement of popula- tonsils and mouth probably carry eighty
tion-wide and individual oral hygiene.17,18 percent of the infective diseases that cause so
One of the first studies measuring the clini- much trouble in later life.” He went on to
cal benefit of removing focal infection in write “teeth with putrescent pulps may
1917 confirmed Billings’ suggestions. The harbour green-producing streptococci and
study was conducted as a retrospective even though they show no redness at the
postal survey, and 23% reported a cure for gums they may be very dangerous to keep in
their arthritis after removal of infective foci. the mouth.”3–5
An additional 46% reported experiencing What followed in dentistry as the result
some improvement in symptoms.5,19 of the “theory of focal infection” was an
One of Billings’ research associates was unprecedented wave of tooth extractions and
Rosenow, a graduate of the Rush Medical the avoidance of conservative dentistry.5,22 All
College where he had been a student of teeth that were endodontically or periodon-
Billings. He used special methods for cultur- tally involved were extracted to prevent a pos-
ing material from various foci of infection. sible focus of infection. This approach came
He obtained a number of pathogenic bacteria to be known as the “hundred percenter.” The
from patients, including streptococci and leading spokesperson for this radical
gonococci, which he injected in animals. He approach was the physiologist, Fisher. He
then tested whether these organisms would regarded a tooth with a root filling as a dead
provoke lesions similar to the secondary man- organ that needs to be extracted.5
ifestations noted in the patients from whom As biomedical research evolved in the
the foci had been removed. Billings used the early 1930s, it also started evaluating concepts
term “elective localization” to note that on a scientific basis. It was then that the
certain strains of pathogenic bacteria (mostly strong belief in the theory of focal infection
streptococci) isolated from the oral cavity of began to decline. What stimulated this decline
the patients had localized to the joints, was the work of Holman, who noted that
cardiac valves, or other areas of the animals.5 Rosenow’s work was fraught with contamina-
Physicians such as Billings and Rosenow tion and that his data were inconsistent.22,23
were prominent and convincing. More and Others noted that Rosenow inoculated
more articles were published and many other animals with such high counts of bacteria
physicians, such as Barker and Cecil, that it was inevitable for every organ or joint
embraced the concept of focal infection. to be affected.24,25 Grossman, in his book Root
Cecil, best known for his textbook of medi- Canal Therapy, noted that Rosenow’s tech-
cine, reported in 1933 that “the keystone of nique “so devastates the laboratory animal
the modern treatment of rheumatoid arthritis that lesions are sometimes produced in almost
is the elimination of the infected foci.”20 In an every tissue and organ of the body.” The fact
article in 1938, Cecil quotes Rosenow who that Rosenow’s work in animal models could
said “the prevention of oral sepsis in the not be reproduced by other investigators
future, with the view to lessening the inci- heavily discredited his theories.25
dence of systemic diseases, should henceforth Cecil, a great proponent of the focal
take precedence in dental practice over the infection theory, together with the rest of the
preservation of the teeth almost wholly for medical community, started to reevaluate his
mechanical or cosmetic purposes.”21 Other approach. He and Angevine published an
leading members of the medical community, article in 1938 that reported a follow-up
study of 156 patients with rheumatoid because “many patients with diseases pre-
arthritis who had teeth and/or tonsils sumably caused by foci of infection have not
removed because of foci of infection. They been relieved of their symptoms by removal
concluded that chronic focal infection was of the foci. Many patients with these same
relatively unimportant in rheumatoid arthri- systemic diseases have no evident focus of
tis because of the 52 patients who had teeth infection, and also foci of infection are,
removed, 47 did not get any better and 3 got according to statistical studies, as common in
worse. In their own words, they concluded apparently healthy persons as those with
that “focal infection is a splendid example of disease.”28 In looking back, it can be consid-
a plausible medical theory which is in danger ered that the theory of focal infection not
of being converted by its enthusiastic sup- only was an easy way to explain the cause of
porters into the status of an accepted fact.”21 many diseases, but also advocated treatment
In 1940, Reiman and Havens26 wrote a that was available to the patients at the time.5
critical review of the theory of focal infec- According to Gibbons,22 the role of econom-
tion in the Journal of the American Medical ics in the spread of the focal infection theory
Association. They reviewed the literature in should not be underestimated. It is easy to
detail and ended the report with the follow- understand that as the era of focal infection
ing paragraph: “It may be said, therefore, came to an end, the lucrative business of
that: (a) The theory of focal infection, in the extracting teeth, removing tonsils, and treat-
sense of the term used here, has not been ing sinuses as a way of treating human dis-
proved, (b) the infectious agents involved are eases gradually diminished. In his article
unknown, (c) large groups of persons whose “Germs, Dr. Billings and the Theory of
tonsils are present are no worse than those Focal Infection,” Gibbons quotes one bacte-
whose tonsils are out, (d) patients whose riologist of the focal infection period saying
teeth or tonsils are removed often continue “The age of specialization stimulates surgery.
to suffer from the original disease for which Operations carry the best fees with them,
they were removed, (e) beneficial effects can and without intimating that economics play
seldom be ascribed to surgical procedures a role in the specialist’s decision, nevertheless
alone, (f) measures are often outweighed by it is only reasonable to regard him as
harmful effects or no effect at all, and (g) human—if he is the proud possessor of sur-
many suggestive foci of infection heal after gical skill, he is more prone to use it.”22
recovery from systemic disease, or when the In dentistry, for almost 50 years (1940–
general health is improved with hygienic and 1989), there was little interest in the effect of
dietary measures.” the mouth on the rest of the body. However,
In 1951, a review by Williams and throughout the second half of the twentieth
Burket27 concluded the following: “There is century, dental scientists continued to ques-
no good scientific evidence to support the tion whether oral infection (and inflamma-
theory that removal of these infected teeth tion) might in some way contribute to a
would relieve or cure arthritis, rheumatic person’s overall health; however, the reasons
heart disease, and kidney, eye, skin, or other given were mostly speculative. They contin-
disorders.” The very strongly worded review ued to suggest that bacteria and bacterial
by Reiman and Havens26 as well as over- products found in the mouth could enter the
whelming new evidence, brought the “era of bloodstream and could in some way be
focal infection” to an end. An editorial in harmful to the body as a whole.29 Not until
the Journal of the American Medical Associ- the last decade of the twentieth century did
ation in 1952 stated that this happened dentistry and medicine start again to con-
sider the relationship of oral diseases, such renewed the interest of physicians and den-
as periodontal disease, as a contributor to tists in the relation of oral to systemic disease.
risk factors for certain systemic diseases. In retrospect, it is now clear that the
advent of reports by Mattila and col-
Oral-Systemic Relationship Revisited leagues—followed soon thereafter by DeSte-
The late 1980s saw an increasing number of fano et al.32 and Offenbacher et al.33—was the
publications implicating an association beginning of a new era of understanding the
between periodontopathogenic bacteria and impact of oral health and disease on overall
certain systemic conditions such as coronary health and disease.25,30 By 1996, the term
artery disease, stroke, and preterm/low-birth- “periodontal medicine” would emerge as sci-
weight babies. Such insinuations had also entists and clinicians in dentistry and medi-
been made early in the twentieth century, but cine began to appreciate the tremendous
this time reports were judged with a more effect that oral disease can have on the body.34
measured response.30 According to Barnett,30 Ironically, the situation over the last
this response was a result of several factors: years is reminiscent of that at the beginning
(a) greater analytical and statistical knowl- of the previous century. A large number of
edge and a better understanding of the con- studies have been published relatively
straints of epidemiologic research in “estab- recently linking many diseases to oral infec-
lishing disease causality”; (b) increased tions. The most common oral infection men-
awareness of the etiology and pathogenesis tioned is periodontitis, and it has been linked
of oral diseases; (c) increased awareness of not only with the traditional diseases such as
the etiology and pathogenesis of associated cardiovascular disease and diabetes, but also
systemic diseases; (d) modern advances in with other diseases such as cancer.35,36 Scien-
the treatment of oral conditions; (e) realiza- tists now know that the existing evidence for
tion that bacteria could in some way be a direct impact of oral infection on systemic
implicated in the development of diseases disease outcomes is plausible and that where
that as yet have an undetermined etiology. the evidence is strongest, as for diabetes, it is
In 1989, Mattila and coworkers31 in time to develop recommendations for dental
Finland conducted a case-control study on and medical publications for comanagement
100 patients who had suffered an acute of patients with both diseases.
myocardial infarction. They compared these The American Heart Association
patients with 102 control subjects selected (AHA) released a report that concluded that
from the community. A full dental examina- periodontal disease is an independent risk
tion was performed on all the subjects factor for cardiovascular disease; however,
studied. In addition, a dental index was com- evidence is not yet available that shows that
puted. This index computed the sum of treating periodontal disease actually reduces
scores from the number of missing teeth, cardiovascular disease.37 The American
carious lesions, periapical lesions, probing Academy of Periodontology (AAP) and the
depths, and the presence or absence of peri- European Federation of Periodontology
coronitis. Dental health was found to be sig- (EFP) jointly organized a workshop dedi-
nificantly worse in patients with a history of cated to periodontitis and its relation to sys-
acute myocardial infarction than that of temic diseases to systematically evaluate the
control subjects. This association remained evidence for the association of periodontal
valid even after adjustment for age, social diseases with diabetes, cardiovascular disease,
class, smoking, serum lipid concentrations, and adverse pregnancy outcomes. In their
and diabetes. It was mainly this study that conclusions, they stated, “the reported asso-
ciation does not imply causality and estab- odontal pathogens and their products into
lishment of causality will require new the circulation have been suggested and are
studies.”36 According to Cullinan and currently the subject of intense research.
Seymour,38 however, “such evidence will The focal infection theory, as proposed
require expensive, long term intervention and defended the first time around, was
studies, which are extremely difficult to carry mainly based on anecdotal evidence and the
out and which may never be done.” Since occasional case report. For the hypothesis not
periodontitis is a very serious problem in its to fall into disrepute the second time around,
own right, it may be appropriate for dentists different levels of evidence must be examined
to concentrate on providing treatment to the to establish a relation between the periodontal
patients affected and to provide treatment condition and the systemic health of the
that contributes to the overall health of patient. Since not all scientific evidence is
patients, since effective management of peri- given the same weight, the stronger the evi-
odontal diseases is accompanied by reduc- dence, the more likely it is that a true relation
tion of risk factors common to chronic dis- exists between these conditions.
eases such as periodontal disease and cardio- Case reports provide us with very weak
vascular disease. evidence and can only suggest a link, but not
a relationship. Case-control studies are
PERIODONTAL/ORAL DISEASE mainly used to identify factors that may con-
AS A RISK FACTOR FOR tribute to a medical condition by comparing
SYSTEMIC DISEASE subjects who have the condition with
Despite many years of history demonstrat- patients who do not, but are otherwise
ing the influence of oral status on general similar. These studies may lead to cross-sec-
health, recent decades have seen an acceler- tional analyses. Observational studies are
ated effort for the prevention and manage- used to examine associations between expo-
ment of these conditions through ground- sures and disease. These studies are relatively
breaking advances. Specifically, periodontitis, inexpensive and frequently used for epidemi-
a chronic infectious and inflammatory ologic studies. However, the fact that they
disease of the gums and supporting tissues, are retrospective and not randomized limits
has been associated with systemic conditions their validity.
such as coronary heart disease and stroke, Cross-sectional analysis studies the rela-
higher risk for preterm, low-birth-weight tion between different variables at a point in
babies, and certain cancers. It has also been time. These types of data can be used to
suggested periodontitis may pose threats to assess the prevalence of acute or chronic
those with chronic disease, such as diabetes, conditions in a population. However, since
respiratory diseases, and osteoporosis.39–42 exposure and disease status are measured at
Periodontal diseases are infections that are the same point in time, it may not always be
caused by microorganisms that colonize the possible to distinguish whether the exposure
tooth surface at or below the gingival preceded or followed the disease. Stronger
margin. These infections affect the gingival evidence is provided with a longitudinal
tissues and can cause damage to the sup- study, in which subject populations are
porting connective tissue and bone. Peri- examined over time. A longitudinal study is
odontal disease can be caused by specific often undertaken to obtain evidence to try
bacteria (e.g., Porphyromonas gingivalis) from to refute the existence of a suspected associ-
the biofilm within the periodontal pocket. ation between cause and disease; failure to
Several pathways for the passage of peri- refute a hypothesis strengthens confidence in
it. Longitudinal studies with controls are smoking, and diabetes. It should be noted
much stronger than those without controls. that these risk factors are common to many
The same applies for intervention trials that chronic, noncommunicable diseases, such as
provide the strongest form of evidence. heart disease, stroke, and diabetes, all of
Unfortunately, these are not only difficult to which are associated with periodontitis.43
conduct, they are expensive, and they involve
many ethical considerations. Periodontitis/Oral Health as a Risk Factor for
Specific Diseases: Evidence for an Association
What Is Risk? Cardiovascular
Risk is the statistical likelihood that certain Oral infections may contribute to cardiovas-
factors are associated with the development cular disease by means of three possible
of disease. Risk can be divided into absolute mechanisms:44
risk, which is the likelihood of acquiring a 1. Direct effect of infectious agent in
certain disease, and relative risk, which is the atheroma formation
likelihood of acquiring a disease when 2. Indirect or host-mediated responses
certain factors are modified, compared with 3. Common genetic predisposition
the same likelihood if they are not. It is easy Bahekar and colleagues39 recently con-
to understand that when true risk factors are ducted a systematic review of the literature
identified, then intervention for those at risk to evaluate whether such an association
can be planned and implemented. exists. This review revealed five prospective
The strength of association between cohort studies involving 86,092 patients for
putative risk factors and a disease state can at least 6 years. The authors considered that
be expressed in odds ratios. An odds ratio of three of the five prospective studies were of
1 indicates an equal chance that an associa- good quality, and both the incidence and
tion will occur. An odds ratio of 2 indicates prevalence of coronary heart disease were
a twofold chance of an association being increased in subjects with periodontal disease
present. Care should be exercised in inferring after adjustments for other variables known
causation from odds ratios. Association does to increase the risk of coronary heart
not, in itself, imply causation. In the interpre- disease. Furthermore, five case-control
tation of odds ratios, it is important for the studies involving 1,423 patients and five
confidence interval of the odds ratio not to cross-sectional studies involving 17,724
traverse 1. If it does, the odds ratio—regard- patients were also evaluated. All supported a
less of magnitude—cannot be relied on. significant relation between periodontal
There has long been an interest in the disease and coronary heart disease. More
role of systemic factors as they affect peri- prospective studies are needed, however, to
odontal disease. A series of studies were prove the assumption that periodontitis may
carried out looking at systemic risk factors be a risk factor for coronary heart disease
for periodontal disease and were summa- and to evaluate risk reduction with the treat-
rized by Genco in 1996.43 In this review, it ment of periodontitis.
was pointed out that in addition to preexist- In planning prospective studies, it is
ing diseases, systemic factors have been iden- important to remember that patients with
tified. These include reduced neutrophil periodontal disease share many of the same
function, stress and coping behaviors, risk factors as patients with cardiovascular
osteopenia, age, gender (with more disease disease. These risk factors include age,
seen in males), hereditary factors, infection gender, lower socioeconomic status, stress,
with periodontal pathogens, cigarette and smoking.45 In addition, a large number
of patients with periodontal disease also nal periodontal infection could be associated
exhibit cardiovascular disease; this could with preterm low birth weight, while con-
indicate that periodontal disease and athero- trolling for known risk factors such as
sclerosis share similar or common etiologic smoking and poor nutrition. Results
pathways.46 The literature also suggests that a observed from the 124 pregnant or postpar-
number of pathogens, antigens, endotoxins, tum mothers who took part in this study
and cytokines of periodontitis might be sig- indicated that periodontal disease represents
nificant contributing factors.47,48 According to a clinically significant risk factor for preterm
Williams et al.,49 controlling for such con- low birth weight. This landmark report by
founding factors when carrying out epidemi- Offenbacher and colleagues was the first of
ologic and observational studies requires its kind.
large numbers of subjects to be enrolled, and In the last 7 years, an explosion of data
these subjects need to be followed over a was released from case-control studies,
long period of time. Common periodontal cohort studies, and clinical trials, as well as
pathogens such as Porphyromonas gingivalis from systematic reviews. Many studies have
and Streptococcus sanguis have been found reported a positive association, but it must
in arterial plaques from carotid endarterec- be concluded that because of different study
tomy samples. Furthermore, periodontal designs, heterogeneity in the way adverse
disease has been associated with elevated pregnancy outcomes were measured, as well
levels of inflammatory markers, such as C- as a lack of adequate analysis for con-
reactive protein. Although there is growing founders, there is still no consistent evidence
evidence that supports a role for C-reactive for or against this association.
protein as a predictive, pathogenic factor for Large-scale prospective intervention
vascular risk, it is recognized that more studies are needed in which adverse preg-
research is needed.39 nancy outcomes and the severity of peri-
Large-scale prospective intervention odontal disease can be clearly defined.
studies are needed to assess whether peri-
odontitis can be considered an effective Diabetes: A Two-Way Relationship
modifiable risk factor in the prevention of It is clear from epidemiologic studies that
cardiovascular disease. diabetes mellitus increases the risk for peri-
odontal disease.53,54 The available literature
Adverse Pregnancy Outcomes highlights the importance of oral health in
Several studies on laboratory animals in the subjects with diabetes, and demonstrates an
1970s and 1980s revealed that bacterial endo- increased prevalence of periodontitis among
toxin (a cell wall component isolated from patients with poorly controlled diabetes.49
Escherichia coli) is capable of producing Patients with controlled diabetes show peri-
spontaneous abortion, low fetal weight, and odontal conditions similar to those of the
malformations.50 Collins and colleagues51,52 healthy population.
successfully demonstrated that oral anaerobes The current literature does not provide
such as P. gingivalis had similar effects. us with conclusive evidence to support a
In 1996, Offenbacher and colleagues33 causal relationship between periodontal
constructed a case-control study with the disease and risk for type 2 diabetes. There is
title “Periodontal Infection as a Possible evidence of an increased risk of periodontitis
Risk Factor for Preterm Low Birth in patients with diabetes, but Taylor and
Weight.” In this investigation, they sought to coworkers55 also showed that patients with
determine whether the prevalence of mater- type 2 diabetes who suffer from periodontitis
have worse glycemic control, suggesting that Williams and colleagues,49 these groups can
not only does diabetes affect periodontitis, provide more immediate answers than
but when a diabetic has periodontitis, it leads studies with a more heterogeneous diabetic
to worsening diabetes or glycemic control. population.
This was followed by a paper by Grossi and
Genco,56 in which periodontal disease and Respiratory Infections
diabetes mellitus were presented in a two- Scannapieco60 describes four possible mecha-
way relationship. This began a long line of nisms of the presence of oral bacteria in the
investigation in which treatment of peri- pathogenesis of respiratory infections:
odontal disease in diabetes was found to 1. The oral cavity might be a reservoir for
contribute to glycemic control, with one of microorganisms that contaminate saliva
the first studies reported by Grossi and col- and is then aspirated into the lungs.
leagues.57 In 2008, a meta-analysis of nine 2. Periodontal disease-associated enzymes
control studies on the subject confirmed that in saliva may facilitate the adherence of
the reduction of glycated hemoglobin with respiratory pathogens in the mucosal
periodontal therapy can be significant, com- surfaces.
parable to other attempts to control glycated 3. Periodontal disease-associated enzymes
hemoglobin.49 Researchers tried to evaluate may destroy protective salivary pellicles,
the effects of periodontal therapy on sys- resulting in fewer nonspecific host
temic inflammatory markers and on defense mechanisms in high-risk
glycemic control.58 Several randomized patients.
control trials and a number of longitudinal 4. Cytokines and other molecules origi-
and observational studies provided some evi- nating from untreated periodontal
dence to support the concept that periodon- tissues are continuously released in
titis can adversely affect glycemic manage- saliva. Aspiration of these may alter
ment. Overall though, it is inconclusive that respiratory epithelium and promote
periodontal treatment results in improvement respiratory pathogen colonization.
of metabolic control and of markers of sys- A systematic review published in 2006
temic inflammation. by Azarpazhooh and Leake61 investigated
Emerging evidence suggests that peri- evidence for a possible etiologic association
odontitis predicts the development of overt between oral health and pneumonia or other
nephropathy and end-stage renal disease in respiratory diseases. They concluded that
patients with type 2 diabetes.41,59 A prospec- there is fair evidence of an association
tive study by Shultis and colleagues41 was between pneumonia and oral health, and
conducted exclusively in individuals with dia- poor evidence of an association between
betes. It also included a proportionally large chronic obstructive pulmonary disease and
number of individuals with kidney disease. oral health. In addition, there is good evi-
Whether treatment of periodontitis will dence that implementation of high-quality
reduce the risk of diabetic kidney disease has and frequent oral health care decreases the
not yet been determined, but this study pro- occurrence and progression of respiratory
vides a rationale for further investigation into diseases among elderly hospitalized or insti-
the connections between periodontal disease tutionalized persons.61
and diabetic progression. There is a need for large-scale prospec-
There is a need for large-scale prospective intervention studies targeting high-risk
tive intervention studies, mainly in specific people of the community, nursing homes,
high-risk groups because, according to and intensive care units.
Osteoporosis
Over the last decade, it has been speculated Supplemental Readings
that by decreasing the patient’s alveolar bone O’Reilly PG, Claffey NM. A history of oral sepsis as a
mass, osteoporosis makes teeth more suscep- cause of disease. Periodontol 2000 2000;23:13–8.
tible to resorption by the periodontal inflam-
matory reaction. Human studies have Gibbons RV. Germs, Dr. Billings and the theory of
focal infection. Clin Infect Dis 1998;27:629–33.
addressed this relationship, and several large-
scale studies showed an association between Mattila K, Nieminen M, Valtonen V, Rasi VP,
osteoporosis and reduced alveolar crestal Kesäniemi YA, Syrjälä SL, Jungell PS, Isoluoma M,
height in postmenopausal women.62 In Hietaniemi K, Jokinen MJ. Association between dental
another study, osteoporosis and periodontal health and acute myocardial infarction. Br Med J
1989;298:779–82.
infection were found to be independent risk
factors for oral bone loss.63 Other studies, Cullinan MP, Seymour GJ. Periodontal disease and sys-
especially longitudinal studies, are necessary temic illness: will the evidence ever be enough? Periodon-
to determine the temporal nature of this tol 2000;2013:62:271–86.
association and to further evaluate it.
Williams RC, Barnett AH, Claffey N, Davis M, Gadsby
Some studies investigated the effect of R, Kellett M, Lip GY, Thackray S. The potential
hormone replacement therapy or vitamin D impact of periodontal disease on general health: a con-
intake on tooth loss.64 In almost all studies, sensus view. Curr Med Res Opin 2008;24:1635–43.
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an association. Evidence for this relationship Med J 1900;2:215–6.
10. Godlee RJ. On some of the medical and surgical
is growing, and a scientifically based under-
complications of pyorrhea alveolaris. Dent Rec
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Certain linkages are stronger than others, Rec 1902;20:200–6.
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suppuration in the mouth and jaws. Br Dent J
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1903;24:733–6.
“hard” evidence, treatment recommenda- 13. Merritt AH. Mouth infection: the cause of sys-
tions need to be guarded. temic disease. Dental Cosmos 1908;50:344–8.
14. Hunter WD. The role of sepsis and antisepsis in birth weight. J Periodontol 1996;67:1103–13.
medicine. Lancet 1911;1:79–86. 34. Rose LF, Genco RJ, Cohen DW, Mealey BL, eds.
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1914;63:899–903. Joint EFP/AAP Workshop on Periodontitis and
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Rheumatol 1994;33:370–7. bowale O, Trevisan M, Levison ME, Taubert KA,
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1938:12:577–84. ciation. Circulation 2012;125:S8–19.
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1928;5:68–136. The prevalence and incidence of coronary heart
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28. Editorial. JAMA 1952;150:490. betes Care 2007;30:306–11.
29. Thoden van Velzen T, Abraham-Inpijn L, Moorer 42. Bobetsis YA, Barros SP, Offenbacher S. Exploring
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the focal infection concept. J Clin Periodontol pregnancy complications. JADA 2006;137:7s–13s.
1984;11:209–20. 43. Genco RJ. Current view of the risk factors for peri-
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An update for the practicing dentist. JADA 44. Renvert S. Destructive periodontal disease in rela-
2006;137:5S–6. tion to diabetes mellitus, cardiovascular diseases,
31. Mattila K, Nieminen M, Valtonen V, Rasi VP, osteoporosis and respiratory diseases. Oral Health
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CHAPTER 5
Diabetes Mellitus: A Medical Overview
Srividya Kidambi, Shailendra B. Patel
INTRODUCTION CLASSIFICATION OF
Diabetes mellitus (DM) is a quintessential DIABETES MELLITUS
metabolic disease whose characteristic phe- Diabetes mellitus is classified into several
notype is loss of control of glucose home- subtypes, which are based on etiology. This
ostasis, but the pathophysiology also affects classification can help in understanding clini-
fat and protein metabolism.1 Resulting cal manifestations and in providing a ration-
hyperglycemia is associated with both short- ale for the treatment offered (Table 1). Most
term and long-term complications, making patients with DM (85–90%) have type 2
early diagnosis and treatment of this condi- disease (defective insulin action and a relative
tion essential. The key hormonal disturbance defect in insulin secretion), whereas another
causing DM can be a defect in insulin secre- 5%–10% have type 1 DM (absolute defect in
tion, in insulin action, or both. Several path- insulin secretion, which requires insulin from
ogenic mechanisms have been proposed for the time of diagnosis). Remaining subtypes
the disease, and more than one mechanism are rare (see Table 1). This chapter focuses
may be at play for the disease to become on the major subgroups: type 1 DM, type 2
clinically evident. This chapter describes the DM, and gestational diabetes mellitus
classification, epidemiology, pathogenesis (GDM); the latter affects fetal and maternal
and pathophysiology, clinical presentations, health and is a risk factor for later develop-
complications, and diagnosis of DM and ment of type 2 DM.
provides a brief overview of treatment
options. EPIDEMIOLOGY
Key educational objectives are to under- According to 2010 estimates, 25.8 million
stand the following: people (or 8.3% of the population) in the
• Diabetes is a true metabolic disorder United States have DM.2–4 About 7 million
caused by disrupting insulin action. of these do not know they have DM and
• Both genetic and environmental present to healthcare providers after a point
factors are involved in causing dia- of no return in preventing complications.3
betes. Prevalence increases with increasing age with
• There are two main forms, type 1 and almost 27% of individuals over the age of 65
type 2, distinguished upon absolute having DM.5 An epidemic of type 2 DM is
and relative insulin deficiency, respec- underway in both developed and developing
tively. worlds, but the brunt is being felt sharply in
• Insulin action is intimately tied to developing countries.6–9 Globally, the number
many other counterregulatory actions. of people with diabetes is expected to rise
• Long-term complications of diabetes from the current estimate of 371 million in
affect every organ in the body. 2012 to 552 million in 2030, making the cost
• Controlling glycemia levels in addition of treating DM and its complications a
to cardiovascular risk factors is pressing economic concern.
important in preventing, delaying, Patients with DM have a two- to four-
and ameliorating disabling or life- fold higher risk for stroke and death from
threatening complications. heart disease compared with people without
Table 1. Etiologic Classification of DM. In addition, DM is the leading cause

Diabetes Mellitus of new cases of blindness and kidney failure
I. Type 1 diabetes (B-cell destruction, usually among adults aged 20 to 74 years (see US
leading to absolute insulin deficiency) Department of Health and Human Services,
A. Immune medicated
B. Idiopathic National Diabetes Statistics, 2011 http://dia-
II. Type 2 diabetes (may range from predominantly betes.niddk.nih.gov/dm/pubs/statistics/index.a
insulin resistance with relative insulin deficiency
to a predominantly secretory defect with insulin spx#allages).
resistance)
III. Other specific types
Periodontal diseases are also more
A. Genetic defects of B-cell function common in people with DM. Among young
1. Chromosome 20, HNF-4a (MODY1)
2. Chromosome 7, glucokinase (MODY2) adults, those with DM have about twice the
3. Chromosome 12, HNF-1a (MODY3) risk of developing periodontal disease com-
4. Chromosome 13, insulin promoter factor-1
(IPF-1; MODY4) pared with those without DM.3 Persons with
5. Chromosome 17, HNF-1b (MODY5) poorly controlled diabetes (HbA1c > 9%)
6. Chromosome 2, NeuroD1 (MODY6)
7. Mitochondrial DNA are nearly three times more likely to have
8. Others
B. Genetic defects in insulin action
severe periodontitis than those without dia-
1. Lipodystrophic syndromes betes.3 Almost one-third of people with DM
2. Type A insulin resistance
3. Leprechaunism have severe periodontal disease with loss of
4. Rabson-Mendenhall syndrome attachment of the gums to the teeth measur-
5. Others
C. Diseases of the exocrine pancreas ing 5 mm or more.
1. Pancreatitis In addition to the enormous morbidity
2. Trauma/pancreatectomy
3. Neoplasia associated with DM, it was the seventh
4. Cystic fibrosis leading cause of death listed on US death
5. Hemochromatosis
6. Fibrocalculous pancreatopathy certificates in 2011. Overall, the risk of death
D. Endocrinopathies
1. Cushing’s syndrome among people with DM is about twice that
2. Acromegaly of those of similar age without DM.
3. Glucagonoma
4. Pheochromocytoma
5. Others PATHOPHYSIOLOGY
E. Drug- or chemical-induced
1. Glucocorticoids The pathophysiology of DM revolves
2. Atypical antipsychotics around impairment of insulin secretion,
3. Pentamidine
4. Diazoxide insulin resistance, or both, resulting in
5. a-Interferon
6. Others reduced utilization of glucose, hyper-
F. Infections glycemia, and impairment of fatty acid
1. Congenital rubella
G. Uncommon forms of immune-mediated metabolism. Symptoms and complications
diabetes of DM are due to hyperglycemia as well as
1. Stiff-man syndrome
2. Anti-insulin receptor antibodies to lack of adequate insulin action.
3. Others
H. Other genetic syndromes sometimes
associated with diabetes Glucose Metabolism
1. Down syndrome
2. Turner’s syndrome
Carbohydrates, broken down mainly into
3. Wolfram’s syndrome glucose, are one of the main energy sources
4. Laurence-Moon-Biedl syndrome
5. Prader-Willi syndrome in most organisms including humans. Con-
6. Others sideration of glucose and insulin metabolic
IV. Gestational diabetes mellitus (GDM)
pathways is crucial to understanding the
Patients with any form of diabetes may require insulin pathophysiology of DM.
treatment at some stage of their disease. Such use of
insulin does not, of itself, classify the patient.
Glucose is derived from three sources:
(Modified with permission, American Diabetes intestinal absorption following digestion of
Association. Diabetes Care 2009;31:(Suppl 1). dietary carbohydrates; glycogenolysis, the
CHAPTER 5 Diabetes Mellitus: A Medical Overview 65
breakdown of glycogen, which is the poly- deficiency of insulin, absolute (as in type 1
merized storage form of glucose; and gluco- DM) or relative (as in type 2 DM), is associ-
neogenesis, the formation of glucose from ated with decreased clearance of blood
precursors including lactate (and pyruvate), glucose from the body and hyperglycemia
amino acids (especially alanine and gluta- (Figure 1).
mine), and, to a lesser extent, glycerol. Only
the liver and kidneys are capable of releasing Role of Insulin in the Body
glucose into circulation by glycogenolysis Insulin is secreted by b-cells of the islets of
and gluconeogenesis. All tissues can use Langerhans, an endocrine organ in the pan-
glucose as a substrate for energy production, creas. The pancreatic islet comprises a group
but only the brain is wholly dependent on of cells, termed a-, b-, and d-cells, sur-
glucose as its main energy source. Thus, rounded by exocrine pancreas. These islets
mechanisms to maintain a steady-state synthesize and release a number of hor-
supply of glucose to the central nervous mones, the classic ones being insulin and
system are integral to metabolic control. amylin from the b-cell, glucagon from the a-
Both insulin-dependent and insulin-inde- cell, somatostatin from the d-cell, and a
pendent pathways can determine whole-body number of other bioactive polypeptides not
clearance of glucose. Glucose is transported discussed here.18 Insulin (as well as amylin) is
into the cells by specific transporters,10 and synthesized as a prohormone, transported to
the next step is phosphorylation to glucose-6- granules where it is processed by a propro-
phosphate by enzymes hexokinase (insulin- tein convertase, resulting in mature insulin,
regulated) or glucokinase (glucose-induced C-peptide (byproduct of proinsulin process-
and regulates insulin secretion). Only then, ing), and amylin.19,20 These are stored in the
glucose can enter metabolic pathways such as mature granules until released on stimulation
glycolysis, glycogen synthesis, hexosamine of the b-cell. Insulin production usually
biosynthesis (alternative pathway to glycoly- exceeds the need, so the unreleased granules
sis), or pentose phosphate pathway (for gener- are destroyed in the lysosomal compartment
ation of nicotinamide adenine dinucleotide of the b-cell. Glucose is the primary stimu-
phosphate [NADPH] and to reduce cellular lant of insulin secretion, and oxidative
oxidative stress).11 It is important to note that metabolism of glucose is required for glucose
entry of glucose into different tissues is regu- to stimulate granule exocytosis.21–25 A number
lated by expression of different glucose trans- of other secretagogues, including hormones,
porters; in muscle and fat, glucose entry is gut peptides, and amino acids, also have the
allowed only via an insulin-dependent ability to provoke insulin secretion.18
translocation of the glucose transporter, Insulin’s primary physiologic function in
GLUT4, to the cell surface, whereas in the the body can be described as anabolic,
brain the glucose transporter, GLUT1, is con- resulting in storage of fuels from ingested
stitutively active and not dependent on insulin carbohydrate and fat (e.g., glycogen and
action. Insulin regulates many of these triglycerides) and regulating catabolism of
processes; it increases cell surface glucose stored fuel. Its main target tissues are skeletal
transporters in insulin-sensitive tissues such as muscle, liver, and adipose tissue, and its
adipose and muscle,12,13 induces hexokinase,14–17 action on these tissues (or lack thereof) is
and inhibits expression of enzymes involved in responsible for systemic effects of insulin.26 If
glycogenolysis and gluconeogenesis. Glucagon insulin is the Yin, a group of hormones such
action results in the opposite effects. Hence, as glucagon, cortisol, and growth hormone
66 ! !! ! Periodontal
! ! Disease
! and Overall Health: A Clinician’s Guide
Figure 1.
! 1Action of
! !Insulin and
! ! Glucagon! Under! Feeding! and
! Fasting
! Conditions
Feeding, satiety,! and! the! neurohumoral

! !
response to !feeding! are! integrated
! by !the! brain, ! especially
! the !hypothalamus
!
! ! ! ! ! ! ! ! ! !
(1A). This consists of the vagal system, incretin hormone secretion, and gut motility hormones, among other mecha- ! ! ! ! ! !
nisms. Upon !feeding ! (1A), the ! neurohormonal
! ! response, ! as well! as! direct ! !glucose! stimulation ! of the !pancreas,
! ! results
! ! of pathways
in activation ! ! that lead ! to ! efficient
! ! insulin
! !
secretion ! well as! a !decrease
as ! ! !in glucagon ! ! secretion!!from the
islets !of Langerhans
! ! ! in the pancreas ! ! !into the portal ! ! tract.! This ! results ! in! increased ! ! liver uptake ! of! glucose, ! inhibition
!
of hepatic! gluconeogenesis,
! ! increased fatty ! !
acid synthesis, ! !
and very-low-density! !
lipoprotein ! (VLDL)
! !
secretion and
increased! glycogen! storage. ! ! ! most! insulin
Although ! is! cleared
! ! by the ! ! liver,! it also reaches
! ! the !central circulation ! !where!
in the! ! fat, it increases
!! !
glucose !
uptake ! and triglyceride ! ! and
storage, ! inhibits ! free ! fatty ! acid ! release.! In ! muscle,!!insulin
!increases !glucose uptake ! !and !glycogen storage; ! ! the
in ! !kidney !it !inhibits !gluconeogenesis. Under ! fasting conditions
(1B), the! neurohumoral ! !
response ! is !switched to maintenance ! ! !of glucose ! levels,
! resulting ! in! decreased
! !!
insulin and
!
increased !
glucagon ! ! with the
secretion, ! resultant! opposite !effects! on! the above-described ! ! target! organs.! ! In the liver, glu-
!
coneogenesis, !glycogenolysis,
! ! ! and fatty acid ! breakdown is stimulated. ! ! ! In adipose
! ! ! fat is mobilized
tissues, ! ! with
!increased ! lipolysis
! ! !
and free-acid ! release. In ! muscle,! decreased ! !
glucose uptake! ! and increase ! fatty !acid catabolism
!! !take
!place. All! these ! actions ! are tightly ! regulated
! ! and! ! coordinated ! ! account
to ! ! all physiologic
for ! ! processes,! ranging ! !
from
!
short-term energy! expenditure ! (e.g., exercise)
! ! to both short- ! and! long-term!fasting. ! In! addition, ! many
! ! other hormones!
(e.g., !cortisol,! growth
! !
hormones, ! catecholamines)
! ! are involved,
! ! are not
but ! described ! here. ! ! !
! ! !
make up the Yang to counteract and keep phorylated IRS lead to activation of multi-
the metabolism ! ! in balance
! ! for energy needs.
! !ple downstream
! ! signaling!pathways! ! and ! ulti-
! Insulin! exerts
! ! its action
! by binding
! ! a
to !
mately to several !
activated protein !kinases.
! ! receptor, ! the insulin receptor
cell-surface !Activation
! of these! protein !kinases
! !
is respon-
(IR), which ! has an extracellular ! ! and ! an sible for! mediating! many of the eventual !
intracellular ! domain. !Intracellular
! !
domain ! ! actions! !of insulin,! including
metabolic !
!
possesses ! !
tyrosine-specific protein ! kinase
! ! ! ! of glucose
translocation ! ! transporters,
! ! activa-
!
activity,! which
! !is activated
! ! by insulin! binding, tion! of glycogen
! ! ! ! and suppression
synthesis, ! !
! !
and phosphorylates ! !
several intracellular pro- !of gluconeogenesis
! ! by the! liver.
! 27 !
! ! insulin
teins, specifically ! receptor ! substrate ! ! to carbohydrate
In addition ! ! ! !!
metabo-
(IRS)-1, -2, !-3 !and -4 (Figure! 2). The phos- ! ! ! insulin
lism, ! has! several
! ! other actions. Its
Figure 2. Insulin Signaling Pathways

TNF IGF1 Insulin Cytokines (IL-6, leptin, etc.)
Plasma membrane
IR A/B
TNFR IGF1R Rec
CAP PTP1B
Cbl IRS1
JNK Shc JAK
Rac IRS2
CDC42 IRS3
TC10 p85 IRS4 STAT
PTEN p110 p55 Node1
PI3K
p110 p50
PDK1, 2 p110 p85 Ras SOCS1, 3
Glucose
uptake aPKC p55
AKT1 Node2
AS160 ERK1
AKT2
Cell growth, ERK2
AKT3 differentiation
Node3
mTOR p90RSK
GSK3
FOXO1
Protein synthesis
Glucose
synthesis
Gluconeogenesis
Copyright 2006 Nature Publishing Group

Nature Reviews | Molecular Cell Biology
Insulin signaling occurs via many pathways and leads to the various actions of insulin. These signaling pathways
interact with many other pathways that are not depicted (e.g., cortisol, epinephrine, glucagon), and the concept of
critical nodes has been evoked to explain some key interactions. Critical nodes form an important part of the signal-
ing network that functions downstream of the insulin receptor (IR—black arrows) and the insulin growth factor-1
receptor (IGF1R—blue arrows). Signaling pathways that are activated by cytokines such as tumor necrosis factor-a
(TNF-a), interleukin-6 (IL-6), and leptin interfere with insulin signaling through cross-talk (orange and red arrows).
Three important nodes in the insulin pathway are the IR, the IR substrates (IRS 1-4—light blue box), the phos-
phatidylinositol 3-kinase (PI3K) with its several regulatory and catalytic subunits (light green box), and the three
AKT/protein kinase B (PKB) isoforms (pink box). Downstream or intermediate effectors as well as modulators of
these critical nodes include:
• Akt substrate of 160 kDa (AS160) • Mammalian target of rapamycin (mTOR)
• atypical protein kinase C (aPKC) • p90 ribosomal protein S6 kinase (p90RSK)
• Cas-Br-M (murine) • Phosphatase and tensin homologue (PTEN)
• Cbl-associated protein (CAP) • Phosphoinositide-dependent kinase 1 and 2 (PDK1
• Cotropic retroviral transforming sequence homologue and 2)
(Cbl) • Protein tyrosine phosphatase-1B (PTP1B)
• Cell-division cycle 42 (CDC42) • Rac
• c-Jun-N-terminal kinase (JNK) • Ras
• Extracellular signal-regulated kinase 1 and 2 (ERK1 • Ras homologue gene family, member Q (ARHQ;
and ERK2) also called TC10)
• Forkhead box O1 (FOXO1) • Signal transducer and activator of transcription (STAT)
• Glycogen synthase kinase 3 (GSK3) • Src-homology-2-containing protein (Shc)
• Janus kinase (JAK) • Suppressor of cytokine signaling (SOCS)
Note: Dashed arrows represent an activation process with less intensity. Reproduced with permission from Nat
Rev Mol Cell Biol 2006;7:85–96.
principle effect on adipose tissue is to sup- A minor subgroup of patients with type 1
press lipolysis and keep circulating free fatty DM are classified as having idiopathic DM
acid levels in check.28,29 These elevated free (nonimmune-mediated or idiopathic or type
fatty acids are thought to inhibit glucose uti- 1B).
lization by peripheral tissues and also Note also that the presence of type 1 or
increase hepatic gluconeogenesis.30 The disor- type 2 DM is not mutually exclusive. With
dered metabolism of fatty acids has been an increase in prevalence of obesity even
proposed as having a major effect on patho- among patients with type 1 DM, insulin
physiology in diabetes.31 Insulin’s effect on resistance is being increasingly noted among
adipose tissue appears to be as important as patients with type 1 DM and may require
its effects on carbohydrate metabolism. some of the strategies used for type 2 DM.
The development of DM thus involves
not only pancreatic islet b-cell dysfunction/ Latent Autoimmune Diabetes in Adults
destruction, but also action of insulin in the A small subgroup of patients share genetic
periphery. Although attention is usually and clinical features of both type 1 and type
focused on insulin, it is important to 2 DM, and tend to become insulin-depen-
acknowledge the role that counterregulatory dent a few months to years into diagnosis,
hormones (the Yang) play to fully under- rather than at the outset.7,35 This group has
stand the pathophysiology of DM. an increased risk for developing diabetic
ketoacidosis (DKA), although many main-
Type 1 DM tain minimal insulin secretion required to
In most patients, type 1 DM is an autoim- stave off DKA.35 These patients have vari-
mune disorder (type 1A) with selective able titers of autoantibodies, usually with a
destruction of the b-cells in the pancreatic lower body mass index (BMI) compared
islets occurring in genetically susceptible indi- with that of a typical type 2 DM patient,
viduals and resulting in absolute insulin defi- and they respond poorly to oral hypo-
ciency.32–34 Autoantibodies are detected as glycemic agents.36 Insulin treatment is recom-
epiphenomenon in 85% to 90% of persons mended since there is progressive absolute
in the beginning stages of the disease, but insulin deficiency in latent autoimmune dia-
the immune damage is cell-mediated, involv- betes in adults, secondary to the progressive
ing CD4+ T-cell dysfunction. Autoantibod- autoimmune damage to the islets.
ies are directed against islet cell, insulin,
other islet cell antigens such as glutamic acid Genetics of Type 1
decarboxylase (GAD65), tyrosine phos- Type 1 DM develops in the background of
phatase–related proteins such as insulinoma strong genetic susceptibility in the context of
associated protein 2 (IA-2 and IA-2ß), and poorly defined environmental factors. Sus-
zinc transporter 8 (ZnT8). Although there ceptibility to type 1 DM seems to be deter-
are no good markers to predict impending mined by multiple genetic loci, and recent
development of type I DM, the presence of advances in genome-wide scanning has
these autoantibodies is helpful in making a begun to elucidate many of these genes.37–43
diagnosis, and testing for one or more of There is a robust association (still < 50% of
these antibodies is recommended to make an genetic contribution) between type 1 DM
accurate diagnosis. In a few patients, autoan- and the major histocompatibility complex
tibodies may have dissipated by the time of (MHC) genes (HLA-DR and HLA-DQ),
diagnosis or an alternate pathway for whereas other loci (e.g., pre-proinsulin,
destruction of pancreatic b-cells is present. PTPN 22 gene, and CTLA-4) have small
effects.44,45 Specific alleles of both DR and of glucose and lipid homeostasis, and a
DQ can either increase or decrease the risk person can maintain normoglycemia as
of type 1 DM. The function of these HLA long as his or her pancreas can increase the
molecules is to present antigens to the production of insulin. However, in geneti-
immune cells, specifically T lymphocytes, cally predisposed individuals, beta-cells are
and sensitize them to autoantigens. unable to increase the insulin production to
The prevalence of type 1 DM in the levels required to compensate for
Western populations is approximately 0.3% insulin resistance, a condition occasionally
in the general population,46 whereas it is 6% termed b-cell exhaustion, and results in
if the father is affected, 4% if a sibling is increasing hyperglycemia.
affected, and 3% if the mother is affected.47,48
Although the risk of DM is much greater Insulin Resistance
for relatives of patients with type 1 DM, The complicated insulin pathway (see Figure
more than 85% of people who develop type 1) highlights multiple points in which disor-
1 DM do not have a first-degree relative dered action in any one of the gene products
with the disease. The risk for an identical involved in the pathways could result in
twin is estimated to be 30% to 50%,49–52 sug- impaired insulin action, in turn resulting in
gesting a strong environmental effect.53 insulin resistance. Despite identifying several
Patients with type 1 DM are also prone to of these processes, the molecular mecha-
other autoimmune diseases such as nisms causing insulin resistance in the major-
Hashimoto’s thyroiditis (hypothyroidism), ity of the patients remain unknown. Apart
vitiligo (loss of skin pigmentation), from the latter intrinsic component of
Addison’s disease (cortisol and aldosterone insulin resistance, certain acquired factors
deficiency), celiac disease (malabsorption of may contribute to the development of
nutrients), and pernicious anemia (vitamin insulin resistance and are reversible to some
B12 deficiency).54 extent. These include obesity, drugs, and
Several environmental factors including glucose toxicity.
viral infections, vaccinations, and certain Obesity predisposes a person to develop
dietary factors such as cow’s milk and insulin resistance and thereby type 2 DM.
cereals have been proposed as the putative Obesity can cause insulin resistance via
triggers to the initiation of destruction of several mechanisms, although other mecha-
pancreatic islets in the setting of appropriate nisms remain to be elucidated.67 One of the
genetic background.55–65 However, except for mechanisms attributed to increased insulin
congenital rubella infection, robust evidence resistance in obesity was decreased insulin
of association is lacking.66 receptor tyrosine kinase activity in the skele-
tal muscle68 and possibly in other tissues.69,70
Type 2 DM Weight loss improves the activity of the
Type 2 DM, previously known as receptor tyrosine kinase activity.71 This and
noninsulin-dependent DM or adult-onset other studies provide evidence that insulin
DM, is the predominant form of DM resistance does not always have to be geneti-
comprising up to 90% of total world cases. cally determined, but can be acquired and
This form of DM is associated with reversed to some extent.72,73 Another hypoth-
impairments in both insulin action (in esis posits that substances secreted by
other words, insulin resistance) and insulin adipose tissue cause tissues to become
secretion.3 Insulin resistance requires ele- insulin-resistant (such as paracrine, autocrine,
vated levels of insulin to perform functions and endocrine factors). These substances
include free fatty acids (which inhibit glucose be the b-cell secretory product amylin.88,89
transport, glucose oxidation, and glucose uti- However, the mechanism for the initiation of
lization)26,30,74 and leptin and tumor necrosis amyloid formation and the deposition in the
factor (TNF-a).75-80 Some products such as islets is not yet clear. It may have both a
free fatty acids may create a vicious cycle in genetic and environmental etiology.90 A
which insulin resistance increases free fatty number of types of insulin secretory abnor-
acid levels, which in turn increase insulin malities have been described in type 2 DM,
resistance. A break in the cycle of progres- including the timing and height of response
sively increasing free fatty acids either by to glucose challenge and other secreta-
decrease in weight (thus reducing the insulin gogues.91–99
resistance) or by treatment with insulin or
insulin sensitizer may alleviate the degree of Genetics of Type 2
insulin resistance defects related to obesity, Much like type 1 DM, type 2 DM is also
some of which seem to be acquired and par- thought to occur in genetically predisposed
tially reversible.81 individuals with superimposed environmen-
A number of drugs can impair glucose tal influences.100–103 Type 2 DM is a complex
tolerance, either by decreasing insulin secre- trait that is transmitted with a pattern of
tion (e.g., octreotide, diazoxide, and organ polygenic inheritance,104–106 which means that
transplant rejection medications such as abnormalities or polymorphisms need to
cyclosporine and tacrolimus), or by increas- occur concurrently in multiple genes for the
ing insulin resistance (glucocorticoids, oral disease to develop. Several aspects of the
contraceptives, several classes of antihyper- development of type 2 DM are under
tensive drugs such as beta blockers, thiazide genetic control including intra-abdominal
diuretics, nicotinic acid, protease inhibitors obesity, insulin resistance, and insulin secre-
used for treatment of HIV infection, and tory defects.107–116 Studies on monozygotic
some of the atypical antipsychotic agents, twins show an extremely high concordance
such as clozapine and olanzapine). rate of close to 90%, which is much higher
Glucose toxicity results from chronic than that of type 1 DM, thus suggesting
exposure of the pancreatic islet cells to sup- higher heritability.117 However, it is not
raphysiologic concentrations of glucose in known which genes predispose to insulin
the blood leading to cellular dysfunction, b- deficiency or insulin resistance. Genetic
cell toxicity, which is to some extent linkage methods have been used to try to
reversible, but may become irreversible over identify type 2 DM genes and have suc-
time.82 In addition, in animals, hyperglycemia ceeded in mapping genes to several loci.118–123
is also associated with insulin resistance by However, unlike type 1 DM, environmental
decreasing the glucose transport into the influences are well characterized.
cells.83,84 Thus, high glucose concentrations
can cause secretory defect as well as increase Ketosis-Prone Diabetes
insulin resistance, but with timely treatment, A subclass of patients presents with diabetic
this can be reversible. ketoacidosis, which is typically associated
The relative secretory defect in type 2 with an absolute insulin deficiency, but these
DM is not associated with immune-medi- subjects, on recovery, do not require insulin
ated destruction of b-cells but amyloid for management. They have no features of
deposits in the islet that are associated with autoimmunity and show a robust ability to
reduction in islet cell mass.85–87 The protein secrete insulin when tested in the postrecov-
component of these deposits was found to ery phase.
CLINICAL PRESENTATION adult disease, although children and young

In general, type 1 DM patients present in a adults with this disease are now being
more acute and dramatic fashion (in part, increasingly diagnosed. The disease can
because they have an absolute insulin defi- evolve over several years, and the natural
ciency) compared with type 2 DM patients, history may differ among patients. Many
who usually have a more insidious presenta- patients with type 2 DM are older than 40
tion. In both cases, the most common symp- years, are overweight or obese, and have an
toms are polyuria (and new-onset nocturia), increased waist circumference (a surrogate
polydipsia, and weight loss. However, type 2 marker for visceral fat accumulation).124 The
DM is an insidious disease and may fester for presence of metabolic syndrome markers
years before a diagnosis is made. Blurry (increased waist–hip ratio, hypertension, low
vision can result from changes in the osmolal- HDL-cholesterol, impaired fasting glucose)
ity of the lens from hyperglycemia. In addi- is strongly predictive of development of type
tion, frequent skin and vaginal infections, 2 DM.125 Although insulin resistance is the
slow healing of skin lesions, or occasionally primary cause of type 2 DM, it is not suffi-
distal neuropathy may be presenting features. cient to cause DM as long as the pancreas
Any of the above-mentioned symptoms in an can secrete enough insulin to compensate.
undiagnosed patient should prompt checking Presentation is usually insidious and goes
of blood glucose concentrations. unrecognized for years, since mild to moder-
ate hyperglycemia may not cause any notice-
Type 1 DM able symptoms. However, this mild hyper-
Type 1 DM, though commonly known as glycemia-associated lipid and blood pressure
juvenile diabetes, can occur at any age, but abnormalities are not entirely benign because
typically presents around the age of puberty. they increase the risk of macro- and
There is a short prodromal phase with microvascular complications.
fatigue, weight loss, polyuria, and polydypsia. Up to 20% of newly diagnosed type 2
In young children, new-onset bedwetting DM patients can manifest signs of diabetic
may be a presenting feature. If these symp- complications. With worsening hyper-
toms go unrecognized, the condition could glycemia, symptoms of polyuria, weight loss,
progress to ketoacidosis, with tachypnea, and other symptoms may then result in the
tachycardia, hypotension, and diabetic condition coming to light. It is not uncom-
ketoacidosis (DKA) and may lead to altered mon for an intercurrent illness, such as
mental state and coma. Frequently, an inter- stroke, myocardial infarction (MI), or infec-
current illness or an infection may be a tion to also uncover diabetes. Rarely, acute
trigger event. Because there is an absolute severe hyperglycemia (over 1–2 days) can
deficiency of insulin, the presentation is lead to a hyperosmolar (hyperosmolar,
acute (days) and needs urgent medical atten- hyperglycemic nonketotic state [HHS]) with
tion. In adults who have an autoimmune altered mental state and coma as an acute
disease or who have had damage (typically presenting feature. Hence, screening in high-
alcohol) or surgery to the pancreas gland, a risk individuals is essential to minimize the
diagnosis of diabetes should be considered risk of these complications. Presentation
for failure to gain weight or unexplained with ketoacidosis occurs rarely in these
weight loss. patients, but may occur in conjunction with
other illnesses such as infection or in stressful
Type 2 DM situations such as acute MI. Type 2 DM
Type 2 DM has long been considered an could be considered to evolve in two stages.
Stage 1 is development of impaired glucose similar to those of type 2 DM.126 With the
tolerance or impaired fasting glucose (also increase in insulin resistance during preg-
termed prediabetes), and stage 2 is the devel- nancy, women who are susceptible to devel-
opment of overt diabetes (Table 2). oping type 2 DM owing to a concomitant
secretory defect may indeed develop type 2
Table 2. Diagnostic Criteria for
DM. Although the risk of fetal develop-
Diabetes Mellitus
mental abnormalities is higher in women
Test Criteria Prediabetes Overt who are diabetic before becoming pregnant,
Mellitus Diabetes
Mellitus with GDM, the diabetes develops at the end
Glycosylated ≥ 5.7 ≥ 6.5 of the second trimester, a time when
hemoglobin (%) organogenesis has already been completed.
Fasting plasma glucose* ≥ 100 ≥ 126 Most women revert to normal glucose toler-
(mg/dL) ance postpartum. Approximately 50% of
Plasma glucose 2-hour 140–199 2 hours: ≥ 200 patients who have had GDM have a recur-
post 75 g oral glucose rence in future pregnancies and a 30% to
tolerance test† (mg/dL)
60% risk of developing established diabetes
Random plasma glucose†† ≥ 200
with symptoms of long term.127 GDM provides a unique
hyperglycemia§ (mg/dL) opportunity to educate women about the
need for lifestyle changes (weight loss, exer-
*
Fasting defined as no caloric intake for 8 hours.
†
Oral glucose tolerance test involves measurement of cise, and improved diet) to prevent overt
plasma glucose at specified time after consuming a glu- DM in the future.
cose load of 75 g or 100 g dissolved in water.
††
Random plasma glucose defined as anytime of the Acute Complications
day without any temporal association to caloric intake.
§
Symptoms of hyperglycemia include polyuria, DKA and HHS are potentially fatal but
polyphagia, polydipsia, and unexplained weight loss. largely preventable acute complications of
untreated DM.128 DKA is most common in
Gestational Diabetes patients with type 1 DM, although it can
Gestational diabetes mellitus (GDM) is a occur in patients with type 2 DM as well;
form of DM that has its initial onset during whereas HHS is more common in patients
the later stage of the second trimester of with type 2 DM. Although these two condi-
pregnancy and that resolves at the end of tions are discussed as two separate entities,
pregnancy. Up to 4% of pregnancies in the they are part of the same spectrum of dis-
United States are complicated by the devel- eases characterized by inadequate insulin.
opment of gestational diabetes. GDM DKA results when there is absolute insulin
during pregnancy increases both fetal deficiency, whereas HHS develops with rela-
growth (macrosomia) and obstetric compli- tive insulin deficiency. However, they do differ
cations. Although screening guidelines differ in the degree of dehydration, ketosis, and
among various groups of physicians, most metabolic acidosis.128 For both disorders, the
agree that screening should be undertaken precipitating factors could be the same,
between 24 and 28 weeks of pregnancy in including missed insulin doses, dehydration,
women who are obese, have a first-degree infection, certain medications, or other major
relative with diabetes, are older than 25 illnesses.128–130 However, restricted water intake
years, and come from a higher risk ethnic resulting from ill health or immobilization,
group (Hispanic, African American, Native compounded by altered thirst response, may
American). Many of the risk factors and contribute to the dehydration and HHS in
the pathophysiologic process for GDM are elderly patients with type 2 DM.129
Diabetic Ketoacidosis from intracellular to extracellular space, from

Diabetic ketoacidosis (DKA) is characterized where it could be excreted in urine along with
by varying degrees of hyperglycemia, ketone- osmotic diuresis, resulting in hypokalemia.
mia, and metabolic acidosis.128,131 When com- Ketones may be detected clinically in the
bined, these three elements give rise to the breath, as these are volatile. Laboratory abnor-
clinical syndrome of DKA, which is associ- malities helpful in making the diagnosis are
ated with dehydration, electrolyte abnormali- hyperglycemia, an increased anion gap (indica-
ties, and altered sensorium. tive of acidosis), a low arterial blood pH (<
As a result of severe insulin deficiency, 7.4 to as low as 6.9), a low bicarbonate level,
unchecked gluconeogenesis, glycogenolysis, elevated lactic acid levels, as well as ketone
and decreased glucose utilization result in bodies. Since ketone body production is part
hyperglycemia.132 Gluconeogenesis is also of a normal response to starvation, their
fueled by increased availability of amino detection, per se, is not indicative of DKA.
acids that are a result of increased catabo- In addition, DKA may be associated
lism, again because of decreased insulin. Ele- with increased levels of proinflammatory
vated blood glucose results in increased cytokines and procoagulant factors. These
plasma osmolality levels (hyperosmolar state) along with dehydration also create a fertile
causing shift of water from the intracellular ground for prothrombotic state.136
space and intracellular dehydration. The
increased plasma osmolality promotes Hyperglycemic Hyperosmolar
osmotic diuresis, resulting in net loss of body Nonketotic State
water and thus initiating a vicious cycle of This condition, HHS, is similar to DKA, but
increased plasma osmolality and progressive differs due to the presence of sufficient insulin
dehydration. The progressive dehydration to prevent lipolysis, and thus acidosis is not a
also leads to reduced tissue perfusion, major factor. Only a tenth of concentration of
hypoxia, and thus the generation of lactic insulin in the blood is required to prevent lipol-
acid, which contributes to the acidosis (see ysis; therefore, ketoacidosis, compared with the
text that follows). Decreased blood pH leads amount needed to stimulate glucose utilization
to reduced insulin action, setting up a and prevention of hyperglycemia is rare in type
vicious cycle. Osmotic diuresis also promotes 2 DM. Since patients with type 2 DM do have
loss of multiple minerals and electrolytes, this residual insulin, they are less likely to
including sodium, potassium, phosphate, develop DKA but are prone to develop severe
calcium, magnesium, and chloride, all of hyperglycemia and dehydration.137 Note that
which need to be replaced. ketosis should not be confused with ketoacido-
Loss of insulin action results in an sis: the former occurs during any period of
increase in lipolysis and an increase in free starvation, whereas the latter reflects absolute
fatty acid production; these fatty acids are insulin deficiency. Mortality from HHS is
metabolized by the liver into ketone bodies higher owing to older age, comorbid illnesses,
(acetone, acetoacetate and beta-hydroxybu- and severity of dehydration.
tyrate, a source of energy for the heart and Clinically, those with DKA and HHS
brain during starvation).133 Initially, the ketone- present with well-known symptoms of
mia may be mild as the body tries to metabo- hyperglycemia and dehydration, such as
lize them.134,135 As the acidosis from tissue polyuria, polydipsia, polyphagia, weight loss,
hypoxia with further reduced insulin action weakness, dry mucosal membranes, tachy-
occurs, excessive ketone bodies are produced. cardia, and hypotension in severe cases.
Acidosis promotes movement of potassium Altered sensorium and, frequently, precom-
atose or comatose situation can be seen in suggesting that other factors such as genetics
both conditions as a result of dehydration. and environment may modulate the develop-
Kussmaul respiration (rapid shallow breath- ment of these complications.
ing), acetone breath, nausea, vomiting, and
abdominal pain can also occur in DKA Ophthalmic Complications
because of the acidosis. Laboratory evalua- Diabetic retinopathy (DR) is the leading
tion reveals high blood glucose and renal cause of blindness in persons between ages 20
and other electrolyte abnormalities. The and 74. Chronic hyperglycemia is thought to
goals of therapy in these patients are restora- be the primary cause of retinal injury because
tion of the circulatory volume and tissue of impaired autoregulation of retinal blood
perfusion, gradual reduction of serum flow, accumulation of sorbitol, and advanced
glucose (rapid reduction may result in cere- glycosylation end products within the retinal
bral edema), and correction of electrolyte cells and extracellular fluid. The severity and
abnormalities and ketosis when present. Pre- progression of DR are variable in each
cipitating causes such as infection should be patient; however, one important predictor of
identified and treated. Intravenous fluids and DR is duration of DM. DR is divided into
insulin infusion form the mainstay of treat- two forms and further classified based on
ment along with frequent monitoring of severity. Nonproliferative DR is characterized
clinical and laboratory parameters and by retinal vascular microaneurysms, blot
adjustment of treatment. hemorrhages, intraretinal microvascular
abnormalities with increased retinal vascular
COMPLICATIONS OF permeability, and alterations in retinal blood
DIABETES MELLITUS flow—all of which lead to retinal ischemia.
Diabetes is a true metabolic disease and can Proliferative retinopathy is characterized by
affect many organ systems over the course of neovascularization in response to retinal
the disease. Such chronic complications are hypoxia, mediated by action of insulin-like
responsible for considerable morbidity and growth factor 1 (IGF-1) and vascular
mortality. These complications can be endothelial growth factor (VEGF). These
divided into microvascular, macrovascular, newly formed blood vessels lack sufficient
and nonvascular and are summarized in strength, rupture easily, resulting in intravitre-
Table 3. The risk of these complications ous hemorrhage, and subsequently lead to
increases as a function of hyperglycemia and fibrosis and retinal detachment, resulting in
duration of DM and are usually first seen blindness. In addition, macular edema can
10 years after diagnosis. occur at any stage of diabetic retinopathy.
Intensive glucose control since the time
Microvascular Complications of diagnosis of DM is necessary for the pre-
Large, randomized clinical trials of individu- vention of onset and progression of
als with type 1 or type 2 DM, such as the retinopathy. Since most patients are asymp-
Diabetes Control and Complications Trial tomatic until late in the disease process, an
(DCCT)138 and the United Kingdom annual exam for early detection and laser
Prospective Diabetes Study (UKPDS),139 photocoagulation (panretinal or focal) can
have conclusively demonstrated that a reduc- prevent blindness.
tion in chronic hyperglycemia prevents or
delays these complications (see Table 3). It Renal Complications
must be noted that not all people with poor Diabetes is the most common cause of renal
diabetes control develop these complications, failure in the United States. The earliest
Table 3. Complications of Diabetes Mellitus
Complication Salient Features

Eye disease: Annual screening should begin at the time of diagnosis in
• Retinopathy (DR) patients with type 2 DM and 5 years after onset of type 1 DM.
• Macular edema
• Cataracts and glaucoma Retinopathy progresses in two stages: Nonproliferative and
proliferative (see text). Laser photocoagulation of retina is the
major modality of treatment to prevent further loss.
Both are more common in patients with DM, occur at a

younger age, and progress faster.
Kidney disease: Annual screening of urine for microalbumin.
• Nephropathy Microalbuminuria (30–300 mg/24 h), potentially reversible.
• Renal failure
Overt proteinuria: >300 mg /24 h, irreversible.
Major cause of renal failure and dialysis requirement.
Generalized symmetric neuropathy: Annual screening for neuropathy by examination of feet and
• Acute sensory monofilament testing.
• Chronic sensorimotor
• Autonomic Podiatry referral should be considered in all patients with
Focal or multifocal neuropathy: neuropathy for custom footwear.
• Cranial, truncal
• Diabetic amyotrophy Pharmacotherapy management of pain remains a challenge.
Coronary artery, peripheral arterial, Leading cause of premature death in type 2 DM.
and cerebrovascular disease Well-developed treatment guidelines and medications for lipid
and blood pressure management.
Smoking cessation is vital.

Infections Strict glycemic control reduces the chance for infections.
Skin changes Most are self-limiting.
Skin infections can be prevented with good glycemic control.
Moisturizing can prevent dryness of the skin.
Necrobiosis lipoidica seen occasionally in type 1 DM patients.

Gum and periodontal disease, Poor oral health associated with increased cardiovascular
tooth loss morbidity/mortality.
Hearing loss Increased sensorineural hearing loss.
Osteoporosis No evidence-based guidelines for management, risk of bone
loss increased by diabetes.
Musculoskeletal Stiff joints and arthralgias much more common than
complications previously suspected.
Diabetic cheiroarthropathy, flexor tenosynovitis, Dupuytren’s

contracture, and Charcot’s joints (secondary to neurologic
deficits) require some intervention.
pathologic changes alter the microcircula- increases excretion of small amounts of

tion, with structural changes in the glomeru- albumin in the urine (microalbuminuria 30–
lar matrix resulting in an increase in 300 mg/d). Fifty percent of these individuals
glomerular filtration rate (GFR). This progress to overt proteinuria (300 mg–1 g/d)
or nephrotic syndrome (urine protein > 1 Charcot’s joints, arch collapse, and sensory
g/d). Urinary protein excretion is exacerbated ataxia. Mononeuropathy is associated with
considerably by uncontrolled hypertension, pain and weakness in one nerve distribution
and the combination of diabetes and hyper- that is self-limiting. Diabetic amyotrophy, seen
tension is the most common predisposing mainly in type 2 DM patients, is associated
factor for end-stage renal disease (ESRD). with pain in the lower limbs followed by
In addition to nephropathy, type IV muscle weakness in major muscles of but-
renal tubular acidosis (and resulting hyper- tocks and thighs. It is a self-limiting condition
kalemia) and predisposition to radiocon- and improves partially in 12 to 24 months;
trast-induced nephrotoxicity are also seen in treatment is supportive. Autonomic neuropathy,
patients with DM. Intensive control of though not well diagnosed, can affect all the
blood glucose, dyslipidemia, and blood pres- major organ systems. Many cardiovascular
sure is recommended to prevent the onset of abnormalities are noted, including resting
microalbuminuria and to prevent progression tachycardia, diminished heart rate variability,
to overt proteinuria or renal failure. silent myocardial ischemia, defective heart rate
Once ESRD ensues, patients are usually and blood pressure response to exercise, and
placed on dialysis. Kidney transplantation is postural hypotension. Altered small and large
generally the optimal renal replacement bowel motility (constipation or diarrhea), gas-
therapy for patients with DM and ESRD, troparesis (anorexia, nausea, vomiting, and
and timing of transplantation influences bloating), and gastroesophageal reflux disease
patient survival, with better survival rates for are the common manifestations of gastroin-
patients who undergo transplantation testinal system involvement. Genitourinary
without ever going through dialysis. systems are also involved and manifest as
bladder hypotonia (incomplete emptying,
Neurologic Complications dribbling, and overflow incontinence), erectile
Approximately 50% of patients with type 1 dysfunction, and female sexual dysfunction.
or type 2 DM develop neuropathy. It is Abnormal sweat production may result in
usually symmetric sensory polyneuropathy, xerosis, cracking of feet, and decreased sweat-
but may also be focal mononeuropathy ing in response to hypoglycemia.
and/or autonomic neuropathy, with loss of Tight glycemic control from the time of
both myelinated and unmyelinated nerve onset of DM is necessary for prevention of
fibers. Up to 50% of individuals with neu- neuropathy. Treatment is difficult once the
ropathy may not be symptomatic. The disease affects various organ systems. Fortu-
pathogenesis has been attributed to ischemic nately, painful polyneuropathy is infrequent
injury from a nonsystemic microvasculitis; and often self-limited. For symptomatic treat-
metabolic and hormonal factors may also ment of painful neuropathy, several therapies
contribute to the nerve fiber damage.140,141 have been tried with limited efficacy, such as
Generalized symmetric polyneuropathy is tricyclic antidepressants, anticonvulsants,
characterized by progressive loss of distal sen- selective serotonin and norepinephrine reup-
sation in glove and stocking distribution fol- take inhibitors, and topical therapies. Treat-
lowed by, in severe cases, motor weakness. ment of Charcot’s foot and arch deformities
Symptoms include pain, tingling, and numb- may involve avoidance of weight bearing,
ness, and physical exam reveals loss of fine special orthotic shoes to prevent ulceration,
touch, vibration, and position sense initially, and, rarely, surgical correction. Treatment for
which may later progress to wasting of small organ-specific complications of autonomic
muscles of the hands and feet resulting in neuropathy is symptomatic.
Macrovascular Complications LDL cholesterol to < 100 mg/dL and

Association of macrovascular complications triglycerides to < 150 mg/dL.
with hyperglycemia is less conclusive and Hypertension is frequently associated
appears to be more related to coexisting con- with DM and can hasten the onset of com-
ditions such as dyslipidemia and hypertension. plications, especially for CVD and nephropa-
Cardiovascular disease (CVD) risk is thy. Management includes aggressive control
increased in those with type 1 and type 2 DM of blood pressure and may require multiple
by twofold in men and fourfold in women. In medications.
addition, patients with diabetes and CVD Patients with DM also are at high risk
have worse outcomes and poorer long-term for congestive heart failure (CHF) (diabetic
survival compared with those without DM cardiomyopathy) independent of CVD and
and CVD. Type 2 DM patients with no prior hypertension, perhaps because of reduced
MI have a similar risk for coronary artery- left ventricular compliance. In addition,
related events as do nondiabetic individuals some drugs such as thiazolidinediones may
who have had a prior MI. Patients with increase the risk of CHF.
insulin resistance and type 2 DM have ele- As a preventive measure, aspirin should
vated levels of plasminogen activator be prescribed for all type 2 DM patients,
inhibitors (especially PAI-1) and fibrinogen, unless contraindicated, although newer
which enhances the coagulation process and guidelines recommend the use of aspirin
impairs fibrinolysis, thus favoring the develop- only in subjects with clinical evidence of
ment of thrombosis. Risk is increased when thrombovascular disease.
retinopathy, nephropathy, hypertension, and
dyslipidemia are associated with DM. DM Miscellaneous Complications
also increases the risk of silent MI owing to Infections
associated autonomic dysfunction. Even DM is associated with greater frequency and
though the risk of both asymptomatic and severity of common infections; in addition,
symptomatic heart disease is increased in some infections are exclusively seen in
patients with DM, all major societies (Ameri- patients with DM. Hyperglycemia results in
can Diabetes Association [ADA] and the impaired cell-mediated immunity and colo-
American College of Cardiology/American nization and growth of various bacterial and
Heart Association [ACC/AHA]) do not rec- fungal species. Apart from hyperglycemia,
ommend routine screening for CVD by either vascular insufficiency and peripheral and
treadmill or pharmacologic stress test. New autonomic neuropathies noted in patients
imaging techniques such as calcium scoring with DM form perfect host factors that pre-
and noninvasive coronary angiography with dispose to infections. Bacterial infections
computed tomography can detect the presence such as styes, boils, carbuncles, and surgical-
of CVD in asymptomatic patients. However, site infections are the most common.
DM is already considered a CVD risk equiva- Common fungal infections include intertrigo,
lent, and maximum medical therapy is recom- caused by Candida albicans, and ringworm
mended to control the risk factors. infections. Asymptomatic bacteriuria is also
Dyslipidemia frequently coexists with commonly seen in patients with DM but
DM, especially type 2 DM, with a typical does not necessitate treatment.
pattern of increased triglycerides, decreased
HDL cholesterol, and increased small-dense Sexual Dysfunction
low-density lipoprotein (LDL) cholesterol Male erectile dysfunction and female sexual
particles. The goals of therapy are to reduce dysfunction are commonly seen in patients
with DM. Male erectile dysfunction can be specific treatment exists for this condition
related to multiple factors including auto- other than to achieve adequate glycemic
nomic nervous system dysfunction, impaired control. Another condition known as dis-
blood flow to penis from vasculopathy, and seminated granuloma annulare can occur in
psychological factors such as depression. All patients with DM and is a benign, asympto-
men with DM should be asked about erec- matic, self-limited papular eruption found in
tile dysfunction and should be examined for patients of all ages. The primary skin lesion
the presence of hypogonadism along with usually is grouped papules in an enlarging
usual DM-related complications. annular shape, with color ranging from
flesh-colored to erythematous and is wide-
Dermatologic Manifestations spread.142 Disseminated granuloma annulare
Dermatologic problems are common in dia- may be treated with one of several systemic
betes, with approximately 30% of patients therapies such as dapsone, retinoids, niaci-
experiencing some cutaneous involvement namide, antimalarials, psoralen plus ultravio-
during the course of their illness. Several let A therapy, fumaric acid esters, tacrolimus,
skin conditions are more common among and pimecrolimus. Consultation with a der-
patients with DM, such as bacterial infec- matologist is recommended because of the
tions, fungal infections, and itching, but are possible toxicities of these agents.
not exclusive to patients with DM. Skin In addition, vitiligo (autoimmune
manifestations generally appear during the destruction of melanocytes) may coexist
course of the disease in patients known to with type 1 DM owing to a common patho-
have diabetes, but they may also be the first logic process. Acanthosis nigricans (hyperpig-
presenting sign of diabetes or may even mentation seen on the neck, axilla, groin,
precede the diagnosis by many years. and extensor surfaces) is associated with
Some conditions occur exclusively in insulin resistance and type 2 DM and is due
patients with DM. Diabetic dermopathy is a to melanocyte replication. Treatment of this
harmless condition that arises owing to small condition is not necessary except for cos-
vessel changes and manifests as oval or cir- metic reasons. The best treatment for this
cular pigmented and scaly patches on the condition is weight loss, which is typically
front of the legs. These lesions are usually the underlying cause, though trials with
asymptomatic and do not need to be topical or systemic retinoids or a topical
treated. Another disease caused by changes vitamin D analogs may help.
in blood vessels is necrobiosis lipoidica dia-
beticorum. This rare disorder begins in the Complications Related to the
pretibial region as painful erythematous Musculoskeletal System
papules that enlarge into glossy plaques with DM is associated with osteoporosis and
irregular borders and atrophic centers. These fracture risk, particularly among those with
patches are deeper than in dermopathy, can type 1 DM.143,144 Bone disease in DM is
be itchy and painful, and can ulcerate. No characterized by reduced bone turnover and
treatment is necessary prior to the ulceration. formation, along with increased resorp-
Bullous diabeticorum is a condition in which tion.145,146 The pathogenesis has been attrib-
blisters can occur on the backs of hands and uted to impaired osteoblast function second-
feet and are self-limiting. One third of ary to reduced insulin and IGF-1 levels and
people who have type 1 DM can develop reduced bone formation due to accumula-
tight, thick, and waxy skin on the backs of tion of advanced glycosylation end products
their hands, known as digital sclerosis. No (AGEs) in collagen from hyperglycemia.147 In
patients with type 2 DM, general bone represents a result of multiple systems gone
density seems to be preserved; however, an wrong, beginning with neuropathy and loss
increased risk of fracture has been attributed of sensation in the feet, vascular disease with
to several reasons including poor bone poor circulation and consequently impaired
quality, falls following hypoglycemia, poor healing, and susceptibility to infections as a
balance due to diabetic neuropathy, foot result of impaired immune response and
ulcers and amputations, poor vision due to poor glycemic control. In addition, foot
cataracts and retinopathy, and orthostatic deformities from muscle weakness and visual
hypotension.144,148–151 defects add to the predisposing factors for
Patients with DM are also at increased foot injury. The manifestations could begin
risk for hand and shoulder disorders such as as cellulitis and progress to abscess forma-
painless limited joint mobility, Dupuytren’s tion, osteomyelitis, and gangrene, which may
contracture, flexor tenosynovitis, adhesive ultimately lead to a need for amputation.
capsulitis, diabetic muscle infarction, and Preventive care is essential and should
carpal tunnel syndrome.152 Limited joint include not only professional care (as listed
mobility (diabetic cheiroarthropathy) has in Table 4) but also self-care on a day-to-day
been attributed to deposition of glycosylated basis. Daily inspection of the feet and
collagen in connective tissue around joints, wearing clean soft socks and properly fitting
resulting in stiffening. The prevalence shoes are among many precautions to take
increases with increased duration of DM to prevent foot ulceration. Once the ulcer is
and probably poor glycemic control.153,154 formed, antibiotics, relief of pressure to the
Available treatment options include physical ulcerated area, and control of blood glucoses
therapy, corticosteroid injections, and surgi- form the mainstay of treatment.
cal repair when indicated.155–157
Mechanisms of Complications
Periodontal Disease Several mechanisms have been proposed to
Oral health is now increasingly recognized as explain the role of hyperglycemia in the
an important part of diabetes management; development of chronic complications.
there is a mutually reciprocal relation Higher blood glucose levels seem to channel
between glycemic control and oral health. glucose into pathways other than glycolysis,
Periodontal infection worsens metabolic thus resulting in products that are detrimen-
control of DM, and improving oral hygiene tal to various tissues, especially connective
improves glycemic control.158,101 People with tissues and vasculature. The following theo-
poorly controlled DM are more likely to ries all have some supportive evidence for
develop gingivitis, dry mouth, dental abscess their role in pathophysiology:
and fungal infections, and slow wound 1. Chronically elevated blood glucose
healing.159 This topic is reviewed in depth levels result in interaction of glucose
elsewhere in this book. with intra- and extracellular proteins,
a process called nonenzymatic glycosy-
The Diabetic Foot lation and results in advanced glycosy-
Diabetic foot is a term commonly used to lation end products (AGEs). AGEs
refer to foot complications in diabetic have been shown to cross-link pro-
patients and is characterized by slow-healing teins and promote glomerular dys-
plantar ulcers from minor trauma. About function and accelerate atherosclerosis.
15% of diabetic patients may experience foot 2. Elevated blood glucose levels may be
ulceration in their lifetime. This condition converted to sorbitol by the enzyme
Table 4. Comprehensive Principles for Preventing DM Complications

Lifestyle changes:
• Diet: Sugar-free diet for type 2 DM, No restrictions for type 1 DM
• Fat 20–35% of total calorie intake, saturated fat < 7% of calories, < 200 mg/d dietary cholesterol
• Exercise: At least 150 minutes/week of aerobic physical activity
• Optimum weight (BMI < 25)
• Smoking cessation
Modifiable risk factors:
• Glycemic control:
• Glycosylated hemoglobin—measured at least twice a year (HbA1c < 7%)
• Self monitoring of blood glucose (SMBG)—no recommended optimal frequency, but probably
should be measured 3–4 times a day in patients who are administering insulin for blood glucose
control (preprandial plasma glucose 90–130 mg/dL, 2-hour postprandial plasma glucose of
< 180 mg/dL)
• Lipid management (LDL < 100 mg/dL, optional goal < 70 mg/dL, HDL > 45 mg/dL in men
and > 55 mg/dL in women and triglycerides <150 mg/dL)
• Blood pressure control (< 130/80 mm Hg, but < 125/75 mm Hg is preferred in those with
nephropathy)
• Aspirin prophylaxis (primary prevention in diabetics over 40 years)
Preventive care:
• Annual screening
• Screening for microalbuminuria
• Annual eye exam
• Podiatric exam
• Annual influenza vaccination
• Pneumococcal vaccination
aldose reductase, after usual pathway flux through the hexosamine pathway,
of glycolysis is saturated. Increased generating fructose-6-phosphate, and
intracellular sorbitol results in alter- alters the glycosylation process of
ation of cellular osmolality and gener- certain proteins.
ates reactive oxygen species, both of 5. In addition, various growth factors
which can result in cellular dysfunc- such as VEGF and TGF are pro-
tion. Although this theory is logical, duced in excess and cause damage to
treatment with aldose reductase the tissues.
inhibitors has not demonstrated a
great clinical benefit in preventing DIAGNOSIS OF
microvascular complications in clinical DIABETES MELLITUS
trials except, possibly, diabetic neu- Screening for diabetes is suggested for adults
ropathy.160–162 over 45 years or for all adults with a BMI of
3. Elevated blood glucose levels result in 25 kg/m2 or more who have one or more
activation of protein kinase C (PKC), risk factors for diabetes (e.g., first-degree rela-
which in turn can alter the transcrip- tives with DM, GDM, hypertension, dyslipi-
tion of genes of certain connective demia, or physical inactivity). Diagnostic cri-
tissue elements and neurons, resulting teria are summarized in Table 2. Recent
in micro- and macrovascular compli- addition of HbA1c for diagnosis of diabetes
cations. Inhibition of PKC is another makes it convenient for patients to be
therapeutic target being studied to screened.163,164 Threshold values for diagnosis
prevent these complications; however, are not chosen arbitrarily but based on their
clinical benefit is not yet clear. ability to predict retinopathy.165,166 Owing to
4. Hyperglycemia also increases glucose intra-individual variation in laboratory
values, it is essential to confirm abnormal used for the management of type I DM.
results on a separate day. Considerable expertise is necessary on the part
of the diabetes management team to interpret
MANAGEMENT OF the large amount of data generated.
DIABETES MELLITUS Long-term assessment of glycemic
Management of prediabetes should be given control is made by measurement of levels of
as much importance as DM itself. Lifestyle glycosylated hemoglobin A1c (HbA1c).
modifications (predominantly exercise and Nonenzymatic glycosylation of hemoglobin
weight loss) as noted in the following text, A1 (A1 being the predominant subtype of
and metformin therapy can decrease the risk hemoglobin in adults) by blood glucose is
of type 2 DM. Hence all patients should be increased when blood glucose levels are persist-
counseled regarding healthy lifestyle changes ently elevated. Normal concentrations are
regardless of their diabetes status. between 4% and 6%, and values above 6%
Goals of management of DM should represent the presence of elevated blood glu-
be to achieve near-normal glucose home- coses. Since erythrocyte life span is 3 months,
ostasis, prevent long-term complications, and HbA1c represents glycemic control over the
possibly prevent progression of the disease. previous 8 to 12 weeks. In patients achieving
Treatment goals are listed in Table 4 and their glycemic goal, the ADA recommends
require a multidisciplinary approach. measurement of HbA1c at least twice per
year. In general, the target A1c should be less
Diabetes Education than 7.0%, but it may be individualized with
Every patient with DM should be taught both lower (e.g., during pregnancy) and higher
diabetes self-management skills. Education (elderly with multiple comorbidities) goals
should include teaching about self-monitor- being acceptable in some patients. In addition
ing of blood glucose (SMBG) using glu- to SMBG, some patients with type 1 DM
cometers, about acute and chronic complica- may need to monitor ketones in their urine,
tions and how to prevent them, about treat- especially in the event of illness or pregnancy.
ment options, insulin administration (if
applicable), recognition and treatment of Lifestyle Modification
hypoglycemia, and about risk behavior mod- Medical nutrition therapy (MNT or diet)
ification such as smoking cessation. and exercise are the central components of
the management of DM. Patient education
Monitoring the Level of Glycemic Control regarding these aspects should be continuous
Good glycemic control can minimize the risk and reinforced at every healthcare visit.
of retinopathy, nephropathy, and neuropathy MNT is important to prevent onset of
in both type 1 and type 2 DM and can type 2 DM by promoting healthy eating
reduce the risk of CVD in patients with type habits and weight loss in those with obesity
1 DM. SMBG, with the help of glucometers, and prediabetes (primary prevention), to
helps day-to-day monitoring of blood glu- manage existing type 1 and type 2 DM (sec-
coses needed for insulin dosing, prevention, ondary prevention), and to prevent compli-
and treatment of hypoglycemia (see Table 4). cations of DM (tertiary prevention).
Continuous glucose monitoring system Although the goals of MNT should be indi-
(CGMS) is a relatively new method that uses vidualized, certain general principles are dis-
an indwelling subcutaneous catheter to cussed here. Certain dietary recommenda-
monitor interstitial fluid glucose and provide tions issued for the general population are
either real-time or retrospective glucose values also applicable to patients with DM. Diet
should be balanced including fruits, vegeta- When complications set in, certain
bles, and fiber and should be lower in satu- dietary restrictions may be necessary, such as
rated fats (< 7%) and trans fats, with avoid- limiting protein intake to 0.8 g/kg body
ance of high-protein foods according to weight per day in patients with overt diabetic
ADA recommendations nephropathy with proteinuria.
In overweight and obese individuals, Exercise is essential to maintain weight
even a modest weight loss of 5% to 10% is loss, improve physical fitness, and reduce
associated with improvement in insulin resist- plasma glucose concentrations. Older diabet-
ance and will prevent development of DM in ics starting a new exercise program may need
those with prediabetes or improve treatment to have medical clearance because of the high
requirements in those who already have DM. prevalence of asymptomatic CVD.
Weight loss may be achieved by either low- Control of hypertension is important in
calorie diet or low-carbohydrate diets (such as diabetic patients to prevent CVD and pro-
the Atkins diet), although effects of the latter gression of diabetic retinopathy and
may be short-lived. Nevertheless, some form nephropathy,167,168 and benefits may be even
of dietary modification is essential for weight greater than glycemic control in patients with
loss. Increased physical activity is also an type 2 DM. The choice of antihypertensive
essential component, especially for maintain- therapy among patients with DM, being the
ing the weight loss achieved by dietary modi- focus of investigation in a number of large
fication. Weight loss medications may be con- clinical trials, has evolved considerably. At
sidered in a few obese individuals in whom least in patients with nephropathy,
they can help achieve weight loss of 5% to angiotensin-converting enzyme (ACE)
10% as recommended; however, the effects inhibitors, and angiotensin receptor blockers
may also be short-lived. Bariatric surgery may (ARBs) seem to be the preferred initial
be the only option for weight loss for some therapy. Chlorthalidone, long-acting dihy-
severely obese persons and can be very suc- dropyridine calcium channel blockers, and
cessful in improving glycemic control as well carvedilol have been associated with better
as weight loss. Detailed discussion of weight cardiovascular and renal outcomes in combi-
loss strategies is beyond the scope of this text- nation with ACE inhibitors or ARBs.
book.
The goal of secondary prevention is to Pharmacologic Treatment
maintain normoglycemia in those with estab- Insulin is the required treatment for type 1
lished DM, in addition to promoting weight DM (oral agents are not indicated for use in
loss in overweight and obese persons. Moni- patients with type 1 DM), whereas patients
toring carbohydrate intake by carbohydrate with type 2 DM can be managed with diet
counting, exchanges, or any other method is therapy alone or may require oral hypo-
essential for achieving glycemic control. glycemic agents and/or insulin or a combina-
Mixed meals (those with protein/carbohydrate tion thereof. Treatment of DM has been rev-
combination or fat/carbohydrate combination) olutionized by the introduction of several
decrease postprandial excursion of blood glu- new agents in the last decade that act on dif-
coses and low glycemic index foods (associ- ferent aspects of diabetes pathology (Table 5).
ated with lower postprandial rise in blood For insulin therapy, there are now many
glucoses) may improve glycemic control. types of insulins that can allow for different
Patients who are on insulin should learn to onset, peak time, and duration of action,
estimate carbohydrate in their diet and match and there are many ways to administer these.
the insulin dose to this carbohydrate. All the insulins used currently are manufac-
Table 5. Oral Hypoglycemic Agents

Agent Characteristic Adverse Effects
Insulin Secretagogues
Sulfonylureas (SU): • Bind and activate the sulfonylurea receptor on ß-cells • Hypoglycemia
-Glipizide • Duration of action and daily doses vary by agent • Weight gain
-Glyburide • May be excreted by liver (glimepiride, glipizide) or
-Glimepiride kidney (glyburide)
Meglitinides: • Bind and activate the sulfonylurea receptor on ß-cells • Generally none, but
-Repaglinide • Short duration of action, quick onset of action, can possible hypoglycemia
-Nateglinide be taken 15 min before meals to target postprandial
hyperglycemia
• Contraindicated in those with gastroparesis and
chronic renal insufficiency
Insulin Sensitizers
Biguanides: • Exact mechanism not characterized, likely a low-grade • GI distress with diarrhea,
-Metformin mitochondrial poison and leads to activation of AMP nausea, crampy
kinase abdominal pains, and
• Decreases hepatic gluconeogenesis and increases dysgeusia. Rarely, lactic
peripheral glucose uptake acidosis can develop in
• Contraindicated in renal insufficiency patients with renal
(GFR < 40 mL/min), age > 80 years, heart failure, insufficiency
hepatic failure, alcohol abuse, acute illness • Can cause contrast
• Promotes modest weight loss and has low risk for nephropathy
hypoglycemia • Levels of vitamin B12 are
lowered, but may not be
clinically significant
Thiazolidinediones: • Activate nuclear transcription factor peroxisome • Weight gain
-Pioglitazone proliferator-activated receptor-gamma (PPAR-g) • Fluid retention, may pre-
-Rosiglitazone • Improve peripheral glucose uptake in skeletal muscle cipitate congestive heart
and fat and reduce free fatty acid levels, thus reducing failure in susceptible indi-
insulin resistance viduals
• Take up to 6–12 weeks to attain optimal therapeutic • Possible increase in risk of
effect bone loss
• Contraindicated in those with heart failure
• No significant risk of hypoglycemia
Agents That Decrease Glucose Absorption
Alpha-glucosidase • Inhibit alpha-glucosidase in the gut and thus prevent • Bloating, diarrhea, and
inhibitors: breakdown of some complex carbohydrates into flatulence due to action of
-Acarbose simple sugars, which then cannot be absorbed colonic bacteria on
-Miglitol • Prevent postprandial glucose excursions undigested carbohydrates
Agents That Increase Renal Glucose Excretion
SGLT2 inhibitors: • Inhibits SGLT2 in kidney to prevent reabsorption of • Dehydration on initiation
-Canaglifozin filtered glucose • Urinary tract infections
• Genital tract infections
Agents That Augment Incretin Pathways
Dipeptidyl peptidase • Inhibit degradation of native GLP-1 and GIP, • Well tolerated and safe in
IV inhibitors: enhancing incretin effect renal failure
Sitagliptin • Clinical experience with this agent is limited • Possible angioedema in
rare cases
GLP-receptor • Injectable only • Rash, skin reactions
agonists: • Acts by mimicking incretins • Nausea
-Exenatide • Can act centrally as well as peripherally • Pancreatitis has been
-Liraglutide • Causes satiety and leads to weight loss reported
tured; animal source insulins are exception- nance (an issue for most type 2 DM patients).
ally rarely used. However, the major side effects of gastroin-
testinal upset (pain and/or diarrhea) can limit
Oral Antidiabetic Agents its use. In addition, a potential side effect is
Sulfonylureas: These time-honored drugs lactic acidosis, an effect that can occur in the
have been available since the 1950s, and context of significant major organ (kidney,
although some older-generation agents (gly- liver, or heart) failure, which is almost negligi-
buride) continue to be used, the more com- ble when metformin is used per prescribing
monly used agents (first-line) are glipizide guidelines. Because metformin is excreted
and glimeperide. Unlike the former, which is through the kidneys, it is not used in subjects
excreted primarily through the kidneys, they with renal impairment and its use is sus-
are metabolized in the liver and are relatively pended when intravenous contrast agents for
safer in the face of deteriorating renal func- radiologic reasons are to be used, since con-
tion. The sulfonylureas result in increased trast nephropathy can result.
insulin secretion from ß-cells by binding to Thiazolidinediones (pioglitazone and
the sulfonylurea receptor (SUR) and are rosiglitazone) act in the adipose and muscle
dosed once or twice a day. The major side tissues to sensitize the action of insulin. Like
effect of these agents is hypoglycemia, espe- metformin, insulin sensitizers have also been
cially when they are used in combination shown to delay and/or prevent the onset of
with other agents, or when renal or liver diabetes when used in prediabetic subjects in
disease exists. The sulfonylureas (together clinical trials (thiazolidinediones are not indi-
with metformin, see following text) are the cated for this use). The main side effect of
most frequently prescribed agents for type 2 these agents is weight gain (both fluid reten-
DM and are now generic. tion and adipose tissue) and has been associ-
Miglitinides: These agents also stimulate ated with potential bone loss, limiting wide-
the SUR, but they have very different kinet- spread use of these agents. However, in sub-
ics; they bind, stimulate, and have a very jects with considerable insulin resistance, thi-
short action time, allowing them to be used azolidinediones are particularly useful to
as meal-time agents. Two such agents, limit or reduce insulin therapy.
repaglinide and nateglinide, are particularly Alpha-Glucosidase Inhibitors: These
useful in the elderly or in subjects in whom inhibitors act by decreasing the glucose
inconsistent eating patterns are an issue. absorption from the intestine. Though effec-
Insulin Sensitizers: These drugs act by tive, their major side effects are intestinal
improving the action of insulin on target upset (e.g., diarrhea and flatulence). Their
tissues (e.g., liver, skeletal muscle, and adipose cost also limits their use.
tissues). This group includes the biguanide Incretins and Incretin-Mimetics: Incretins
metformin (whose principle action is to are the hormones that, upon a dietary chal-
inhibit hepatic gluconeogenesis, but also lenge, amplify glucose-stimulated insulin
improves skeletal muscle uptake of glucose secretion, decrease glucagon action, and may
and decreases intestinal glucose uptake) and improve islet cell health (though the latter
thiazolidinediones (pioglitazone and rosiglita- has been demonstrated only in animal
zone), which act primarily on adipose and models).169 There are two known incretins;
skeletal muscle to improve insulin action. glucagon-like-peptide-1 (GLP-1) and gastric-
Metformin is one of the most commonly inhibitory-peptide (GIP). Incretins are pro-
used oral agents (if not first-line), since it produced in intestinal L cells (GLP-1) or K cells
motes some weight loss, or weight mainte- (GIP). In response to nutrients, they stimu-
late insulin secretion in a glucose-dependent glucose; thus, it seems ideal to prevent blood
fashion, inhibiting glucagon secretion, glucose from remaining at levels higher than
slowing gastric emptying, reducing appetite, the renal threshold for glucose filtration. As
and improving satiety. They act by binding a result of the induced glycosuria, some
to their cognate receptors and are inactivated weight loss is also observed since calories will
in the bloodstream by dipeptidyl peptidase be lost.
IV (DPP-IV). Inhibitors to DDP-IV have Combination Therapy: It is common
now been created that increase their activity. (and often necessary) to use combination
One FDA-approved inhibitor to DPP-IV is therapy for management of type 2 DM.
sitagliptin, although others are likely to be Combination therapy is predicated on ensur-
approved in the near future (e.g., vildagliptin, ing that each of the components acts in a dif-
alogliptin). Because the mechanism of action ferent pathway, thereby ensuring synergism of
is related, one injectable agent, exenatide, is action. The most common combinations are
discussed here; it also uses the incretin a sulfonylurea agent and an insulin sensitizer,
pathway. This drug was identified as the but triple therapies with a sulfonylurea agent,
active agent in the saliva of the Gila monster insulin sensitizer, and a DDP-IV inhibitor are
that causes hypoglycemia. Exenatide binds used. Metformin and thiazolidinediones can
and activates the GLP-1 receptor and in be used together, since they target different
addition acts in the hypothalamus to sup- tissues to improve insulin sensitivity and act
press feeding and increase satiety. Sitagliptin through different pathways.
is generally well tolerated, although it has With all combination therapies, the risk
not been on the market long enough to con- of hypoglycemia is increased and may
clude it is generally safe. Exenatide is also require appropriate dose titration. In general,
generally well tolerated, although nausea, when insulin therapy is initiated, many of
vomiting, and diarrhea are common, but the oral agents, except the insulin sensitizers,
may settle down with continued use. Rarely, are discontinued.
pancreatitis has been reported with exenatide
and is under review. Insulin Therapy
Sodium-Glucose Cotransporter 2 Exogenous insulin can be administered to
(SGLT2) Inhibitors: This is a new class of replace or supplement endogenous produc-
drugs recently approved by the FDA for tion of insulin. It is usually administered by
treatment of type 2 DM. SGLT2 is injection, which is the cause of much phobia
expressed in the proximal tubule and medi- associated with insulin therapy. For type 1
ates reabsorption of 90% of filtered glucose; DM patients, insulin is the mainstay and in
its inhibitors promote the renal excretion of most patients, frequent multiple dosing
glucose, thereby modestly lowering elevated (basal and bolus) is common. Insulin should
blood glucoses in patients with type 2 also be considered as the initial therapy in
DM.170 These agents promote urinary excre- certain individuals with type 2 DM, such as
tion of glucose; the kidney filters glucose those with renal or hepatic disease and any
when the blood glucose is higher than ~200 acute illness. However, most patients with
mg/dL, but this glucose is reabsorbed via type 2 DM may eventually need insulin as
SGLT2 in the proximal tubules. These the disease progresses and relative insulin
inhibitors prevent the filtered glucose reab- deficiency develops. A significant disadvan-
sorption. As a result of increased glucose tage of currently available preparations and
and sodium in the filtrate, a mild diuresis methods of delivery is that the insulin
results. This process affects only filtered directly enters the systemic circulation; this is
unlike the action of endogenous insulin, may need to be added later.

which is released into the portal venous In the past, insulin was derived from
system. No insulin regimen or method of porcine and bovine sources. This has been
delivery can mimic the pancreas. However, replaced by recombinant human insulin (e.g.,
insulin therapy should mimic physiologic NPH or regular insulin) or analog insulins,
release of insulin, which is characterized by a which are modified to produce varying levels
continuous basal secretion to prevent fasting of onset of action ranging from fast-acting
hyperglycemia and gluconeogenesis and by (analog insulins such as aspart, lispro, and
prandial insulin release with meals to prevent glulisine) to longer-duration (glargine,
postprandial hyperglycemia, especially in detemir) insulins (Table 6). Duration and
patients with type 1 DM, who lack endoge- peak of action are altered by changing the
nous insulin production. In the fasting state, chemical characteristics of the human insulin
long-acting basal insulin is used, which has a molecule. For example, regular insulin aggre-
flat profile without a peak. At mealtime, a gates to form hexomers, which requires the
bolus injection of fast-acting insulin is given body to break it down into monomers before
to produce a peak coinciding with the its action. Therefore, a longer time to onset of
absorption of ingested carbohydrate. In action is required compared with that of
patients with type 2 DM, some endogenous rapid-acting analog insulins, which have full
insulin secretion continues and is capable of biologic activity but less tendency to aggre-
providing some coverage of mealtime caloric gate and remain as monomers. Several differ-
intake. Insulin is usually initiated in a single ent premix insulins, containing a mixture of
long-acting dose, given either in the evening an intermediate-acting insulin (typically
or just before bedtime. However, other doses NPH) and a short-acting insulin (regular
Table 6. Types of Insulin and Their Profiles
Type Characteristic Action in Hours
Rapid-acting insulin: • Analog insulins Onset of action: < 1 hour
-Lispro • Altered amino acid sequence promotes Peak action: 1–2 h
-Aspart insulin monomers that are rapidly absorbed Duration of action: 2–3 h
-Glulisine • Injected shortly before meals
• Shorter duration of action results in fewer
hypoglycemic episodes
Short-acting insulin: • Soluble human insulin, generic Onset of action: 0.50–1 h
-Regular • Injected 30–60 minutes before meals for Peak action: 2–4 h
optimal action; failing to do so results in Duration of action: 4–6 h
postprandial hyperglycemia
• Less convenient than rapid-acting analogs
Intermediate-acting in- • Formed by adding protamine to human Onset of action: 2–3 h
sulin: insulin, generic Peak action: 4–6 h
-NPH (isophane • Acts as both basal and bolus insulin due to a Duration of action: 6–8 h
suspension) peak at 4–6 h
• Hypoglycemia a problem due to these peaks
Long-acting insulin: • Insulin analogs Onset of action: 1–4 h
-Glargine • Lesser incidence of hypoglycemia than NPH Peak action: none
-Detemir insulin Duration of action:
• Glargine: Provides consistent level in plasma up to 22 h
over long duration
• Detemir: Binds to albumin via fatty acid
chain, hence slower absorption and consistent
levels, shorter duration than glargine
insulin or newer short-acting analogs), are tremendous advances in computer technol-

available to provide basal-bolus insulins in a ogy have enabled the infusion set to be
predetermined ratio for convenience. reduced to the size of a pager and at the
The basis for any successful insulin same time perform exceptional tasks.171
therapy is the ability of the patient to Typically, the abdomen is the site where
monitor his or her own blood glucose using the cannula is implanted; however, it can be
glucometers, with the information that implanted in any convenient location on the
equips the patient to adjust the insulin dose, body. A normal pancreas secretes a basal
diet, and exercise to allow for normo- amount of insulin continuously throughout
glycemia and prevent hypoglycemia. Insulin the day to keep blood glucose in the desired
therapy is associated with the risk of signifi- range between meals and overnight and a
cant weight gain and hypoglycemia. bolus is secreted with food intake to control
postprandial hyperglycemia. The pump can be
Insulin Delivery Systems programmed to mimic this endogenous pan-
All of the currently used delivery systems creatic secretion and allows multiple basal rates
inject insulin through the skin and into the based on exercise and activity level. The pump
subcutaneous tissue. As previously men- is an open-loop system, which requires the
tioned, the most commonly used technique pump-wearer to decide how much basal or
is administration by syringe and hypodermic bolus dose is to be given. In addition to elimi-
needle. These needles now have a special nating multiple daily injections, it can deliver
coating to help them enter the skin as pain- small amounts of insulin with great accuracy172
lessly as possible. Another device is an and can decrease hypoglycemia due to the
insulin pen, which looks like a pen with car- peakless nature of rapid-acting continuous
tridges, but the cartridges are filled with insulin infusion.172–174 CSII can and should
insulin rather than ink. A short needle is probably be used in all patients with type 1
attached to the tip of the pen. Users need to DM, since these patients have physiologic
turn a dial to select the desired dose of insulin requirements.175 However, it can be
insulin and press a plunger on the end to especially advantageous to certain patients
deliver the insulin just under the skin. This who are runners, pregnant, shift workers, or
method is frequently used now with patients those who have gastroparesis.171,176–179 CSII may
who are on the run; the pen is safely stored also be used in patients with type 2 DM and
at room temperature and is convenient to who may limit weight gain.180 Even though a
keep in one’s pocket or purse. host of patients may be candidates for pump
Continuous subcutaneous insulin infu- therapy, not all of them would be eligible to
sion (CSII), also known as insulin pump receive one. Patients must be well motivated
therapy, delivers insulin through a tiny soft and able to understand basic insulin pharma-
tube attached to a cannula that is implanted cology and insulin pump technology. In addi-
under the skin through a needlestick (infu- tion, they must recognize that this technology
sion set). The tubing on the other end is does not substitute for their good decision-
connected to an external device containing a making and involves frequent checks of blood
computer chip, an insulin reservoir that can glucoses, interpreting them, and deciding
hold up to 300 units of rapid-acting insulin whether and how to treat them. Typically,
and a pumping system. The infusion set those who are able to follow intensive multiple-
needs to be changed once every 3 days. First dose regimen but not able to achieve glycemic
developed in 1976, the prototype was large control because of obvious disadvantages of
and inconvenient to use. Since that time, bolus regimens will benefit most from CSII.
Several innovations are coming to this time, its niche appears to be in poorly
pump technology at a rapid pace, with controlled type 1 (and type 2) DM for
remote controls to program the dose to patients already on intensive insulin regimens
those that wirelessly connect glucometers but whose glucose profile shows postpran-
and the pump. However, the most antici- dial hyperglycemia not adequately addressed
pated technology for a long time has been a by increasing the dose of pre-meal rapid-
closed-loop device like a closed-loop pan- acting insulin. Because of its effect on body
creas system. Such a system would include a weight, pramlintide seems to be most attrac-
continuous glucose sensor that would trans- tive for patients who are overweight. Insulin
mit glucose readings in real time to the dosage may need to be reduced because of
insulin pump, which in turn would respond an increased risk of hypoglycemia.
by infusing the exact amount of basal and Pancreas and Islet Transplantation:
bolus insulin required to reach glycemic Transplantation of whole pancreas or isolated
targets. Some prototypes of this technology islet cells is a treatment option for patients
are already commercially available. with type 1 DM to restore glucose-regulated
endogenous insulin production. Islet cell
Other Therapies transplantation is still performed in a con-
Pramlintide: Amylin is a hormone that is trolled research setting, whereas solid organ
usually cosecreted with insulin in response to pancreas transplantation is usually carried out
glucose by pancreatic b-cells. Its effects are in conjunction with renal transplantation
mostly on the gut and include suppression of (thus most patients are those with renal
glucagon secretion, retardation of gastric failure). If successful, both forms of trans-
emptying, and promotion of satiety, comple- plantation eliminate or reduce the need for
menting insulin’s action in establishing intensive insulin therapy to attain near
glucose homeostasis. Patients with type 1 normal glycemic control, which has been
and type 2 DM have been shown to have associated with severe hypoglycemia.181 Whole
deficiency of amylin as well as of insulin. pancreas transplantation, performed alone or
However, amylin is relatively insoluble in in combination with kidney transplantation
aqueous solution and aggregates on plastic or after kidney transplantation, is limited by
and glass. A synthetic amylin analog, pram- organ availability, graft failure, and morbidity
lintide is currently approved for use along associated with immunosuppressive therapy
with insulin in patients with type 1 and type and surgical complications.182 Improvements
2 DM who are inadequately controlled with in surgical techniques and immunosuppres-
their current regimens. It is given before sive therapy regimens have helped reduce
meals, usually in conjunction with prandial morbidity and mortality, making this a viable
insulin, but in a separate subcutaneous injec- therapeutic alternative for treatment of
tion. The major role of pramlintide is to DM.183 The greatest promise of islet cell
decrease postprandial glucose excursions, sta- transplantation is the possibility of immuno-
bilizing glycemic control. In clinical trials, the suppression-free transplantation, allowing for
absolute reduction in HbA1c is modest the prevention of the high rates of side effects
(0.3%–0.5%), although it is associated with associated with these medications. As of now,
mild weight loss, which distinguishes it from pancreas transplantation has a higher rate of
insulin therapy. Side effects are nausea and insulin independence (55% at 3 years) com-
vomiting, especially at higher doses. A pared with islet cell transplantation (35% at 3
common dosing schedule (3 times daily) also years), although there are no direct compari-
makes it inconvenient for many patients. At son studies.
COMPLICATIONS OF TREATMENT cortisol increase. These hormones stimulate

Intensive control of DM is recommended to glycogenolysis and gluconeogenesis in an
prevent microvascular complications, but it is attempt to correct hypoglycemia. In individu-
important to recognize the limitations of als with DM, these thresholds may not be the
such intensive therapy. Goals of treatment same as for healthy individuals. The blood
should be individualized based on age, glucose level at which the counterregulatory
comorbidities, and financial restrictions. mechanisms are initiated changes to a higher
Aggressive attempts to achieve glycemic level in those with poorly controlled DM
control can be associated with hypoglycemia, (who often have symptoms of hypoglycemia
weight gain, transient worsening of diabetic at normal glucose levels) and to lower levels
retinopathy and neuropathy in the short in people with recurrent hypoglycemia. A
term, and the need for increased healthcare continuing fall in blood glucose levels results
services. Most serious of these is hypo- in autonomic symptoms initially (due to nor-
glycemia, which occurs most frequently with epinephrine, acetylcholine, and epinephrine
insulin therapy, and may also occur with sec- released from adrenal gland and sympathetic
retagogues. Other agents are less likely to nervous system) and then to neuroglycopenic
cause hypoglycemia unless given in combina- symptoms.
tion with insulin or secretagogues. Weight Autonomic symptoms and signs are
gain occurs with most (insulin, insulin secret- palpitations, tremors, anxiety, sweating,
agogues, and thiazolidinediones) but not all intense craving for food, and rise in blood
(metformin, alpha-glucosidase inhibitors, pressure and pulse rate. Neuroglycopenic
and exenatide) therapies that improve symptoms are the direct result of central
glycemic control. This is partially due to the nervous system neuronal glucose depriva-
anabolic effects of insulin and the reduction tion. They include behavioral changes, con-
in glycosuria. In the DCCT, individuals with fusion, fatigue or weakness, visual changes,
the greatest weight gain were found to seizure, loss of consciousness, and, rarely if
exhibit increases in LDL cholesterol and hypoglycemia is severe and prolonged, death
triglycerides as well as increases in blood or permanent neurologic damage. Clearly
pressure (both systolic and diastolic) similar adrenergic symptoms serve as a warning sign
to those seen in individuals with type 2 DM for the patient to recognize developing hypo-
and insulin resistance. These effects could glycemia and abort the downward spiral by
increase the risk of CVD. ingesting carbohydrate before hypoglycemic
neuroglycopenia symptoms develop. Once
Hypoglycemia neuroglycopenia develops, patients are no
Hypoglycemia (low blood glucose) may occur longer able to take care of themselves and
as a result of absolute insulin excess or need assistance (severe hypoglycemia).
insulin/glucose mismatch. Risk factors include However, some patients may have hypo-
increased dose of insulin, administration at glycemia unawareness, which is characterized
the wrong time, exercise (increased glucose by impairment of sympathoadrenal response
utilization), decreased food intake (missed against hypoglycemia. These impaired
meals), alcoholism (which interferes with glu- responses create a vicious cycle of recurrent
coneogenesis), and renal failure (decreased iatrogenic hypoglycemia. Hypoglycemia
insulin clearance). When blood glucose levels unawareness, and to some extent the reduced
reach a threshold of around 70 to 80 mg/dL, epinephrine component of defective glucose
counterregulatory hormones such as counterregulation, is reversible within as few
glucagon, epinephrine, growth hormone, and as 2 to 3 weeks of scrupulous avoidance of
hypoglycemia in most affected patients. duration of a hypoglycemic episode is a func-

Risk for hypoglycemia should be mini- tion of the pharmacodynamic profile of the
mized in every patient by education, inquiry drug that induced it. A severe episode caused
about hypoglycemia at every healthcare visit, by a sulfonylurea overdose can be prolonged,
and assessment of hypoglycemia awareness. and hospitalization for prolonged treatment
Hypoglycemia occurs more frequently in and observation is often necessary. Glucagon,
patients who are being treated with intensive which forms an important part of the treat-
insulin therapy. It can be minimized by ment plan, apart from correcting hypo-
reducing the glycemic control goal to that glycemia rapidly, may result in transient
which can be accomplished safely and by hyperglycemia, nausea, and vomiting. The
making sure the patient’s glucometer is accu- glycemic response with glucagon is transient,
rately calibrated. and hence should be followed by either
Most episodes of hypoglycemia are mild glucose infusion or a meal, depending on the
to moderate (with or without symptoms) and patient’s mental status. The patient should be
can be effectively treated by oral glucose sup- prescribed a glucagon kit, and friends and
plementation; parenteral treatment is neces- family should be taught to recognize the
sary in patients who are unwilling or unable symptoms of hypoglycemia and to be famil-
to take carbohydrate orally (Table 7). The iar with the use of glucagon kits.
Table 7. Identification and Treatment of Hypoglycemia

Symptoms of Hypoglycemia Signs of Hypoglycemia
• Shakiness • Tremors
• Anxiety • Tachycardia
• Palpitations • Sweating
• Increased sweating • Confusion, inappropriate behavior
• Hunger
General Principles:
• Treatment should be initiated as soon as possible
• All patients should be given instructions as to how to treat hypoglycemia.
• In a healthcare institution, staff should not wait for lab results or wait for response from a
physician
• If blood glucose is extremely low on the glucometer, e.g., < 40 mg/dL, blood should be drawn
and sent to the lab for accurate blood glucose level, since the precision of glucometers is low at
extremely low blood glucose levels
Treating the Conscious Hypoglycemic Patient:
• Treat with ~ 15 g of simple carbohydrates orally
• ½ can of regular soda
• 4 oz of regular fruit juice or
• 3–4 glucose tablets
• Repeat fingerstick glucose in 15 minutes
• If blood glucose is < 60 mg/dL, repeat 15 g of simple carbohydrates and check blood glucose in
15 minutes. Continue this protocol until blood glucose is > 60, then follow with a mixed snack
• Ascertain cause and if hypoglycemia not likely to recur, ask patient to discuss the hypoglycemia
with his or her physician
Treating the Unconscious Hypoglycemic Patient or Otherwise Unable to Consume Oral Carbohydrate:
With IV access
• 25–50 g of 50 % dextrose can be given immediately
Without IV access
• Glucose gel can be applied to the mouth or rectum in the semi-obtunded patient
• Treat with 1 mg glucagon intramuscularly or subcutaneously; patient should regain
consciousness in 15–20 minutes
• Repeat the blood glucose in 15 minutes
Pregnancy and DM adjustments should be made preemptively.

Maternal hyperglycemia at the time of con- More frequent antenatal fetal testing is rec-
ception from either type 1 or type 2 DM ommended to recognize signs of fetal dis-
greatly increases the risk of spontaneous tress. In addition, timing of delivery is closely
miscarriages and multiple congenital birth monitored to avoid peripartum complica-
defects. In addition, DM in pregnancy is an tions, with most obstetricians choosing to
independent risk factor for pregnancy- deliver before 41 weeks.
induced hypertension and preeclampsia.126
Women with DM who become pregnant are CONCLUSIONS
at considerable risk for the development DM is an ancient disease that is becoming
and/or progression of DM during preg- more prevalent throughout the world.
nancy. They need frequent and additional Although there is a strong genetic predisposi-
examinations during pregnancy and 1 year tion toward developing type 1 or type 2 DM,
postpartum even if they have had dilated eye environmental factors are a critical compo-
exam prepregnancy. Uncontrolled blood glu- nent because the rise in incidence is occurring
coses in the last trimester are associated with at a much faster pace than genetics alone can
fetal macrosomia (due to high blood glu- produce. The key pathophysiologic distur-
coses reaching the fetus and stimulating fetal bance is centered on insulin action, which is
insulin production, which increases fetal intimately involved with almost every meta-
growth), polyhydramnios (increased amniotic bolic process and endocrine pathway. Under-
fluid due to high blood glucoses), and standing the pathophysiology necessitates a
sudden fetal death. Intensive control of DM comprehension of all disrupted metabolic
from the prepregnancy period to throughout pathways. For example, insulin regulates not
the pregnancy along with aggressive fetal only glucose metabolism, but also fatty acid,
surveillance and perinatal care can improve cholesterol, and amino acid metabolism in
the outcomes.126 Insulin requirement cell growth and cell division, acting as a
increases throughout the pregnancy because balance to other hormones that perform the
the pregnancy is an inherently insulin-resis- opposite function.
tant state. The precise mechanisms for Long-term disturbances of these path-
increase in insulin resistance are not known, ways are responsible for devastating compli-
but placental hormones such as human pla- cations: diabetes is a major cause of
cental lactogen and progesterone and, to retinopathy and blindness, renal failure and
some extent, increased fat deposits during dialysis requirement, premature CVD (heart
the pregnancy seem to mediate the insulin attacks, stroke, and peripheral vascular
resistance. These factors may interfere with disease), and loss of limbs. Many other
binding of insulin to its receptor or may act organs or systems are now recognized to be
at the level of cell signaling pathway behind affected by diabetes, such as all aspects of
the insulin receptor. The glucose targets oral health. Although diabetes is diagnosed
during the pregnancy are more stringent so with well-defined biochemical criteria, it is
that fetal macrosomia can be avoided. increasingly appreciated that any level of ele-
Insulin is the preferred treatment for vated glycemia (an indication of reduced
management of DM during pregnancy, not insulin action) leads to greater cardiovascular
only in those with type 1 DM but also in morbidity and mortality. An increasingly
those with type 2 DM and GDM. Insulin sophisticated group of therapies are available
requirements drop precipitously in the imme- to manage this disorder to improve the
diate postpartum period, so necessary health of the patient.
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CHAPTER 6
Hyperglycemia/Diabetes Mellitus
and Periodontal Infection Adversely
Affect Each Other
Wenche S. Borgnakke
INTRODUCTION diabetes with its complications. Through

Diabetes, prediabetes, and periodontal dis- such relatively simple and straightforward
eases are common chronic diseases world- but concerted effort, a potentially large gain
wide. This chapter provides a description of may be obtained in improving the quality of
the evidence regarding the two-way relation- life of those with diabetes while reducing the
ship between periodontal disease and hyper- immense burden of diabetes and its sequelae
glycemia in both otherwise healthy individu- on patients, their families, and employers, as
als and in those with prediabetes or mani- well as society as a whole.
fest diabetes. The educational objective is to provide
This mutually adverse relationship an overview of the current evidence among
shows the following characteristics: humans regarding the following topics,
1. Elevated blood glucose level (hyper- reflecting the organization of the chapter:
glycemia) adversely affecting periodon- I. Effect of Hyperglycemia on Peri-
tal health. odontal Health
2. Periodontal infection adversely affect- II. Effect of Periodontal Infection on
ing blood glucose levels, leading to: Blood Glucose Levels in Health,
a. Decreased glycemic control in people Prediabetes, Diabetes, and Diabetes
with diabetes Complications:
b. Increased risk for diabetes complica- A. Nonintervention, descriptive studies
tions B. Intervention studies: effect of
c. Elevated blood glucose levels or nonsurgical periodontal therapy
development of prediabetes in other- on glycemic control in type 2
wise healthy individuals, develop- diabetes
ment of type 2 diabetes in those with III. Advice for Patients with (or at Risk
prediabetes, and possibly develop- for) Diabetes and Their Healthcare
ment of gestational diabetes Providers
All healthcare professionals should under-
stand the role and importance of oral health I. EFFECT OF HYPERGLYCEMIA
in managing patients with diabetes or those ON PERIODONTAL HEALTH
who are at risk. Attaining or maintaining Periodontitis had for many years been
healthy periodontal tissues to be as free of known as a complication of diabetes and in
infection and its subsequent inflammation as 1993 was suggested to be considered the
possible—including nonsurgical periodontal sixth such complication by the Director of
treatment if needed—may amount to an the National Institute of Dental Research,
important, novel avenue for improving Dr. Harold Löe.1 However, this notion had
glucose control in people with type 2 dia- not gained sufficient attention in the medical
betes or for helping to prevent development community until rather recently, despite
or progression of prediabetes and manifest efforts to disseminate the concept in the
medical community, for instance, by includ- ifest diabetes, based on representative data
ing such information in medical textbooks2,3 from the National Health and Nutrition
and other books and publications targeted Examination Survey (NHANES).16
to both medical and dental healthcare stu- As can be seen in the dotted graph, over
dents and practitioners.4-6 It has become one third are obese. An additional one third
increasingly evident in the last few years that are overweight with BMI between 25 and
the presence of high blood glucose levels, < 30 kg/m2, leaving only one third of adults
that is, hyperglycemia, as seen in those with as underweight or of normal weight. Just 20
uncontrolled diabetes, is the important years ago, only in two states were as many as
factor, rather than simply a diagnosis of dia- one in five adults obese. Figure 2 shows par-
betes.7 This realization is contrary to the still allel trends in obesity and diabetes by state.
widespread belief that merely having diabetes Not only is the prevalence of diagnosed dia-
predisposes to periodontitis. In those with betes increasing at an alarming rate over time,
type 2 diabetes, the level of hyperglycemia the number of states in which > 7.5% of indi-
positively correlates with periodontal probing viduals have diabetes now outnumbers those
depth (PPD).8 That is, the higher the average with lower prevalence. This has severe conse-
blood glucose level is over time, the deeper quences for premature mortality, lost produc-
the PPD. On the contrary, the clinical peri- tivity, and human suffering, and results in
odontal health status in people with well- immense costs to society.
controlled diabetes is usually similar to that
observed in those without diabetes,9 and Obesity and Periodontitis
their periodontium responds similarly to Not only are obesity and hyperglycemia
periodontal treatment10 and extractions.11-13 linked through underlying inflammatory
Because of the high—and steadily mechanisms, obesity also affects the peri-
increasing—prevalence of diabetes globally, odontium. For example, among 186 French
the medical and dental practitioner will likely subjects 35 to 64 years of age, BMI was sta-
encounter many patients with diabetes. The tistically associated with missing teeth, PPD,
International Diabetes Federation (IDF) esti- and plaque index after adjustment for poten-
mates that 382 million (8.3%) people world- tial confounders including insulin resistance.17
wide have diabetes mellitus, with almost 50% Similarly, obesity—especially central (abdomi-
of these (175 million) being undiagnosed. nal) adiposity assessed by waist-to-hip ratio—
Another 316 million with impaired glucose was associated with a greater risk of peri-
tolerance (IGT) are at risk.14 By 2035, the odontitis in a population of adults 70 years
IDF expects 592 million people to live with and older in the San Juan metropolitan area
manifest diabetes, with another 471 million of Puerto Rico.18 Therefore, it is important
having impaired glucose tolerance, totaling to control for obesity when interpreting
almost 1 billion persons globally. study results, since obesity functions as a
According to the most recent estimates confounder. That is, observed differences in
by the Centers for Disease Control and Pre- outcomes between groups may be due to dif-
vention (CDC), diabetes affects 29.1 million fering obesity rates in the study groups and
or 9.3% of the US population, of whom 20 not to the agent under study.
million are diagnosed with diabetes, and 8.1 An intervention study not only identi-
million are unaware of their disease.15 Similar fied overweight/obesity (BMI) as an inde-
to that found in many other countries, pendent predictive factor for poorer out-
Figures 1 and 2 illustrate the US parallel pop- comes of nonsurgical periodontal treatment,
ulation prevalence trends in obesity and man- it also suggested that this negative effect was
CHAPTER 6 Adversely Affect Each Other 101
Figure 1. Prevalence of Total Confirmed Diabetes* and Obesity† in US Adults > 20 years in
NHANES (7,385 participants for 1988–1994; 5,680 participants for 1999–2004; and 6,719
participants for 2005–2010)
*Both hemoglobin A1c > 6.5% and fasting glucose > 126 mg/dL (> 7.0 mmol/L).
†Body mass index (BMI) > 30 kg/m2.
Source: Selvin E et al. Ann Intern Med 2014;160:517–25.16 Reprinted with permission.
Figure 2. Prevalence of Obesity and Diabetes Among US Adults > 18 Years by State
Source: http://www.cdc.gov/diabetes/surveillance/diabetes_slides.htm.
of a magnitude similar to that of cigarette nosing—not only screening—diabetes, and

smoking.19 Another study demonstrated that selected the cut-point as 6.5%. That is,
obese individuals who had undergone persons with 6.5% HbA1c or higher are classi-
bariatric surgery and lost at least 40% of fied as having diabetes21 (Table 1).
their presurgery body weight showed a sig- The degree to which diabetes is con-
nificantly improved response to periodontal trolled or managed is usually assessed by
treatment.20 measuring the percent of glycated hemoglo-
bin A1c (HbA1c) in the blood, also known as
Hyperglycemia/Diabetes Types “long-term blood sugar,” rather than the
The terms hyperglycemia, prediabetes, and momentary concentration of glucose when
diabetes refer to states in which blood glucose fasting or at random. HbA1c is a measure of
levels are elevated. Only recently has it how much glucose has been present in the
become apparent that hyperglycemia also blood and has irreversibly bound to the
plays a role in otherwise healthy individuals, hemoglobin in the red blood cells over their
as well as in those with prediabetes and dia- lifetime. A miniscule amount of blood from a
betes. Table 1 shows various types of hyper- simple fingerstick can be analyzed chair-side,
glycemia and their case definitions.21-23 Based and the result indicates the level of control of
on a systematic review, the World Health glycemia during the previous 60 to 90 days,
Organization (WHO) recommended as measured as percent of HbA1c. Healthy
recently as 2011 the use of HbA1c for diag- persons have an HbA1c level of ≤ 5.6%.23 The
Table 1. Glycated Hemoglobin Levels (HbA1c) and Plasma Glucose Levels: (A) HbA1c and
Corresponding Average Plasma Glucose Levels;22 (B) Classification of Diabetes Status by
HbA1c21 and Fasting Plasma Glucose Levels.23
HbA1c A) Average Plasma Glucose22 B1) B2) Fasting Plasma Glucose23 Diabetes
% mg/dL (CI) mmol/L (CI) HbA1c %21 mg/dL mmol/L Status
4 ~68 ~3.8
5 97 (76–120) 5.4 (4.2–6.7) <5.6 < 100 < 5.6 Healthy
5.6 ~114 ~6.4
5.7 ~117 ~6.5
6 126 (100–152) 7.0 (5.5–8.5) 5.7–6.4 100–125 5.6-6.9 Prediabetes
6.4 ~137 ~7.7
6.5 ~140 ~7.8
7 154 (123–185) 8.6 (6.8–10.3)
8 183 (147–217) 10.2 (8.1–12.1)
9 212 (170–249) 11.8 (9.4–13.9) > 6.5 > 126 > 7.0 Diabetes
10 240 (193–282) 13.4 (10.7–15.7)
11 269 (217–314) 14.9 (12.0–17.5)
12 298 (240–347) 16.5 (13.3–19.3)
Panel (A): Translating glycated hemoglobin level (HbA1c) into estimated average blood glucose concentration.
Each percentage point HbA1c is equivalent to a mean glucose level of ~29 mg/dL or ~1.6 mmol/L.
Numbers in italics are estimates.
CI, confidence interval.
Source: Modified from Nathan DM et al. Diabetes Care 2008;31:1473–8.22
Panel (B): Diabetes classification based on HbA1c and fasting plasma glucose concentration.
Fasting: defined as no caloric intake for at least 8 hours; prediabetes: increased risk for development of
manifest diabetes.
Source: Modified from Diabetes Care 2014;37(Suppl 1):S81–90.23
current general therapeutic target for HbA1c is evidence for a relation between the sus-
to achieve a level less than 7%, but this is tai- pected putative agent and the outcome, with
lored to the individual patient.24 cross-sectional studies providing the lowest
level of strength, followed by case-control
Evidence from Epidemiologic Studies and cohort studies; well-conducted system-
There is growing evidence that hyper- atic reviews and meta-analyses of well-con-
glycemia/diabetes adversely affects periodontal ducted randomized controlled trials (RCTs)
health, in particular that the degree of hyper- provide the strongest available evidence.
glycemia in health or in prediabetes, and level Intervention studies are described in a sepa-
of glycemic control in manifest diabetes, is rate section. Because of ethical, method-
associated with poorer periodontal health. ologic, and practical limitations of experi-
The evidence that diabetes adversely mental studies for answering questions
affects periodontal health and vice versa is about causation for many types of health-
provided by studies conducted in various related issues, other study designs are also
parts of the world. The variety in the body of used. It is important to keep in mind that
evidence stems not only from the geographic RCTs would not be appropriate for address-
origins of the reports, but is also determined ing the question of whether diabetes/hyper-
by the designs and methods of conducting glycemia (putative agent) causes periodonti-
the studies, because these factors help deter- tis (outcome) in initially healthy individuals.
mine the kinds of conclusions about causality This is because it would be unethical to use
that can be inferred from the results.25 an intervention in humans that causes dia-
However, with today’s chronic diseases that betes in the experimental group. Results
are multifactorial in nature, it is often difficult from studies of the following epidemiologic,
to identify one specific cause, since many risk nonintervention design provide evidence
factors are at play simultaneously. with increasing level of strength for poten-
tially causal relationships.
Analytic Epidemiologic Study Designs
The three main types of analytic, nonexperi- Cross-Sectional Studies
mental study designs used to explore or Most scientific reports are cross-sectional
identify potential relations in human health studies that provide information about the
are the cross-sectional, case-control, and association between diabetes and the preva-
cohort study designs.25 These three study lence of periodontal diseases. The latter may
designs are considered observational studies be assessed by using one or more of several
because they do not include treatment or measures of periodontal health (e.g., gingivi-
intervention, even though one also tis, bleeding on probing [BOP], periodontal
“observes” the effect of the intervention in probing depth [PPD], clinical attachment
the latter. Therefore, the term epidemiologic loss [CAL], and radiographic bone loss).
(among people) is used in this chapter rather Cross-sectional studies can provide informa-
than observational. tion on the prevalence, extent, and severity
The study designs differ in the way of periodontal disease in people with hyper-
study participants are selected and the rela- glycemia/diabetes at a single point in time.
tion in time between the occurrence of Studies of prevalence additionally allow us
exposure to the putative (suspected) causal to compare the differences in percent or pro-
factor and the occurrence of the disease or portions of individuals with periodontal
condition (outcome). They also differ with disease between those with and without dia-
respect to the highest level of strength of the betes or between those with diabetes with
differing levels of glycemic control. The that in persons with prediabetes, the hyper-
studies reporting the extent of periodontal glycemia seemingly overshadowed the sever-
disease assess the number of teeth or sites ity of periodontal disease. This was also the
affected: How many? or Which proportion? case in another study pertaining to habitual
Studies of severity assess the periodontal chewing of gutka (betel nut), in which peri-
destruction by considering the magnitude of odontal inflammation was heightened in
pocket depth or attachment loss: How healthy individuals, but obscured in gutka
serious is the worst periodontal breakdown? users with prediabetes.29,30 When the severity
The majority of cross-sectional studies of periodontal disease is obscured by ele-
report that more persons with hyperglycemia vated glucose levels, poor periodontal health
have periodontal disease, and in a dose- can go unnoticed by clinicians. Nonetheless,
dependent manner, that is, severity of peri- nonchewers with type 2 diabetes still had
odontal diseases increases with higher blood poorer clinically assessed periodontal health
glucose levels. A few illustrative reports on than both gutka chewers and nonchewers
special topics are briefly mentioned in the without type 2 diabetes.29
following text. A fourth study explored the effect of
Authors reported from a study con- glycemic control in those with prediabetes on
ducted among 350 children 6 to 13 years of perceived oral health, clinical parameters,
age with and without diabetes (99% had and radiographic alveolar bone loss.30 Partici-
type 1) a statistically significant association pants with prediabetes had more self-
between number of bleeding sites and degree assessed gingival bleeding, pain on chewing,
of glycemic control; that is, the number of dry mouth, and oral burning sensations, as
bleeding sites increased with increasing well as poorer clinically and radiographically
HbA1c values (with higher HbA1c indicating assessed periodontal health.
poorer control).26 Around the primary teeth,
the risk for bleeding was increased by 35% Case-Control Studies
and around permanent teeth by 57% in chil- In case-control studies of Puerto Rican chil-
dren with diabetes, compared with children dren ages 6 to 12 years31 and Kuwaiti children
without diabetes. Hence, children with dia- ages 4 to 14 years32 with type 1 diabetes, those
betes have a higher risk for gingival bleeding with diabetes, particularly those with high
than that of their healthy peers, especially in HbA1c levels,31 had a higher risk for plaque
those with higher BMI and longer duration and gingivitis measured as BOP, compared
of diabetes. A study among adolescents in with that of similar children without diabetes.
Chile showed that diabetes is a potential pre-
disposing factor for necrotizing ulcerative Cohort Studies
gingivitis (NUG), with double the chance for Since cohort (longitudinal) studies follow the
NUG in those with diabetes.27 same individuals over time, they can assess
Javed and colleagues28 have conducted incidence (development of new cases) and
cross-sectional studies among persons with progression of periodontal disease, where
prediabetes that merit attention. One was incidence is a measure of the rate of new
specifically designed to study the relative cases and progression is a measure of the
effect of hyperglycemia and cigarette worsening of already existing periodontal
smoking on periodontitis in people with pre- disease over time. Longitudinal studies allow
diabetes. It confirmed that BOP was signifi- quantification of the degree to which hyper-
cantly reduced in smokers with and without glycemia/diabetes increases the risk for peri-
prediabetes. More importantly, it concluded odontal disease, as well as its extent, severity,
or progression. Cohort studies provide (HPFUS) who were on average 54 years old,
descriptive, noninterventional evidence sup- dentate, and free of periodontitis at baseline,
porting the role of hyperglycemia/diabetes were followed up from 1986 to 2006 by bien-
contributing to poorer periodontal health. nial questionnaires.33 The 2,285 men (6%)
Because the time sequence is known—that is, with type 2 diabetes had a significant,
the researchers know whether hyperglycemia adjusted 29% greater risk of developing peri-
or periodontal disease existed first—this odontitis. Furthermore, this risk was 49%
study design can allow for conclusions that greater with less than the median total intake
contribute to establishing a causal relation- of fruit and vegetables.
ship between hyperglycemia/diabetes and
poorer periodontal health. Such temporality- Tooth Loss
based directionality allows us to speak about The ultimate result of untreated periodontal
“effect” of the agent on the outcome—in this infection would be losing a tooth.34 Peri-
case, the effect of hyperglycemia on periodontitis is widely assumed to be the main
odontal health. Consequently, the evidence cause of tooth loss in adults, even though
from longitudinal studies can support a caries is responsible for more lost teeth, even
causal relationship. among the very old, in some studies.35
Most studies conclude that people with Although most clinical studies on oral health
poorer glycemic control have worse periodontal in people with diabetes provide some infor-
health than those with better glycemic control mation of the number of teeth present, only
who again have better periodontal health than a few focus on exploring the relation
those without elevated blood glucose levels. between diabetes and tooth loss.
Only a few examples of such studies are given
to illustrate the type of studies. Cross-Sectional Studies
The first study of its kind followed 92 Patel and coworkers36 analyzed data from
patients with chronic, moderate to advanced 2,508 persons 50 years and older who partic-
periodontitis over 5 years of periodontal ipated in the national population study
maintenance therapy.9 They were matched for NHANES 2003–2004 cycle. They concluded
sex and smoking into three groups: 23 had that the percentage of people with diabetes
poorly controlled (HbA1c ≥ 6.5%) and 23 had who were edentulous was much higher than
well-controlled (HbA1c < 6.5%) diabetes, that in persons free of diabetes. A full 20% of
whereas 46 belonged to a nondiabetes control edentulous individuals also had diabetes. The
group. Those with poor control had about adjusted chance of having no natural teeth
three times greater risk for progression of was 2.25 times higher in people with diabetes
periodontitis (odds ratio [OR] 2.9), especially than among those without; and among the
among those who smoked (OR 3.7), and for dentate with diabetes, the average number of
tooth loss (OR 3.1) when compared with the missing teeth was 9.8 compared with 6.7
groups with well-controlled diabetes or those among those with no diabetes. Regrettably,
without diabetes. Remarkably, those with the authors did not report tooth loss by level
well-controlled diabetes had the same risk as of glycemic control.
those without diabetes. This example high- Similarly, a Thai study of 605 adults
lights the influence of glycemic control and (379 with and 226 without diabetes) ages 20
the importance of maintaining a good peri- to 86 years concluded that diabetes and tooth
odontal status (Figure 3). loss were directly associated, with those with
A total of 35,247 male participants of diabetes having 1.7 times greater chance for
the Health Professionals Follow-Up Study having lost teeth.37 Among 1,354 Finnish men
Figure 3. Periodontal Measures over 5 Years in Patients in Periodontal Maintenance with

Poor (PGC) and Good (GGC) Glycemic Control Compared with Healthy Individuals
(NDC, No Diabetes Control): A, Mean PPD. B, Mean CAL. C, BOP. D, Plaque Index
*† PGC > NDC (P < .01); *† and GGC = NDC (P > .05).
*Statistically significant increase in PI per Year (P < .05).
†Statistically significant increase in PPD, CAL, and BOP per year (P < .05).
BOP, bleeding on probing; CAL, clinical attachment loss; PI, plaque index; PPD periodontal probing depth.
Source: Costa FO et al. J Periodontol 2013;84:595–605.9 Reprinted with permission from the American Academy of Periodontology.
45 to 74 years of age, 534 or 39% had meta- associated with poorer periodontal health
bolic syndrome.38 More specifically, on adjust- status (PPD and CAL) and more tooth loss
ment for potential confounders, tooth loss in men and women on average 50 years old.42
was found to be significantly associated with Persons with periodontitis and diabetes had a
glycemic control. mean of 20 natural teeth compared with 25
Mexicans between 30 and 60 years with in the diabetes-free persons.
type 2 diabetes of at least 5 years’ duration
and with mean HbA1c of 8.0 (± 1.38)% had Longitudinal Studies
significantly greater tooth loss than the nondi- In the US HPFUS mentioned earlier, the men
abetes control group, namely 5.7 (± 3.7) with type 2 diabetes lost significantly more
versus 3.5 (± 2.9) teeth (P = .034).39 Similar teeth over the 20-year span, namely, 10%
findings were reported among Croatians with more than their diabetes-free colleagues.33 The
a mean age of 55 years and having had dia- first prospective study on glycemic control–
betes an average of 10.6 years, with the related progression of periodontitis and loss of
number of missing teeth increasing with teeth for individuals in periodontal treatment
disease duration.40 Moreover, 154 Sudanese maintenance therapy was conducted in Brazil
with type 2 diabetes had lost more teeth than with the results published in 2013.9 During the
the 303 without diabetes, with 74.0% versus 5-year maintenance period, persons with poor
90.4% having more than 21 natural teeth glycemic control (HbA1c > 6.5%) experienced
remaining.41 A study in Colombia demon- greater tooth loss, compared with those with
strated that high blood glucose levels were good glycemic control or no diabetes. Those
with poor control had a 3.1 times greater risk ogy and study populations limits the possi-
of losing teeth. An even greater risk, namely bility that the same biases or confounding
4.1 times, was seen in those who also smoked. factors apply in all the studies and therefore
provides support for concluding that diabetes
SUMMARY: I. EVIDENCE FOR is a risk factor for periodontal disease inci-
EFFECT OF HYPERGLYCEMIA ON dence, progression, and severity. In addition,
PERIODONTAL HEALTH substantial evidence supports a dose-
Although there are exceptions, the majority response relationship. That is, with increasing
of studies conclude that the prevalence, levels of hyperglycemia, the adverse effects
extent, or severity of periodontal disease is on periodontal health become greater.
greater in people who have elevated blood Finally, there are no studies with superior
glucose levels, especially in those with poor design features to refute this conclusion.
glucose control. People with poorly con- Examples of comprehensive reviews of the
trolled diabetes are more likely to have studies in this body of literature are pre-
deeper periodontal pockets, greater attach- sented in reports by Mealey and Ocampo,43
ment loss, and more radiographic bone loss Lamster et al.,44 Taylor and Borgnakke,3,45
than people who do not have diabetes. A Taylor et al.,46 and Borgnakke and Genco.2
dose-response relation exists, such that the
worse the hyperglycemia is, the more nega- II. EFFECT OF PERIODONTAL
tively it affects the periodontium. Also, INFECTION ON BLOOD GLUCOSE
people who have had uncontrolled diabetes LEVELS IN HEALTH, PREDIABETES,
for longer periods tend to have poorer peri- DIABETES, AND DIABETES
odontal health, particularly more clinical COMPLICATIONS
attachment or radiographic bone loss. The next section describes an effect going in
The preponderance of studies reporting the opposite direction, namely, periodontal
on the mutually adverse associations infection adversely affecting blood glucose
between hyperglycemia and periodontal levels. Only recently are we beginning to
health are cross-sectional and involve con- understand that this is important also in
venience samples of patients—principally healthy persons who may eventually develop
from hospitals, dental schools, and clinics, prediabetes and ultimately type 2 diabetes if
but also from larger population-based the elevated glucose levels persist and increase.
studies. However, a growing body of evi- Periodontal infection contributes to the
dence from longitudinal studies provides chronic systemic inflammatory burden. As
additional support for the association part of the general immune response to
between diabetes and periodontal disease. infection for which energy is needed to
These studies were conducted in different combat the “intruder,” periodontal infection
settings and different countries, with different elevates the concentration of sugar in the
ethnic populations and age mixes, and with blood, just like any other infection elsewhere
a variety of measures of periodontal disease in the body. Effects of periodontal infection
status (e.g., gingival inflammation, pathologic on the local and general systemic inflamma-
PPD, loss of periodontal attachment, and tory responses are described in more detail
radiographic evidence of alveolar bone loss). in Chapter 3.
The studies use different parameters to assess A growing body of evidence supports
periodontal disease occurrence (prevalence, the long-time clinical observation that peri-
incidence, extent, severity, and progression). odontal infection adversely affects glycemic
Hence, this inevitable variation in methodol- control.47 We recognize that making every
effort to decrease elevated blood glucose Ylöstalo, Taylor, and Genco47 conducted a
levels is very important, to improve glycemic systematic review of epidemiologic observa-
control and prevent complications not only tional evidence for the effect of periodontal
in persons with diabetes due to the chronic disease on diabetes-related measures. Studies
hyperglycemia, but also in individuals with that permitted determination of directional-
prediabetes—and even in healthy individuals. ity of observed effects and that met the eligi-
Periodontal infection ultimately contributes bility criteria were included. The authors
to a greater risk of complications of diabetes concluded that a small body of evidence
that are caused by persistently high levels of supports significant adverse effects of peri-
blood glucose. Diabetes complications are odontal disease on glycemic control, diabetes
potentially fatal, such as heart disease and complications, and development of type 2
other cardiovascular events; stroke; (and possibly gestational) diabetes. However,
nephropathy (diseases of the kidney, ulti- there were only a limited number of eligible
mately leading to end-stage renal disease studies, several of which included small
[ESRD] that requires renal dialysis for sur- sample sizes. Furthermore, exposure (peri-
vival); neuropathy (diseases of peripheral odontal parameters) and outcome (glycemic
and autonomic nerves); retinopathy (diseases measures) parameters varied among the
of the retina, possibly leading to partial or studies; therefore, the generalizability of their
complete blindness); extremely decreased results was limited. Also, the heterogeneity
wound healing; and amputations. among the studies prevented any meaningful
Mediators important in periodontal meta-analysis to be conducted. The authors
inflammation, such as tumor necrosis concluded that the current evidence suggests
factor-alpha (TNF-a), interleukin-6 (IL-6), that periodontal disease adversely affects dia-
and interleukin-1-beta (IL-1b), are shown to betes outcomes and that further longitudinal
have important systemic effects on glucose studies are warranted.47
and lipid metabolism as well as on insulin
action, resulting in development of insulin Glycemic Control in Type 2 Diabetes
resistance and diabetes, as suggested by The first—now classic—longitudinal epi-
Grossi and Genco in 1998.48 Genco et al.49 demiologic study was conducted by the
proposed a model that linked inflammation National Institute of Diabetes and Digestive
to obesity, diabetes, and periodontal infec- and Kidney Diseases among the Pima
tion in 2005. Indians in Arizona, USA, whose diabetes
Metabolic and immune systems are prevalence is unusually high. Reports from
among the most fundamental for survival. this study are the first to provide evidence for
Their regulations are highly integrated, and the formerly expressed hypothesis that peri-
the proper function of each is dependent on odontal infection can adversely affect dia-
the other. Dysfunctions of this central inter- betes. One report found that subjects with
face can lead to several chronic metabolic type 2 diabetes in good to moderate control
diseases, particularly obesity, type 2 diabetes, and with severe periodontitis at baseline were
and cardiovascular disease. Collectively, these about six times more likely to have devel-
diseases currently constitute the greatest oped poor glycemic control 2 years later
threat to global human health and welfare. than those without severe periodontitis at
baseline.50
A. Evidence from Nonintervention Studies Even though the cross-sectional study
Periodontal infection is a risk factor for eleva- design cannot indicate causality, one unique
tion of blood sugar level. In 2013, Borgnakke, such study conducted in Mexico merits
mention. Among 127 pregnant women with pared with individuals who were periodon-
type 2 diabetes, those with periodontitis were tally healthy at both baseline and 5 years
more likely to have poorer glycemic control, later.54 Similarly, in another prospective
after controlling for presence of a urinary cohort study among 1,023 Japanese systemi-
tract infection and/or cervicovaginal infection cally healthy persons 20–56 years of age
and a measure of compliance with recom- (mean 37.3 years), having baseline patho-
mended medical treatment for the diabetes.51 logic PPDs was associated in a dose-
Consequently, the authors speculate that response manner with having developed one
periodontal infection may present a hitherto or more components of metabolic syndrome
unnoticed factor contributing to lack of 4 years later.55 In a retrospective cohort study
glycemic control and therefore should be among 961 Japanese 40–79 years of age,
considered by prenatal care teams. Saito et al.56 concluded that each additional
millimeter mean probing depth corre-
Development of Hyperglycemia in sponded to an increase of 0.13 percentage
Healthy Persons points of HbA1c over the previous 10 years.
Recent evidence has demonstrated that peri- Moreover, increasing mean probing depth,
odontal infection leads to elevated blood but not CAL, corresponded to the develop-
glucose levels also in healthy individuals who ment of glucose intolerance.
do not have diabetes or even prediabetes.
Development of Type 2 Diabetes
Cross-Sectional Studies In addition to evidence supporting periodon-
Analyzing NHANES 1999–2004 data from tal disease as a potential risk factor for devel-
3,616 persons with periodontal examina- oping diabetes complications, evidence is also
tions, Demmer’s group found periodontal emerging that periodontal disease may be a
infection to be associated with insulin resist- risk factor for type 2 diabetes and possibly
ance,52 which increased linearly with each 1 for gestational diabetes. Demmer and col-
mm increase in mean PPD, but was unasso- leagues57 investigated the association between
ciated with CAL. A study in India compris- periodontal disease and the development of
ing 200 diabetes-free persons 50 years and new (i.e., incident) diabetes cases in a repre-
older compared four sex- and age-matched sentative sample of the US population, ana-
groups of 50 with increasing periodontitis lyzing data from the first National Health
severity assessed by tooth mobility from and Nutrition Examination Survey
none to grade 3.53 Levels of both glycohe- (NHANES I) and its Epidemiologic Follow-
moglobin and serum C-reactive protein up Study (NHEFS). The average follow-up
increased significantly with periodontitis period for the 9,296 individuals in the analy-
severity in a dose-response fashion, except sis was 17 years—the period from 1971 to
that the mobility increase from grade 1 to 2 1992. The study was a cohort study design
was not statistically significant. because the information on the exposure
(i.e., the hypothesized causal factor), the
Longitudinal Studies presence or absence of periodontal disease,
A large population-based study (N = 2,793; was known at the time the study began, and
age range 20–81) was conducted in Pomera- the outcome (development of diabetes) was
nia in former East Germany among people assessed subsequently. This study concluded
who did not have diabetes at baseline. Those that having periodontal disease was signifi-
with periodontitis at baseline had approxi- cantly associated with a 50% to 100% (up to
mately a fivefold increase in HbA1c com- twofold) greater risk for type 2 diabetes after
controlling for other established risk factors showed a continuous association between the
for diabetes. risk of cardiovascular complications and
One prospective58 and two retrospec- glycemia; every percentage point decrease in
tive56,59 longitudinal studies were conducted HbAlc (e.g., from 9% to 8%), was associated
in Japan and explored the effect of peri- with a 25% reduction in diabetes-related
odontitis on the development of type 2 dia- deaths, 7% reduction in all-cause mortality,
betes. The prospective study over 5 years and 18% reduction in combined fatal and
among 6,125 employees 30 to 69 years old nonfatal myocardial infarction.63
and 77% males found that having a PPD ≥ The following examples are provided to
6 mm led to type 2 diabetes.58 Another illustrate the types of studies that constitute
workplace screening study over 6.5 years the evidence that associates diabetes compli-
(range: 2–7 years) among 5,848 persons cations with periodontal disease by diabetes
between 30 and 59 years also concluded that type.
such deep pockets lead to type 2 diabetes.59 Two reports do not specify diabetes
However, after adjustment for potential con- type. The only US national survey that
founders, only women with PPD of 4–6 mm assessed microvascular hemorrhaging at two
were statistically significantly more likely to different body locations is the NHANES
develop type 2 diabetes. In a community- 1988–1994. Persons with 20% or more sites
based study in Hisayama, Japan, among with gingival bleeding on probing had a 57%
almost 1,000 individuals ages 40–79, baseline significantly increased chance of also having
deep pockets (mean > 2.0 mm) as well as bleeding in the retina, a sign of systemic
high CAL (mean > 2.5 mm) were signifi- microvascular injury and a common compli-
cantly associated with impaired glucose tol- cation of diabetes.64 A study of 73 Japanese
erance and with manifest diabetes 10 years indicated 2.8 times greater risk for retinopa-
later.56 The relationship was dose-dependent, thy in those with radiographic alveolar bone
so that each additional millimeter PPD cor- loss greater than the median compared with
responded to an increase of 0.13 HbA1c those at or below the median, with the sever-
percentage points. ity of retinopathy increasing with magnitude
of bone loss.65
Diabetes Complications
It is widely recognized that long-term poor Type 1 Diabetes
glycemic control is a major determinant for There is emerging evidence from observa-
the development of chronic complications of tional studies regarding the association
diabetes. Results from the landmark Diabetes between periodontal disease and risk for dia-
Control and Complications Trial (type 1 diabetes complications. Thorstensson and col-
betes) and the UK Prospective Diabetes leagues66 studied 39 case-control pairs of indi-
Study (UKPDS, type 2 diabetes) demon- viduals with mostly type 1 diabetes for 6
strated that attaining and maintaining good years median follow-up time in Jönköping,
glycemic control can reduce the risk for and Sweden. In each pair, the cases had severe
slow the progression of microvascular compli- alveolar bone loss and controls had gingivitis
cations in patients with types 1 and 2 diabetes, or minor alveolar bone loss. The authors
respectively.60–62 In addition, the UKPDS found at their follow-up medical assessments
observed a 16% reduction (P = .052) in the that cases were significantly more likely than
risk of combined fatal or nonfatal myocardial controls to have prevalent proteinuria and
infarction and sudden death. Further epi- cardiovascular complications including tran-
demiologic analysis from the UKPDS sient ischemic attacks, angina, myocardial
infarction, and intermittent claudication, as calcification of advanced atherosclerotic

well as stroke. plaque. In a study in Iran among 213
persons with type 2 diabetes with and
Type 2 Diabetes without diabetic retinopathy and 73 healthy
Two reports from the longitudinal study of controls, the risk for retinopathy was signifi-
type 2 diabetes and its complications in the cantly higher in those with periodontitis, and
Gila River Pima Indian Community in the severity of the two conditions was
Arizona address nephropathy and cardiovas- strongly correlated.70 In Brazil, a study
cular disease. Saremi and colleagues67 studied among 122 persons with type 2 diabetes
a cohort of 628 individuals for a median showed that those with PPDs of 4 mm or
follow-up time of 11 years. Individuals with more had over six times greater risk of
severe periodontal disease had 3.2 times having neuropathic foot ulcers (OR: 6.6; CI:
greater risk for cardiorenal mortality (i.e., 2.3–18.8; P ≤ .001), compared with those
ischemic heart disease and diabetes-related with no pathologic periodontal pockets.71
nephropathy combined) than those with no,
mild, or moderate periodontal disease. This Importance of Diabetes Complications
estimate of significantly greater risk persisted The crucial importance of preventing the
while controlling for several major risk development or at least the severity of com-
factors of cardiorenal mortality including plications of diabetes can be illustrated by a
age, sex, diabetes duration, HbA1c, body 2014 study of Swedish data from 20,836
mass index, hypertension, blood glucose, individuals with type 2 diabetes derived from
cholesterol, electrocardiographic abnormali- the National Diabetes Registry.72 The life
ties, macroalbuminuria, and smoking. In the expectancy at the time of experiencing their
second report, Shultis et al.68 found in a first major diabetes complication (myocardial
group of 529 adults that periodontitis and infarction, stroke, heart failure, amputation,
edentulism were significantly associated with or renal failure) could be calculated and
the risk of developing overt nephropathy changed over time by complication type. In
and ESRD. The incidence of macroalbu- addition to cigarette smoking, renal failure
minura was 2.0, 2.1, and 2.6 times greater in manifested as low estimated glomerular fil-
individuals with moderate or severe peri- tration rate and albuminuria, significantly
odontitis or in those who were edentulous, increases mortality risk. As mentioned,
respectively, compared with those with no or studies have demonstrated that periodontal
mild periodontitis. The corresponding inci- disease is associated with such mortality
dences of ESRD were 2.3, 3.5, and 4.9 times factors, so it could be speculated that attain-
greater. ment of periodontal health could positively
A comparison of 791 persons 52–74 affect the mortality rate.
years of age with type 2 diabetes with 5,257
persons without diabetes participating in the Development of Gestational Diabetes
Atherosclerosis Risk in Communities Two US case-control studies explored the
(ARIC) study in four communities in as potential role of periodontitis in developing
many US states showed that those with gestational diabetes (GDM). Regardless of
severe periodontal disease had greater inci- which of three case definitions for periodon-
dence of coronary heart disease and subclin- titis was applied, Xiong and colleagues73
ical heart disease.69 The latter was assessed demonstrated that among 53 women with
by increased carotid intima media thickness GDM and 106 pregnant women without,
(≥1 mm) and acoustic shadowing revealing that GDM, in a dose-response manner, was
associated with both PPD and attachment ment that can be provided in general dental
loss. Dasanayake’s team investigated whether offices and supplemented with home oral
pregnant women who develop GDM, com- hygiene measures.
pared with pregnant women who do not The majority of nonsurgical treatment
develop GDM, had poorer clinical peri- studies report a statistically significant decrease
odontal health and/or demonstrated higher in HbA1c, whereas others do not demonstrate
levels of other biologic markers of periodon- any decrease or one that is not significant.
tal disease approximately 2 months before The latter result often occurs because of a
their GDM diagnosis.74 The other biologic lack of statistical power provided by the small
markers included bacteriologic (dental number of study subjects. The relatively small
plaque and cervicovaginal samples), numbers of participants in most of the studies
immunologic, and periodontitis-related are primarily due to the immense resources
inflammatory mediator analytes. Women required for conducting clinical trials, espe-
who had higher vaginal levels of Tannerella cially those with a long follow-up period.
forsythia, a bacterium known to be associ- Table 2 displays systematic reviews that
ated with periodontitis, were statistically sig- include meta-analyses conducted by pooling
nificantly more likely to develop GDM than results from sufficiently similar studies to
women with lower levels. Therefore, the attain more statistical power and hence gain
authors conclude that Tannerella forsythia in more strength to support the conclusions.75-81
the vaginal flora is a potential risk factor for Before publication of results from
gestational diabetes. several subsequently conducted confirmatory
RCTs that show similar results, especially for
SUMMARY: II. EVIDENCE FOR initially uncontrolled diabetes, the well-
EFFECT OF PERIODONTAL respected Cochrane Review Group con-
INFECTION ON GLUCOSE LEVELS cluded in 2010, based on only three eligible
A. NON-INTERVENTION STUDIES RCTs: “The evidence gathered suggested
A small, but growing body of evidence sug- that there may be small but significant
gests that periodontal infection contributes improvement in blood sugar control from
to the systemic inflammatory burden and treating preexisting gum disease in people
subsequently is associated with increased with Type 2 diabetes mellitus.”78
blood glucose levels. Such periodontal A study of periodontal treatment called
disease–initiated hyperglycemia contributes Diabetes and Periodontal Therapy Trial
to elevated glucose levels in healthy individu- (DPTT) was recently published,83,84 in which
als and to the development of prediabetes, the authors reported finding no significant
type 2 diabetes, and possibly gestational dia- effect on HbA1c in persons with type 2 dia-
betes, as well as diabetes complications. betes 3 and 6 months after nonsurgical peri-
odontal treatment. The recruitment was
B. EVIDENCE FROM ended early “due to futility.” Of the 1,756
INTERVENTION STUDIES people screened, 514 were randomized, of
Nonsurgical periodontal treatment decreases whom 240/257 in the treatment group and
blood sugar level. The most important ques- 236/257 in the control group completed the
tion of relevance to clinical practice and study. The treatment consisted of scaling
management of diabetes is whether it is pos- and root planing completed during at least
sible to improve blood sugar control by min- two sessions. Oral hygiene instruction (OHI)
imizing the periodontal infection by means was provided together with 0.12% chlorhexi-
of professional nonsurgical periodontal treat- dine gluconate for twice-daily rinsing for the
Table 2. Effect of Nonsurgical Periodontal Treatment on Glycemic Control in People with

Type 2 Diabetes: Meta-Analyses Published August 6, 2014
Meta-Analysis # Studies # RCTs Pooled # Subjects HbA1cChange 95% CI P value
Janket et al. 200575 5 1 268 -0.66%* -2.2; 0.9 ns
Darré et al. 200876 9 9 485 -0.46%‡ -0.82; -0.11 .01
Teeuw et al. 201077 5 3† 180 -0.40%‡ -0.77; -0.04 .03
Simpson et al. 201078 3 3 244 -0.40% -0.78; -0.01 .04
Cochrane Review
Sgolastra et al. 201379 5 5 315 -0.65% -0.88; -0.43 < .05
Engebretson & Kocher 201380 9 9 775 -0.36% −0.54; -0.19 <.0001
Liew et al. 201381 6 6 422 -0.41% -0.73; -0.09 .013
*Weighted.
†Remaining two non-RCT studies are clinical controlled trials.
‡Standardized mean difference.
CI, confidence interval; HbA1c, glycated hemoglobin; ns, nonsignificant; RCT, randomized controlled trial.
Source: Reprinted with permission from Borgnakke WS, Chapple ILC, Genco RJ, et al. J Evid Base Dent Pract.
Published online May 22, 2014.82
following 2 weeks. The participants returned therapy. When periodontal health, or near
3 and 6 months later for one session of health, is not attained, no significant effect
about 1 hour of scaling and root planing can be expected on the HbA1c level, simply
and OHI, whereas the control group at their because periodontal infection and the elicited
baseline, 3-, and 6-month visits received OHI host inflammatory responses persist.
only. At the conclusion of the study, control The researchers and their study partici-
group participants were offered scaling and pants were not able to obtain acceptable
root planing. periodontal health and therefore could not
The authors claim that their treatment draw any firm conclusions regarding any
resulted in significantly improved periodontal effect on HbA1c. These and other shortcom-
health, but did not mention that this signifi- ings of this study are described in three
cance was statistical in nature only. Unfortu- Letters to the Editor, which appear in the
nately, the treatment provided did not clini- May 14, 2014 issue of JAMA,85-87 along with
cally improve the periodontal status suffi- the DPTT authors’ response thereto.88 In
ciently, per commonly accepted standards addition, a more detailed review was re-
for nonsurgical periodontal therapy. At the posted online on May 22, 2014, ahead of
end of the study, the treatment group had a publication of the printed version in the Sep-
plaque score of 72.1% sites/person (down tember 2014 issue of the Journal of Evi-
from 86.7% at baseline), and 41.6% of the dence-Based Dental Practice.82 A plain
sites had BOP (down from 60.6%). More- summary of the DPTT report was pub-
over, 30.6 sites and 15.7 sites per person, lished in the May 2014 issue of the Journal
respectively, had PPD ≥ 4 mm and PPD ≥ 5 of the American Dental Association (JADA)
mm, respectively, which corresponds to without comments or critique.89
20.1% and 10.2% of the sites that still had
pathologic pockets. The gingival index had Effect of Prophylaxis Only
decreased by 0.4, namely, from 1.4 to 1.0. A study with particular clinical relevance,
These clinical periodontal measures fall short especially for populations with limited access
of the generally accepted standards for clini- to advanced professional dental services,
cally successful nonsurgical periodontal merits special mention. In collaboration
between a Chilean dental school and a Effects of Full-Mouth Extraction

private dental practice, Lopez and team27 Randomizing 58 patients with serious, incur-
studied subjects with moderate and severe able periodontitis requiring full-mouth extrac-
periodontitis in groups with no diabetes and tion into one group receiving such removal
with type 2 diabetes, the latter divided by of all teeth and the other group not receiving
glycemic control into subgroups with good any care, Khader and colleagues91 reported
[mean HbA1c = 6.2 (±0.0)%; range 4.8– that the HbA1c level and fasting blood
6.9%] and poor [mean HbA1c = 8.6 (±1.3)%; glucose levels decreased significantly from
range 7–10.5%] glycemic control, respectively. 8.6% at baseline to 7.4% after 3 months and
Even though the glycemic control did not continued to decrease to 7.3% at 6 months
change, all the periodontal parameters after extraction. Upon adjustment, the treat-
(mean CAL and PPD; proportions of sites ment group HbA1c level decrease by 1.23 per-
with CAL ≥3 mm, PPD ≥ 4 mm, BOP, centage points was still significantly higher
plaque) improved significantly in both than the decrease of 0.28 in the control
groups, with and without diabetes, with group. Therefore, the authors suggest that
remarkable similarity in periodontal health full-mouth tooth extraction could result in an
at the end of the 9-month study, despite the improvement in glycemic control among
nondiabetes group being nonsignificantly people suffering from type 2 diabetes.
heavier [mean BMI = 31.1 (±3.9) kg/m2;
range 23.0–40.0 kg/m2] versus [28.8 (±4.0) Antibiotics in Periodontal Management
kg/m2; range 24.0–37.7 kg/m2]. This study in Diabetes
demonstrates that 3-monthly, routine pro- To date, no clear-cut evidence supports a
phylaxis (scaling and coronal plaque removal requirement for the use of antibiotics in
and polishing), supported with home care combination with nonsurgical periodontal
instructions, can successfully prevent any treatment in order to observe an improve-
progression of periodontitis in every partici- ment in glycemic control associated with
pant, regardless of the presence of diabetes nonsurgical periodontal therapy in those
and the level of glycemic control. This with type 2 diabetes. In some studies, it actu-
finding is interesting, not only because ally was the comparison group who did not
routine prophylaxis was demonstrated to receive antibiotics who had the greatest
maintain periodontal health—and possibly improvement in glycemic control,92 although
to prevent deterioration of glycemic control, other studies conclude that such adjunct
provided all other factors were stable during local or systemic antibiotics enhance the clin-
the study—but also because these findings ical outcome.
contradict the results of a well conducted It is important to note that evidence is
systematic review by the Cochrane Collabo- emerging that contradicts the dogma that
ration.90 people with diabetes are more prone to
This comprehensive review concluded: infections and heal more slowly. This long-
“There is insufficient evidence to determine time belief seems to be unsupported by sci-
the effects of routine scale and polish treat- entific evidence, which is a very important
ments,” when attempting to determine realization. For instance, Huang et al.13 com-
whether the routine “prophies” usually pro- pared the healing time upon tooth extraction
vided at regular dental check-ups, also in in 224 persons with type 2 diabetes who
people with low risk for periodontitis, actu- took oral anti-diabetes medications with 232
ally are clinically effective for periodontal diabetes-free individuals with no other condi-
health.90 tions known to delay wound healing.
Observing more delayed healing in the report a positive effect on the blood glucose
younger control group, the authors con- level. The magnitude of this improvement of
cluded that persons with well controlled type HbA1c is similar to that expected by adding a
2 diabetes taking oral hypoglycemic medica- second antidiabetic oral medication to met-
tion should be treated as persons without formin, thus representing an important clini-
diabetes in conjunction with dental extrac- cal significance. Since the evidence also
tions. Others reported normal socket healing demonstrates that nonsurgical periodontal
without antibiotics in both nondiabetes and treatment is effective in improving periodontal
type 2 diabetes participants, despite poor health, it is recommended that people with
glucose control in the latter.11,12 In a letter to diabetes or those who are at risk thereof, as
the editor of the British Journal of Oral and well as individuals with no diabetes, attain
Maxillofacial Surgery,93 the authors suggest, and maintain a periodontium as healthy as
“the use of perioperative prophylactic antibi- possible as part of overall health and well-
otics for routine extractions in controlled dia- being. There is need, however, for well-con-
betic patients is not justified and not evi- trolled RCTs to determine the extent to which
dence-based in the same way as it is not and in which patients’ resolution of periodon-
indicated in non-diabetic patients. In today’s tal disease affects glycemic control and, more
world of antibiotic-resistant infections, our importantly, complications of diabetes.
responsibility to avoid unnecessary use of
antibiotics has increased.” The problem of III. ADVICE FOR PATIENTS WITH
antibiotic resistance is addressed also in (OR AT RISK FOR) DIABETES AND
recent publications.94,95 THEIR HEALTHCARE PROVIDERS
For some years, attention has focused on the
SUMMARY: II. EVIDENCE FOR importance of attaining and maintaining
EFFECT OF PERIODONTAL good oral health for persons with diabetes.
INFECTION ON GLUCOSE LEVELS Most recently, it has become apparent that
B. INTERVENTION STUDIES controlling periodontal infection may play a
In the body of literature consisting of both role in management of blood glucose levels
RCTs and non-RCTs, there is marked het- in health, prediabetes, and manifest diabetes.
erogeneity in the studies’ designs, geographic An increasingly loud call for interprofes-
locations, source populations, conduct, sional collaboration in a patient-centered,
length of follow-up for glycemic control health-promoting setting is heard. Examples
assessment, types of participants and their of professional advice and guidelines that are
baseline periodontal disease and glycemic publicly available and free of charge are pro-
control status, inclusion of control groups, vided in the following text.
periodontal treatment protocols, periodontal The group of experts who scrutinized
measures assessed, case definitions for peri- the scientific evidence for links between peri-
odontitis, sample size and power to detect odontal disease and diabetes at the Novem-
differences in periodontal and metabolic ber 2012 EFP/AAP workshop agreed on
response, and specific hypotheses tested. The advice or guidance for patients who have
details of the variation in this body of litera- prediabetes, gestational, and manifest dia-
ture have been extensively described in betes, or who are at risk thereof. Also, such
several reviews, including those displayed in guidance was agreed upon for the medical
Table 2. and dental care providers of these patients.
Despite such dissimilarities, intervention All the guidelines are displayed in the publi-
studies among people with type 2 diabetes cally available consensus report that may be
accessed at http://onlinelibrary.wiley.com/doi/ org/content/144/7/860.full.pdf+html.

10.1111/jcpe.12077/pdf.96 The American Diabetes Association
An 11-page guideline booklet called Oral offers advice on oral health and hygiene with
Health for People with Diabetes provided by several links at http://www.diabetes.org/
the International Diabetes Federation (IDF) living-with-diabetes/treatment-and-care/oral-
is freely available at http://www.idf.org/ health-and-hygiene/.
webdata/docs/OralHealth_EN_RTP.pdf.97 Finally, the American Dental Associa-
Every year in January, the American tion provides information and guidance via
Diabetes Association publishes in Diabetes its Mouth HealthyTM program regarding dia-
Care an update of the diagnosis and classifi- betes and oral health at http://www.mouth-
cation of diabetes mellitus,23 along with healthy.org/en/az-topics/d/diabetes.
updated Standards of Medical Care in Dia-
betes that may be freely viewed at CHAPTER SUMMARY
http://care.diabetesjournals.org/content/37/Su AND CONCLUSIONS
pplement_1/S14.full.pdf+html.24 Dental care The evidence reviewed in this chapter sup-
has only been mentioned by listing in a table ports the mutually adverse effects of hyper-
on components of the comprehensive dia- glycemia/diabetes mellitus and periodontal
betes evaluation as part of the Medical infection:
History (“Other: Psychosocial problems, 1. Hyperglycemia/poorly controlled diabetes
dental disease”), along with “Dentist for leads to greater development, extent,
comprehensive periodontal examination” severity, and progression of periodontal
under “Referrals.” For the first time, a brief breakdown. There is also some evidence
passage in the body of the text is included in that gestational diabetes may adversely
2014, with its own subheading “Periodontal affect periodontal health.
Disease” in section VII. Assessment of 2. Periodontal infection, especially the
Common Comorbid Conditions. It reads: severe form, with its subsequent inflam-
“Periodontal disease is more severe, but not matory responses, elevates blood sugar
necessarily more prevalent, in patients with levels in healthy persons as well as in
diabetes than in those without.98 Current evi- those with prediabetes and type 2 dia-
dence suggests that periodontal disease betes. Such periodontal infection–initi-
adversely affects diabetes outcomes, although ated hyperglycemia contributes to
evidence for treatment benefits is currently poorer glycemic control in persons with
lacking.”47 Although the author of this diabetes and to the development of pre-
chapter disagrees with the first and last state- diabetes and eventually manifest dia-
ments, this is a welcome step toward betes, and perhaps to the development
acknowledgement by the American Diabetes of gestational diabetes, in individuals
Association that oral health is an important with no prior diabetes. Furthermore,
component of diabetes management. evidence suggests that periodontal
“Gum disease can raise your blood disease is associated with increased risk
sugar level” is the title of the “For the Dental for diabetes complications.
Patient” page in the July 2013 issue of 3. Clinically successful nonsurgical, routine
JADA.99 It briefly summarizes in plain lan- periodontal treatment in persons with
guage the aforementioned first systematic type 2 diabetes has consistently been
review of the effects of periodontal infection demonstrated in seven meta-analyses
on blood glucose levels47 and is publically and in additional more recent individ-
available for distribution at http://jada.ada. ual studies to lead to a decrease in
HbA1c of about 0.4 percentage points 3 Borgnakke WS, Ylöstalo PV, Taylor GW, Genco RJ.
months after intervention. This is a Effect of periodontal disease on diabetes: systematic
review of epidemiologic observational evidence. J Clin
magnitude similar to adding a second Periodontol 2013;40(Suppl 14):S135-52. Available at:
oral antidiabetes medication to met- http://onlinelibrary.wiley.com/doi/110.1111/jcpe.2013.1140.i
formin and hence is of clinical signifi- ssue-s1114/issuetoc; summarizing webcast available at:
cance in managing type 2 diabetes. http://www.scivee.tv/ node/58235; supporting information
While treating periodontal infection in available at:http://onlinelibrary.wiley.com/doi/1110.1111
/jcpe.12080/suppinfo. Accessed 10 June 2014.
people with diabetes is clearly an impor-
tant component in maintaining oral Chapple IL, Genco R; Working group 2 of joint
EFP/AAP workshop: Berglundh T Borgnakke W, Eick-
health, it may also play an important holz P, Engebretson S, Genco R, Graves D, Grossi S,
role in establishing and maintaining Hasturk H, Kocher T, Lalla E, Lamster I, Lang N,
good glycemic control in those with Mealey B, Meyle J, Nesse W, Paquette D, Preshaw P,
type 2 diabetes and thereby possibly Taylor G, Taylor J, Van der Velden U, Walter C,
delaying the onset or progression of Ylöstalo P. Diabetes and periodontal diseases: consen-
sus report of the joint EFP/AAP workshop on peri-
type 2 diabetes and complications of odontitis and systemic diseases. J Clin Periodontol
diabetes. 2013;40(Suppl 14):S106-12. Available at: http://onlineli-
Consequently, dental health professionals brary.wiley.com/doi/10.1111/jcpe.12077/pdf. Accessed 10
may fulfill an important role when collaborat- June 2014.
ing with other healthcare providers100 in a Genco RJ, Genco FD. Common risk factors in the
patient-centered approach to maintaining or management of periodontal and associated systemic
diseases: the dental setting and interprofessional collabo-
improving the health of their mutual patients
ration. J Evid Base Dent Pract 2014;14(Suppl 1):4-16.
with diabetes or those at risk. This would ulti-
American Dental Association. Gum disease can raise
mately improve the quality of life of individu-
your blood sugar level. J Am Dent Assoc 2013;144:860.
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Am Dent Assoc 2008;139:19S-24S.
Arora N, Papapanou PN, Rosenbaum M, Jacobs DR, Taylor GW, Borgnakke WS. Periodontal disease: associ-
Jr., Desvarieux M, Demmer RT. Periodontal infection, ations with diabetes, glycemic control and complications.
impaired fasting glucose and impaired glucose toler- Oral Dis 2008;14:191-203.
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age? Gerodontology 2010;27:19–25. viewed at: http://www.scivee.tv/node/58235. Accessed
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CHAPTER 7
Atherosclerosis: A Pervasive Disease
Affecting Global Populations
Originally contributed by Stanley Wang and Sidney Smith
Updated and edited by Timothy C. Nichols
INTRODUCTION atherosclerosis range from stable angina,

Atherosclerotic disease results from the resulting from myocardial ischemia caused by
pathologic formation of plaques in arterial stable coronary arterial plaques that reduce
walls. Plaque development, or atherogenesis, luminal cross-sectional area and restrict blood
is a complex process with many underlying flow, to acute coronary syndrome (ACS) char-
inflammatory molecules participating in acterized by unstable, ruptured coronary ath-
increasingly well-understood pathways. The erosclerotic plaques with superimposed occlu-
consequences include a wide variety of clini- sive or nearly occlusive thrombosis. ACS can
cal syndromes involving different organs be further subdivided into non-ST elevation
with a common underlying deficiency— ACS—such as unstable angina—or ST eleva-
inadequate blood supply due to reduction of tion and non-ST elevation myocardial infarc-
blood flow to the target organ. tion, depending on the degree of luminal
This chapter reviews the clinical mani- occlusion following plaque rupture and intra-
festations of atherosclerosis and explores its coronary thrombosis.
underlying molecular pathophysiology. Another location for atherosclerotic
Understanding the underpinnings of athero- disease is the cerebrovascular bed. As with
sclerosis is crucial to appreciating the poten- coronary atherosclerosis, clinical manifesta-
tial interplay between atherosclerosis and tions of cerebrovascular atherosclerosis vary,
periodontal disease, which is discussed in the depending on the stability of the arterial
next chapter. plaques. Stable disease may lead to chronic
symptoms of dementia, whereas unstable
TYPES OF atherosclerosis may lead to transient ischemic
ATHEROSCLEROTIC DISEASE attacks (sometimes called ministrokes) or a
Atherosclerosis may occur in any arterial larger stroke with major neurologic sequelae.
bed; the most clinically relevant are the coro- Atherosclerotic disease also occurs in
nary, cerebrovascular, and peripheral arterial the aorta or the peripheral arteries, manifest-
circulation. Atherosclerotic plaques may be ing as obstructive disease or dilating
stable or unstable, based on whether the aneurysms. In addition, atherosclerosis is
plaque has ruptured. More recently, studies thought to contribute to valvular heart dis-
have shed additional light on “vulnerable” eases such as aortic stenosis.2,3
atherosclerotic plaques, which were most
likely stable plaques that have developed a MECHANISMS OF
propensity for rupture. ATHEROMA FORMATION
Coronary heart disease is the most clini- Atherosclerotic disease is thought to progress
cally evident form of atherosclerotic disease, from microscopic endothelial events, which
affecting over 17 million Americans according eventually lead to plaque development,
to the American Heart Association’s 2013 sta- growth, and rupture. Many complex mecha-
tistical update.1 Manifestations of coronary nisms appear to contribute to the formation
of atheromatous plaques. The initiating a rich lipid core, macrophages, and other
process involves endothelial injury, which inflammatory cells.11 Recently, myocardial
may occur as a result of mechanical, bio- infarction and stroke in mice were shown to
chemical, or immunologic factors. At the cel- accelerate atherosclerosis progression by a
lular level, the process begins with the mechanism that liberates hematopoietic stem
recruitment of monocytes into the arterial and progenitor cells from bone marrow niches
wall through the effect of specific molecules, via sympathetic nervous system signaling.12
including the chemoattractants interleukin Thus, in animal models, atherogenesis appears
(IL)-1 and tumor necrosis factor-alpha to have a positive feedback loop.
(TNF-a ).4 Selectins and antigens on the
leukocyte surface mediate cell attachment Role of Inflammation in
and movement.5 Endothelial cell adhesion Atherosclerotic Disease
molecules (especially vascular cell adhesion Although the precise mechanisms of atheroge-
molecule 1 and intercellular adhesion mole- nesis are not completely understood, at the
cule 1) interact with leukocyte integrins, molecular level, atherosclerotic plaques appear
causing the monocytes to adhere to the to arise from an inflammatory reaction to car-
endothelium and subsequently migrate diovascular risk factors.13,14 Chronic inflamma-
across it.6 After these cells move into a tion underlies the processes of plaque forma-
subendothelial position, monocytes trans- tion and progression, and although the mech-
form into macrophages and begin to secrete anism(s) causing plaque rupture is not com-
many inflammatory cytokines, proteases, pletely understood, acute inflammatory
and metalloproteinases. processes are likely involved.
Subsequently, the macrophages both On a molecular level, many mediators
accumulate and oxidize low-density-lipoprotein of inflammation have been identified, and
cholesterol (LDLC), becoming the foam cells more than 50 have been classified by struc-
that are a characteristic feature of atheroscle- ture and function. Some of these cytokines
rotic plaques.7 C-reactive protein (CRP) or “protein cell regulators”15 are proinflam-
appears to stimulate the process of LDLC matory, including IL-1, IL-12, IL-18, inter-
uptake by macrophages,5 which may explain feron gamma, and TNF-a . Others are anti-
why statin treatment of patients with elevated inflammatory, including IL-4, IL-10, IL-13,
CRP levels appears to be clinically beneficial.8 and transforming growth factor-beta.
Ongoing LDLC deposition and chronic These inflammatory cytokines stimulate
inflammation lead to plaque growth, and the nuclear factor-kappa-B (NF-κB) path-
hemodynamic mechanisms appear to play an way in macrophages and endothelium,
important role as well.9 leading to the increased production of a
Plaque rupture may occur at any point in myriad of proteins, including cellular adhe-
the process and can be clinically silent or overt, sion molecules, chemokines, growth factors,
producing significant clinical events. In an esti- and nitric oxide synthase.16 Enhanced activ-
mated two-thirds of patients with acute coro- ity of the NF-κB pathway appears to corre-
nary syndromes, the inciting event is rupture late with an increased risk of developing ath-
of a previously stable coronary plaque that erosclerotic plaques.
had been less than 50% to 70% occlusive.10
Ruptured plaques have distinctive histopatho- RISK FACTORS FOR
logic features: a relatively thin fibrous cap that CARDIOVASCULAR AND
has ruptured with superimposed thrombosis CEREBROVASCULAR DISEASES
and hemorrhage into the plaque that contains Traditional risk factors for cardiovascular
CHAPTER 7 Atherosclerosis: A Pervasive Disease Affecting Global Populations 125
disease include dyslipidemia, hypertension, Obesity

obesity, insulin resistance, diabetes mellitus, Obesity with visceral adiposity is another
tobacco use, and cocaine use. A common emerging atherosclerotic risk factor. Adipose
denominator among these seemingly varied tissue acts as a metabolically active and
risk factors is inflammation. dynamic endocrine organ with proinflamma-
tory actions. Adipocytes secrete many
Dyslipidemia inflammatory cytokines, including IL-6 and
Dyslipidemia appears to contribute directly TNF-a .27 Although cytokine levels vary in
to atherosclerotic disease, with the risk of proportion to overall adiposity, visceral
cardiac events rising in direct proportion to adipose tissue appears to contribute to
plasma cholesterol levels,17 especially choles- inflammation to a greater degree than does
terol particles containing apolipoprotein B subcutaneous fat.28 There is an inverse rela-
(including LDLC).18 These data are used to tion between visceral adiposity and plasma
establish guidelines for recommending target levels of the anti-inflammatory adipocyte-
cholesterol levels.19 The primacy of choles- derived protein, adiponectin.29 Lower
terol in initiating atherosclerosis has been adiponectin levels correlate with reduced
shown in many molecular studies, but may insulin sensitivity and a higher risk of dia-
be most evident in studies of fetal aortas, in betes mellitus,30 as well as endothelial dys-
which quantitative and qualitative analyses function, increased inflammation, and clini-
of fatty streaks have shown that native cally significant atherosclerotic events such as
LDLC uptake in the intima precedes LDLC myocardial infarction.31
oxidation and subsequent endothelial activa-
tion and monocyte recruitment.20 Oxidized Insulin Resistance
LDLC appears to increase endothelial Almost two-thirds of the population in the
expression of cellular adhesion molecules, United States is overweight or obese, and
attracting monocytes and promoting their more than one-fourth of the population
differentiation into macrophages. LDLC also meets diagnostic criteria for insulin resist-
stimulates the release of proinflammatory ance, a multiplex cardiovascular risk factor
cytokines from macrophages. Apolipoprotein that arises from the interplay between adi-
B particles containing the lipoprotein(a) posity and inflammation.32 Insulin resistance
moiety appear to be particularly athero- (IR) is defined as a decreased biologic
genic.21,22 In addition, the ratio of response to normal concentration of serum
apolipoprotein B to apolipoprotein A holds insulin, which over time leads to compensa-
promise in the prognostication of cardiovas- tory hyperinsulinemia and often presages
cular disease across multiple populations.23 development of type 2 diabetes mellitus.33
Although fully manifested diabetes mellitus
Hypertension is a greater risk for cardiovascular disease
Systemic hypertension contributes by than isolated IR without hyperglycemia, the
enhancing monocyte preactivation, increas- presence of IR is a major independent risk
ing production of IL-1 and TNF-a ,24 and factor with relative risk ratios between 2.2
raising circulating levels of cellular adhesion and 2.7 when multifactorial linear regression
molecules.25 Studies have shown a clear rela- analysis is used to assess risk.33–35
tion between elevated high-sensitivity CRP
levels in normotensive patients and the risk Diabetes Mellitus
of developing incident hypertension, under- Diabetes mellitus appears to be associated
scoring its inflammatory nature.26 with inflammation, which may explain its
close relation to atherosclerosis. Studies have is at least partially mediated by alpha adren-
shown that adipose tissue and macrophages ergic stimulation), and direct hemodynamic
recruited into adipose tissue release effects of nicotine. Cigarette use has gradu-
cytokines, including IL-1, IL-6, and TNF-a. ally declined in the United States in the last
These cytokines act on (1) the liver to 40 years, but remains a public health
promote dyslipidemia and dysfibrinogene- problem with approximately 20% of the
mia, (2) adipose tissue to stimulate leptin population continuing to smoke.43
secretion, and (3) the pituitary gland to
increase secretion of adrenocorticotropic Cocaine Use
hormone.36 Moreover, serum levels of Cocaine use causes hemodynamic effects as
various inflammatory markers and media- well as significant inflammation and is likely
tors (CRP, fibrinogen, IL-6, plasminogen proatherogenic.44 Studies in mice suggest that
activator inhibitor 1, and serum amyloid A) cocaine increases the expression of cellular
correlate with the degree of hyperglycemia.37 adhesion molecules and promotes greater
Evidence is accruing to suggest that the for- neutrophil adhesion to the coronary
mation and accumulation of advanced endothelium.45 In human cells, cocaine expo-
glycation end products (AGEs) may be a sure appears to increase the expression of
pathophysiologic link between diabetes and gene coding for numerous inflammatory
cardiovascular disease, mediated in part by markers, such as IL-1, IL-6, and TNF-a .46
the receptor for AGEs (RAGE).38 RAGE,
an immunoglobulin that binds multiple EPIDEMIOLOGY OF
ligands and spurs production of toxic reac- HEART DISEASE AND STROKE
tive oxygen species, is emerging as a potential Although the overall death rate from cardio-
therapeutic target for antagonists designed to vascular diseases declined by 32.7% between
reduce atherosclerosis and ischemia-reperfu- 1999 and 2009, cardiovascular diseases
sion injury.39 Another potential therapeutic remain the number one cause of mortality
target that is attracting interest is protein in the United States, accounting for 32.3% of
kinase C (PKC) beta, an intracellular signal- all deaths in the United States in 2009.1
ing molecule that plays a key role in the Based on 2004 International Classification of
development of diabetic complications.40 Disease-10 data from the Centers for Disease
Experimental PKC inhibitors have been Control and Prevention, cerebrovascular dis-
shown to delay or even stop the progression eases (including stroke) account for ~1 in
of microvascular complications. One such every 19 deaths.1,47
agent has been submitted for regulatory The prevalence and suboptimal control
clearance for the treatment of diabetic of traditional risk factors remain issues for
retinopathy.41 many Americans.1 Data from the 2005–2006
National Health and Nutrition Examination
Tobacco Use Survey suggest that 30% or more of adults
Cigarette smoking contributes to coronary failed to undergo cholesterol screening in the
heart disease through at least four patho- previous 5 years, and an estimated 31.9
physiologic pathways,42 including induction million adults had total cholesterol levels of
of a hypercoagulable state through increased 240 mg/dL or greater (goal < 200). Similarly,
plasma levels of factor VII and thrombox- achieving adequate blood pressure control
ane A2, reduction in oxygen delivery as a has proved to be challenging. In 2003 and
result of carbon monoxide generation, vaso- 2004, only 44% of blood pressure recordings
constriction of the coronary arteries (which in approximately 176 million individuals
demonstrated readings lower than the goal high blood pressure and related sequelae,55
of 140/90 mm Hg.48 An estimated 154.7 including stroke mortality and morbidity.56
million US adults are overweight or obese.
Among children between ages of 2 and 19, CONCLUSION
23.9 million are overweight or obese and It is clear that more study is needed regard-
12.7 million meet the criteria for obesity.1 ing the development, progression, treatment,
While smoking rates have declined over the and expression of atherosclerotic diseases at
past 40 years in the United States, it was esti- all levels—from molecular to global perspec-
mated in 2012 that 21.6% of men and 16.5% tives. Great opportunity remains to reduce
of women over 18 years of age smoke, and the impact of atherosclerosis—a largely pre-
18% of students between grades 9 through ventable disease. Moving forward, interna-
12 report current cigarette use.1,49 Control of tional coalitions such as that initiated by the
cholesterol levels, blood pressure, obesity, World Heart Federation are likely to play a
and tobacco use are among the greatest clin- crucial role in promoting improvements in
ical challenges and opportunities for preven- global cardiovascular health.57
tion of cardiovascular disease.
Supplemental Readings
TRENDS IN DISEASE PATTERNS Shah PK. Inflammation and plaque vulnerability. Car-
IN DEVELOPED AND diovasc Drugs Ther. 2009;23(1):31–40.
DEVELOPING WORLDS
Libby P. Inflammation in atherosclerosis. Arterioscler
Globally, cardiovascular disease (predomi-
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CHAPTER 8
Association Between Periodontal
Disease and Atheromatous Diseases
David W. Paquette, Robert J. Genco
INTRODUCTION inflammation in vessels. Putative infections

Atheromatous diseases constitute a broad set that may at least exacerbate atherosclerosis
of chronic vascular conditions, including car- include cytomegalovirus, herpes simplex
diovascular disease (CVD), which encom- virus, Chlamydia pneumoniae, Helicobacter
passes coronary artery disease (CAD), cere- pylori, and periodontal disease.3 Over the last
brovascular disease (i.e., stroke), and periph- two decades, observational studies in human
eral arterial disease (PAD). These diseases are populations have consistently shown a
major causes of morbidity and mortality in modest but significant association between
human populations worldwide. For example, periodontal disease and atheromatous dis-
in the United States, atherosclerosis affects eases. In addition, animal models chronically
one in four persons and contributes to 39% exposed to periodontal infective agents have
of deaths annually.1 CVD accounts for 29% demonstrated more rapid progression of ath-
of deaths worldwide and ranks as the second erosclerosis. Finally, early intervention studies
leading cause of death after infectious and in human subjects suggest that periodontal
parasitic diseases.2 disease treatment may improve surrogate
In atherosclerosis, large- to medium-sized markers associated with atherosclerosis and
muscular arteries and large elastic arteries CVD. The objective of this chapter is to
become occluded with fibrolipid lesions or provide the reader with a strong understand-
“atheromas.” End-stage complications or ing of the evidence implicating a relation
events associated with atherosclerosis include between periodontal disease and atheroma-
coronary thrombosis, acute myocardial infarc- tous diseases.
tion (MI), and cerebral vascular accident or
stroke. As presented in the preceding chapter, EVIDENCE FROM HUMAN
traditional risk factors related to behaviors, OBSERVATIONAL STUDIES
diet, lifestyle, and family history do not Patients with periodontal disease share many
appear to fully account for the development of the same risk factors as patients with
of atherosclerosis. Furthermore, despite con- atheromatous diseases, including age, gender
tinued preventive efforts addressing modifiable (predominantly male), lower socioeconomic
risk factors, mortality rates from CVD have status, stress, and smoking.4 In addition, a
remained virtually unchanged over the last large percentage of patients with periodontal
decade in developed countries. disease also exhibit atherosclerosis or CVD.5
These observations suggest that periodontal
Role of Inflammation disease and atherosclerosis share similar or
Currently, clinicians and investigators appre- common etiologic pathways. Several recent
ciate that inflammation appears to play a systematic reviews of the available evidence
pivotal role in the pathogenesis of atheroscle- support an association between periodontal
rosis—from the development of the “fatty disease and atheromatous diseases. A 2012
streak” to plaque rupture. This appreciation systematic review conducted by the Ameri-
has intensified the search for chronic expo- can Heart Association’s Committee on
sures or infections that potentially cause Rheumatic Fever, Endocarditis and
Kawasaki Disease and published in Circula- positive association between periodontal

tion, concluded that the observational studies disease and atheromatous diseases (Table 1).
to date support a consistent association Mattila and coworkers11 first reported that
between periodontal disease and atheroma- poor oral health (including periodontal
tous diseases independent of known con- disease) was a predictor of MI among a
founders.6 Although the authors acknowl- Finnish population of 100 case patients and
edged that the contribution of periodontal 102 control subjects. Using a Dental Severity
disease to atheromatous diseases is biologi- Index score as a measure of periodontal and
cally plausible, they cautioned that the endodontic infections as well as dental caries,
cumulative evidence does not currently the investigators found that individuals with
support a causative relationship. Despite the evidence of oral infections were 30% more
paucity of definitive evidence on causation, likely to present with MI compared with
an Editors’ Consensus Report published in subjects with no oral infections. This associa-
the American Journal of Cardiology and the tion was significant after adjusting for
Journal of Periodontology makes recommen- known risk factors such as age, total choles-
dations for patient information, medical and terol levels, hypertension, body mass index,
dental evaluations, and risk factor treatment and cigarette smoking. In a follow-up publi-
for patients with periodontitis who are at cation in the same population, these investi-
risk for atherosclerotic disease.7 gators documented a significant and specific
association between dental infections and
Meta-Analyses severe coronary atheromatosis in males.12
A number of meta-analyses on the athero- More recently, Arbes and others13 evaluated
sclerosis-periodontal disease association have available cross-sectional data from the Third
been conducted in an attempt to pool the National Health and Nutrition Survey
available evidence and apply statistical (NHANES III). Accordingly, for cases with
methods to estimate an overall effect and severe clinical attachment loss and periodon-
any significance. Meurman and colleagues8 titis, the odds ratio for MI was 3.8 (95% CI:
reported a 20% increase in the risk for CVD 1.5–9.7) compared with that of periodontally
among patients with periodontal disease healthy controls. In addition, the probability
(95% CI: 1.08–1.32) and an even higher risk of a coronary event rose with increasing
ratio for cerebrovascular disease or stroke, periodontitis severity. Although the discussed
varying from 2.85 (95% CI: 1.78–4.56) to case-control studies do not provide informa-
1.74 (95% CI: 1.08–2.81). Similarly, Khader tion on the chronicity of exposure and
and colleagues9 and Vettore10 reported rela- disease, they do indicate that the association
tive risk estimates of 1.19 (95% CI: 1.08– has relative strength, is specific, and follows
1.32) and 1.15 (95% CI: 1.06–1.25), respec- an exposure-response relationship.
tively. These meta-analyses of the available
observational human data lend credence to Cohort Studies
the hypothesis that periodontal and athero- Longitudinal cohort studies, in contrast,
matous diseases are associated with one provide a higher level of evidence since they
another in various populations. properly document that periodontitis exposure
precedes the CVD (Table 2). Beck and col-
Case-Control Studies leagues14 evaluated 1,147 males ages 21 to 80
Case-control studies, which select subjects who were participants in the Normative Aging
with the dependent disease and assess expo- Study and who were free of CAD at baseline.
sure (risk), have consistently supported a The periodontal status of this population was
CHAPTER 8 Association Between Periodontal Disease and Atheromatous Diseases 133
Table 1. Summary of Evidence from Case-Control Studies Investigating an Association Between

Periodontal and Atheromatous Diseases in Human Populations
Periodontal Outcome Cardiovascular

Reference Study Design Population or Exposure Outcome Findings and Conclusions
Mattila et al. 198911 Case control 100 cases and Dental Severity Index Evidence of MI Dental health significantly
102 controls (sum of scores for caries, from EKG and worse in patients with MI
periodontal disease, elevated enzyme versus controls after adjust-
periapical pathosis, and levels (creatinine ing for smoking, social
pericoronitis) phosphokinase class, serum lipids, and dia-
isoenzyme) betes
Mattila et al. 199312 Case control 100 cases Dental Severity Index Clinical diagnosis or Significant association
radiographically con- between dental infections
firmed MI and severe coronary athero-
matosis in males (but not
females)
Arbes et al. 199913 Case control 5,564 subjects Percent attachment loss Self-reported MI Positive association between
(NHANES III) of all teeth (>3 mm) periodontal disease and
and categorized CHD (OR=3.8 for severe
according to four levels attachment loss) after
adjusting for age, gender,
race, etc.
Söder et al. 200528 Case control 82 cases and Clinical periodontitis Carotid IMT values Significant association
31 controls defined as having ≥1 between periodontal disease
site with a pocket depth and carotid atherosclerosis
≥5 mm (OR=4.64)
Andriankaja et al. 200626 Population-based 537 cases and Various including con- Incident MI Significant association
case control 800 controls tinuous CAL, PD, and between periodontal disease
missing teeth; also and incident MI regardless
various case definitions of measurement or
definition of periodontal
disease used, after adjusting
for multiple potential
confounders
Andriankaja et al. 200727 Population-based 574 cases and Mean CAL Incident MI Significant association
case control 887 controls between periodontal disease
and incident MI in both
genders, and in non-
smokers as well as smokers,
after adjusting for multiple
potential confounders
Lu et al. 200832 Case control 3,585 subjects Percent attachment loss PAD defined Significant association
(NHANES III) of all teeth (>3 mm) ABI <0.9 between periodontal disease
and categorized accord- and PAD (OR=2.25 for
ing to four levels severe attachment loss)
after adjusting for age,
gender, race, poverty, and
traditional risk factors for
PAD
Chen et al. 200833 Case control 25 PAD cases Clinical periodontitis PAD diagnosed via Significant association
and 32 controls defined as having at clinical symptoms, between periodontitis and
least one probing site ABI, and angio- PAD (OR=5.45) after
with PD ≥ 4 mm or graphic finding adjusting for age, gender,
CAL ≥ 4 mm in each diabetes, and smoking
quadrant
ABI = ankle-brachial pressure index; CAL = clinical attachment loss; EKG = electrocardiogram; IMT = intima-media wall thickness; MI = myocardial
infarction; NHANES = National Health and Nutrition Survey; OR = odds ratio; PAD = peripheral arterial disease; PD = probing depth.
Table 2. Summary of Evidence from Cohort Studies Investigating an Association Between

Periodontal and Atheromatous Diseases in Human Populations
Reference Population or Exposure Outcome Findings and Conclusions
Beck et al. 199614 1,147 males Percent radiographic alveo- Incidence of total and Periodontal disease is associated
(Normative lar bone loss fatal CAD and stroke with moderate risk for CAD
Aging Study) (OR=1.5-1.9) and stroke after
adjusting for age and CVD risk
factors (OR=2.9)
DeStefano et al. 199315 9,760 subjects Subjects classified with no Hospital admission or Periodontitis is associated with
(NHANES I) periodontal disease, with death due to CAD small increased risk for CAD
gingivitis, periodontitis, (RR=1.7) among males
(≥4mm probing depth) or
edentulous
Wu et al. 200016 9,962 subjects Subjects classified with no Incident cases of stroke Compared to periodontal health,
(NHANES I periodontal disease, with relative risk for stroke with peri-
and follow-up) gingivitis, periodontitis (≥4 odontitis was 2.1 and significant
teeth with overt pocketing),
or edentulous
Hujoel et al. 200017 8,032 dentate Periodontal pocketing and Death or hospitalization Periodontitis was not associated
adults attachment loss due to CAD or revascu- with a significant increased risk
(NHANES I) larization obtained from for CAD
medical records
Howell et al. 200118 22,037 male sub- Self-reported presence or Incident fatal and nonfa- No significant association
jects (Physician’s absence of periodontal tal MI or stroke between self-reported periodon-
Health Study I) disease at baseline tal disease and CVD events
Elter et al 200419 8,363 subjects Severe periodontitis Prevalent CAD Significant associations for
(ARIC Study) defined as clinical attach- attachment loss (OR=1.5) and
ment loss ≥3 mm at ≥10% tooth loss (OR=1.8) with preva-
of sites or tooth loss (<17 lent CAD
remaining teeth)
Beck et al. 200120 6,017 subjects Severe periodontitis Carotid artery IMT Periodontitis may influence
(ARIC Study) defined as clinical attach- ≥1mm atheroma formation (OR=1.3)
ment loss ≥3 mm at ≥30%
of sites
Beck et al. 200521 15,792 subjects Serum antibodies to peri- IMT ≥1mm Presence of antibody to C.
(ARIC Study) odontal pathogens rectus was associated with
carotid atherosclerosis (OR=2.3)
Hung et al. 200422 41,407 males Self-reported tooth loss at Incident fatal and nonfa- For males with tooth loss, the
from the HPFS baseline tal MI or stroke relative risk for coronary heart
and 58,974 disease was 1.36. For females
females from the with tooth loss, the relative risk
NHS was 1.64.
Joshipura et al. 200423 468 males from Self-reported “periodontal Serum CRP, fibrinogen, Self-reported periodontal disease
the HPFS disease with bone loss” at factor VII, tPA, LDL was associated with significantly
baseline cholesterol, von higher levels of CRP, tPA and
Willebrand factor and LDL cholesterol after controlling
soluble TNF receptors 1 for age, cigarette smoking,
and 2 alcohol intake, physical activity,
and aspirin intake
Engebretson et al. 200524 203 subjects from Radiographic alveolar Carotid plaque thickness Severe periodontal bone loss was
INVEST bone loss via ultrasonography independently associated with
carotid atherosclerosis (OR=3.64)
Table 2. Cont’d Summary of Evidence from Cohort Studies Investigating an Association

Between Periodontal and Atheromatous Diseases in Human Populations
Reference Population or Exposure Outcome Findings and Conclusions
Desvarieux et al. 200525 1,056 subjects Subgingival bacterial Carotid artery IMT Severe periodontal bone loss was
from INVEST burden ≥1mm independently associated with
carotid atherosclerosis
(OR=3.64)
Pussinen et al. 200429 6,950 Finnish Serum antibodies to P. gin- Incident fatal or Seropositive subjects had an OR
subjects in the givalis or A. actino- nonfatal stroke of 2.6 for stroke
Mobile Clinic mycetemcomitans
Health Survey
Pussinen et al. 200530 1,023 males in Serum antibodies to A. Incident MI or CAD Subjects with the highest tertile
the Kuopio actinomycetemcomitans death of A. actinomycetemcomitans
Ischemic Heart antibodies were two times more
Disease Study likely to suffer MI or CAD
death (RR=2.0) compared with
those with lowest tertile of anti-
bodies levels
Abnet et al. 200531 29,584 rural Tooth loss Incidence of fatal MI Tooth loss was associated with
Chinese subjects or stroke an increased odds for death from
MI (RR=1.29) and stroke
(RR=1.12)
ARIC = Atherosclerosis Risk in Communities; CAD = coronary artery disease; CRP = C-reactive protein; CVD = cardiovascular disease; HPFS =
Health Professional Follow-up Study; IMT = intima-media wall thickness; INVEST = Oral Infections and Vascular Disease Epidemiology Study; LDL
= low density lipoprotein; MI = myocardial infarction; NHANES = National Health and Nutrition Survey; NHS = Nurses Health Study; OR = odds
ratio; RR = relative risk; tPA: tissue plasminogen activator.
assessed using the percent alveolar bone loss marital status, systolic blood pressure, total
observed in dental radiographs. Over an 18- cholesterol levels, body mass index, diabetes,
year follow-up period, 207 men developed physical activity, alcohol consumption,
CAD, 59 died from CAD, and 40 experi- poverty, and cigarette smoking. Accordingly,
enced strokes. Odds ratios adjusted for age those with preexisting clinical signs of peri-
and established cardiovascular risk factors odontitis were 25% more likely to develop
were 1.5 (95% CI: 1.04–2.14), 1.9 (95% CI: CAD compared to those with minimal peri-
1.10–3.43), and 2.8 (95% CI: 1.45–5.48) for odontal disease, after adjusting for other
periodontal bone loss and total coronary known risk factors or confounders. Males
heart disease, fatal coronary heart disease, younger than 50 with periodontitis in this
and stroke, respectively. When Beck and col- study were 72% more likely to develop CAD
leagues14 graphed the cumulative incidence of compared with their periodontally healthy
coronary heart disease or events versus base- counterparts. Similarly, Wu and colleagues16
line mean alveolar bone loss, they noted a evaluated the potential contribution of peri-
linear relation such that increasing severities odontitis to stroke risk within this same
of periodontitis were accompanied by NHANES I population (n = 9,962 adults).
increasing occurrences of CVD (Figure 1). The investigators reported that the presence
Another cohort study conducted by of clinical periodontitis significantly
DeStefano and colleagues15 assessed this risk increased the risk for fatal and nonfatal
relationship among 9,760 adults followed up strokes twofold. Increased relative risks (RR)
for 14 years in NHANES I. Several poten- for total and nonhemorrhagic strokes were
tially confounding variables were also exam- observed for both genders, whites, and
ined, including age, gender, race, education, African Americans with periodontitis.
Figure 1. Linear Relationship Between Cumulative Coronary Artery Disease (%) Versus
Bone Loss Among Male Participants in the Normative Aging Study
Source: J Periodontol 1996;67:1123–37.14 Reproduced with permission from the American Academy of Periodontology.
In contrast, two prominent cohort Professional Follow-up Study (HPFS), the
studies failed to detect any significant associ- Nurses Health Study (NHS), the Oral Infec-
ation between periodontitis and atheroma- tions and Vascular Disease Epidemiology
tous diseases in primary or secondary analy- Study (INVEST), and the Western New
ses. Hujoel and cohorts17 reexamined data York MI/Perio Studies conducted in the
from the NHANES I population over a United States. Other studies have involved
longer, 21-year follow-up period and populations from Sweden, Finland, and
reported a nonsignificant hazard ratio of China.
1.14 (95% CI: 0.96–1.36) for periodontitis Elter et al.19 and Beck and colleagues20,21
and CAD. In addition, Howell and col- collected periodontal clinical data on 6,017
leagues found no association between self- persons ages 52 through 75 years, who par-
reported periodontal disease and CVD ticipated in the ARIC study. The investiga-
events for 22,037 participants in the Physi- tors assessed both the presence of clinical
cians’ Health Study I.18 Accordingly, the rela- CAD (as manifested by MI or revasculariza-
tive risk for physicians with self-reported tion procedure) and subclinical atherosclero-
periodontal disease and subsequent CVD sis (carotid artery intima-media wall thick-
events over a mean 12.3 years was 1.13 (95% ness [IMT] using B-mode ultrasound) as
CI: 0.99–1.28). These studies suffer from dependent variables in the population. Indi-
their overadjustment of confounders or mis- viduals with both high attachment loss (≥
classification of exposures with the long 10% of sites with attachment loss > 3 mm)
follow-up or with self-reporting methods. and high tooth loss (< 17 remaining teeth)
exhibited elevated odds of prevalent CAD
Population Studies compared with individuals with low attach-
Different findings from several large, world- ment loss and low tooth loss (OR = 1.5,
wide population studies provide supportive 95% CI: 1.1–2.0 and OR = 1.8, CI: 1.24–2.4,
and positive evidence for an association. respectively).19
These studies include Atherosclerosis Risk in A second logistic regression analysis
Communities Study (ARIC), the Health indicated a significant association between
severe periodontitis and thickened carotid cation by smoking indicated that all micro-
arteries after adjusting for covariates such as bial models significant for smokers were also
age, gender, diabetes, lipids, hypertension, significant for subjects who had never
and smoking (Figure 2).20 Accordingly, the smoked, except for Porphyromonas gingivalis.
odds ratio for severe periodontitis (i.e., 30% Thus, clinical signs of periodontitis are asso-
or more of sites with ≥ 3-mm clinical attach- ciated with CAD and subclinical atheroscle-
ment loss) and subclinical carotid atherosclerosis in the ARIC population, and exposures
rosis was 1.31 (95% CI: 1.06–1.66). In a third to specific periodontal pathogens signifi-
Figure 2. Mean IMT by Quintiles of Extent of AL ≥3 mm and by Periodontitis (Perio) Case
Status in the ARIC Study Visit 4 (n=601). **P < 0.05; ***P < 0.0001. Adjusted for ARIC
Field Center; Persons with Reported or Detected Myocardial Infarction Excluded
Note: IMT was significantly higher for the upper two quintiles of subjects affected with attachment loss and
for those with severe periodontitis. Source: Arterioscler Thromb Vasc Biol 2001;21:1816–22.20 Reproduced
with permission.
report, these investigators quantified serum cantly increase the risk for atherosclerosis in
IgG antibody levels specific for 17 periodon- smoking and nonsmoking subjects.
tal organisms using a whole bacterial Hung and colleagues22 assessed self-
checkerboard immunoblotting technique.21 reported periodontal disease outcomes and
Analyzing mean carotid IMT (≥ 1 mm) as incident CVD in two extant databases,
the outcome and serum antibody levels as HPFS (n = 41,407 males followed up for 12
exposures for this same population, the years) and NHS (n = 58,974 females fol-
investigators noted that the presence of anti- lowed up for 6 years). After controlling for
body to Campylobacter rectus increased the important cardiovascular risk factors, males
risk for subclinical atherosclerosis twofold with a low number of reported teeth (≤ 10 at
(OR = 2.3, 95% CI: 1.83, 2.84). In particu- baseline) had a significantly higher risk of
lar, individuals with both high C. rectus and CAD (RR = 1.36, 95% CI: 1.11–1.67) com-
Peptostreptococcus micros antibody titers had pared with males with a high number of
almost twice the incidence of carotid athero- teeth (25 or more). For females with the
sclerosis than did those with only a high C. same reported extent of tooth loss, the rela-
rectus antibody (8.3% versus 16.3%). Stratifi- tive risk for CAD was 1.64 (95% CI: 1.31–
2.05) compared with women with at least 25 thickness. The investigators next collected
teeth. The relative risks for fatal CAD events subgingival plaque from 1,056 subjects and
increased to 1.79 (95% CI: 1.34, 2.40) for tested for the presence of 11 known peri-
males and 1.65 (95% CI: 1.11–2.46) for odontal bacteria using DNA techniques.25
females with tooth loss, respectively. In a The investigators found that cumulative peri-
second report, the investigators evaluated the odontal bacterial burden was significantly
association between self-reported periodontal related to carotid IMT after adjusting for
disease and serum elevations in CVD bio- CVD risk factors. Whereas mean IMT
markers cross-sectionally in a subset of values were similar across burden tertiles for
HPFS participants (n = 468 males).23 Serum putative and health-associated bacteria, IMT
biomarkers included C-reactive protein values rose with each tertile of etiologic bac-
(CRP), fibrinogen, factor VII, tissue plas- terial burden (Aggregatibacter actinomycetem-
minogen activator (tPA), low-density comitans, P. gingivalis, Treponema denticola,
lipoprotein cholesterol (LDLC), von Wille- and Tannerella forsythia; Figure 3). Similarly,
brand factor, and soluble tumor necrosis white blood cell values (but not serum CRP)
factor receptors 1 and 2. In multivariate increased across these burden tertiles. These
regression models controlling for age, ciga- data from INVEST provide evidence of a
rette smoking, alcohol intake, physical activ- direct relation between periodontal microbi-
ity, and aspirin intake, self-reported peri- ology and subclinical atherosclerosis inde-
odontal disease was associated with signifi- pendent of CRP.
cantly higher levels of CRP (30% higher
among periodontal cases compared with Western New York Population Study
nonperiodontal cases), tPA (11% higher), A population-based, case-control study of
and LDLC (11% higher). These analyses MI and periodontal disease was conducted
reveal significant associations between self- in Western New York that included approxi-
reported number of teeth at baseline and mately 1,485 subjects ages 35 to 69 years.26
risk of CAD, and between self-reported peri- Cases were survivors of incident MI, and
odontal disease and serum biomarkers of matched controls were randomly selected
endothelial dysfunction and dyslipidemia. from residents in the same region. The
observed association between periodontal
The INVEST Study disease and incident MI was consistent
The INVEST population study was planned across different measurements and/or case
a priori and conducted exclusively to evaluate definitions of periodontal disease, including
the association between CVD and periodon- attachment loss, pocket depth, alveolar
tal outcomes in a cohort population. Enge- crestal height, and number of missing teeth,
bretson and colleagues24 reported that for a respectively. Odds ratios ranged from 2.19 to
group of 203 stroke-free subjects (ages 54–94) 1.04, the lowest associated with missing
at baseline, mean carotid plaque thickness teeth. All associations were statistically signif-
(measured with B-mode ultrasound) was sig- icant at the P <.05 level. In a second study
nificantly greater among dentate subjects from the same group,27 the association
with severe periodontal bone loss (≥ 50% between periodontal disease and incident MI
measured radiographically) than among was found in both genders, with an odds
those with less bone loss (< 50%). Indeed, ratio of 2.08 (95% CI: 1.47–2.94) in women
the group noted a clear dose-response rela- and 1.34 (95% CI: 1.15–1.57) in men. An
tion when they graphed subject tertiles of important finding from this study is that the
periodontal bone loss versus carotid plaque association between periodontal disease and
Figure 3. Mean Carotid Intima-Media Wall Thickness (IMT) Across Tertiles of Bacteria Burden
(Etiologic, Putative, and Health-Associated) for Participants in the INVEST Trial
Adjusted for age, BMI, smoking, systolic blood pressure, race/ethnicity, gender, diabetes, education, LDL cholesterol,
and HDL cholesterol. Source: Circulation 2005;111:576–82.25 Reproduced with permission.
incident MI was independent of the possible with values in periodontally healthy controls.28
confounding effects of smoking, since it was Multiple logistic regression analyses identified
found in both cigarette smokers (OR = 1.49, periodontal disease as a principal independ-
95% CI: 1.26–1.77) and nonsmokers (OR = ent predictor of carotid atherosclerosis with
1.40, 95% CI: 1.06–1.86) after adjusting for an odds ratio of 4.64 (95% CI: 1.64–13.10).
age, gender, body mass index, physical activ- Pussinen and associates29 monitored antibody
ity, hypertension, cholesterol, diabetes, and responses for A. actinomycetemcomitans and
total pack-years of smoking. This is an P. gingivalis among 6,950 Finnish subjects for
important finding because there is an active whom CVD outcomes over 13 years were
debate among authors suggesting that available (Mobile Clinic Health Survey).
smoking is a causal confounding factor Compared with the subjects who were
between periodontal disease and CVD. The seronegative for these pathogens, seropositive
positive association of periodontal disease subjects had an odds ratio of 2.6 (95% CI:
and MI in nonsmokers provides strong evi- 1.0–7.0) for a secondary stroke. In another
dence that periodontal disease can affect report on 1,023 males (Kuopio Ischemic
coronary heart disease independent of Heart Disease Study), Pussinen and col-
smoking. leagues30 observed that patients with MI or
CAD death were more often seropositive for
Population Studies in Europe and Asia A. actinomycetemcomitans than the control
Consistent associations between periodontal subjects who remained healthy (15.5% versus
outcomes and atherosclerosis have been 10.2%). In the highest tertile of A. actino-
demonstrated among populations in Europe mycetemcomitans antibodies, the relative risk
and Asia. For 131 adult Swedes, mean for MI or CAD death was 2.0 (95% CI: 1.2–
carotid IMT values were significantly higher 3.3) compared with the lowest tertile. For P.
in subjects with clinical and/or radiographic gingivalis antibody responses, the relative risk
evidence of periodontal disease compared was 2.1 (95% CI: 1.3–3.4).
Abnet and colleagues31 have published and 32 generally healthy control subjects.33
findings from a cohort study of 29,584 Polymerase chain reaction was used to iden-
healthy, rural Chinese adults monitored for tify P. gingivalis, T. denticola, A. actino-
up to 15 years. Tooth loss (evaluated as an mycetemcomitans, Prevotella intermedia,
exposure outcome for periodontal disease) Cytomegalovirus (CMV), Chlamydia pneu-
and mortality from heart disease or stroke moniae, and H. pylori in tissue specimens
were modeled as independent variables. Indi- obtained at the time of bypass grafting.
viduals with greater than the age-specific After adjusting for age, gender, diabetes, and
median number of teeth lost exhibited a sig- smoking, periodontitis increased five-fold the
nificantly increased risk of death from MI risk of having PAD (OR = 5.45, 95% CI:
(RR = 1.28, 95% CI: 1.17–1.40) and from 1.57–18.89). In addition, periodontopathic
stroke (RR = 1.12, 95% CI: 1.02–1.23). bacteria were detected in approximately half
These elevated risks were present in men and of the atherosclerotic specimens. In contrast,
women regardless of smoking status. Collec- CMV or C. pneumoniae was detected in only
tively, these findings indicate consistent asso- 4% of specimens, and H. pylori was detected
ciations for periodontal disease and patho- in none of the specimens.
genic exposures with CVD. In the third study involving an Asian
Indian cohort, 532 with gingivitis and 282
Observational Studies on Peripheral with periodontitis were assessed for early
Artery Disease peripheral vascular changes including pulse
Three recent observational studies have wave velocity, arterial stiffness, and ankle-
focused on the relation between periodontal brachial index using computed oscillometry
disease and PAD. The study population for methods.34 Accordingly, periodontitis patients
the first of these reports consisted of 3,585 exhibited significantly higher degrees of
participants who were 40 or older in peripheral atherosclerosis as measured by
NHANES III during 1999 to 2002.32 PAD brachial pulse wave velocity and the ankle-
was defined as an ankle-brachial pressure brachial index. Collectively, these early obser-
index of < 0.9, and the presence of peri- vational data suggest a higher likelihood of
odontal disease was based on clinical attach- PAD among subjects with periodontal
ment severity scores (i.e., 0%, 1–15%, 16– disease and suggest that DNA sequences
33%, and more than 33% of sites with clini- specific to periodontal pathogens may be
cal attachment loss ≥ 3 mm). Although 4.8% present in some PAD lesions.
of subjects were recognized as having PAD,
multiple logistic regression analyses indicated BIOLOGIC PLAUSIBILITY AND
that periodontal disease was significantly EVIDENCE FROM ANIMAL MODELS
associated with PAD (OR = 2.25, 95% CI: Since periodontal infections result in low-
1.20–4.22) after adjusting for age, gender, grade bacteremias and endotoxemias in
race, poverty, traditional risk factors of affected patients,35,36 systemic effects on vas-
PAD, and other potential confounding cular physiology via these exposures appear
factors. Systemic markers of inflammation biologically plausible. Four specific pathways
(CRP, white blood cell count, fibrinogen) have been proposed to explain the plausibil-
were also associated with clinical attachment ity of a link between CVD and periodontal
loss or periodontitis. infection. These pathways (acting independ-
A second case-control study included 25 ently or collectively) include (1) direct bacter-
patients diagnosed with PAD (aortoiliac ial effects on platelets; (2) autoimmune
and/or femoropopliteal occlusive disease) responses; (3) invasion and/or uptake of
bacteria in endothelial cells and oral pathogens in atheromatous tissues.45,46 In

macrophages; and (4) endocrine-like effects addition, macrophages incubated in vitro
of proinflammatory mediators.37,38 In with P. gingivalis and low-density lipoprotein
support of the first pathway, two oral bacte- uptake the bacteria intracellularly and trans-
ria, P. gingivalis and Streptococcus sanguis, form into foam cells.47 In the last potential
express virulence factors called “collagen-like pathway, systemic proinflammatory media-
platelet aggregation-associated proteins,” tors are upregulated for endocrine-like effects
which induce platelet aggregation in vitro in vascular tissues, and studies consistently
and in vivo.39,40 Second, autoimmune mecha- demonstrate elevations in CRP and fibrino-
nisms may play a role since antibodies that gen among periodontally diseased subjects
cross-react with periodontal bacteria and (Figure 6).16,48
human heat shock proteins have been identi-
fied (Figure 4).41,42 In one recent study, CVD Murine Model
patients with extensive periodontal pocketing Experiments with animal models demon-
(≥ 4 sites with pocket depth ≥ 4 mm) had strate that specific infections with periodon-
not only higher levels of subgingival tal pathogens can actually accelerate athero-
pathogens such as P. gingivalis and T. for- genesis. For example, inbred heterozygous
sythia but also significantly increased anti- and homozygous apolipoprotein E (apoE)-
body responses to heat shock protein 50 rel- deficient mice exhibit increased aortic athero-
ative to those CVD subjects with limited sclerosis when challenged orally or intra-
pocketing (≤ 1 site with pocket depth ≥ 4 venously with invasive strains of P. gingi-
mm).43 Third, Deshpande and colleagues44 valis.49–52 In one of these experiments, Lalla
have demonstrated that P. gingivalis can and colleagues51 randomized 50 male
invade aortic and heart endothelial cells via homozygous apoE-null mice to either topical
fimbriae (Figure 5). Several investigative inoculation with P. gingivalis (strain 381
groups have independently identified specific orally and anally because of the coprophagic
Figure 4. Infection-Induced Stimulation of Accelerated Atherosclerosis by Autoimmune Responses
or “Molecular Mimicry”
Note: Specific antibodies directed toward bacterial heat shock proteins cross-react with human heat shock proteins, leading to
endothelial cell damage, monocyte recruitment, elevated circulating lipids such as oxidized LDL (ox-LDL), and atherogenesis.
Source: J Dent Res 2006;85:106–21.37 Reproduced with permission.
Figure 5. Invasion of the Vascular Endothelium by Pathogenic Bacteria Resulting in Induction of

Local Inflammatory Responses
Note: This includes expression of cell adhesion molecules (CAMs), toll-like receptors (TLRs), chemokines, and cytokines.
These events culminate in monocyte recruitment, elevations in oxidized LDL (ox-LDL), and accelerated atherogenesis. Source:
J Dent Res 2006;85:106–21.37 Reproduced with permission.
nature of the animals) over 3 weeks or leukin 6, and increased aortic expression of
antibiotics plus vehicle (sterile phosphate- vascular cell adhesion molecule 1 and tissue
buffered saline) on the same schedule. factor. P. gingivalis DNA was localized in the
Accordingly, P. gingivalis-infected animals aortic tissue from a limited number of
displayed evidence of local periodontal infec- infected mice, but not in any noninfected
tion and marked alveolar bone loss. Infected controls. Most important, morphometric
animals also exhibited serum IgG responses analyses revealed a statistically significant
to P. gingivalis, elevated serum levels of inter- 40% increase in mean atherosclerotic lesion
Figure 6. Persistent Periodontal Infection May Promote Atherosclerosis via Chronic Upregulation of
Inflammatory Cascades
Note: These include tumor necrosis factor-alpha (TNF- a), interleukin-1 (IL-1), interferon (IFN), IL-8, monocyte chemo-attrac-
tant protein-1 (MCP-1), and C-reactive protein (CRP). Source: J Dent Res 2006;85:106–21.37 Reproduced with permission.
area for P. gingivalis-infected animals com- Porcine Model

pared with controls. Similarly, Brodala and colleagues54 have
In another study involving apoE-defi- demonstrated accelerated atherogenesis in a
cient mice with spontaneous hyperlipidemia, pig bacteremia model. Accordingly, the inves-
injections with live or heat-killed A. actino- tigators allocated pigs (N = 36) to either low-
mycetemcomitans or A. actinomycetemcomi- or high-fat diets. They sensitized some animals
tans lipopolysaccharide accelerated atheroscle- with heat-killed P. gingivalis (109 organisms)
rosis relative to mice injected with vehicle.53 In and then challenged them with live P. gingi-
addition, A. actinomycetemcomitans challenge valis (106–107 organisms) injected intravenously
also promoted mRNA expression of innate three times weekly over a 5-month period.
immune signaling molecules such as Toll-like Other animals that were sensitized with P.
receptors and NOD-like receptors while gingivalis (no live challenge) or that were
enhancing low-density lipoprotein oxidation, treated with saline served as controls. Results
events implicated in atheroma formation. indicated that P. gingivalis-challenged pigs
developed significantly more coronary and these experiments suggest that both the host
aortic atherosclerosis than controls in the low- response and the virulence of specific P. gingi-
fat (normocholesterolemic) group and nearly valis strains appear to be important variables
as significant in the high-fat (hypercholes- in these infection-atherogenesis models.
terolemic) group (Figure 7). P. gingivalis was
detected by polymerase chain reaction in EVIDENCE FROM HUMAN
arteries from most (94%) of the challenged INTERVENTION STUDIES
pigs, but not from controls. This finding sug- Human evidence demonstrating beneficial
gests that P. gingivalis bacteremia may exert effects of periodontal therapy on atheroma-
an atherogenic stimulus independent of high tous disease outcomes is limited and indirect
cholesterol levels in pigs. at present.58 In an initial intervention trial,
Figure 7. Histology of Right Coronary Artery Atherosclerosis from Study Pigs
A: Coronary artery from a P. gingivalis-sensitized and challenged pig (Group 1) fed low-fat diet (immunohistochemical staining);
smooth muscle cells comprise the majority of cells in the lesion. B: Higher magnification of rectangle in A. C: Coronary artery
from a pig fed a high-fat diet and injected with saline control (Group 6). D: Coronary artery from a P. gingivalis–challenged pig
fed a high-fat diet (Group 5). E: Coronary artery from a P. gingivalis–sensitized pig fed low-fat diet (Group 3). AP indicates ather-
osclerotic plaque; L, lumen. Source: Arterioscler Thromb Vasc Biol 2005;25:1446–51.54 Reproduced with permission.
Summary of Animal Studies D’Aiuto and colleagues59 demonstrated that

It is worth noting that a wide range of P. gin- periodontitis patients treated with scaling
givalis doses was used in these murine and and root planing exhibited significant serum
porcine studies. Even though the clinically rel- reductions in the CVD biomarkers, CRP
evant dose for human subjects is unknown at and interleukin 6. In particular, patients who
present, it probably varies greatly.55–57 The clinically responded to periodontal therapy
reader should note that P. gingivalis challenges in terms of pocket depth reductions were
enhanced atherosclerosis despite different four times more likely to exhibit serum
routes of administration and dosing regimens decreases in CRP compared with patients
in both species. Although P. gingivalis’ 16 with a poor clinical periodontal response.
ribosomal DNA could be detected in athero- A recent retrospective cohort study
mas from some but not all of the animals, using national health insurance data and
involving over 700,000 Taiwanese subjects vious coronary event including MI, coronary
investigated whether dental prophylaxis or artery bypass graft surgery, or coronary
periodontal treatment was associated with transluminal angioplasty 3 to 36 months
reduced incidence of ischemic stroke.60 Sub- before enrollment) and who met study crite-
jects were first stratified as either periodonti- ria for periodontal disease (≥ 3 teeth with
tis cases versus non-cases. Periodontitis cases probing depths ≥ 4 mm, ≥ 2 teeth with inter-
were further divided into a dental prophy- proximal clinical attachment loss ≥ 2 mm,
laxis group, an intensive periodontal treat- and ≥ 10% of sites with bleeding on
ment group (subgingival curettage, root probing). Three-hundred-three eligible partic-
planing, flap surgery and/or extraction), and ipants were enrolled, and all subjects received
a no-treatment group based on insurance extractions for hopeless teeth. Thereafter,
coding. Incident stroke rates were then subjects were randomized to receive either
assessed over a 10-year follow-up period. periodontal therapy (intensive treatment
The incidence of stroke among periodontitis group consisting of scaling and root planing
non-cases was 0.32%/year. In contrast, peri- at baseline) or community-based dental care
odontitis cases who received dental prophy- (control group). Serum samples obtained at
laxis had the lowest stroke rate (0.14%/year). baseline (before randomization) and at 6
Periodontitis patients with intensive treat- months were analyzed for levels of high-sen-
ment or tooth extraction had a higher stroke sitivity (hs) CRP. The intensive treatment
rate (0.39%/year), and subjects with no treat- protocol significantly improved periodontal
ment had the highest stroke rate probing parameters over 6 months, but the
(0.48%/year). After adjusting for con- treatment did not significantly improve mean
founders, the dental prophylaxis group and serum hsCRP levels in the overall popula-
the intensive treatment case group had sig- tion. In secondary analyses, it was noted that
nificantly lower hazard ratios (HR) for 48% of the community care control group
stroke than the non-case group (HR 0.78 received some form of preventive or peri-
and 0.95, 95% CI: 0.75–0.81 and 0.91–0.99, odontal therapy over the 6-month study
respectively), whereas the no-treatment group period (e.g., dental prophylaxis, scaling and
had a significantly higher hazard ratio for root planing, and/or periodontal surgery).
stroke (HR 1.15, 95% CI: 1.07–1.24), espe- When the investigators stratified for any
cially among the youngest (20–44) age group treatment and obesity, they detected a treat-
(HR 2.17, 95% CI: 1.64–2.87). These retro- ment effect on hsCRP levels clustered among
spective cohort data suggest that preventive the non-obese subjects (Figure 8). Among
and active interventions for periodontal non-obese individuals in the community who
disease are associated with lowered stroke received no treatment, 43.5% had elevated
rates at least among Taiwanese subjects. hsCRP (> 3 mg/L) at 6 months. In contrast,
18% of subjects receiving any treatment
The PAVE Study exhibited elevated hsCRP values. Logistical
In 2009, Offenbacher and collaborators61 regression modeling indicated that any treat-
published results from the Periodontitis and ment among all subjects resulted in a statisti-
Vascular Events (PAVE) pilot study, which cally significant reduced odds ratio for high
was conducted to investigate the feasibility of hsCRP (OR = 0.42, 95% CI: 0.18–0.99). The
a randomized secondary-prevention trial. effects were even stronger among the non-
Accordingly, five clinical centers recruited obese subjects, with an even lower odds ratio
participants who had documented CAD (≥ for having high hsCRP at 6 months with any
50% blockage of one coronary artery or pretreatment (OR = 0.26, 95% CI: 0.09–0.72).
Figure 8. Percent of Subjects with Elevated Serum High Sensitivity C-Reactive Protein (hsCRP)
> 3 mg/L at 6 Months by Treatment Group and Stratified by Obesity for the Periodontitis and
Vascular Events (PAVE) Pilot Study
*P = .009; †P = .03; ‡P = .04; §P = .006; Tx = treatment; Prophy = prophylaxis; SRP = scaling and root planing. Vertical
dashed line designates that “Any Tx” is a composite of the three treatment groups. Source: J Periodontal 2009;80:190–201.61
Reproduced with permission from the American Academy of Periodontology.
These data suggest that crossover from the periodontitis patients with “complete mouth
control arm may be high within intervention disinfection” (scaling and root planing, peri-
studies and that any periodontal disease treat- odontal flap surgery, and extraction of hope-
ment effect on hsCRP levels may be exagger- less teeth within a 2-week interval) and
ated among non-obese patients. observed significant improvements in
The data summarized in Figure 8 also endothelial function (flow-mediated dilation
suggest that even a dental prophylaxis, which of the brachial artery) and serum biomark-
includes supragingival removal of plaque ers such as interleukin 6. Similarly, Seinost
and oral hygiene instruction, has an effect on and colleagues63 tested endothelial function
systemic inflammation. From Figure 8 it can in 30 patients with severe periodontitis versus
be seen that those in the Community Screen- 31 periodontally healthy control subjects.
ing Group receiving prophylaxis who were Before interventions, flow-mediated dilation
non-obese had a significant reduction in was significantly lower in patients with peri-
serum CRP levels (P = .009). It is reason- odontitis than in control subjects. Periodonti-
able, therefore, to recommend good oral tis patients with favorable clinical responses
hygiene practices in cardiovascular patients, to nonsurgical periodontal therapy (i.e.,
including tooth brushing with a toothpaste scaling and root planing, topical and peroral
containing active ingredients that have antimicrobials plus mechanical retreatment)
antigingivitis, as well as antiplaque effects. exhibited concomitant improvements in
flow-mediated dilation of the brachial artery
Studies of Endothelial Function and serum hsCRP concentrations.
At least three other human intervention In a larger third trial, Tonetti and
trials have evaluated the effects of periodon- colleagues64 documented endothelial
tal disease interventions on endothelial func- responses for 120 medically healthy patients
tion, another surrogate outcome for athero- with severe periodontitis. Subjects in this trial
sclerosis. Elter and colleagues62 treated 22 were randomized to either community-based
periodontal care (control) or intensive peri- levels of hsCRP, interleukin 6, E-selectin,

odontal treatment (extraction of hopeless and von Willebrand factor were significantly
teeth, scaling and root planing, plus locally higher. However, by 60 and 180 days, sub-
administered minocycline microspheres). At jects receiving the intensive treatment exhib-
24 hours post-treatment, intensive flow- ited significantly improved flow-mediated
mediated dilation was significantly lower in dilation and improved plasma levels of
the intensive treatment group than in the soluble E-selectin compared with such
control treatment group (Figure 9), and factors in control subjects.
Figure 9. Flow-Mediated Dilation and Nitroglycerin-Mediated Dilation Over 6 Months for
Periodontitis Subjects Treated with Intensive Therapy versus Community Controls
Note: Monitored over a 6-month period for periodontitis subjects treated with intensive therapy vs community controls. Source:
N Engl J Med 2007;356:911–20.64 Reproduced with permission.
The effects of periodontal therapy on should be knowledgeable about this consis-

end-stage events in patients with atheroma- tent association and the potential preventive
tous diseases have yet to be determined in benefits of periodontal interventions.
controlled clinical trials; however, the avail-
able evidence suggests that periodontal inter- Supplemental Readings
ventions may be associated with 3- to 6- D’Aiuto F, Orlandi M, Gunsolley JC. Evidence that
month improvements in serum inflamma- periodontal treatment improves biomarkers and CVD
tory biomarkers and endothelial function outcomes. J Periodontol 2013;84(Suppl):S85–105.
that are predictive of atheromatous diseases.
Dietrich T, Sharma P, Walter C, Weston P, Beck J. The
A recent study has shown that statins, a epidemiological evidence behind the association between
common treatment for CVD, can affect peri- periodontitis and incident atherosclerotic cardiovascular
odontal disease.65 The investigators com- disease. J Periodontol 2013;84(Suppl):S70–84.
pared high-dose (80 mg) versus low-dose (10
Lockhart PB, Bolger AF, Papapanou PN, Osinbowale
mg) atorvastatin in a randomized controlled O, Trevisan M, Levison ME, Taubert KA, Newburger
trial. They found that periodontal inflamma- JW, Gornik HL, Gewitz MH, Wilson WR, Smith SC Jr,
tion as assessed by 18F-fluorodeoxyglucose Baddour LM; American Heart Association Rheumatic
positron emission tomography (FDG-PET) Fever, Endocarditis, and Kawasaki Disease Committee
of the Council on Cardiovascular Disease in the Young,
was significantly reduced in the high-dose Council on Epidemiology and Prevention, Council on
atorvastatin group. Furthermore, they found Peripheral Vascular Disease, and Council on Clinical
that changes in periodontal inflammation Cardiology. Periodontal disease and atherosclerotic vas-
correlated with changes in carotid inflamma- cular disease: does the evidence support an independent
association? A scientific statement from the American
tion. These data raise the possibility that a Heart Association. Circulation 2012;125:2520–44.
portion of the beneficial impact of statins on
atherosclerosis relates to reduced inflamma- Tonetti MS, Van Dyke TE; working group 1 of the
tion in extracardiac tissues as, for example, joint EFP/AAP workshop. Periodontitis and atheroscle-
rotic cardiovascular disease: consensus report of the
the periodontium. This is the first random- Joint EFP/AAP Workshop on Periodontitis and Sys-
ized controlled trial to report beneficial temic Diseases. J Periodontol 2013;84 (Suppl):S24–9.
effects of cardiovascular treatment on those
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Van Dyke TE, Genco RJ. Results from the Peri- ation between periodontitis and incident athero-
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to study effects of periodontal therapy in a sec- 67. Tonetti MS, Van Dyke TE; Working group 1 of
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effects of periodontal therapy on vascular 2013;84(Suppl):S24–9.
CHAPTER 9
Adverse Pregnancy Effects
Silvana P. Barros, Steven Offenbacher
PREGNANCY COMPLICATIONS: that periodontal infections can serve as a

OVERVIEW distant site of infection, affecting prematurity
Despite much research and healthcare effort, and fetal growth. Despite the evidence sup-
preterm birth (PTB, < 37 weeks’ gestation) porting an association and the biologic data
remains a major public health problem, and suggestive of causality, the evidence support-
children born preterm have a higher risk of ing the ability of maternal periodontal treat-
morbidity and mortality. This contributes to ment to prevent prematurity is still equivo-
over one third of all US infant mortalities cal. The association remains strong between
and is linked to major, long-term morbidi- the two conditions, but not all treatment
ties.1 Although pregnancy complications are studies show significant reduction in preterm
clearly multifactorial in nature and involve a deliveries. In other words, the findings
complex molecular and biologic interplay of suggest that managing periodontal disease in
mother and fetus, many studies suggest that pregnancy is difficult and that treatment to
periodontal infections may be potentially control periodontal disease may not disrupt
one of the causes of adverse pregnancy out- the biologic basis of oral infection–mediated
comes. Furthermore, in women who have pregnancy complications.
preterm delivery, direct biologic evidence Some studies suggest that the treatments
shows that periodontal organisms are associ- are ineffective in reducing prematurity,
ated with amniotic fluid inflammation, depending on the nature and timing of the
intrauterine fetal exposure, and fetal inflam- treatment provided. These findings suggest
mation. that if periodontal disease is a cause of pre-
More recently, epigenetics has been pos- maturity, it may be a nonmodifiable cause of
tulated as another mechanism linking the disease, or at least our treatment protocols
early developmental environment to adult are not optimized to yield potential benefits.
diseases. Differences in fetal DNA methyla- As we understand the associations between
tion are evident in fetuses born preterm periodontal infection and systemic health
versus full term, and altered methylation has and we begin to examine intervention
been associated with infection status studies, the concept has emerged that the
(chorioamnionitis). It has been suggested treatments that we use to control oral mani-
that patterns established at birth may provide festations of periodontal disease may not be
insight into long-term consequences associ- sufficient to control the systemic effects of
ated with PTB.2 Thus, since the first publica- oral infection. In spite of the tremendous
tion in 1996 linking infection by periodontal amount of association data gathered from
pathogens with pregnancy complications,3 studies around the world, as well as the bio-
numerous studies have explored the associa- logic plausibility and mechanistic incrimina-
tion. These studies include case-control, lon- tion of causality, we have not yet identified
gitudinal, and intervention studies in how to treat or prevent periodontal infection
humans as well as models of experimental from having deleterious effects on the fetal–
periodontal infections in pregnant rodents, placental unit.
rabbits, and monkeys. In the last decade, evi- In this chapter, we discuss the evidence
dence has continued to support the concept linking periodontal diseases to pregnancy
CHAPTER 9 Adverse Pregnancy Effects 153
and neonatal development abnormities. We susceptibility during pregnancy is thought to

highlight the animal models data as well as be attributable to changes in gingival tissue
the population studies in humans. Recently structure, the nature and quality of the host
published meta-analyses and reviews are response, and alterations in the oral biofilm
cited as background information to focus the composition. Pregnancy provides a special
discussion on recent trials and the interpreta- opportunity for the emergence of the biofilm
tion of findings that bear on clinical practice pathogens. Increases in serum progesterone
and healthcare policy. The key learning serve to increase the gingival crevicular fluid
objectives include the following: flow rate, altering conditions within the sub-
1. To understand the types of obstetric gingival sulcus and leading to increased
complications that have been associ- levels of Porphyromonas species. Moreover,
ated with periodontal disease. an overgrowth of the Socransky red and
2. To learn the evidence linking peri- orange complexes contributes to an
odontal disease to obstetric compli- increased prevalence of gingivitis and sever-
cations, as it relates to other risk ity of periodontal disease during pregnancy.
factors for adverse pregnancy out- The gingival tissues themselves are
comes. affected by the hormonal increases that lead
3. To gain insight into the current to increased synthesis of hyaluronic acid and
models of pathogenesis that establish to glycosaminoglycan aggregates, which
biologic plausibility and the evidence osmotically induce tissue edema and gingival
from human and animal models that enlargement. These changes lead to greater
support these mechanisms, including clinical inflammation. The typical inflamma-
new findings on the role of epigenet- tory appearance demonstrating the changes
ics associated with bacterial infection. in gingival tissue architecture has been well
4. To appreciate how this information described and emphasizes that neovascular-
impacts our thinking regarding the ization within the gingival tissues increases
clinical management of the pregnant during pregnancy, since the gingival changes
mother and the potential implica- almost mirror those of the uterus during this
tions for maternal–child health. hormonal barrage. Finally, the maternal
5. To underscore the importance of oral immune response changes during pregnancy
hygiene and periodontal health in and can be best characterized as a relative
women prior to conception to state of immunotolerance (discussed further
increase the likelihood of healthy in the text that follows), which serves to
birth outcomes, given our current protect the fetus from host-versus-graft
inability to mitigate adverse out- immunorejection. Thus, alterations in the
comes during pregnancy. maternal immune response likely contribute
to the increase in gingival inflammation that
ASSOCIATION OF PREGNANCY occurs during pregnancy.
WITH PERIODONTAL DISEASE
Epidemiologic and longitudinal studies have TYPES OF OBSTETRIC ADVERSE
clearly shown that pregnancy is associated EVENTS ASSOCIATED WITH
with an increase in gingival inflammation PERIODONTAL DISEASE
and a worsening of periodontal status. Peri- Maternal infections have long been recog-
odontal diseases, including gingivitis and nized as increasing risk for pregnancy com-
periodontitis, affect approximately three out plications such as PTB, fetal growth restric-
of four pregnant women.3 This increased tion, preeclampsia, fetal loss (spontaneous
abortions and fetal demise), and stillbirth. nancy outcomes, but in fact it increases the
Although these obstetric complications relevance of oral infection in the manage-
differ in clinical presentation and outcomes, ment of maternal–child health outcomes,
there are similarities in terms of pathogene- since the effects of oral infection would be
sis, reflecting common inflammatory effec- exaggerated in a person with this trait. More
tor pathways that result in disease. Oral specifically, preeclampsia has been conceptu-
infection in the mother appears to be one ally characterized as a hyperinflammatory
potential stimulus for this inflammatory state, which is linked to the fact that more
effector mechanism, but it is not the only than 30% of the leukocytic cells in the pla-
cause. Rather, oral infection appears to be cental decidual layer in normal pregnancy
just one factor triggering inflammatory are macrophages. Macrophages in the pla-
events that result in a variety of obstetric cental tissue are important cytokine produc-
complications. Furthermore, there is not ers and may be “pivotal regulatory cells” for
sufficient evidence to suggest that the effects controlling trophoblast cell invasion in the
of periodontal infection are limited to one maternal vascular system. Macrophages may
particular obstetric complication. Thus, the have cytolytic effects, presumably by the pro-
lack of specificity is likely attributable to a duction of cytotoxic cytokines, and hyperac-
commonality of pathologic signals or to the tivation may be linked to placentation
presence of an unknown, underlying defects and pregnancy complications.
inflammatory trait that places the mother at In the following text, we discuss prema-
risk for both periodontal disease and turity and fetal growth obstetric complica-
obstetric complications. tions and summarize the evidence linking
It is possible that mothers with obstetric these obstetric outcomes to periodontal
complications have a genetic trait that creates disease. The condition of preeclampsia is dif-
an abnormal hyperinflammatory response ferent in clinical presentation and pathogene-
that can result in pregnancy complications sis and is discussed separately. The data
and can simultaneously be associated with linking periodontal disease to fetal demise
more severe periodontal disease. Indeed, and stillbirth are limited and are included
obstetric complications exhibit familial under both human and animal discussions.
aggregation, suggesting a genetic component.
However, such hyperinflammatory traits may PRETERM BIRTH AND FETAL
create the genomic structure that enables GROWTH RESTRICTION
infectious agents to disseminate and cause In the United States, preterm birth (PTB),
pathology of the fetal–placental unit. An defined as birth of an infant born before
underlying inflammatory factor that places a 37 weeks of completed gestation or before
mother at risk for both conditions would 259 days of gestational age,4 is occurring at
create the possibility of oral infections—or an increasing rate in the population, with a
any other infection—to increase the risk of rise of 13% for the period of 1981–1989 and
obstetric complications. Thus, the impor- 16% for 1990–2002.5,6 Furthermore, in 2004,
tance of oral infection is even more relevant low birth weight (LBW; < 2,500 g) affected
to obstetric risk in the presence of a hyperin- 8.1 % of live births, an increase from 7.6% in
flammatory trait. One might consider that 1998. Although weight at birth and gesta-
the presence of a genetic predisposition tional age are highly correlated, in many
might diminish the importance of oral infec- countries the determination of gestational
tion as a mitigating factor in abnormal preg- age by date of last menstrual period and
ultrasound are not routinely performed; birth at less than 32 weeks of completed ges-
therefore, LBW becomes a worldwide tation. The risk of serious postnatal compli-
reporting standard. The increased rate of cations, disability, and mortality increases sig-
prematurity is due to three factors: our nificantly at earlier gestational ages. In
inability to identify all causal risk factors, Figure 1, representative statistics from the
our inability to adequately control known state of North Carolina demonstrate the
risk factors, and our improved ability to national trend. About 50% of the preterm
support survival of the smallest and most deliveries occur near-term between 35 and 37
premature babies. As a result, the incidence weeks of gestation, and the rate of morbid-
of PTB and LBW deliveries has actually ity and mortality in this group is relatively
increased in most industrialized nations.7–9 low, compared with earlier gestations. One
With prematurity remaining the leading can see (Figure 1) that the rate of mortality
cause of perinatal morbidity and mortality increases rather steeply at earlier gestations,
worldwide and with widespread recognition with about 16% mortality at 32 weeks.
that inflammation is responsible for a sub- Understanding the potential causes of
stantial percentage of PTBs,10–12 maternal prematurity is important because it is the
periodontal disease has gained prominence leading cause of death in the first month—
as a potentially modifiable risk factor for up to 70% of all perinatal deaths.18 Even late
adverse pregnancy outcomes. premature infants, those born between 34
Systemic dissemination of oral pathogens and 37 weeks, have a greater risk of feeding
with subsequent maternal, fetal, and/or pla- difficulties, thermal instability, respiratory dis-
cental inflammatory responses has been asso- tress syndrome, jaundice, and delayed brain
ciated with pregnancy complications.13,14 Fur- development.13 Prematurity is responsible for
thermore, periodontal disease and the sys- almost 50% of all neurologic complications
temic bacteremias caused by periodontal in newborns and leads to lifelong complica-
pathogens are significant contributors to a tions in health that include but are not
systemic maternal inflammatory response limited to visual problems, developmental
during pregnancy, which involves cytokine- delays, gross and fine motor delays, deafness,
mia and the release of acute-phase proteins and poor coping skills. The increase in mor-
by the liver, such as C-reactive protein bidity among survivors also increases
(CRP). Inflammation in turn can serve as an markedly at an earlier gestational age.
independent biochemical threat to the fetal– In many ways, the fetus physiologically
placental unit by inducing labor, rupture of functions as a foreign body with parasitic
membranes, and early parturition. These properties. The placenta is an invasive fetal-
inflammatory processes can extend to the derived tissue and is efficient in its ability to
developing fetus to also threaten the health take nutrients from the mother. If the
of the neonate, an effect that may persist into mother is nutritionally deprived, the
childhood and even into adulthood by early mother’s reservoirs are depleted first. All the
intrauterine exposures that permanently placental nutrient exchange molecules have
affect neurologic and metabolic systems. higher binding affinities than those of the
Most of these concepts have been demon- mother to favor a unidirectional nutrient and
strated in animal models and reflected in vitamin exchange from mother to fetus. For
human data.15–17 example, if the mother is starving, the mater-
Normal term deliveries occur at 40 nal liver shrinks to one third of its normal
weeks; PTB is defined by delivery at less size during pregnancy and the fetus contin-
than 37 weeks’ gestation. Very PTB means ues to grow. Thus, any impairment in fetal
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A ! ! ! Guide !
! ! ! ! ! ! ! ! ! ! ! !
! ! ! ! ! ! ! ! ! ! !
Figure 1.! Percent Infant!Death Rate
! and
! Births! by Gestational
! ! !Age! !
Vital !statistics from

! years
! 1999–2000
! (single
! births
! only),
! N =! 349,688.
! !
growth is believed to be attributable to ture rupture of membranes (PPROM), one
impairments in nutrient exchange or third as a consequence of preterm labor, and
impaired growth factor secretion via placen- one third everything else, including
tal damage rather than to maternal-based preeclampsia and medical and fetal indica-
nutrient impairments. Prematurity, on the tions for delivery. Inflammation can extend
other hand, is due to maternal responses beyond the maternal membranes and uterus
that involve uterine smooth muscle contrac- to promote prematurity but can also reach
tion and rupture of the membranes. This is the placenta and fetus to impair growth and
a maternal tissue response triggered by an damage fetal tissues. Impaired growth or
inflammatory biochemical cascade. Infection growth restriction can occur at any gesta-
can be one important source of inflamma- tional age, even full-term babies can be small
tion, but fetal stress can be another source of for gestational age (SGA, typically defined as
inflammation that targets the maternal birth weight lower than the tenth percentile
uterine smooth muscle and/or the membrane of weight for gestational age). Many of the
integrity. Either or both can be involved in molecular and cellular inflammatory effector
pregnancy complications. pathways that underlie the pathogenesis of
About one third of preterm delivery PTB are also involved in growth restriction
occurs as a consequence of preterm prema- and developmental problems ranging from
respiratory distress to cognitive and learning more attenuated association demonstrated by

disabilities. For example, fetal neurologic the prospective studies. However, the optimal
tissues are especially susceptible to damage timing of periodontal disease treatment for
through cytokines, such as interferon gamma prevention of adverse pregnancy outcomes is
(IFN-g), which induce apoptosis and impair still a subject for future investigation.21
development of synapse connections among Thus, the consensus of the available
embryologic neurons.19 data support the concept that maternal peri-
Although advances in technology help odontal disease is associated with prematu-
to save infants who are born premature or rity. The specifics of maternal infection have
LBW, the lifelong problems associated with been studied in a few publications, and some
these conditions have not declined. trends appear. First, antenatal maternal
Potential risks to a baby born with fetal disease status or periodontal progression
growth restriction include the following: during pregnancy is most strongly associated
• Increased risk for motor and neuro- with earlier deliveries. That is, periodontal
logic disabilities infection as an exposure appears to confer
• Chromosomal abnormality greater risk to the pregnancy early in gesta-
• Hypoglycemia tion, as illustrated in Figure 2. As the expo-
• Increased risk for hypoxia sure occurs closer to term, the risk dimin-
• Decreased oxygen levels ishes, but remains statistically significant at
Selected neonatal complications after greater than 1.0. For example, the hazards
PTB include the following: ratio of delivery at 32 weeks of gestational
• Chronic lung disease age for moderate to severe periodontal
• Developmental delay disease is about 3.7, but less than 2.0 by 35
• Growth impairment weeks (see Figure 2). A similar relation can
• Periventricular leukomalacia be seen with bacterial vaginosis, a vaginal
• Respiratory distress syndrome infection that increases risk of prematurity.
• Hearing impairment Thus, as the fetal–placental unit nears deliv-
• Intraventricular hemorrhage ery, it appears less susceptible to infectious
and inflammatory challenge.
ASSOCIATION OF PRETERM BIRTH Another more direct assessment that
AND FETAL GROWTH RESTRICTION periodontal pathogens may translocate to
WITH PERIODONTAL DISEASE the fetal–placental unit derives from data
The human data supporting an association generated by other laboratory techniques
between maternal periodontal disease and such as polymerase chain reaction (PCR)
PTB have been recently reviewed by Ide and and immunochemistry. Specifically, León
Papapanou.20 In this systematic review, the and colleagues22 found that from the nine
high degree of heterogeneity of the study bacteria tested only Porphyromonas gingivalis
populations, as well as differences in method- seemed to invade the amniotic cavity, since it
ology, are highlighted. The authors found 18 was detected in the amniotic fluid of women
publications suitable for qualitative analysis, with threatened preterm labor. P. gingivalis
including five case-control, three cross-sec- and Actinobacillus actinomycetemcomitans
tional, and 10 prospective studies. This sys- have also been found in the placentas of
tematic review revealed a positive, independ- women with PTB or preeclampsia.23–25
ent association between maternal periodonti- Moreover, in a case of PTB the oral species
tis and PTB and LBW emerging from cross- Bergeyella was identified in the amniotic
sectional and case-control studies with a fluid.26 Fusobacterium nucleatum is also one
Figure 2. Hazards Ratio for Preterm Delivery at Various Gestational Ages Based on
Maternal Periodontal Status
Source: Offenbacher S, Beck J. Has periodontal treatment failed to reduce adverse pregnancy outcomes? The answer
may be premature. J Periodontol 2007;78:195–7. Reproduced with the permission of the American Academy of
Periodontology.
of the most common isolates from the amni- always good indicators of the risk for preg-
otic fluid of patients with preterm low birth nancy complications. This point is best illus-
weight and intact membranes, but has also trated by a secondary analysis of the Oral
been detected in the chorionic tissues of Conditions and Pregnancy (OCAP) study,
high-risk pregnant women.27,28 Finally, P. gin- which tries to examine the role of these
givalis, F. nucleatum, and Capnocytophaga various maternal-fetal compartments simul-
have been found in neonatal gastric aspirates taneously.
obtained from complicated pregnancies, indi- Figures 3 through 5 represent secondary
cating a possible bacterial translocation to analyses of previously published findings
fetal organs.29 that are reorganized to reflect the adverse
Note that periodontal pathogens have outcome based on the timeline of pregnancy
also been detected in the amniotic/fetal–pla- complication, that is, gestational age deliver-
cental tissues of women with normal preg- ies of less than 37 weeks, less than 35 weeks,
nancies.23 Moreover, studies have shown that and less than 32 weeks. We include as poten-
it is possible to isolate bacteria considered as tial exposure variables all the available mater-
periodontal pathogens from periodontally nal clinical findings:
healthy subjects.30 On this basis, it is • Antenatal status: periodontal health,
unknown (1) what factors determine mild and moderate/severe disease
whether the translocation of these pathogens • Incident disease: progression during
to the fetal–placental unit will contribute to pregnancy
pregnancy complications and (2) whether the • Microbiologic status: (subgingival counts
clinical parameters of periodontal disease are of orange complex organisms antena-
tally (red and other complexes not signif- delivery, as defined by gestational age of less
icant) than 37 weeks indicates that there are three
• Antenatal maternal antibody (mater- variables significantly associated with preterm
nal IgG to orange complex organisms) delivery. In decreasing order of effect, they
• Fetal exposure, as indexed by fetal are race, progression of periodontal disease,
cord blood IgM seropositivity to oral and severity (moderate/severe) of periodontal
organisms at delivery (red plus orange) disease. It is significant that incident disease
• Traditional maternal risk factors such (increase of pocket depth by more than 2
as age, first pregnancy, and smoking mm with a pocket depth of at least 4 mm at
By including all these variables in a postpartum in more than four sites) is the
single model, our original OCAP sample size most important periodontal predictor of
of 1,020 decreases to 439 for this analysis, gestational age if less than 37 weeks. This
largely because of the lack of cord blood includes even periodontally healthy mothers
data for measuring fetal exposure, bacterial who developed incident periodontal disease
counts, and serum antibody levels. Nonethe- during pregnancy. Mild periodontal disease
less, we have statistically significant logistic had no effect on the rate of prematurity, nor
models for each adverse outcome, and it is did any microbial or antibody markers.
informative to appreciate how these different However, the overall area under the curve
exposures relate to the gestational age at (AUC) for this model is only 0.65, so the
delivery. The data are displayed using effects of periodontal disease parameters are
receiver operator curves (ROC) showing the statistically significant, but are weak predic-
area under the curve for each exposure vari- tors. For this reason, measuring only mater-
able, which reflects the magnitude of the nal periodontal status antenatally without
effect and the area for the overall model. In measuring periodontal progression might
these three models, we include all variables easily result in null findings of association
and highlight those in red that are statisti- with PTB.
cally significant (i.e., 95% Wald confidence Figure 4 illustrates the model for gesta-
limits do not include 0.5). tional age of less than 35 weeks, which is
In Figure 3, the association with preterm associated with much greater neonatal mor-
Figure 3. Secondary Analysis of Risk Outcome Group (< 37 Weeks’ Gestation)
Figure 4. Secondary Analysis of Risk Outcome Group (< 35 Weeks’ Gestation)
bidity. Approximately 50% of all preterm potential protective role of the maternal anti-
deliveries occur between 35 and 37 weeks’ body response. Most important, in Figure 5
gestation, but most of the newborns have fetal exposure now occurs in this model.
lower morbidity or mortality than those at This is consistent with the previous discus-
gestational age of less than 35 weeks, sions of periodontal progression with high
whereas those at gestational age of less than bacterial load in the absence of protective
32 have the highest morbidity and mortality maternal antibody leading to increased fetal
rates. For gestational age of less than 35 challenge and adverse outcomes.
weeks, again race is the major explanatory In Figure 5, we are examining the
variable. However, the antenatal periodontal highest risk outcome group for those deliver-
status is no longer significant in the model, ies at less than 32 weeks. In this model only
only progression is. Furthermore, the mater- three variables are predictive—race (non-
nal microbial load (orange complex) and the Caucasians = African Americans and His-
interaction with maternal serum IgG levels panics), periodontal disease progression, and
to the orange complex are both significant fetal exposure. Other variables contribute to
contributors. There is a significant interac- the overall model as the overall AUC is
tion term here between the maternal antena- 0.935. Thus, for this highest risk group and
tal IgG to orange complex and the level of earliest event, maternal progression and fetal
the organisms in the plaque. The risk occurs exposure are the most important oral com-
when the maternal serum levels are low and ponents of risk.
the microbe levels are high. This suggests a Although the key periodontal pathogens
lack of protective antibody. Recently, Singer possess specific virulence factors that enable
and colleagues31 linked high oxidative stress them to colonize, evade host defenses, and
to poor IgG response to the commensal invade host tissues, in the case that periodon-
biofilm in a community-based study. This is tal pathogens reach, while alive, the fetal–pla-
interesting in the context of the reports of cental unit, it is unclear whether they will
high oxidative stress as a risk factor for remain in a planctonic form or will develop
abnormal pregnancy outcomes and the a biofilm, as in the case of dental plaque.32
Figure 5. Secondary Analysis of Highest Risk Outcome Group (> 32 Weeks’ Gestation)
Recently, the presence of a particulate matter following oral–genital transfer. However,

in the amniotic fluid, recognized as “amni- because not all women who experience preg-
otic fluid sludge,” was associated with the nancy complications have genital infections
presence of bacteria and intra-amniotic and because periodontal pathogens and/or
inflammation. Electron microscopy provided their byproducts may enter the blood circu-
evidence that this sludge was indeed a lation, these pathogens very likely may
biofilm. Whether several different periodon- translocate to the fetal–placental unit by
tal pathogens are necessary to translocate to hematogenous spread. It is possible that
the fetal–placental unit and form a biofilm disease progression may potentially facilitate
or whether periodontal pathogens could col- dissemination. It is interesting that Campy-
onize a biofilm formed by other extraoral lobacter rectus is associated with the clinical
bacteria remains a mystery.33 sign of bleeding on probing and has been
Since evidence indicates that periodontal implicated as a key fetal pathogen.34 To date,
pathogens, dead or alive, may reach the two studies in humans provide evidence of
fetal–placental unit, the question arises as to this route of infection. In one case, the same
the origin of these pathogens. The current clonal type of uncultivated oral Bergeyella
paradigm indicates that most intrauterine was identified in the subgingival plaque and
infections originate in the lower genital tract, the amniotic fluid of a woman with PTB,
with the infectious agents ascending into the whereas no Bergeyella cells were detected in
otherwise sterile womb. Usually, the amni- the mother’s vaginal tract.26 In the second
otic membranes and the placenta are the case, oral F. nucleatum was identified as the
first to be infected, followed by the fetus via cause of a term stillbirth and was isolated
the blood vessels of the umbilical cord or from the lung and stomach of the infant.
the aspiration of the infected amniotic The same clonal type of F. nucleatum was
fluid.10 Hence, it is reasonable to suggest that present in the subgingival plaque of the
periodontal pathogens may enter the amni- mother, but not in her vaginal or rectal
otic space as a result of ascending infection microflora.35
Besides periodontal pathogens, the Proinflammatory cytokines released in

adverse effects on pregnancy could be medi- the maternal circulation along with the tran-
ated by the release of major components of sient bacteremia from periodontal tissues may
the bacterial cell wall (i.e., lipopolysaccha- also induce a low-grade systemic inflamma-
rides [LPS] or other virulence factors). LPS tion by stimulating the production by the liver
in the systemic circulation can bind either to of acute-phase reactants such as CRP and
serum proteins or to LPS-binding proteins fibrinogen. Elevated levels of plasma CRP
and reach the maternal–fetal interface. As could amplify the inflammatory response at
described later, local host cells may interact the fetal–placental interface through comple-
with these byproducts and produce inflam- ment activation, tissue damage, and induction
matory cytokines (tumor necrosis factor of proinflammatory cytokines. Thus, CRP
alpha [TNF-a], interleukin 1 [IL-1], and IL- has been associated not only with periodontal
6) and mediators (prostaglandin E2 [PGE2]). disease, but also with pregnancy complica-
Since, during pregnancy, the innate proin- tions such as PTB, intrauterine growth restric-
flammatory immune response is strictly regu- tion (IUGR), preeclampsia, and gestational
lated within the uterus to prevent immuno- diabetes mellitus.44–47
logic rejection of the fetal allograph, this Although pregnant women with moder-
local increase in proinflammatory mediators ate to severe periodontal disease have ele-
may disrupt this delicate balance and elicit vated levels of serum CRP,48 to date, only a
an inflammatory burden that may contribute few studies have evaluated the association
to preterm rupture of the membranes and between pregnancy complications and CRP
uterine contraction, which may, in turn, lead levels in patients with periodontitis. Thus,
to miscarriage or preterm delivery. several reports indicate that elevated CRP
Patients with periodontitis also experi- levels in pregnant women with periodontitis
ence an increase in the production of proin- appear to mediate PTB and preeclampsia,49–51
flammatory cytokines and mediators from whereas others found no such association.52
periodontal tissues. Once released, they may Perhaps periodontal disease and CRP
diffuse in the gingival crevicular fluid or share a common risk factor predisposing
enter the blood circulation and reach the certain persons to a hyperinflammatory
placenta–fetus interface. IL-1, IL-6, and response.
TNF-a could stimulate the production of Other, less common, adverse pregnancy
prostaglandins in the chorion and, in con- outcomes (e.g., diabetes, small-for-gestational-
junction with the maternally derived PGE2 age birth weight, miscarriage) may also be
generated at the gingival level and released in associated with maternal periodontal infec-
the circulation, may exacerbate cervical tion. Infants who are small for gestational age
ripening and uterine contraction, leading to (less than the 10th percentile for birth weight)
an increased risk for PTB. However, have significantly higher neonatal mortality
although elevated serum and amniotic fluid rates when compared with appropriate- and
levels of these cytokines and mediators have large-for-gestational-age infants.4
been associated with various adverse preg-
nancy outcomes,35–37 evidence is limited and PREECLAMPSIA
mostly negative that the elevation of these Risk Factors and Complications
mediators in either the gingival crevicular Preeclampsia is a pregnancy complication
fluid, the serum, or the amniotic fluid are recognized by new-onset gestational hyper-
associated with pregnancy complications in tension and proteinuria. It is considered one
periodontitis patients.38–43 of the most significant health problems in
human pregnancy, and it complicates 8% to in the placenta protecting the fetus from
10% of all pregnancies. The disorder affects maternal immune attack by reducing cell-
both mothers and their infants with consid- mediated immunity.57 Fetal cells contribute to
erable fetal mortality and morbidity owing the process by producing immunosuppressive
to the effects of the disease on the fetus as cytokines, chemokines, and prostaglandins
well as to prematurity. The induced delivery that dampen T-lymphocyte proliferation and
in women, to prevent the progression of export high levels of immune suppressive
preeclampsia, is responsible for 15% of all hormones such as progesterone. Case reports
PTBs.53 In the last two decades, appreciation have linked gastrointestinal, urinary, and
that preeclampsia is a multisystem syndrome lower genital tract infections to the develop-
characterized by vasoconstriction, metabolic ment of preeclampsia.58
changes, endothelial dysfunction, activation Maternal clinical periodontal disease at
of the coagulation cascade, and increased delivery has been associated with an
inflammatory response has redirected increased risk of preeclampsia, independent
research. Intravascular inflammation and of the effects of maternal age, race, smoking,
endothelial cell dysfunction, with altered pla- gestational age at delivery, and insurance
cental vascular development, is believed to status. In addition, clinically active disease, as
be central to the pathogenesis of preeclamp- measured by periodontal disease progression,
sia.54 Cardiovascular, central nervous, renal, was also associated with an increased risk of
respiratory, hepatic and coagulation systems preeclampsia.59
are affected to variable extents, increasing
maternal blood pressure with proteinuria Association of Preeclampsia with
during pregnancy. Risk factors for Periodontal Disease
preeclampsia include obesity, diabetes, and Boggess and colleagues59 were the first inves-
inflammation.55 tigators to report an association between
Women with preeclampsia are three to maternal clinical periodontal infection and
four times more likely to deliver a small-for- the development of preeclampsia. In a longi-
gestational-age infant than are women tudinal study of over 1,000 women, the pres-
without preeclampsia. Conservatively esti- ence of periodontal infection at delivery, or
mated, 20,000 PTBs at less than 34 weeks disease worsening during the course of preg-
occur annually in the United States as a nancy, was associated with a twofold
result of complications of preeclampsia. increased risk for preeclampsia compared
Potential mechanisms associated with with that of women without periodontal
preeclampsia include direct local effects of infection or progression. Since that report,
infectious agents on endothelium (on vascu- several other investigators have demonstrated
lar smooth muscle cells and/or on an association between maternal periodontal
macrophages within the atherosclerotic infection and preeclampsia. Canakci and
lesion) or amplification of the systemic colleagues58 reported that women with
inflammatory response.56 There are epidemi- preeclampsia were three times more likely to
ologic data supporting the premise that have periodontal infection than healthy nor-
chronic infection could link preeclampsia to motensive women and that periodontal
later atherosclerosis, especially given the disease also affects the severity of preeclamp-
increased susceptibility to chronic infection sia. In another case-control study, Barak and
due to reduced cell-mediated immunity in associates24 also found that women with
pregnancy (helper T cell type 1 [Th1]), which preeclampsia had more severe periodontal
is the outcome of the trophoblastic activity disease compared with healthy controls, with
significant elevation in gingival crevicular been suggested that this difference in preva-
fluid levels of PGE2, IL-1 , and TNF-a . In lence may partly explain the observed
another study, women with preeclampsia increased risk in preterm delivery and fetal
were found to have worse periodontal infec- growth restriction among African Ameri-
tion compared with healthy women. In addi- cans.23 Studies exploring the connection
tion, two “red complex” microorganisms, P. between maternal infection with specific peri-
gingivalis and Tannerella forsythensis, were odontal pathogenic organisms and periodon-
more prevalent in the oral plaque among tal disease progression in relation to fetal
preeclamptic women compared with con- immune response to oral pathogens have
trols.60 All these studies raise the question as generally supported the notion that peri-
to whether periodontal treatment may be a odontitis is independently associated with
potential preventive intervention therapy for PTB and LBW.
preeclampsia through periodontal infection In 2001, Madianos and colleagues32
control. analyzing clinical data from the first 812
deliveries from OCAP, a cohort study of
ASSOCIATION OF PERIODONTAL pregnant mothers, demonstrated that both
DISEASE AND ADVERSE antepartum maternal periodontal disease
PREGNANCY EVENTS and incidence/progression of periodontal
Human Studies disease are associated with PTB and growth
Several studies suggest a significant associa- restriction after adjusting for traditional
tion between maternal periodontal disease obstetric risk factors. The high prevalence of
and pregnancy complications such as prema- elevated fetal IgM to C. rectus among pre-
ture delivery and preeclampsia.24,60,61 mature infants raised the possibility that this
Since the first reported case-control specific maternal oral pathogen contributed
study in humans,3 published in 1996 and as a primary fetal infectious agent eliciting
showing that mothers with premature, LBW prematurity.
babies have more severe periodontal disease With the objective to determine whether
independent of other traditional obstetric risk oral bacteria can be found in the amniotic
factors, many other studies have explored the cavity, Bearfield and associates42 collected
potential association between maternal peri- samples, including dental plaque and amni-
odontal disease and prematurity and LBW. otic fluid from 48 women attending for elec-
These studies have been generally, but not tive cesarean section delivery. Data analysis
universally, supportive of an association. indicated that Streptococcus spp. and F.
Moderate to severe periodontal disease nucleatum in the amniotic fluid may have an
(defined as 15 or more sites with 5 or more oral origin. Han and colleagues26 have also
mm of probing depth) is highly prevalent demonstrated that the exact same maternal
among pregnant women, with about 15% clonal type of oral organism can be isolated
affected during the first trimester and overall from the amniotic fluid in cases of PTB.
about 25% showing worsening periodontal More recently, Lin and colleagues,63
progression during pregnancy.14,32,62 Both exploring the underlying microbial and anti-
antenatal periodontal disease and progres- body responses associated with bacterial
sion during pregnancy appear to confer risk complexes most often linked with periodon-
for preterm delivery, and the strength of the titis, conventionally termed “orange” and
association increases at earlier gestational “red” microbial clusters, have found that
deliveries. Periodontal disease is twice as high levels of periodontal pathogens and low
prevalent among African Americans; it has maternal IgG antibody response to peri-
odontal bacteria during pregnancy are asso- they may induce pregnancy complications.
ciated with an increased risk for preterm Similar results occurred when various peri-
delivery, with higher levels of periodontal odontal microorganisms were injected into
pathogens measured antepartum in the the pregnant animals. Hence, in the chamber
preterm deliveries compared with the term model, P. gingivalis has been shown to
deliveries. Overall, the data from meta-analy- induce IUGR and elevated numbers of
ses that combine data from several studies resorptions in golden hamsters. Note that
continue to demonstrate a significant associ- the severity of these complications depended
ation between periodontal disease severity on the extent of the inflammatory response
and abnormal pregnancy outcomes. in the chamber as evaluated by the increased
levels of TNF-a and PGE2.64 IUGR, and
Animal Studies increased resorptions (analogous to miscar-
The studies that tried to evaluate the biologic riages) have also been demonstrated after
mechanisms behind the possible association intrachamber injection of P. gingivalis or C.
between periodontal disease and adverse rectus in mice.65–67 It is worth noting that
pregnancy outcomes used hamsters, mice, besides oral C. rectus, other Campylobacter
and rabbits. Several experimental models have species have been shown to be implicated in
been used to simulate in a simplified and the induction of pregnancy complications,
reproducible manner a periodontal infection especially in abortions of sheep and cattle.68
in these pregnant animals. Thus, periodontal Moreover, in humans, C. fetus, C. jejuni, and
bacteria or their pathogenic products (LPS) C. coli have been associated with abortion,
have been injected in the blood circulation PTB, and perinatal sepsis, whereas in mice
mimicking bacteremia. In other experiments, intravenous injection of these campylobac-
a metal chamber/cylinder was placed subcu- ters results in IUGR, impaired fetal develop-
taneously and periodontal bacteria were ment, and increase in resorptions.69,70 Finally,
injected in the chamber creating a distant site IV injection of F. nucleatum in mice resulted
of infection. Because of the open ends of the in premature delivery, stillbirths, and nonsus-
chamber, bacteria and/or their released tained live births.71
byproducts could leave the chamber and Since, in these animal models, infection
enter the systemic circulation, mimicking a with periodontal pathogens/byproducts
periodontal infection that takes place at a dis- could cause pregnancy complications, investi-
tance from the fetal–placental interface. gators tried to elucidate whether these
The first experiments occurred in microorganisms disseminate systemically and
golden hamsters. When P. gingivalis LPS was translocate to the fetal-placental unit. In the
injected intravenously before and during chamber model in mice, C. rectus DNA was
pregnancy, there was an increase in fetal found in the maternal liver and placenta of
malformation, IUGR, and resorptions. The infected dams.66 Similarly, P. gingivalis DNA
frequency and severity of these adverse preg- was detected in maternal liver, uterus, and
nancy outcomes were dose-dependent and placenta of the IUGR fetuses. Furthermore,
similar to those occurring after IV injection infected dams with IUGR fetuses presented
with E. coli LPS.64 This was the first proof with elevated levels of serum TNF-a and P.
of principle experiment to suggest a possible gingivalis-specific IgG antibodies and
association of periodontal disease with reduced levels of IL-10.65 However, IV infec-
adverse pregnancy outcomes. Specifically, it tion of mice with F. nucleatum was restricted
demonstrated that when periopathogenic inside the uterus, without spreading systemi-
byproducts enter the systemic circulation, cally. In studies by Arce and colleagues,72 C.
rectus was able to effectively invade human microorganisms are necessary. Recent reports
trophoblasts (BeWo) in culture but not by Arce and colleagues74 indicate that oral
murine trophoblasts (SM9-1) and showed a infection with the human periodontal
trend for more invasiveness than C. jejuni. C. pathogens C. rectus and P. gingivalis is able
rectus challenge significantly upregulated to induce fetal growth restriction and placen-
both mRNA and protein levels of IL-6 and tal inflammation and enhance Toll-like
TNF-a in a dose-dependent manner in receptors 4 (TLR4) expression in a murine
human trophoblasts, but did not increase pregnancy model. Pregnant mice were sacri-
cytokine expression in murine cells, suggest- ficed at embryonic day (E) 16.5, and placen-
ing a correlation between invasion and tas were collected and analyzed for TLR4
cytokine activation. mRNA levels and qualitative protein expres-
Both the chamber and the IV infection sion by real-time PCR and immunofluores-
models indicate that periodontal pathogens cence. TLR4 mRNA expression was found
may translocate to the fetal–placental com- to be increased in the C. rectus-infected
partment; however, there is a controversy group (1.98 +/- 0.886-fold difference, P <
concerning the activation of the systemic .01, ANOVA) compared with controls.
inflammatory/immune response and the dis- Microscopic analysis of murine placentas
semination of pathogens to other maternal showed enhanced immunofluorescence of
organs. It has been suggested that the TLR4 in trophoblasts, mainly in the placen-
chamber model represents a chronic infec- tal labyrinth layer. Also, combined oral infec-
tion, since P. gingivalis is repeatedly inocu- tion with C. rectus and P. gingivalis signifi-
lated systemically through the chamber, cantly reduced the overall fecundity com-
whereas the IV infection more closely resem- pared with controls (16.7% vs 75%, infected
bles an acute infection that mimics predomi- vs noninfected mice, respectively, P = .03,
nantly bacteremia. In the case of the acute Kaplan-Meier). The results supported an
infection, bacterial translocation is organ- enhanced placental TLR4 expression after
specific (i.e., only in the placenta), and this is oral infection with periodontal pathogens,
likely due to the immune suppression in the consistent with the known TLR4 activation
placenta, which allows the bacteria to prolif- in human placental inflammation and
erate freely, whereas the bacteria are killed by preterm pathogenesis.
the immune cells in the liver.73 Periodontitis Periodontal pathogens and/or their
is usually a chronic infection in which tran- byproducts may not need to be part of
sient bacteremias occur; hence, both models biofilms to have a deleterious effect on preg-
may coexist and explain the somewhat nancy. In a recent study, a diverse group of
diverse results in systemic inflammation oral bacteria were found to translocate to the
elicited by pregnant women. In addition, mouse placenta following IV injection with
both models support the hematogenous dis- pooled human saliva or subgingival plaque
semination of the periodontal pathogens from the deep pockets of periodontitis
without however, excluding the possibility of patients. Many of these bacteria have been
an ascending infection from the lower genital associated with pregnancy complications in
tract that may also occur in humans. humans, and the majority of them are oral
It is also clear that both models present commensal organisms.75 This is consistent
with a serious limitation, since they simulate with studies in humans in whom the fetus
more a mono-infection rather than an infec- may be exposed to various periodontal
tion organized in biofilms, in which the pres- pathogens.32 Also, it demonstrates the possi-
ence and collaboration of different types of bility that these pathogens may organize in
biofilms, as indicated by the recent finding of actinomycetemcomitans and P. gingivalis.

bacterial biofilms formed in the amniotic This is consistent with intrauterine infections
fluid from complicated pregnancies in in humans that lead to adverse pregnancy
humans.33 The tropism of oral organisms to outcomes.78 In murine placenta, inflamma-
the nutrient-rich fetal–placental unit may be tory responses induced by F. nucleatum and
analogous to the concept of anachoresis first C. rectus seem to be mediated via TLR-4.74,79
described by Ascoli in the early 1900s, which Histologically, this inflammatory
describes the fact that organisms disseminate response is accompanied by an increase in
systemically to seek out nutrient-rich envi- the inflammatory infiltrate, predominantly
ronments, such as those associated with by neutrophils, in the decidua, whereas F.
inflammation. nucleatum also stimulates decidual necrosis.79
In mice, the pattern of fetal–placental It is interesting that C. rectus infection
interface infection by F. nucleatum parallels induces major alterations in the structure of
that in humans. First, F. nucleatum is the placenta as indicated by the decrease in
detected in placental blood vessels. Maybe the size of the labyrinth.67 The labyrinth is
because of the slow blood flow in the the area of the placenta in which the
venous sinuses, the bacteria have the oppor- exchange of nutrients and waste between
tunity to invade the endothelial cells lining mother and fetus takes place. Hence, its
the vessels, cross the endothelium, proliferate diminished volume may imply insufficient
in the surrounding tissues, and finally spread nutrition of the fetus and consequently
to the amniotic fluid.71 These data suggest impaired growth and LBW. Furthermore,
that bacteria can survive in the oxygen-rich structural damage in the placenta may
blood circulation and reach the placenta. disrupt the normal blood flow between fetus
Moreover, they demonstrate that invasion and mother, affecting the maternal blood
may be an important virulence mechanism pressure and leading to preeclampsia.
for placental infection. In fact, it has been Using mRNA expression microarray
shown, that FadA adhesin of F. nucleatum technology, C. rectus infection in mice has
plays a critical role in this process.76 IV injec- been demonstrated to attenuate the expres-
tion of P. gingivalis into pregnant rats also sion of genes related to placental and fetal
caused strain-dependent colonization in the growth, such as platelet-derived growth
placenta, whereas C. rectus is able to invade factor (PDGF) which is the main placental
human trophoblast cells in vitro.72,77 Placental angiogenic factor, and insulin-like growth
colonization by all three bacteria has been factor-2 (IGF-2).80 The question that arose is
associated with intrauterine infections in whether infection reduced the size of the
humans, but perhaps other invasive peri- labyrinth that led to a decreased expression
odontal pathogens may have similar proper- of these genes or whether infection induced
ties as well.23,32 the attenuation in gene expression that
Colonization of periodontal pathogens resulted in impaired placental development.
in the placenta results in the induction of The question was partially answered by the
local inflammatory responses. Specifically, in examination of the expression of the murine
IUGR placenta infected with P. gingivalis, IGF-2 gene. This gene belongs to the group
there is an increase in IL-2 and IFN-g, of “imprinted genes” whose expression is
whereas IL-10 is reduced, indicating a shift dictated mainly by the methylation status of
in Th1/Th2 cytokine balance. IL-6 and their promoter. C. rectus infection induced
TNF-a are also elevated after stimulation of hypermethylation of the promoter of IGF-2,
human decidual cells with F. nucleatum, A. which was associated with the attenuation of
its expression.81 Since these epigenetic only primates and humans have preterm
changes are inherited in somatic cells, infec- deliveries. At moderate dosages of bacterial
tion of the fetus could alter the expression of challenge, there are enhanced maternal
imprinted genes and possibly affect the off- membrane and uterine inflammatory
spring throughout life. changes compared with those seen at lower
Finally, C. rectus infection elevated the dosages, but now there are also exposures
rates of neonatal mortality in mice. In the that reach the fetal tissues, beginning with
surviving pups, C. rectus was detected in the the placenta. Placental inflammation is asso-
brain and induced a local inflammatory ciated with alterations in placental architec-
response, which was accompanied by an ture that cause the incomplete development
increase in apoptosis and defects in nerve of the labyrinth zone of the placenta. This is
myelination.67 Similarly, human neonates the portion of the placenta that exchanges
exposed to both C. rectus and P. gingivalis nutrients from the maternal side to the fetal
are found to be twice as likely to be admit- side, and its incomplete development is asso-
ted to the neonatal intensive care unit ciated with impaired fetal growth. In rodents,
(NICU), whereas preterm infants have an one can see a clear linkage between placental
increased risk in developing neurodevelop- exposure of the organisms and fetal out-
mental, behavioral, and learning problems.82 comes. For example, a pregnant mouse
Early studies in animal models using would typically have seven to eight fetal
oral organisms as a challenge in the 1980s pups, each with their own placenta and
demonstrated a dose response that is related membranes. A maternal challenge of 107
to obstetric outcomes. At low microbial chal- colony-forming units (CFU)/mL of P. gingi-
lenges, there is a mild systemic inflammatory valis during pregnancy, as an example, would
response, which is associated with transient cause three of the eight fetuses to have
increases in circulating cytokines, like TNF-a impaired growth, and these would be runted.
and increases in activation of the hepatic Analysis of placentas from all eight fetuses
acute-phase response as evidenced, for shows that when P. gingivalis is found within
example, in mice by increases in serum the placenta, the fetus is runted, whereas P.
amyloid A (SAA). In rodents, the major gingivalis-negative placentas would have
acute-phase reactant is SAA, compared with normal-sized fetuses. Increasing the concen-
CRP in humans. Not only is there a mild tration to 3×107, one sees three normal
systemic inflammatory response at low levels fetuses, four runts, and two that have been
of challenge, there is also mild inflammation resorbed (fetus is nonviable). At even higher
of maternal amniotic membranes, increase bacterial concentrations, there are more
of inflammatory mediators within the amni- resorptions and more runts, with some runts
otic fluid, and uterine smooth muscle irri- having congenital anomalies. Thus, the
tability. The membranes and the uterus are higher the dose of microbial challenge, the
maternal tissues that become inflamed at low more severe the effect on fetal development
levels of microbial challenge. In humans, this and the possibility of birth defects among
inflammation would be associated with survivors. This suggests that many of these
earlier rupture of membranes and uterine infection-mediated complications appear as
contraction leading to preterm delivery. part of a continuum beginning with prema-
However, there are no animal models of turity to very preterm to growth restriction
preterm delivery. For example, in rodents to fetal loss and anomalies. Thus, when con-
there are changes in inflammatory mediators sidering the human condition, the level and
and histologic evidence of inflammation, but the timing of the exposure likely have a
major influence on the type of obstetric maternal challenge with C. rectus resulted in
complication observed. C. rectus infecting the fetal brain. This brain
Early work with pregnant rodent tropism is analogous to that seen during a
models exploring the role of maternal peri- maternal syphilis infection in humans. In the
odontitis as a potential maternal–fetal stres- rodent, this challenge was associated with
sor demonstrated that low-grade challenges increasing fetal brain levels of TNF-a
with oral organisms during pregnancy mRNA and attendant growth restriction.
resulted in impaired fetal growth that was This was accompanied by alterations in neu-
demonstrated using a chronic subcutaneous rodevelopment with altered myelination and
infection model and challenge with P. gingi- white matter damage in the hippocampus.67
valis.65 Later, using the same distant chronic In 2007, Bobetsis and colleagues81
infection model in mice and challenging with reported that, in addition to the inflamma-
P. gingivalis and C. rectus, it was also tory placental response triggered by maternal
demonstrated that low-grade infections with infections, there were also structural abnor-
oral organisms were associated with dissemi- malities in placental development with
nation to the fetal unit. These studies have impaired formation of the placental
shown the ability of the oral organisms to labyrinth zone. This zone is the point of
translocate hematogenously to the placental maternal–fetal vascular anastomoses that
tissues and cause growth restriction.65,83 The regulate nutrient and oxygen exchange and is
importance of placental dissemination was rich in spongiotrophoblasts, which secrete
convincingly demonstrated when it was growth factors such as IGF that stimulate
shown that those placentas that harbored fetal growth and development. In humans,
oral organisms had growth-restricted fetuses, impairment of placental IGF-2 expression is
whereas placentas from normal-sized litter- associated with intrauterine growth restric-
mates from the same mother had nonin- tion. Therefore, we examined whether the
fected placentas. Thus, once at the site of the alterations in placental structure seen in our
placenta, P. gingivalis has been shown to pregnant mouse infection model were related
modulate both fetal growth and the local to IGF-2 suppression in murine IUGR. Not
Th1/Th2 immune response.65 Evidence from only did Bobetsis and collaborators demon-
pregnant murine infection models indicates strate that IUGR was associated with low
that maternal challenge with P. gingivalis that IGF-2 placental expression, but that this
resulted in growth restriction was also associ- suppression was due to alterations in the pla-
ated with increases in maternal TNF-a and cental chromatin structure. This alteration in
a suppression of IL-10 within the serum.67 chromatin structure specifically involved
This was accompanied by an increase in pla- altered DNA methylation of the IGF-2 pro-
cental mRNA expression of IFN-g and IL-2 moter, which is termed an epigenetic modifi-
as well as a decrease in IL-10, IL-4 and cation, since it does not involve a sequence
TGF-a. Thus, P. gingivalis challenge was change but does result in a change in gene
associated with an overall increase in the pla- expression, which can persist even following
cental Th1/Th2 ratio, consistent with the gene replication.81 These investigators
observed shifts seen in human growth reported that the bacterial infection induced
restriction. epigenetic modification of placental tissues
In rodents and humans, there is no represented by hypermethylation of the IGF-
blood-brain barrier early in gestation, and 2 gene, with consequent downregulation of
organisms that cross the placenta can also this gene, which plays a critical role in fetal
reach the brain. In rodent models, a distant growth and development programming.84
With these findings, investigators pro- increase the rate of adverse events, suggest-
posed a new mechanism linking an environ- ing that periodontal treatment during preg-
mental infectious and inflammatory insult to nancy may be safe. Nonetheless, one large
now include epigenetic modifications. Epige- multicentered study conducted by
netic modifications carry important conse- Michalowicz and colleagues89 that was
quences for development, since they can be included in this treatment meta-analysis
permanently retained in the genome. These failed to show any obstetric benefits, suggest-
potentially permanent alterations may in ing that additional treatment studies need to
part explain the poor prognosis of the infant be conducted to better understand the
born small for gestational age (SGA), potential risks and benefits of periodontal
because the modifications that occur in utero care. Also, Offenbacher and colleagues90
due to alterations in methylation patterns reported data from a multicenter, random-
may persist for the entire life of the offspring. ized, controlled clinical trial investigating
This was proposed as a new hypothesis pregnant women with periodontal disease
underlying the linkages found between who received periodontal therapy and stan-
preterm delivery and diseases of the offspring dard obstetric care to reduce obstetric risk;
that account for a wide spectrum of adult- the results indicated that periodontal therapy
onset diseases that include neurologic impair- during pregnancy did not alter the rates of
ments and adult-onset conditions, such as PTB, or fetal growth restriction. However, it
diabetes and cardiovascular disease.85,86 This was also reported that the progression of
concept raises the possibility that intrauterine periodontal disease could not be controlled
exposure to oral organisms of maternal by the treatment rendered between baseline
origin may have more permanent effects that and delivery in 40.7% of the treatment
extend beyond the prenatal period. group, and only a small proportion of the
women treated for periodontal disease
INTERVENTION TRIALS achieved what would be considered peri-
Early clinical trials that have provided periodontal health.
odontal treatments with scaling and root Thus, it remains to be proven whether
planing have shown promise for preventing periodontal disease is a reversible cause of
PTB. A landmark study by Lopez and col- PTB or pregnancy complications. Further-
laborators87 suggested that periodontal treat- more, the linkage with neonatal health and
ment may reduce the rate of preterm deliver- the recent discovery of intrauterine epige-
ies fivefold. However, many additional clini- netic influences raise important questions for
cal trials are still in progress. The data are future studies to determine the impact of
encouraging, but not conclusive. A recent maternal infection on the health of the baby
meta-analysis conducted by Polyzos and col- from birth through adulthood.
leagues88 summarized the available data from
seven randomized trials and reported that FUTURE STUDIES
overall treatment reduced prematurity. The Clearly, additional research is needed to
overall reported odds ratio was 0.48; 95% understand the effects of periodontal treat-
CI, 0.23-1.00; P = .049. Thus, there is ment on pregnancy outcomes. Many clini-
marked consistency between the two meta- cians and scientists continue to debate when
analyses in that periodontal disease increases the findings from association studies and
the risk 2.8-fold and treatment potentially treatment studies enable us to infer causality.
decreases the risk twofold. Furthermore, the Some suggest that the Bradford Hill criteria
treatment provided does not appear to of causality (strength, consistency, specificity,
temporality, biologic gradient, biologic plau- ferent potencies. Furthermore, the emphasis
sibility) need to be applied before we con- has been artificially placed on periodontal
sider public health consequences. However, disease and the importance of clinical signs
not all causes of disease are modifiable. For and responses to treatment rather than on
example, bacterial vaginosis is generally understanding the role of these commensal
believed to be a cause of prematurity, and organisms in pregnancy. Hence, how all
yet most intervention trial studies fail to these organisms interact with each other or
show any benefits of treatment. This sug- act separately to induce pregnancy complica-
gests that the treatments either confer addi- tions is still far from understood. In addi-
tional risk unto themselves or fail to modify tion, the host’s susceptibility with regard to
the components of the vaginal infection that its ability to control the infection and
confer risk. Note that maternal periodontal whether an underlying genetic predisposition
health is in itself an extremely important due to a hyperinflammatory trait places
outcome regardless of the potential influence women at risk for both periodontal disease
on pregnancy. Thus, as long as periodontal and pregnancy complications remain impor-
care can be provided safely, it is difficult to tant missing pieces of the puzzle.
imagine a downside to improving maternal
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68. Simor A, Karmali M, Jadavji T, Roscoe M. placentas in an infection-induced intrauterine
Abortion and perinatal sepsis associated with growth restriction model: a microarray analysis.
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1986;8(3):397–402. 81. Bobetsis YA, Barros SP, Lin DM, Weidman JR,
69. Guerrant RL, Lahita RG, Winn WC, Roberts Dolinoy DC, Jirtle RL, et al. Bacterial infection
RB. Campylobacteriosis in man: pathogenic promotes DNA hypermethylation. J Dent Res
mechanisms and review of 91 bloodstream in- 2007;86(2):169–74.
fections. Am J Med 1978;65(4):584–92. 82. Bobetsis YA, Barros SP, Offenbacher S. Explor-
70. O’Sullivan A, Dore C, Boyle S, Coid C, Johnson ing the relationship between periodontal disease
A. The effect of campylobacter lipopolysaccha- and pregnancy complications. J Am Dent Assoc
ride on fetal development in the mouse. J Med 2006;137(Suppl 2):7S–13S.
Microbiol 1988;26(2):101–5. 83. Offenbacher S, Riche E, Barros S, Bobetsis Y,
71. Han YW, Redline RW, Li M, Yin L, Hill GB, Mc- Lin D, Beck J. Effects of maternal Campylobac-
Cormick TS. Fusobacterium nucleatum induces ter rectus infection on murine placenta, fetal and
premature and term stillbirths in pregnant mice: neonatal survival, and brain development. J Pe-
implication of oral bacteria in preterm birth. In- riodontol 2005;76(11-s):2133–43.
fect Immun 2004;72(4):2272–9. 84. Constancia M, Hemberger M, Hughes J, Dean
72. Arce RM, Diaz PI, Barros SP, Galloway P, Bo- W, Ferguson-Smith A, Fundele R, et al. Placen-
betsis Y, Threadgill D, et al. Characterization of tal-specific IGF-II is a major modulator of pla-
the invasive and inflammatory traits of oral cental and fetal growth. Nature
Campylobacter rectus in a murine model of fe- 2002;417(6892):945–8.
toplacental growth restriction and in tro- 85. Allin M, Rooney M, Griffiths T, Cuddy M,
phoblast cultures. J Reprod Immunol Wyatt J, Rifkin L, et al. Neurological abnormal-
2010;84(2):145–53. ities in young adults born preterm. J Neurol
73. Han Y. Oral health and adverse pregnancy out- Neurosurg Psychiatry 2006;77(4):495–9.
comes–what’s next? J Dent Res 2011;90(3):289–93. 86. Mericq V. Prematurity and insulin sensitivity.
74. Arce RM, Barros SP, Wacker B, Peters B, Moss Horm Res 2006;65( Suppl 3):131–6.
K, Offenbacher S. Increased TLR4 expression in 87. Lopez NJ, Da Silva I, Ipinza J, Gutierrez J. Pe-
murine placentas after oral infection with peri- riodontal therapy reduces the rate of preterm
odontal pathogens. Placenta 2009;30(2):156–62. low birth weight in women with pregnancy-as-
sociated gingivitis. J Periodontol 2005;76(11 periodontal disease and the risk of preterm birth.
Suppl):2144–53. N Engl J Med 2006;355(18):1885–94.
88. Polyzos NP, Polyzos IP, Mauri D, Tzioras S, 90. Offenbacher S, Beck JD, Jared HL, Mauriello
Tsappi M, Cortinovis I, et al. Effect of peri- SM, Mendoza LC, Couper DJ, Stewart DD,
odontal disease treatment during pregnancy on Murtha AP, Cochran DL, Dudley DJ, Reddy
preterm birth incidence: a metaanalysis of ran- MS, Geurs NC, Hauth JC; Maternal Oral Ther-
domized trials. Am J Obstet Gynecol apy to Reduce Obstetric Risk (MOTOR) Inves-
2009;200(3):225–32. tigators. Effects of periodontal therapy on rate
89. Michalowicz BS, Hodges JS, DiAngelis AJ, Lupo of preterm delivery: a randomized controlled
VR, Novak MJ, Ferguson JE, et al. Treatment of trial. Obstet Gynecol 2009:114(3):551–9.
CHAPTER 10
Oral Health and Diseases of the
Respiratory Tract
Frank A. Scannapieco, Joseph M. Mylotte
INTRODUCTION terial pneumonia was categorized into

Because the surfaces of the oral cavity are several subtypes: community-acquired pneu-
contiguous with those of the trachea and monia, aspiration pneumonia, hospital-
lower airway, pathogenic bacteria that colo- acquired (nosocomial) pneumonia, ventila-
nize the oral cavity can be aspirated into the tor-associated pneumonia, and nursing
lower airway to cause infection. These bacte- home-associated pneumonia. In all cases,
ria can be exogenous pathogens, which are connections have been made with oral health
not normal members of the oral flora, or status. However, in 2005, a new category was
endogenous, opportunistic commensal created called healthcare-associated pneumo-
organisms. In addition, oral inflammation, nia or HCAP.6 HCAP was defined as pneu-
for example in the form of periodontal monia occurring in a diverse group of
disease, results in release of biologically patients, including those undergoing home
active inflammatory mediators and infusion therapy or wound care or chronic
hydrolytic enzymes into the oral fluids, which dialysis, recently hospitalized patients, or
may also be aspirated into the airway to nursing home residents. The common
incite inflammation and increase susceptibil- denominator for this diverse group was the
ity to infection. Recent evidence suggests supposed high risk for pneumonia caused by
that oral bacteria and oral inflammation are multidrug-resistant organisms such as methi-
associated with respiratory diseases and con- cillin-resistant Staphylococcus aureus or
ditions with significant morbidity and mor- resistant gram-negative bacilli. As a result,
tality. Furthermore, some respiratory illnesses treatment guidelines for HCAP include
(such as asthma) may have an effect on oro- broad-spectrum antibiotic therapy. Since the
facial morphology or even on the dentition. publication of the ATS/IDSA (American
This chapter discusses several important res- Thoracic Society/Infection Diseases Society
piratory diseases that may be influenced by of America) guideline describing HCAP,
the oral microflora or oral inflammation. there has been considerable concern that this
Much of the material presented has been group is too diverse, and nursing home-
previously reviewed and discussed.1–5 associated pneumonia (NHAP) is clearly the
most important infection in this category.7
PNEUMONIA The authors also note that although NHAP
Pneumonia is an infection of the lungs tends to be associated with a higher mortal-
caused by bacteria, mycoplasma, viruses, ity rate than community-acquired pneumo-
fungi, or parasites. Bacterial pneumonia is a nia, recent studies have found that the preva-
common and significant cause of mortality lence of multidrug-resistant organisms as an
and morbidity in human populations. Pneu- etiologic agent in this group is low. There-
monia, together with influenza, is an impor- fore, in this chapter NHAP is reviewed as a
tant cause of death throughout the world. distinct entity rather than being grouped
Pneumonia also contributes to morbidity together as part of HCAP. In addition, an
and decline in quality of life as well as in increasing number of studies have evaluated
increased medical care costs. Formerly, bac- methods for improving oral hygiene in
CHAPTER 10 Oral Health and Diseases of the Respiratory Tract 177
nursing home residents as a method of arette smoking, usual contact with children,
reducing rates of pneumonia. sudden changes of temperature at work,
inhalation therapy (particularly containing
Community-Acquired Pneumonia steroids), oxygen therapy, asthma, and
Community-acquired pneumonia (CAP) is chronic bronchitis all to be independent risk
an important cause of morbidity and mor- factors for CAP. It is interesting to note that
tality. Bacterial pneumonia is often preceded a visit to a dentist in the previous month was
by viral infection or Mycoplasma pneumo- an independent protective factor for CAP,
niae infections, which diminish the cough presumably by encouraging improvements in
reflex, interrupt mucociliary clearance, and oral hygiene, which can limit colonization by
enhance pathogenic bacterial adherence to respiratory pathogens. A recent case-control
the respiratory mucosa to foster the chain of study assessed the association between peri-
events that may eventually lead to CAP.8 odontal infections and CAP in a group of
The major etiologic agents of CAP are patients admitted to a hospital.12 A total of
viruses, such as respiratory syncytial virus 140 patients were enrolled, with 70 patients
and rhinovirus. Bacterial causes of CAP having CAP (case group) and the other 70
include group B streptococci or gram-nega- patients being diagnosed with other systemic
tive enteric bacteria early in life, as well as diseases (control group). Chronic periodonti-
Streptococcus pneumoniae. S. pneumoniae tis was more common in patients with CAP
and Haemophilus influenzae are often the (case: 61.4 %; control: 41.4 %), and the pres-
cause of CAP in adults. ence of moderate or severe chronic peri-
odontitis increased the risk for CAP over
Epidemiology fourfold, even after adjusted for age, ethnic-
About 4 million CAP cases occur in the ity, gender, and smoking.
United States each year.9 Most of these
patients are treated outside the hospital. For Symptoms and Diagnosis
example, a recent large, population-based Common clinical symptoms of CAP include
cohort study of 46,237 seniors aged 65 and cough, fever, chills, fatigue, dyspnea, rigors,
older were observed over a 3-year period.10 and pleuritic chest pain.9 Depending on the
The overall rate of CAP ranged from 18.2 pathogen, a patient’s cough may be persistent
cases per 1,000 person-years among persons and dry, or it may produce sputum. Other
aged 65 to 69 years to 52.3 cases per 1,000 presentations may include headache and
person-years among those 85 and older. In myalgia. Certain bacteria, such as Legionella,
this population, 59.3% of all pneumonia may induce gastrointestinal symptoms.
episodes were treated on an outpatient basis. Chest radiography is a critical tool for
Overall, CAP results in more than 600,000 the diagnosis of pneumonia. A typical posi-
hospitalizations, 64 million days of restricted tive chest radiograph shows consolidation
activity, and 45,000 deaths annually. within the lung lobe, or a more diffuse infil-
tration.9 However, chest radiography per-
Risk Factors formed early in the course of the disease
Risk factors for CAP are age, male gender, may be found to be negative.
chronic obstructive pulmonary disease, A worrisome recent development is the
asthma, diabetes mellitus, congestive heart emergence of community-acquired methi-
failure, and smoking.10 In a study of 1,336 cillin-resistant Staphylococcus aureus (MRSA)
patients with CAP and 1,326 controls for infections, including CAP.13 Although it is still
risk factors,11 multivariate analysis found cig- a rare infection, it has been found in one
study that the median age of MRSA patients, vated risk of aspiration of oral contents into
four of whom died, was 21 years, and usually the lung, such as those with dysphagia or
a short interval occurred between the devel- depressed consciousness, and is very common
opment of respiratory symptoms and the in the nursing home setting. Aspiration pneu-
detection of disease.13 monia may also occur in the community.
Most adults inhale small amounts of
Treatment oropharyngeal secretions during sleep.
Antibiotics are the cornerstone of treatment However, the small number and typically avir-
for CAP. Guidelines for the treatment of CAP ulent nature of the commensal microflora, as
were originally published in 1993 and have well as defense mechanisms such as coughing,
been revised several times. The most recent ciliary action, and normal immune mecha-
guideline was published in 2007 by the Ameri- nisms all work together to prevent onset of
can Thoracic Society in collaboration with the infection. However, circumstances that
Infectious Diseases Society of America.14 The increase the volume of aspirate, especially the
reader is referred to this guideline for specific number of organisms in the aspirate, increase
treatment recommendations. the risk of pneumonia. The risk of aspiration
The focus for CAP is typically on short- pneumonia is lower in patients without teeth
term outcomes; however, it is becoming as well as in patients who receive aggressive
more apparent that sometimes there are oral care18 (explained in further detail below).
long-term negative consequences of CAP, However, little information is available regard-
particularly in the elderly.15 For example, a ing the effect of periodontal therapy in the
large study of the Medicare database used a prevention of aspiration pneumonia in vul-
matched case-control design to evaluate 1- nerable populations.
year mortality rate of 158,960 older CAP
patients compared with that of 794,333 Nosocomial Pneumonia
control subjects hospitalized for reasons (Hospital-Acquired Pneumonia)
other than CAP.16 The 1-year mortality rate Hospital-acquired pneumonia (HAP),
for CAP patients exceeded that of control defined as pneumonia occurring with onset
subjects (40.9% vs 29.1%, respectively); the over 48 hours after admission to the hospi-
differences could not be explained by the tal, is a common infection in the hospital,
types of underlying diseases. These findings often causing considerable morbidity and
suggest that the consequences of CAP in the mortality, as well as extending the length of
elderly are important to long-term survival stay and increasing the cost of hospital care.
and thus should be prevented.15 HAP can be further divided into two sub-
types: ventilator-associated pneumonia
Aspiration Pneumonia (VAP) and nonventilator-associated pneu-
Aspiration pneumonia is an infectious process monia. Pneumonia is the most common
caused by the inhalation of oropharyngeal infection in the intensive care unit (ICU)
secretions colonized by pathogenic bacteria.17 setting, accounting for 10% of infections in
Aspiration pneumonia is differentiated from the ICU.19
aspiration pneumonitis, which is typically VAP is the second most common hospi-
caused by chemical injury after inhalation of tal-acquired infection.20,21 It is a leading cause
sterile gastric contents. Aspiration pneumonia of death in critically ill patients in the ICU,
is often caused by anaerobic organisms with estimated prevalence rates of 10% to
derived from the oral cavity (gingival crevice), 65% and mortality rates of 25% to 60%,
and often develops in patients with an ele- depending on the study, patient populations,
and medical/surgical conditions involved.19,22–27 1998, with 1,441 subjects having complete
VAP and other forms of HAP are independ- data.36 The investigators found that the inci-
ent risk factors for mortality in hospitalized dent mobility limitation and higher mean
patients regardless of the severity and type of dental plaque score were the only modifiable
underlying illness.28 An episode of HAP adds risk factors for pneumonia. Another study
approximately 5 to 6 days to the length of found that in 89 cases of 138 (64.5%), the
hospital stay and thousands of dollars in cost dental plaques of dependent elderly were
to medical care.22–27 Patients with VAP typi- colonized by potential respiratory
cally have a significantly longer stay in the pathogens.37 Therefore, dental plaque must
ICU, with a longer ventilation dependency.29 be considered a specific reservoir of colo-
The onset of pneumonia can easily double nization and subsequent aspiration pneumo-
the length of the patient’s hospital stay, and nia in dependent elderly.
the cost of VAP treatment has been esti-
mated to average as high as $40,000 per The Oral Cavity as a Reservoir of
patient.30,31 Respiratory Infection
The oral cavity may be an important source
Nursing Home-Associated Pneumonia of bacteria that cause infections of the lungs.
NHAP is the most important common Dental plaque, a tooth-borne biofilm that
infection affecting nursing home residents initiates periodontal disease and dental
because of the high morbidity and mortality caries, may host bacterial species as part of
associated with this infection.32 Pneumonia is the normal flora that are capable of causing
also a common reason for transfer of resi- respiratory infection or may become colo-
dents from a nursing home to a hospital.33 nized by exogenous respiratory pathogens.
Incidence of NHAP in a published series Oral pathogens may then be shed from the
has varied from 0.3 to 2.5 episodes per 1000 oral biofilm and released into the oral secre-
resident care days.34 Independent predictors tions, which then are aspirated into the respi-
of NHAP that have been identified in multi- ratory tract.
ple studies include poor functional status,
use of a nasogastric tube or feeding tube, Mechanics Causing Pulmonary Infection
chronic lung disease, tracheostomy, increas- Bacteria causing community-acquired pneu-
ing age, male gender, and inadequate oral monia are typically species that normally
care.34 colonize the oropharynx such as S. pneumo-
The importance of oral hygiene as a niae, H. influenzae, and M. pneumoniae.
risk factor for NHAP was particularly Nosocomial pneumonia is, in contrast, often
emphasized in a study by Quagliarello et caused by bacteria that are not common
al.,35 who found that among 613 residents in members of the oropharyngeal flora such as
five nursing homes in New Haven, Connecti- Pseudomonas aeruginosa, S. aureus, and
cut, followed up prospectively for radiologi- enteric gram-negative bacteria. These organ-
cally confirmed pneumonia, only inadequate isms colonize the oral cavity in certain set-
oral care and dysphagia were independently tings, for example, among institutionalized
associated with pneumonia. A more recent subjects and people living in areas served by
study from this group described a prospec- unsanitary water supplies. Respiratory
tive observational cohort study of 3,075 well- pathogens, such as S. aureus, P. aeruginosa,
functioning community-dwelling adults aged and Escherichia coli, are found in substantial
70 to 79 enrolled in the Health, Aging, and numbers on the teeth in both institutional-
Body Composition Study from 1997 to ized elders38 and intensive care patients.39
One cubic millimeter of dental plaque digestive tract has been suggested as a source
contains about 100 million bacteria and may of nosocomial pneumonia, but recently oral
serve as a persistent reservoir for potential and dental bacterial colonization has been
pathogens, both oral and respiratory bacte- proposed as being the major source of bac-
ria. Oral and respiratory bacteria in the teria implicated in the etiology of VAP.43 It is
dental plaque are likely shed into the saliva likely that bacteria that first colonize the
and then aspirated into the lower respiratory dental plaque can be shed and attach to the
tract and lungs to cause infection.1,40 Indeed, tubing that passes through the oral cavity
the commensal, or normal, microflora of the into the lung (Figure 1).
oral cavity, especially periodontal disease- In the institutionalized elderly, aspira-
associated anaerobic bacteria that reside in tion of saliva seems to be the main route by
the subgingival space, often cause aspiration which bacteria enter the lungs to cause aspi-
pneumonia in patients who have a high risk ration pneumonia. Dysphagia seems to be
for aspiration, such as those with dysphagia an important risk factor, even a predictor, of
or neurologic impairment affecting the swal- aspiration pneumonia.44 For example, the
lowing apparatus. major oral and dental risk factors for aspira-
Cytokines and enzymes induced from tion pneumonia in veteran residents of
the periodontally inflamed tissues by the oral nursing homes were number of decayed
biofilm may also be aspirated into the lungs teeth, periodontitis, oral S. aureus coloniza-
where they may stimulate local inflammatory tion, and requirement of help with feeding.45
processes preceding colonization of In another study of 613 elderly nursing
pathogens and the actual lung infection.1,40 home patients, inadequate oral care and
Other possible mechanisms that may explain swallowing difficulties were also associated
pulmonary infection are inhalation of air- with pneumonia.35
borne pathogens and translocation of bacte- Dentate status may constitute a risk for
ria from local infections via bacteremia. pneumonia and respiratory tract infections:
patients with natural teeth develop aspiration
Patients at Risk pneumonia more often than edentulous sub-
In a healthy subject, the respiratory tract is jects.46,47 Cariogenic bacteria and periodontal
able to defend itself against aspirated bacte- pathogens in saliva or dental plaque have also
ria. However, patients with diminished sali- been shown to be risk factors for aspiration
vary flow, decreased cough reflex, swallowing pneumonia in nursing home patients.44,45 It is
disorders, poor ability to perform good oral well known that the teeth and gingival
hygiene, or other physical disabilities have a margin are places that favor bacterial colo-
high risk for pulmonary infections. Mechani- nization, and periodontal pockets may serve
cally ventilated patients in an ICU with no as reservoirs for potential respiratory
ability to clear oral secretions by swallowing pathogens. Previous studies have shown that
or coughing, have a particularly high risk for enteric bacteria colonize periodontal
developing VAP, especially when the ventila- pockets.48,49 Periodontitis, along with abun-
tion lasts for more than 48 hours.41 Oral bac- dant dental plaque, together may facilitate
terial load increases during intubation, and colonization of dental plaque by respiratory
higher dental plaque scores predict risk of pathogens and therefore promote pneumonia.
pneumonia.42 Anaerobic bacteria are fre-
quently found to colonize the lower respira- Identification of Bacterial Strains
tory tract in mechanically ventilated Several recent published studies have clearly
patients.41 Colonization of bacteria in the demonstrated the genetic identity of bacterial
CHAPTER
! 10 Oral! Health! and! Diseases! of! the
! Respiratory
! Tract 181
Figure 1.
! Bacteria Associated
! with
! Dental
! Plaque
!
Bacteria !associated with

! dental
! plaque
! are
! shed
! from
! the! biofilm
! to attach
! ! to the ! !tubing,
! which! facilitates
! entry !of the
bacteria
! ! into the ! lower
! airway.
! !Source: !Inside Dentistry 2007;3(Special
! Issue 1):12–6.
! Reproduced
! with
! permission.!
strains from dental plaques with isolates from from the corresponding dental plaque. A
the lower
! airway ! from
! ! mechanically ! !!venti-! subsequent study ! also ! assessed ! the genetic !
lated patients
! with
! ! suspected pneumonia. ! For ! relation
!! between
! ! strains ! of respiratory
example, !strains ! ! of potential
! respiratory
! pathogens ! first
! isolated ! from the ! oral ! cavity
pathogens
! ! recovered
! ! from lung fluid ! were and! those later
! ! isolated ! ! from bronchoalveo-
! !
compared !by pulsed-field
! ! ! gel electrophoresis
! ! lar lavage
! ! fluid from
! ! patients
! ! admitted ! ! to a
with! isolates
! of ! the same! species ! from the trauma
! critical! ! care !unit ! undergoing
dental plaque ! of critically ! ill! residents
! ! of mechanical
! ! ! ventilation
! ! with ! suspected
! ! VAP.
51
long-term care ! ! ! facilities transferred

! ! ! to an Pulse-field
! ! gel! electrophoresis
! ! and! mul-
intensive
! care unit.50 Of !13 isolates ! recovered
! ! tilocus sequence
! ! typing ! were used
! to ! deter-
!
from bronchoalveolar
! ! ! lavage fluid,
! ! nine respi-
! ! mine the! genetic ! relatedness
! of
! strains
ratory
! pathogens
! appeared
! ! ! ! genetically
! ! identi- obtained! from ! oral,! tracheal, ! and ! bron-
cal !to isolates of ! the! same species ! recovered ! choalveolar! lavage ! samples. Isolates of
! ! ! ! ! ! ! ! ! !
! ! ! ! ! ! ! ! ! ! !
182 ! Periodontal Disease and Overall ! Health: ! A Clinician’s
! !Guide !
! ! ! ! !
! ! ! ! ! !
S. aureus, ! P. aeruginosa, ! !
Acinetobacter ! to reduce pulmonary ! ! infections
! ! have been !
! ! ! ! !
species, and enteric species recovered from examined in both mechanically ventilated!
! ! ! ! ! ! !
plaque from ! ! patients
most ! !
were !
indistin- ICU ! patients and ! !
nonventilated ! elderly
! ! ! !
guishable from isolates recovered from patients. ! ! 52–54 These studies have mostly
bronchoalveolar ! !
lavage fluid! (Figure! 2). included chemical ! intervention
! using ! topical
!
! ! ! ! !
These studies suggest that respiratory antimicrobial agents such as CHX and beta- ! ! ! ! ! !! !
! ! !
pathogens isolated from the lung are often dine. Fewer studies have evaluated the effec-! ! ! ! !
!
genetically ! indistinguishable
! ! from strains! ! of !tiveness ! of traditional ! ! oral! mechanical
! !
! ! ! ! ! !
the same species isolated from the oral hygiene. Oral topical CHX reduces pneumo- ! ! ! ! !
cavity! in !patients! who receive ! ! mechanical ! nia! in mechanically ! ventilated ! patients ! and
!ventilation! and ! ! ! !
who are admitted to the may even decrease the need ! ! ! for! systemic ! IV
! ! ! ! ! !!
hospital from both nursing homes and the antibiotics or shorten the duration of ! ! ! !
!
community. Thus, dental ! !
plaque is! an mechanical ! ventilation ! in !the ICU.56–60 Also,
!important reservoir
! !
for VAP infection. ! ! !
oral application of CHX ! ! in the
! early! postin-
Figure 2.! Pulse-Field Gel !Electrophoresis
! Patterns! with Dendrogram
! ! for Pseudomonas
! ! ! aeruginosa Isolates
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These !results demonstrate

! ! the
that ! bacterial
! !
isolates ! the
from ! supragingival
! !
dental !
plaque ! tracheal
(SG), ! !
secretions
! ! ! ! ! ! ! ! ! ! ! ! ! !!
(TS), and bronchoalveolar lavage (BAL) from the same subject with suspected pneumonia are genetically identical.
Source: Heo et! al. Clin
! Infect Dis 2008;47:1562–70.51 ! !
Oral Intervention to Reduce tubation period lowers the numbers of cul-

Pulmonary Infections tivable oral bacteria and may delay the devel-
Recent systematic reviews of the literature opment of VAP.61 Studies validating the effec-
have substantiated the link between poor oral tiveness of oral CHX on reducing pneumo-
health and pneumonia.52–55 Oral interventions nia, however, are not unanimous. For
example, gingival decontamination with CHX significantly decreased pneumonia in resi-

gel significantly decreased the prevalence of dents in long-term care facilities.72–74
oropharyngeal colonization by pathogenic However, in an earlier study by the same
bacteria in ventilated patients, but this was research group, oral care with both brushing
not sufficient to reduce the incidence of respi- and antimicrobial gargling had an effect only
ratory infections.62 Another study reported on febrile days but not on incidence of
that a significant reduction in pneumonia pneumonia.75 Professional cleaning by a
using CHX rinse in ICU patients was dental hygienist once a week significantly
achieved only after 24 hours of intubation.63 reduced the prevalence of fever and fatal
Other studies demonstrated no benefit from pneumonia in 141 elderly patients in nursing
CHX rinsing with regard to pneumonia homes.76 Similar once-a-week professional
reduction in critically ill patients.64 In our own oral cleaning significantly reduced influenza
randomized trial, the application of CHX infections in an elderly population.77
once or twice a day was found not to have Dental plaque is known to form clearly
great impact on the quantity of potential res- visible masses in the teeth in a few days, but
piratory pathogens in the oral cavity of these studies suggest that improved oral care
mechanically ventilated subjects, with the even without chemical agents and even if
exception of S. aureus, which was significantly not performed daily not only reduces the
reduced in numbers after exposure to CHX.65 oral bacterial, viral, and fungal load, but
The efficacy of oral CHX decontami- also may have an effect on reducing the risk
nation to reduce VAP needs further investi- of pneumonia. Therefore, more studies are
gation, since no clear reduction in mortality needed to find the simplest oral decontami-
rate has been demonstrated. In addition to nation method to reduce pulmonary infec-
CHX, other antiplaque agents have been tions in elderly nursing home patients.
investigated. Antimicrobial gels including Oral cleansing reduces pneumonia in
polymyxin B sulfate, neomycin sulfate, and both edentulous and dentate persons, suggest-
vancomycin hydrochloride66 or gentamicin/ ing that oral colonization of bacteria con-
colistin/vancomycin67 also reduce VAP. tributes to nosocomial pneumonia to a
Several studies have demonstrated that greater extent than periodontitis does.
mechanical oral care, in some cases in com- However, intervention studies of the treat-
bination with povidone iodine, significantly ment of periodontitis on the incidence of
decreases pneumonia in ventilated ICU pneumonia have not been performed because
patients.68,69 Although the electric toothbrush of the complexities required in investigating
can reduce the amount of dental plaque in ICU or bed-bound nursing home patients. In
ventilated subjects,70 it appears that tooth edentulous people, dentures may easily serve
brushing alone was not an effective addition as a similar reservoir as teeth for oral and res-
to an oral care protocol either to reduce the piratory bacterial colonization if not cleaned
number of oral potential respiratory properly and daily.
pathogens or to reduce pneumonia.60,71
Institutionalized but nonventilated Suggestions for Oral Care of Hospitalized
patients, mainly elders living in nursing and Nursing Home Residents to Prevent
homes, appear to also benefit from improved Respiratory Infection
oral care by showing lower levels of oral Many studies demonstrate that improved
bacteria and fewer pneumonia episodes and oral hygiene can reduce the risk of pneu-
febrile days. Daily tooth brushing and monia in vulnerable patients. This raises the
topical oral swabbing with povidone iodine question as to what is the present status of
oral hygiene practice in hospitals and 6. Use of one oral rinse over another is
nursing homes. In light of the recent find- considered questionable (with the
ings just described, routine nursing practice exception of CHX 0.12% in cardiac
needs to include more rigorous oral care surgical patients).
procedures. 7. Tap water should not be used for oral
A survey assessed the type and fre- hygiene in the critically ill (it is often
quency of oral care provided in ICUs in the contaminated with potential respira-
United States, as well as the attitudes, beliefs, tory pathogens).
and knowledge of health care personnel.78 8. Subglottic suctioning in mechanically
The findings showed that although 512 (92%) ventilated patients limits aspiration of
of 556 respondents perceived oral care to be contaminated secretions.
a high priority, the primary oral care proce- 9. Although the optimal frequency for
dures involved the use of foam swabs, mois- oral hygiene has never been evaluated,
turizers, and mouthwash. Interventions brushing at least twice a day is sug-
thought to reduce oral colonization by respi- gested.
ratory pathogens, such as tooth brushing and 10. Although the optimal duration for
antiseptic rinses such as CHX, appear to be oral care has never been evaluated,
used infrequently in critical care settings.79 brushing, i.e., oral cleansing for 3 to 4
No official guidelines promulgated by minutes using a brush that allows
professional societies or regulatory agencies access to all areas of the mouth, is
have been published to date. However, a suggested.
recent paper described clinical practice guide- 11. No evidence supports the use of indi-
lines for oral hygiene in critically ill patients80 vidual, clean storage devices for oral
based on a systematic literature review fol- hygiene tools, but the guideline com-
lowed by prospective consideration of the mittee recommends the use of desig-
evidence during a consensus development nated containers.
conference. From this, several recommenda- Other measures to consider for intu-
tions were offered to guide clinicians in the bated patients may include removal of all
care of vulnerable patients: dental appliances on admission to the critical
1. Provision of effective oral care is an care unit, periodic repositioning of the tube,
important strategy in reducing noso- and deflation of the cuff. Removal of hard
comial pneumonia. deposits (e.g., tartar/calculus) from the teeth
2. A designated oral care protocol should be considered if possible before
should be used. admission (as in the case of elective surgery).
3. Systematic clinical assessment of the Placement of the patient’s head to the side
oral cavity using standardized or place in semi-Fowler’s position (semire-
methods (to include the condition of clined body position) also minimizes inad-
the teeth, gums, tongue, mucous vertent aspiration.
membranes, and lips).
4. The use of a soft-bristled brush CHRONIC OBSTRUCTIVE
removes debris and subsequent plaque. PULMONARY DISEASE
5. Mouth swabs (foam and cotton) Patients with chronic obstructive pulmonary
should be used when there is a con- disease (COPD) have chronic airflow
traindication to brushing (e.g., obstruction due to narrowing of the airways,
because of bleeding gums associated with excess production of sputum resulting
with thrombocytopenia). from chronic bronchitis and/or emphysema.81
Chronic bronchitis is defined as the result of remains underreported because of the diffi-
irritation to the bronchial airway and exces- culties in the diagnosis of COPD. COPD is
sive secretion of mucus sufficient to cause the fourth leading cause of morbidity and
cough with expectoration for at least 3 mortality in the United States and is pro-
months of the year over 2 consecutive jected to become the fifth most common
years.82 Emphysema results from distention cause of morbidity and the third most
of the air spaces distal to the terminal bron- common cause of mortality worldwide by the
chiole with destruction of the alveolar septa. year 2020. After adjusting for sociodemo-
Although this condition is associated with graphic factors and smoking status, estimated
certain symptoms, the definitive diagnosis of mean excess cost of COPD is $4,932 per
emphysema can only be made histologically. patient.87 Direct medical costs in the United
States were estimated to be $18 billion in
Epidemiology 2002. Inpatient costs are greater than outpa-
Chronic bronchitis is quite prevalent, with tient costs, and emergency costs ($8.3 vs $7.8
20% to 30% of all adults over the age of 45 billion) and hospital and medication costs
years having some history of this condition,83 account for most resources spent.88
typically as a sequela of smoking. The inci-
dence of emphysema is less well known Pathogenesis
because the main tool for noninvasive diag- COPD is the result of chronic airflow limita-
nosis (CT scanning) cannot be practically tion resulting from an inflammatory
applied in population studies. Although it is response to inhaled particles and gases in the
rare to find lungs completely free of emphy- lung, in most cases delivered from tobacco
sema postmortem, most individuals do not smoking.89 Smoking is related to
show well-defined histologic evidence of macrophage-predominant inflammation and
emphysema and do not have clinical symp- airspace enlargement. High concentrations
toms of the disease. of reactive oxygen species (ROS) in tobacco
The most significant risk factor for smoke results in oxidative stress. Resulting
COPD is prolonged cigarette smoking. recruitment of macrophages leads to release
Other environmental risk factors include of proteases such as macrophage elastase
chronic exposure to toxic atmospheric pollu- (matrix metalloproteinase (MMP)-12), which
tants (e.g., second-hand smoke). Possible seems to be a key pathogenic factor in
genetic risk factors include a defective emphysema. For example, a MMP-inhibitor,
alpha1-antitrypsin gene, variant alpha1- AZ11557272, prevented smoke-induced
antichymotrypsin, alpha2-macroglobulin, increases in lung inflammatory cells, lavage
vitamin D-binding protein, and blood group desmosine (a marker of elastin breakdown)
antigen genes.84 These genetic defects are and serum tumor necrosis factor (TNF)-
found in only a small percentage of individ- alpha in a guinea pig model of cigarette
uals with COPD. smoke-induced COPD.90
Worldwide, the prevalence of physiologi- COPD is a complex disease that is
cally defined COPD in adults aged 40 years influenced by a variety of environmental and
or older is approximately 9% to 10%.85 In genetic factors. Several environmental
2001, about 12.1 million adults older than 25 factors, such as cigarette smoking and air
years of age were diagnosed with COPD in pollution, have been strongly associated with
the United States, and another 24 million the initiation and progression of the disease.
showed impaired lung function.86 It is likely Clearly, not all smokers get the disease. Thus,
that the estimated COPD in the community other factors—likely genetic—may help
explain why some persons develop COPD hypoxemic patient. Noninvasive ventilation
and others do not.91,92 It is well known that has been used as a palliative treatment to
COPD is related to alpha-1-antitrypsin defi- reduce dyspnea.
ciency,93,94 although severity of disease is A recent systematic review of the litera-
affected by other risk factors such as gender, ture concluded that antibiotics effectively
history of asthma, chronic bronchitis, and reduce treatment failure and mortality rates
pneumonia. Some evidence has been pre- in COPD patients with severe exacerba-
sented demonstrating that COPD sometimes tions.98 However, antibiotics may not be gen-
clusters in families. Genetic factors may also erally indicated for patients with mild to
influence susceptibility to respiratory infec- moderate exacerbations.
tions leading to acute COPD exacerbations,
that is, episodes of worsening COPD symp- COPD and Oral Health
toms (shortness of breath, quantity and Associations between respiratory diseases
color of phlegm) often triggered by an infec- and oral health in community-dwelling pop-
tion with bacteria or viruses that may last for ulations were initially assessed by analysis of
several days. It appears that, to date, the National Health and Nutrition Exami-
attempts to associate COPD experience with nation Survey I (NHANES I) data.99 This
specific genetic polymorphisms, for example, database contains information on the general
targeting cytokine or global promoter genes, health status of 23,808 persons. Of these,
have proved to be inconclusive.92 365 individuals reported a respiratory condi-
A major complication of COPD is the tion, categorized as confirmed chronic respi-
occurrence of periodic disease exacerbations, ratory disease (chronic bronchitis or emphy-
which have recently been associated with sema) or acute respiratory disease (influenza,
bacterial infection,95,96 typically by nonty- pneumonia, acute bronchitis). After control-
pable H. influenzae, S. pneumoniae, and ling for gender, age, and race, subjects with
Moraxella catarrhalis. Viral infection has confirmed chronic respiratory disease had a
also been implicated in initiating this significantly greater oral hygiene index than
process.97 Acute exacerbations of COPD are those without respiratory disease. Further-
thus often treated using empiric antibiotic more, subjects with acute disease tended to
therapy. The cost of therapy for affected have more decayed teeth than those without
patients is extraordinarily high. Treatment disease. No other statistical associations were
failure from routine antimicrobial therapy noted between any of the other measures of
can lead to hospitalization, respiratory oral health and acute respiratory disease.
failure, and death. Antibiotic therapy for Also, no associations were noted between
exacerbations of COPD can also lead to the periodontal index and either acute or
emergence of bacterial antibiotic resistance chronic diseases.
and increased costs. Another study found periodontal
disease, measured as alveolar bone loss that
Treatment occurred between baseline and later meas-
A mainstay of therapy for COPD is inhaled urements from periapical radiographs, to be
drug therapy. In severe cases, lung volume an independent risk factor for COPD in
reduction surgery has been shown to reduce adult males enrolled in the VA Normative
mortality, increase exercise capacity, and Aging study.100
improve quality of life. Supplemental oxygen These results were supported by a subse-
during exercise reduces exertional breathless- quent study that measured associations
ness and improves exercise tolerance of the between poor oral health and chronic lung
disease, and this study was able to carefully influenza or pneumonia.

control for a number of potentially con- Another study examined the relation
founding variables. Data from NHANES III, between airway obstruction and periodontal
which documented the general health and disease in a cohort of 860 community-
nutritional status of randomly selected dwelling elders enrolled in the Health, Aging,
United States subjects from 1988 to 1994, and Body Composition Study (Health
were analyzed.101 This cross-sectional, retro- ABC).102 Results showed that, after stratifica-
spective study of the NHANES III database tion by smoking status and adjustment for
included a study population of 13,792 sub- age, race, gender, center, and number of
jects 20 years of age and older having at least pack-years, those with normal pulmonary
six natural teeth. A history of bronchitis function had significantly better gingival
and/or emphysema was recorded from the index (P= .036) and loss of attachment (P=
medical questionnaire. Lung function was .0003) scores than those with airway obstruc-
estimated by calculation of the ratio of forced tion. Thus, a significant association between
expiratory volume after 1 sec (FEV1)/forced periodontal disease and airway obstruction
vital capacity (FVC). Oral health status was was noted, especially in former smokers.
deduced from the Decayed Missing Filled Also, an association between chronic
System (DMFS/T) index (summary of cumu- periodontitis and severe COPD was sup-
lative caries experience), gingival bleeding, ported by a recent study that demonstrated a
gingival recession, gingival pocket depth, and greater prevalence of chronic periodontitis in
periodontal attachment level. 130 patients with very severe COPD than
Subjects with COPD had, on average, that in 50 patients with other very severe res-
more periodontal attachment loss (CAL 1.48 piratory diseases.103 The prevalence of peri-
± 1.35- mean ± SD) than those without odontitis was found to be 44% in the COPD
COPD (mean CAL 1.17 ± 1.09). To simulta- group compared with 7.3% in the non-
neously control for multiple variables that COPD group. This difference was significant
may confound statistical analysis, gender, age, after adjustment for age, gender, and number
race, education, income, dental treatment of pack-years smoked.
history, alcohol consumption, diabetes status, Several parameters related to periodon-
and smoking status were considered in a tal health have been associated with the
logistic regression model against history of COPD exacerbation, including the amount
COPD. The risk for COPD appeared to be of plaque on the teeth, number of teeth, and
significantly elevated when mean attachment infrequent toothbrushing.104 Moreover, a
loss (MAL) was found to be severe (mean recent meta-analysis was performed that
attachment loss; MAL ≥2.0 mm) compared evaluated data from 14 studies involving
with periodontal health (<2.0 mm MAL: 3,988 COPD patients.105 A significant associ-
odds ratio 1.35, 95% CI: 1.07–1.71). Further- ation between pulmonary disease and
more, the odds ratio was 1.45 (95% CI: 1.02– COPD was identified.
2.05) for those who had ≥3.0 mm MAL. A
trend was also noted in that lung function Chronic Lung Disease in
appeared to diminish as the amount of Hospitalized Patients
attachment loss increased. No such trend was Dental plaque may serve as a reservoir of
apparent when gingival bleeding was consid- respiratory pathogen colonization in hospi-
ered. No other statistical associations were talized patients with chronic lung dis-
noted among any of the measures of oral eases.106 Using a checkerboard DNA-DNA
health and acute respiratory diseases, such as hybridization technique to determine prev-
alence of eight respiratory pathogens and Diagnosis and treatment of community-acquired

eight oral pathogens, species such as S. pneumonia. Am Fam Physician 2006;73:442–50.
10. Jackson ML, Neuzil KM, Thompson WW, Shay
aureus, P. aeruginosa, Acinetobacter bau- DK, Yu O, Hanson CA, et al. The burden of
mannii, and Enterobacter cloacae were community-acquired pneumonia in seniors: results
detected in plaque from 29 of the 34 of a population-based study. Clin Infect Dis
(85.3%) hospitalized patients, whereas only 2004;39:1642–50.
12 of 31 (38.7%) nonhospitalized subjects 11. Almirall J, Bolibar I, Serra-Prat M, Roig J, Hospi-
tal I, Carandell E, Agusti M, Ayuso P, Estela A,
had colonizations. These results indicate Torres A. New evidence of risk factors for com-
that dental plaque may serve as a reservoir munity-acquired pneumonia: a population-based
of infection in hospitalized patients with study. Eur Respir J 2008;31:1274–84.
chronic lung diseases. 12. de Melo Neto JP, Melo MS, dos Santos-Pereira
SA, Martinez EF, Okajima LS, Saba-Chujfi E.
Periodontal infections and community-acquired
CONCLUSION pneumonia: a case-control study. Eur J Clin Micro-
Ample research now supports associations biol Infect Dis 2013;32:27–32.
between oral health, especially dental plaque 13. Durrington HJ, Summers C. Recent changes in the
and periodontal disease, and respiratory dis- management of community acquired pneumonia
in adults. Br Med J 2008;336:1429–33.
eases such as nosocomial pneumonia and 14. Mandell LA, Wunderink RG, Anzueto A, Bartlett
COPD. Further research may allow develop- JG, Campbell GD, Dean NC, Dowell SF, File
ment and routine implementation of simple TM Jr, Musher DM, Niederman MS, Torres A,
and effective strategies to prevent respiratory Whitney CG. Infectious Diseases Society of
disease in vulnerable populations. America/American Thoracic Society consensus
guidelines on the management of community-
acquired pneumonia in adults. Clin Infect Dis
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CHAPTER 11
Osteoporosis
Hector F. Rios, William V. Giannobile
INTRODUCTION properties according to metabolic and me-

Bone as a tissue represents a highly dy- chanical requirements.12–14 The skeletal
namic biologic system that comprises a se- adaptation mechanism is primarily exe-
ries of tightly regulated and synergistic cuted by processes of bone resorption and
anabolic and catabolic events that lead to bone formation and referred to collec-
proper metabolic and skeletal structural tively as bone remodeling (Figure 1). Bone
homeostasis. Multiple factors may nega- is resorbed by osteoclasts, after which new
tively influence these processes leading to bone is deposited by osteoblastic cells.15
decreased bone mass, decreased density, From the perspective of bone remodeling,
altered microarchitecture, and increased it has been proposed that osteoclasts rec-
bone fragility. The term osteoporosis has ognize and are targeted to skeletal sites of
been collectively used to refer to condi- compromised mechanical integrity and
tions in which the ability of the skeletal tis- initiate the bone-remodeling process for
sue to respond and adapt to the purpose of inducing the generation of
environmental and physiologic challenges mechanically competent new bone.16
is compromised. Because of the above- The remodeling process takes place in
mentioned factors, microdamage accumu- bone multicellular units (BMUs) (Figure
lation and increased fracture susceptibility 2). A BMU comprises (1) a front of os-
can occur. Within this context, numerous teoclasts residing on a surface of newly re-
proinflammatory cytokines have been sorbed bone referred to as the resorption
identified as important determinants of front, (2) a compartment containing ves-
bone loss.1–7 A significant increased pro- sels and pericytes, and (3) a layer of os-
duction of proinflammatory cytokines oc- teoblasts on a newly formed organic
curs in conditions such as periodontitis, a matrix known as the deposition front. In
disease initiated by bacterial plaque Figure 2, the resorption front is clearly vi-
biofilms. The impact of osteoporosis on sualized by the cells stained for tartrate-
host susceptibility to periodontal break- resistant acid phosphatase (TRAP). The
down is clinically relevant.8–11 This chapter number of new and active BMUs is regu-
reviews and evaluates the available litera- lated by a variety of hormones and cy-
ture regarding the association between tokines, which dictate the spatiotemporal
these two complex multifactorial condi- synchronization and coupling of the ana-
tions, their effect on disease extent and bolic and catabolic remodeling events.
severity, and the coexisting mechanisms by The molecular and cellular pathogen-
which they may affect the overall bone esis of osteoporosis has been an area of
structural integrity and homeostasis. significant research for more than a
decade. Proteins that serve as “master
OSTEOPOROSIS AND switches” have been identified (Figure 3).
BONE REMODELING These key molecules serve as signals that
Bone is a highly dynamic tissue with the coordinate activities of osteoblasts and os-
capacity to adapt based on physiologic teoclasts during bone remodeling. This new
needs. Hence, bone adjusts its mechanical molecular biology frontier has trig-
Figure 1. Bone Remodeling
The bone remodeling cycle involves a complex series of sequential steps that are highly regulated. The activation
phase of remodeling is dependent on the effects of local and systemic factors on mesenchymal cells of the osteoblast
lineage.
P These cells interact with hematopoietic precursors to form osteoclasts in the resorption phase. Subsequently,
there is a reversal phase during which mononuclear cells are present on the bone surface. They may complete the
resorption process and produce the signals that initiate formation. Finally, successive waves of mesenchymal cells dif-
ferentiate into functional osteoblasts, which lay down matrix in the formation phase. Source: Mediators of periodon-
tal osseous destruction and remodeling: principles and implications for diagnosis and therapy. J Periodontol
2002;73:1377–91. Reproduced with the permission of the American Academy of Periodontology.
Figure 2. Bone Multicellular Units (BMUs)
Va
V scular St
Vascular ructure (Y
Structure Yellow)
(Yellow)
Osteoblasts
Osteoblasts
Osteoclastts (R
Osteoclasts ed)
(Red)
Bone remodeling occurs in local groups of osteoblasts and osteoclasts called BMUs; each unit is organized into a
reabsorbing front of osteoclasts, followed by a trail of osteoblasts reforming the bone to fill the defect left by osteo-
clasts. The red staining (tartrate resistant acid phosphatase) highlights the resorption front. Note the increased
number of multinucleated osteoclasts in this area.
CHAPTER 11 Osteoporosis 195
Figure 3. Bone Formation/Resorption Coupling
Bone formation and resorption processes are mutually and intimately linked. The osteoblastic/stromal cells provide
an osteoclastogenic microenvironment by the presentation of RANKL to the osteoclast precursor, triggering their
further differentiation and fusion that leads to the formation of multinucleated and active osteoclasts. This process is
modulated by inhibitors of these interactions such as the osteoprotegerin (OPG) molecule. In addition, the bone for-
mation by osteoblasts depends on the preceding resorption by osteoclasts.
gered significant innovation in the field factor 6 (TRAF6), which enhances the ac-
and further develops our understanding of tivity of important osteoclast intracellular
the principles of bone pathophysiology. protein kinases. The Src kinase is highly
Differentiation from osteoclast precursor expressed in osteoclasts and acts as a me-
cells to fully activated multinucleated os- diator of multiple pathways regulating os-
teoclasts depends critically on the presence teoclast activity.19 Several key regulatory
of receptor activator of nuclear factor transcription factors and enzymes are en-
kappa-B ligand (RANKL), a member of hanced to promote the differentiation,
the tumor necrosis factor (TNF) family. proliferation, multinucleation, activation,
RANKL is abundantly expressed by bone- and survival of osteoclasts. T cells also
forming osteoblasts as well as bone mar- stimulate osteoclast activation by this
row stromal cells and activates its receptor, same pathway. In this case, besides OPG,
RANK, expressed on osteoclasts.17 a second mechanism slows down the acti-
Parathyroid hormone (PTH) and vitamin vation. Interferon gamma (IFN-g) stimu-
D3 have receptors in osteoblasts and stro- lates the degradation of TRAF6 and
mal cells, where they promote the tran- blocks the signal arriving from RANK.20
scription of RANKL and limit the When osteoclasts are fully differenti-
production of osteoprotegerin (OPG), a ated and attached to bone, this synchro-
naturally occurring antagonist of nizes the release of H+ and Cl– into the
RANKL.17,18 resorption lacunae via the v-ATPase pro-
After RANKL-induced RANK stim- ton pump and the voltage-gated chloride
ulation, activated RANKL couples to an channel CLC-7. As a result, acidification
adaptor protein, TNF receptor-associated of this space occurs and profoundly in-
duces mineral degradation. In addition, deposition (Figure 4). It is also well

the osteoclasts deliver cathepsin K known that the parathyroid glands react
(CatK), a key proteinase, into this space.21 to low calcium levels by secreting parathy-
This results in increased collagen degra- roid hormone (PTH), which increases
dation and breaks down bone. CatK is a bone resorption to ensure sufficient cal-
critical determinant of resorptive activity cium in the blood.
by osteoclasts that remove bone of poor In postmenopausal osteoporosis, a
quality, where microcracks have accumu- lack of estrogen leads to increased BMUs
lated over time. and altered remodeling due to uncoupling
In addition, hormonal factors have a of bone formation and bone resorption.
major impact on the rate of bone resorp- This process results in too little bone
tion; lack of estrogen increases bone re- being laid down by osteoblasts compared
sorption as well as decreases the with the amount of bone resorbed by os-
formation of new bone. Osteocyte apop- teoclasts.24 Such disruption in the normal
tosis occurs in states of estrogen defi- remodeling events compromises the abil-
ciency.22,23 In addition to estrogen, calcium ity to adapt to external and internal de-
metabolism plays a significant role in mands. Without an efficient coupling
bone turnover, and deficiency of calcium mechanism, each remodeling event results
and vitamin D leads to impaired bone in net loss of bone, which ultimately com-
Figure 4. Calcium and Bone Metabolism
Calcium homeostasis is of major importance for many physiologic processes necessary to maintain health. The
balance of serum ionized calcium blood concentrations results from a complex interaction between parathyroid
hormone (PTH), vitamin D, and calcitonin. The figure reflects how input from the diet and from the bones and
excretion via the gastrointestinal tract and urine maintain homeostasis. Vitamin D is involved in the absorption of
calcium, whereas PTH stimulates calcium release from the bone, reduces its excretion from the kidney, and assists in
the conversion of vitamin D into its biologically active form (1,25-dihydroxycholecalciferol). Decreased intake of
calcium and vitamin D and estrogen deficiency may also contribute to calcium deficiency.
promises the bone strength owing to re- failure to shift the cortical bone outward
sulting altered architecture (Figure 5). from the neutral axis—a change that in-
The affected skeletal integrity in os- creases resistance to bending.
teoporosis is characterized by cortical and In summation, the interaction of ge-
trabecular thinning as well as loss of tra- netic and environmental factors on bone
becular connectivity. In addition, the loss underlies the development of fragile
number of osteons per unit volume of bone tissue, decreasing the inherent ca-
bone decreases, offering less resistance to pacity of the skeleton to adapt and re-
crack initiation and propagation owing to spond adequately to structural needs.
a larger interstitial bone between osteons.
The reduced bone quality in osteoporosis OSTEOPOROSIS AND
is also reflected by a decrease in cell den- BONE MINERAL DENSITY
sity. The reduced osteocytic density in in- Osteoporosis severely compromises the
terstitial bone reduces the ability to detect skeletal integrity. However, fractures tend
damage and thus to remove it. If bone to occur late in the disease process. Today,
formation is decreased in the BMU as a it is generally accepted that the bone min-
result of reduced osteoblast numbers, eral density (BMD) measurement is the
then reduced synthesis of osteocytes may most valuable parameter to identify pa-
also contribute to the deficit in this cell tients who are more susceptible or at
type, which is considered the orchestrator greater risk for fractures. The widespread
of bone remodeling. Reduced periosteal availability and popularity of bone den-
bone formation in adulthood contributes sitometry have led to a widely accepted
to fragility because endocortical resorp- definition proposed by the World Health
tion is not compensated for, so there is Organization (WHO) in 1994, based on
both failure to offset cortical thinning and BMD measurements in standard devia-
Figure 5. Altered Cortical and Trabecular Architecture in Osteoporosis
Trabecular Density
Cortical Thickness
In osteoporosis, there is a decreased cortical thickness in addition to a marked decrease in trabecular number and
connectivity. As this process continues over time, there is further deterioration of the internal architecture with a sig-
nificant impact on the ability of the bone to sustain compressive forces without failure.
tion units called T-scores25 (Figure 6). itate the diagnosis. However, the primary
Essentially, the T-score indicates the etiology that leads to the appearance of
difference between an individual’s BMD the condition may vary considerably. Our
and the normal BMD achieved by a young ability to recognize and classify etiologic
adult. As illustrated in Figure 7, the WHO differences among conditions that may
defines four main levels of osteoporosis appear clinically similar have an impact
risk assessment based on T-scores: on our ability to successfully treat these
• Normal bone mineral density is patients. Primary osteoporosis is simply
found when the T-score is ≥ –1. the form seen in older persons and women
• Osteopenia refers to a low BMD after menopause in which bone loss is ac-
T-score between –1.0 and –2.5. celerated over that predicted for age and
• Osteoporosis is diagnosed when an sex. Secondary osteoporosis results from
individual has a T-score ≤ –2.5. a variety of identifiable conditions.
• Osteoporosis is considered to be
established when an individual has Primary Osteoporosis
one or more fragility fractures in There are two forms of primary osteo-
addition to a T-score ≤ –2.5. porosis: type I and type II. The determin-
ing factor for the actual existence of
Types of Osteoporosis osteoporosis, either type I or type II, is the
The clinical
" "presentation of osteoporosis amount of calcium remaining in the skele-
includes several characteristics that facil- ton and whether it places a person at risk
Figure 6. Bone Mineral Density (BMD)

% % "
!"#$%&'" #$%&'($)"*#+","-.'/0"%)'12"3$%/"*#+"
!"
4.'/0"%)'12"&2%/)%()")$56%7./"
Dual-energy x-ray absorptiometry (DEXA) is considered the preferred technique for measurement of BMD. The
sites most often used for DEXA measurement of BMD are the spine, femoral neck, and forearm. The World Health
Organization (WHO) defines osteoporosis based on T-scores. T-scores refer to the number of standard deviations
above or below the mean for a healthy 30-year-old adult of the same sex as the patient.
Figure 7. Proposed Mechanism of Action

(Coexistingchallenges
(Co-existing challenges that
that may influence
influence periodontal
periodontalintegrity
integrityininosteoporotic
osteoporoticpatients)
patients )
Multiple coexisting challenges may influence periodontal integrity in the osteoporotic patient. A microbial, inflamma-
tory, and mechanical front may create an overwhelming situation for the host to maintain the integrity of the attach-
ment apparatus. Systemically, estrogen deficiency may enhance the progression of marginal periodontitis, either by
causing increased expression of osteotropic cytokines or by decreasing the amount of alveolar bone. Locally, the
microbial byproducts, an increased number of proinflammatory cytokines, and a structurally altered alveolar bone
due to significant reduction in bone mass may increase the susceptibility of tissue breakdown and therefore facilitate
the progression of periodontal disease.
of fracture. Someone who has exception- Type II osteoporosis (senile osteo-
ally dense bones to begin with will proba- porosis) typically happens after the age of
bly never lose enough calcium to reach the 70 and affects women twice as frequently
point at which osteoporosis occurs, as men. Type II osteoporosis results when
whereas a person with low bone density the process of resorption and formation of
could easily develop osteoporosis despite bone are no longer coordinated, and bone
losing only a relatively small amount of breakdown overcomes bone building. This
calcium. occurs with age in everyone to some de-
Type I osteoporosis (postmenopausal gree. Type II affects trabecular and cortical
osteoporosis) generally develops in women bone, often resulting in fractures of the
after menopause when the amount of es- femoral neck, vertebrae, proximal
trogen in the body greatly decreases. This humerus, proximal tibia, and pelvis. It may
process leads to an increase in the resorp- result from age-related reduction in vita-
tion of bone (the bones lose substance). min D synthesis or resistance to vitamin D
Type I osteoporosis occurs in 5% to 20% activity (possibly mediated by decreased or
of women, most often between the ages of unresponsive vitamin D receptors in some
50 and 75 because of the sudden post- patients). In older women, types I and II
menopausal decrease in estrogen levels, often occur together.
which results in a rapid depletion of cal-
cium from the skeleton. It is associated Secondary Osteoporosis
with fractures that occur when the verte- Secondary osteoporosis is caused by other
brae compress together causing a collapse conditions, such as hormonal imbalances,
of the spine, and with fractures of the hip, certain diseases, and medications (e.g.,
wrist, or forearm caused by falls or minor corticosteroids). Secondary osteoporosis
accidents. Type I accounts for the signifi- accounts for less than 5% of cases of os-
cantly greater risk of osteoporosis in teoporosis. Causes include endocrine dis-
women versus men. ease (e.g., glucocorticoid excess,
hyperparathyroidism, hyperthyroidism, such as rheumatoid arthritis, ankylosing

hypogonadism, hyperprolactinemia, dia- spondylitis, and inflammatory bowel dis-
betes mellitus), drugs (e.g., glucocorticos- ease. Current evidence suggests that osteo-
teroids, ethanol, dilantin, tobacco, porosis that develops during chronic
barbiturates, heparin), and other condi- inflammation may result from the inhibi-
tions (e.g., immobilization, chronic renal tion of bone formation and is associated
failure, liver disease, malabsorption syn- with systemic overproduction of proin-
dromes, chronic obstructive lung disease, flammatory mediators, such as cytokines,
rheumatoid arthritis, sarcoidosis, malig- nitric oxide (NO), and prostaglandins. In
nancy, prolonged weightlessness as found patients with periodontal disease and con-
in space flight). comitant postmenopausal osteoporosis, the
possibility exists that the lack of estrogen
OSTEOPOROSIS AND influences the activities of bone cells and
INFLAMMATION immune cells in such a way that the pro-
Emerging clinical and molecular evidence gression of alveolar bone loss is enhanced.
suggests that inflammation also exerts sig-
nificant influence on bone turnover, induc- ALVEOLAR BMD
ing osteoporosis. Numerous pro- VS SKELETAL BMD
inflammatory cytokines have been impli- Systemic factors can lead to loss of BMD
cated in the regulation of osteoblasts and throughout the body, including bone loss
osteoclasts, and a shift toward an activated in the maxilla and mandible. The resulting
immune profile has been hypothesized as local reduction of BMD in the jaw bones
an important risk factor.1 Chronic inflam- can set the stage for more rapid loss of
mation and the immune system remodeling alveolar crestal height because a compa-
characteristic of aging, as well as of other rable challenge of bacteria-derived bone-
pathologic conditions commonly associ- resorbing factors can be expected to result
ated with osteoporosis, may be determinant in greater alveolar bone destruction than
pathogenic factors.6 in an individual with normal bone mass.
The cellular and molecular pathogenic In addition, systemic risk factors such as
mechanisms in inflammation-induced oste- smoking, diabetes, diet, and hormone lev-
olysis and sclerosis have been explored ex- els affect systemic bone levels and may
tensively. There is substantial evidence that also affect periodontitis.
bone remodeling is a tightly regulated and Oral bone loss has been shown to be
finely balanced process influenced by sub- associated with osteoporosis and low
tle changes in proinflammatory and in- skeletal BMD. In their search for oral ra-
hibitory cytokines as well as hormones and diographic changes associated with osteo-
cellular components that act primarily but porosis, most investigators have focused on
not exclusively through the RANK/ measures of jaw bone mass or morphol-
RANKL/OPG system. Therefore, an acute ogy. The commonly used assessment of
or chronic imbalance in the system due to oral bone includes radiographic measures
infection or inflammation could contribute of loss of alveolar crestal height, measures
to systemic (or local) bone loss and in- of resorption of the residual ridge after
crease the risk of fracture.15 tooth loss, and assessment of oral BMD.
Generalized osteoporosis and an in- Tools used to measure bone mass include
creased risk of fracture are commonly ob- single and dual photon absorptiometry,
served in chronic inflammatory diseases dual-energy x-ray absorptiometry
(DEXA), quantitative computed tomogra- tors could be expected to result in greater

phy (QCT), and film densitometry. alveolar crestal bone resorption than in a
Mandibular mineral content is re- person with normal bone mass. In addition
duced in subjects with osteoporotic frac- to this finding, systemic risk factors such
tures.26 Furthermore, the BMD of buccal as smoking, diabetes, diet, and hormone
(but not trabecular) mandibular bone cor- levels affect systemic bone level and may
relates with osteoporosis (low skeletal also affect periodontitis. Although peri-
BMD).27,28 Mandibular density (measured odontal disease has historically been
with a DEXA scan) also correlates with thought to be the result of a local infec-
skeletal BMD.29 tious process, others have suggested that
Using film densitometry, most inves- periodontal disease may be an early mani-
tigators have found that the optical den- festation of generalized osteopenia.38
sity of the mandible is decreased in Several potential mechanisms have
subjects with osteoporosis (low skeletal been proposed by which osteoporosis or
BMD) compared with that of controls. In systemic bone loss may be associated with
addition, mandibular radiographic opti- periodontal attachment loss, reduction of
cal density correlates with vertebral BMD alveolar bone height or density, and tooth
in osteoporotic women,30 control (nonos- loss. One of these mechanisms states that
teoporotic) women,31 and women with a low BMD or loss of BMD may lead to
history of vertebral fracture.32,33 Reduc- more rapid resorption of alveolar bone
tion in cortical and subcortical alveolar after insult by periodontal bacteria. With
bone density has also been reported to less dense oral bone to start, loss of bone
correlate with osteoporosis (low skeletal surrounding the teeth may occur more
BMD) in longitudinal studies.34–36 As re- rapidly. Another mechanism proposes
ported by Hildebolt in 1997, the prepon- that systemic factors affecting bone re-
derance of the evidence indicates that the modeling may also modify the local tissue
jaws of subjects with osteoporosis show response to periodontal infection. Persons
reduced bone mass.37 Table 1 summarizes with generalized bone loss are known to
the available data regarding the relation have increased systemic production of cy-
between systemic and oral bone loss. tokines (i.e., interleukin-1 [IL-1] and
IL-6) that may have effects on bone
ASSOCIATION BETWEEN throughout the body, including the bones
OSTEOPENIA AND INCREASED of the oral cavity. Periodontal infection
SEVERITY OF ALVEOLAR BONE has been shown to increase local cytokine
LOSS AND TOOTH LOSS production that, in turn, increases local
It is hypothesized that periodontitis results osteoclast activity resulting in increased
from bacteria that produce factors that bone resorption. A third potential mech-
cause loss of collagenous support of the anism is related to genetic factors that pre-
teeth, as well as resorption of alveolar dispose an individual to systemic bone
bone. Systemic factors can lead to loss of loss and that would also influence or pre-
BMD throughout the body, including dispose an individual to periodontal de-
bone loss in the maxilla and mandible. The struction. Also, certain lifestyle factors
resulting local reduction of BMD in the such as cigarette smoking and suboptimal
jawbones could set the stage for more rapid calcium intake, among others, may put in-
marginal bone loss because a comparable dividuals at risk for development of both
challenge of bacterial bone-resorbing fac- systemic osteopenia and oral bone loss.
Table 1. Studies on the Relationship Between Systemic and Oral Bone Loss
Study Type
Studies Oral Systemic Cross-sectional Longitudinal Correlation
Earnshaw et al. a Tooth count Lumbar BMD √ NO
Bone height/
Elders et al.b Lumbar BMD √ NO
Tooth count
Bone height/
Klemetti et al.c Skeletal BMD √ YES
Tooth count
Krall et al.d Tooth loss Skeletal BMD √ YES
Mandibular Femoral neck
Jeffcoat et al. e √ YES
BMD BMD
Lumbar/Femoral
Hildebolt et al.f CAL √ YES
neck BMD
Normal
Kribbsg CAL √ NO
osteoporosis
CAL/
Tezal et al.h Skeletal BMD √ YES
Bone height
von Wowern et al.i CAL Forearm BMD √ YES
Normal
Payne et al.j Bone height/ Osteopenia √ YES
Bone density Osteoporosis
Normal
Yoshihara et al.k CAL √ YES
Osteopenia
BMD = bone mineral density; CAL = clinical attachment loss.

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g. Kribbs PJ. Comparison of mandibular bone in normal and osteoporotic women. J Prosthet Dent
1990;63:218–22.
h. Tezal M, Wactawski-Wende J, Grossi SG, Ho AW, Dunford R, Genco RJ. The relationship between
bone mineral density and periodontitis in postmenopausal women. J Periodontol 2000;71:1492–8
i. von Wowern N, Klausen B, Kollerup G. Osteoporosis: a risk factor in periodontal disease. J Periodon-
tol 1994;65:1134–8.
j. Payne JB, Reinhardt RA, Nummikoski PV, Dunning DG, Patil KD. The association of cigarette smok-
ing with alveolar bone loss in postmenopausal females. J Clin Periodontol 2000;27:658–64.
k. Yoshihara A, Seida Y, Hanada N, Miyazaki H. A longitudinal study of the relationship between peri-
odontal disease and bone mineral density in community-dwelling older adults. J Clin Periodontol
2004;31:680–4.
ROLE OF CALCIUM IN duced in an inflammatory process in post-

MODERATING THE menopausal women with estrogen defi-
RELATIONSHIPS BETWEEN ciency, compared with an inflammatory
OSTEOPOROSIS AND process in women with normal estrogen
PERIODONTAL DISEASE levels.14,41 In addition, in the presence of a
Osteoporosis and osteopenia may influ- mechanically challenging environment
ence periodontal disease and tooth loss.39 such as the oral cavity, the amount of mi-
Although many studies suggest that in crocracks accumulating in the alveolar
elderly men and women, maintenance of bone may further signal osteoclasts in an
normal BMD is associated with improved attempt to repair the already compro-
tooth retention, the evidence is still incon- mised osseous architecture.12,13
clusive. Hormone replacement therapy
and calcium and vitamin D supplements OSTEOPOROSIS AND
used to prevent or treat osteoporosis ap- ORAL IMPLANTS
pear to have beneficial effects on tooth re- The impact of osteoporosis in alveolar
tention as well.40 Future prospective bone quality and its potential influence on
studies, including randomized clinical tri- the implant therapy outcome has been
als, are needed to confirm these findings. well studied.42–47 Several investigations
have reported successful implant place-
PROPOSED MECHANISM ment in osteoporotic individuals.47–50 No
The integrity of the periodontium in pa- correlation between DEXA scores and
tients with osteoporosis faces many coex- implant failure has been found as shown
isting challenges. Local and systemic by case-control studies.49 A retrospective
factors have an impact on the host’s abil- study analyzing 16 patients with osteo-
ity to maintain the homeostasis within porosis who received implant therapy
these tissues. Hypothetically, three differ- showed an overall implant survival rate of
ent challenges may be influencing the pe- 97% in the maxilla and 97.3% in the
riodontal integrity in patients with mandible with a follow-up time of 6
osteoporosis, thereby increasing peri- months to 11 years.51
odontal disease susceptibility and the ag- Implant success in patients with os-
gravation of the local signs of disease teoporosis as it relates to the presence of
(Figure 7). marginal bone loss around implants has
In the context of systemic and local also been reported. von Wowern and col-
reduced bone mass due to systemic osteo- laborators reported no implant failures in
porosis, it is possible that superimposed any of the osteoporotic and healthy pa-
inflammation-induced bone resorption tients, although marginal bone loss in-
may lead to enhanced progression of creased around the implants placed in
bone loss. This is particularly true with re- patients with osteoporosis.52
spect to the roles of the proinflammatory Bone-to-implant contact (BIC) is al-
cytokines (e.g., IL-1, TNF-a, and IL-6) tered in osteoporotic conditions.53,54 BIC
and the osteoclastogenic cytokine is significantly decreased in osteoporosis.
RANKL.14 In primary osteoporosis, the In a preclinical study by Cho and collab-
modulatory effect of estrogen in the ex- orators,54 the greatest decreases in BIC
pression of the bone-resorbing cytokines were noted when an osteoporotic state
IL-1, TNF-a, and IL-6, is absent. There was induced after osseointegration had
are greater levels of these molecules pro- occurred. BIC in the osteoporosis group
was reported as 50% compared with 79% tion.55 Two therapeutic approaches are cur-
in the control group. The results of these rently available: (1) antiresorptive drugs,
studies imply that although osseointegra- which slow down bone resorption; and (2)
tion of implants in osteoporotic bone is anabolic drugs, which stimulate bone for-
possible, the long-term stability of im- mation (Figure 8).
plants may be compromised by disease.
The literature supports dental im- Antiresorptive Drugs
plants as a viable treatment option for pa- Bisphosphonates
tients with osteoporosis. However, it is In confirmed osteoporosis, bisphospho-
important to understand that owing to nate drugs are considered first-line treat-
the altered bone metabolism, less BIC ment in women. The most frequently
may occur with a higher risk of marginal prescribed bisphosphonates are presently
bone loss. However, more studies are sodium alendronate (Fosamax) 10 mg/day
needed to determine the long-term effects or 70 mg/once per week, risedronate (Ac-
of osteoporosis in this patient population. tonel) 5 mg/day or 35 mg/once per week,
and/or ibandronate (Boniva) once per
PHARMACOLOGIC MECHANISMS month. A 2007 manufacturer-supported
OF THERAPEUTICS study suggested that in patients who had
Perhaps the most dynamic and prolific as- suffered a low-impact hip fracture, yearly
pect in the field of osteopenia and osteo- infusion of 5 mg zoledronic acid reduced
porosis research lies in the discovery and risk of any fracture by 35% (from 13.9%
development of novel targets that lead to to 8.6%), vertebral fracture risk from
promising treatment options with potential 3.8% to 1.7%, and nonvertebral fracture
adaptation for treatment of periodontal risk from 10.7% to 7.6%. This study also
disease or for promotion of osseointegra- found a mortality benefit of 28% (9.6% of
Figure 8. Chemotherapeutics to Treat Bone Loss
In general, two groups can be distinguished among all of the known chemotherapeutic agents: (1) antiresorptive
agents and (2) anabolic agents. These exert beneficial effects in the treatment of the osteoporotic patient by targeting
distinct cell populations or by modulating the interaction of certain cells.
the study group had died of any cause possess a tertiary structure that allows
after 1.9 years compared with 13.3% of them to bind to the estrogen receptor.58
the control group). Unlike estrogens, which are uni-
Oral bisphosphonates are relatively formly agonists, SERMs exert selective
poorly absorbed and must therefore be agonist or antagonist effects on various
taken on an empty stomach with no food estrogen target tissues. The mechanism of
or drink to follow for the next 30 minutes. mixed agonism/antagonism may differ de-
They are associated with esophagitis and pending on the chemical structure of the
therefore sometimes poorly tolerated; SERM, but in general, it appears to be re-
weekly or monthly administration (de- lated to the ratio of coactivator to core-
pending on the preparation) decreases the pressor proteins in different cell types and
likelihood of esophagitis and is now the the conformation of the estrogen receptor
standard regimen. Although intermittent induced by drug binding. This in turn de-
dosing with the intravenous formulations termines how strongly the drug/receptor
such as zolendronate prevents oral toler- complex recruits coactivators relative to
ance problems, these agents are implicated corepressors.
at higher rates in a rare but debilitating Clinically, the benefits of SERM
oral affliction called osteonecrosis of the therapy on bone are well established. In
jaw (ONJ). postmenopausal women with osteoporo-
sis, SERM treatment decreases markers
Estrogen of bone turnover by 30% to 40% after 1
Estrogen deficiency in menopause is a year and increases bone density 2% to 3%
major cause of osteoporosis in women. It after 3 years. It also decreased the inci-
acts to maintain bone mass, and its with- dence of vertebral fractures by 30% to
drawal leads to accelerated bone resorp- 50%.59–62
tion. Estrogen protects bone by inducing a Although control studies evaluating
paracrine signal originating in osteoblasts oral bone loss are needed, SERMs appear
leading to the death of preosteoclasts,56 to have excellent therapeutic potential for
therefore establishing an appropriate ratio minimizing local and systemic conse-
between bone-forming osteoblasts and quences of postmenopausal osteoporosis.
bone-resorbing osteoclasts in part through
the induction of osteoclast apoptosis. Es- Strontium Ranelate
trogen replacement therapy remains a Oral strontium ranelate belongs to a class
good treatment option for the prevention of drugs called dual action bone agents
of osteoporosis and is being studied as a (DABAs). It stimulates the calcium sens-
way of preventing oral bone loss. Hor- ing receptors and leads to the differentia-
mone replacement therapy and calcium tion of preosteoblasts to osteoblasts,
and vitamin D supplements appear to have which increases bone formation. In addi-
beneficial effects on tooth retention.57 tion, it enhances the secretion of osteo-
protegerin by osteoblasts, thereby
Selective Estrogen Receptor Modulators inhibiting osteoclast differentiation in re-
Selective estrogen receptor modulators lation to the RANKL system, which leads
(SERMs) selectively bind to estrogen re- to the decrease in bone resorption.63
ceptors and inhibit bone resorption and Strontium ranelate is taken for the
turnover. This is possible because they treatment of osteoporosis to prevent ver-
lack the steroid structure of estrogens but tebral and hip fracture. In post-
menopausal women with osteoporosis, zymatic bone degradation, the use of

strontium ranelate 2 g/day increased cathepsin K inhibitors has emerged as a
BMD.64 In regard to vertebral fractures, novel therapeutic approach. Odanacatib is
strontium ranelate treatment was associ- currently the only cathepsin K inhibitor
ated with reductions of vertebral fractures under clinical investigation. In phase 1 stud-
of 49% compared with data from control ies, odanacatib at an oral dose of 50 mg and
groups.65 Strontium ranelate has also 100 mg once per week significantly reduced
shown significant efficacy against periph- serum markers of bone turnover.71,72
eral fractures and hip fractures.66
Although strontium ranelate appears Saracatinib
to be protective against fractures in the Other promising agents are the Src kinase
patient with osteoporosis and increases inhibitors. The effect of impaired osteo-
BMD values, it is not yet FDA approved clastic functions in Src-deficient mice pro-
for therapeutic use in the United States. vided the rationale to explore the skeletal
effects of this class of inhibitor. In a phase
Denosumab 1 trial, the Src kinase inhibitor saracatinib
Denosumab is a neutralizing human mon- (AZD0530) was evaluated and showed
oclonal antibody to RANKL, mimicking similar results to those once triggered by
the biologic function of OPG.67 Clinical odanacatib.73
studies evaluating the clinical efficacy
using an intermittent regimen either every Chloride Channel and Proton
3 or every 6 months demonstrated a strong Pump Inhibitors
inhibition of bone resorption as observed Other strategies involve inhibition of
by up to 88% reduction in the levels of Atp6v0d2, a subunit of v-ATPase that is
serum C-telopeptide, an indicator of bone required for acidification and the voltage-
remodeling, with a rapid onset of action 3 gated chloride channel ClC-7. The chlo-
days after administration and with a sus- ride channel inhibitor NS3736 prevents
tained, but reversible, antiresorptive ef- bone loss through a marked antiresorp-
fect.68,69 At 1 year, denosumab treatment tive effect, without impeding on bone for-
significantly increased bone mineral den- mation markers.74
sity, especially in the lumbar spine and to
a minor extent in the total hip and the dis- Anabolic Drugs
tal radius. The clinical benefits of deno- Teriparatide (1-34 PTH)
sumab were similar to or exceeded those Two forms of parathyroid hormone,
induced by alendronate and revealed dose- rhPTH 1-84 (intact hormone) and rhPTH
dependency.69 Although not detected in the 1-34 (N-terminal fragment, teriparatide),
original pivotal clinical trial, in a seven- are approved for the treatment of osteo-
year open label extension two patients re- porosis. PTH is a potent hormone with
ceiving Denosumab for osteoporosis catabolic and anabolic effects in bone.
treatment presented ONJ lesions which ac- Teriparatide (Forteo, recombinant human
counts for a prevalence of 0.061%.70 PTH (1-34)) has been shown to be effec-
tive in osteoporosis management.75,76 It
Other Emerging Approaches stimulates osteoblasts, thus increasing
Odanacatib their activity. Currently, teriparatide is
Based on the concept that the protease used mostly for patients with established
cathepsin K plays an important role in en- osteoporosis who have particularly low
BMD, several risk factors for fracture, or hibiting SOST have shown the potential
no tolerance of oral bisphosphonates. It to inhibit alveolar bone loss in a preclini-
is given as a daily injection with a pen- cal model of periodontal disease. The ad-
type injection device. The use of PTH or ministration of sclerostin antibodies
teriparatide has been demonstrated to (Scl-Ab) was able to both prevent and
have strong potential for oral and cranio- treat experimental periodontitis in a ro-
facial bone regeneration.77 dent model system. This approach sug-
The response of the alveolar bone to gests that bone anabolics such as SOST
PTH has been evaluated by several inves- inhibitors have potential in increasing
tigators.78–80 In an animal study by Miller alveolar bone density in the context of pe-
and collaborators,79 PTH was found to riodontal diseases.88
significantly increase crestal bone levels in
the mandibles of ovariectomized rats. A EFFECTS OF OSTEOPOROSIS
recent preclinical investigation demon- THERAPY ON THE ORAL CAVITY
strated the ability of teriparatide to pro- Osteoporosis therapy in general is prima-
mote dental implant osseointegration.81 rily aimed at improving BMD values as
Recent evidence has suggested strong po- measured by DEXA, a characteristic that
tential of teriparatide to promote clinical is associated with reduced risk of osteo-
attachment level gain and alveolar bone porosis fracture. However, important
regeneration when combined with peri- bone quality properties dependent on
odontal surgical procedures.82 Further- bone turnover and its variations are often
more, there is proof-of-concept data that affected and result in undesirable condi-
teriparatide may have a place for the treat- tions. The oral cavity, because of the con-
ment of ONJ.83 stant high mechanical demands and
complex microbial challenges, is at an in-
Other Emerging Approaches creased risk of developing debilitating se-
Sclerostin Antibody quelae secondary to pharmacologic
The gene SOST encodes the osteocyte- osteoporosis therapy. Therefore, it is nec-
specific protein known as sclerostin. Inac- essary to support the need for comprehen-
tivating mutations of this gene result in sive oral health screenings before
two rare bone disorders characterized by initiating a pharmacologic regimen that
high bone mass, van Buchem disease, and could lead to altering bone quality prop-
sclerosteosis.84,85 These findings highlight erties. This is of great importance in the
the role of sclerostin in the homeostasis case of long-term-acting medications
of bone mass and provide the bases to tar- such as bisphosphonates, particularly
get sclerostin with monoclonal antibodies with its intravenous high-dose regimens.
to enhance bone formation. In a preclini- Bisphosphonates, potent inhibitors
cal postmenopausal osteoporosis study, of bone resorption, should in theory pro-
treatment with a sclerostin antibody in- tect from periodontal and systemic bone
creased bone mass at all skeletal sites and loss, since the two processes are funda-
completely prevented bone loss associated mentally similar. A small number of
with estrogen deficiency.86 In a phase 1 placebo-controlled, randomized trials
study, a single dose of a sclerostin anti- have been conducted to test this hypothe-
body was well tolerated and increased sis. The results are collectively equivocal.
bone formation markers.87 More recently, However, a positive effect in subjects with
the delivery of monoclonal antibodies in- low alveolar bone mass at baseline and re-
ceiving bisphosphonate therapy in addi- to the lack of consistency for the diagnosis
tion to proper periodontal maintenance of these cases.
has been reported. A more recent trial Another important, modifiable fac-
based on the local delivery of a 1% alen- tor contributing to increased bone
dronate gel in periodontal disease patients fragility and loss is inadequate intake of
undergoing scaling and root planing sig- vitamin D. Results of recent studies cor-
nificantly improved clinical parameters of roborate its value to oral bone health, re-
periodontal health. The local administra- vealing that subjects taking oral calcium
tion of bisphosphonates promotes os- (1,000 mg or more daily) and vitamin D
seointegration and dental implant (400 IU or less daily) supplementation
fixation.89 However, bisphosphonates for had better clinical parameters of peri-
alveolar bone loss is considered caution- odontal health and less periodontal at-
ary because of its reported association tachment loss compared with individuals
with ONJ lesions. who did not take supplements.92–94 Fur-
The American Society of Bone and thermore, vitamin D deficiency at the
Mineral Research (ASBMR) defines time of periodontal surgery has been re-
ONJ-confirmed lesions as areas of ex- ported to negatively affect treatment out-
posed bone in the maxillofacial region that comes for up to 1 year—an important
have not healed within 8 weeks after iden- suggestion that implicates vitamin D sta-
tification by a healthcare provider in a pa- tus as a valuable indicator to enhance
tient who received bisphosphonate postsurgical periodontal healing.95
treatment and was not exposed to radia- Hormone replacement therapy
tion therapy in the craniofacial region.90,91 (HRT) has also been associated with a
Based on the review of both published positive effect on the oral cavity. In a co-
and unpublished data, the risk of ONJ as- hort of 488 elderly women, Krall and col-
sociated with oral bisphosphonate therapy laborators96 found an association between
for osteoporosis seems to be low, esti- postmenopausal HRT and tooth reten-
mated at between 1 in 10,000 patients and tion. They also found an association be-
less than 1 in 100,000 patient-treatment tween duration of HRT and tooth
years. However, the incidence of ONJ is retention. The odds of being edentulous
rapidly evolving, and the true incidence were reduced by 6% for each year of HRT
may be higher. The risk of ONJ in patients therapy. Their study suggests that post-
with cancer treated with high doses of in- menopausal HRT protects against tooth
travenous bisphosphonates is clearly loss and reduces the risk of edentulism.
higher—in the range of 1 to 10 per 100 pa-
tients (depending on the duration of ther- SUMMARY
apy). For this reason, oral bisphosphonate Although the causality between systemic
therapy is probably to be preferred, and bone loss and oral bone loss has not been
prescribing advice now recommends any fully elucidated, the current evidence
necessary dental work to be carried out demonstrates a plausible association be-
before initiating treatment. It is important tween the two disease entities. Studies sug-
to highlight that, although this area is the gest that individuals with either systemic
focus of multiple efforts across disciplines, or oral bone loss should be closely man-
an objective assessment of risks and ben- aged with a clinical protocol that mini-
efits of this class of drugs for alveolar mizes further deterioration of systemic or
bone health remains a difficult task owing oral bony structures.97–99 Additional ran-
domized, controlled clinical trials are eling following fatigue damage. Bone 1993;14:
needed to clarify the causality and/or as- 103–9.
14. Lerner UH. Inflammation-induced bone remo-
sociation between systemic and oral bone deling in periodontal disease and the influence
loss. of post-menopausal osteoporosis. J Dent Res
2006;85:596–607.
Acknowledgment 15. Raisz LG. Pathogenesis of osteoporosis: con-
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Kenneth Rieger and Mr. Chris Jung for their assis- 16. Parfitt AM. Targeted and nontargeted bone re-
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origination and progression. Bone 2002;30:5–7.
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CHAPTER 12
Periodontitis and Rheumatoid Arthritis
INTRODUCTION The learning objectives for this chapter

Two of the most common chronic inflam- are:
matory diseases affecting humans are peri- 1. Understand the potential associations
odontitis and rheumatoid arthritis. Both between rheumatoid arthritis and periodontitis.
conditions are characterized by an exuberant 2. Explore the various hypotheses under-
inflammatory reaction in the local tissues as- lying the association between oral health,
sociated with significant soft and hard tissue periodontal disease, and rheumatoid arthritis.
destruction. Furthermore, these conditions 3. Understand the clinical relevance of
have similar patterns of natural history, and such an association.
their pathogenesis—orchestrated by im-
munogenetics, cellular infiltration, enzymes, PERIODONTAL DISEASES
and cytokines—is similar. It is not surprising Although periodontal diseases manifest as a
that the treatment and management implica- wide variety of inherited and acquired con-
tions of both periodontitis and rheumatoid ditions affecting the periodontium, gingival
arthritis include treatment of the clinical diseases and destructive periodontal diseases
symptoms, modulation of the inflammatory (e.g., chronic periodontitis) comprise the ma-
response, and surgical options. jority of periodontal conditions.1 Plaque-
Onset of inflammation in periodontitis induced gingivitis, as its name suggests, is
is related to host responses to bacteria confined to the gingival tissues, whereas the
within the subgingival biofilm, but the of- various forms of periodontitis affect all
fending stimulus in rheumatoid arthritis components of the periodontium (gingival,
remains unknown. Nonetheless, given the alveolar bone periodontal ligament, and ce-
very similar pathologic processes, when peri- mentum). In general, both conditions
odontitis and rheumatoid arthritis coexist in demonstrate all the classic signs and symp-
the same patient, the plausibility of a toms of chronic inflammation, including
common underlying pathogenic mechanism redness and swelling of the tissues, loss of
(not etiology) is worthy of further consider- architectural form, and reduced function
ation. (Figure 1). If the inflammatory response is
Since this chapter was first published in not contained by the host, or is left un-
2010, there has been increasing interest and treated, then inflammatory destruction can
activity in investigating the association be so severe as to put the teeth at risk, with
between periodontal disease and rheumatoid tooth loss as the possible outcome of peri-
arthritis. This revised chapter provides an odontal disease. The diagnosis of gingivitis
updated commentary using new literature or periodontitis is largely based on the
published from 2008 to March 2013. During results of a dental and medical history and
this time, 54 scientific articles (not including of a clinical examination investigating pa-
reviews) were identified as providing either rameters such as pocket depth, gingival in-
confirmatory or new knowledge to this field. flammation, clinical attachment loss, furca-
This chapter’s aim is to provide an update tion involvement, tooth mobility, radi-
on the association between these two ographic evidence of bone loss, and tooth
chronic inflammatory diseases. loss. Although a plethora of laboratory
CHAPTER 12 Periodontitis and Rheumatoid Arthritis 215
Figure 1. Clinical and Radiographic Appearance of Periodontitis and Rheumatoid Arthritis
A. Clinical appearance of chronic periodontitis. C. Clinical appearance of rheumatoid arthritis.

B. Radiographic appearance of chronic periodontitis. D. Radiographic appearance of rheumatoid arthritis.
diagnostic tests have been proposed, to date, tion. Clinically, this condition is character-
none has proved to be particularly useful. ized by joint swelling, joint tenderness to pal-
Currently, periodontitis is considered to pation, morning stiffness, severe motion im-
be a family of related diseases that may pairment and progressive degeneration of
differ in their natural history, cause, rate and synovial-lined joints, and radiographic evi-
pattern of progression, and response to dence of joint changes (see Figure 1).3
treatment.2 Etiologic, genetic, and environ- Onset of rheumatoid arthritis can be
mental factors are thought to account for acute or subacute and may include a palin-
this variability. The critical factor in establish- dromic onset, monoarticular presentation
ing the presence of periodontitis is the devel- (both slow and acute forms), extra-articular
opment of a subgingival bacterial biofilm. synovitis (tenosynovitis, bursitis), polymyal-
However, note that although the bacterial in- gia-like onset, and general symptoms
fection is necessary, it is not sufficient for the (malaise, fatigue, weight loss, fever). Several
disease to develop, and many other factors laboratory tests assist in the diagnosis of
must be present for overt periodontitis to rheumatoid arthritis, which include measure-
become clinically evident. ment of erythrocyte sedimentation rate,
acute-phase proteins, plasma viscosity, and
RHEUMATOID ARTHRITIS measurement of citrullinated proteins. Of
Rheumatoid arthritis is a chronic inflamma- these, erythrocyte sedimentation rate and
tory disease and, like periodontal disease, serum C-reactive protein levels provide the
demonstrates the classic signs of inflamma- best information about the acute-phase re-
tion—swelling, pain, heat, and loss of func- sponse. C-reactive protein levels correlate well
Table 1. Disease Activity in Periodontitis and Rheumatoid Arthritis

Periodontitis Rheumatoid Arthritis
Well-Maintained Periodontitis Self-limiting Rheumatoid Arthritis
Periodontitis commences but, by following simple treat- After commencement of the disease it does not
ment, can be contained, and with appropriate mainte- progress to more severe forms.
nance, very little progression occurs.
Downhill Periodontitis Easily Controlled Rheumatoid Arthritis
Established periodontitis can be largely controlled with a When the disease becomes established, its progression
combination of simple and complex treatments. Some can be largely controlled through simple treatments
further progression may occur but is usually small. such as first-line medications.
Extreme Downhill Periodontitis Progressive Rheumatoid Arthritis
Once established and despite various treatment proto- After becoming established, the disease continues to
cols, the disease progresses over time (not necessarily in progress and cause significant joint damage. Advanced
a linear manner) and may even result in tooth loss. treatments such as second-line medications and disease-
modifying antirheumatic drugs are of little help in
stopping disease progression.
Adapted from Mercado et al., 2003.22
with clinical assessment and radiographic mission of longer than 3 years. Moreover,
changes. Recently, a test that is positive for most patients experience disease progression
citrullinated peptides has been established, while taking these medications.6 In general,
with its high sensitivity and specificity, and is patients with rheumatoid arthritis have a
very close to a diagnostic test for rheumatoid number of poor prognostic indicators (Table
arthritis.4 Historically, the extent of anatomic 1). This implies that they have significant sys-
changes occurring in joints of patients with temic impairment of the inflammatory and
rheumatoid arthritis has been assessed by ra- immune responses, which would normally be
diography. More recently, ultrasonography protective against such a disease.
and magnetic resonance imaging have gained As with rheumatoid arthritis, periodon-
acceptance for studying joint, tendon, and titis manifests in three general forms: rapid
bursal involvement in those with rheumatoid progression, moderate progression, and no
arthritis. The clinical course of rheumatoid progression of periodontal disease.7 More re-
arthritis fluctuates, and its prognosis is unpre- cently, these forms have been termed aggres-
dictable. In most situations, rheumatoid sive or chronic and may exist in either stable
arthritis is considered a multifactorial disease, or active disease.1
resulting from a combination of host, envi-
ronmental, and genetic influences. INFLAMMATION
In both rheumatoid arthritis and periodonti-
TYPES OF RHEUMATOID ARTHRITIS tis, inflammation is likely initiated by antigen
AND PERIODONTITIS stimulation (in the form of peptide or viru-
In general, rheumatoid arthritis can be classi- lence factors), and the subsequent cascade of
fied into three types, depending on its mani- acute and chronic inflammation leads to a
festation and the patient’s response to treat- vicious cycle of continuous release of proin-
ment: self-limited, easily controlled, and pro- flammatory mediators perpetuated by the
gressive.5 It appears that for most people di- host’s own cells. Both the resident cells (syn-
agnosed with rheumatoid arthritis, disease ovial cells in rheumatoid arthritis; ker-
progression is inevitable. Even after treat- atinocytes, fibroblasts, and osteoblasts in pe-
ment with second-line medications, only a riodontitis) and the migrating inflammatory
very small percentage of patients undergo re- cells all are active players responsible for the
destruction observed in these two chronic in- rheumatoid arthritis is mainly orchestrated
flammatory diseases (Figure 2). by cytokines and enzymes released by resi-
During the pathogenesis of both peri- dent and migrating cells that act via direct
odontitis and rheumatoid arthritis, an abun- and indirect means. The enzymes degrade
dant release of cytokines and other proin- most extracellular matrix proteins and are
flammatory mediators occurs (Table 2). Al- largely responsible for matrix destruction seen
though these mediators are present during in periodontitis and rheumatoid arthritis. The
normal tissue homeostasis, it is during inflam- major enzymes responsible for tissue destruc-
matory processes, as seen in periodontitis and tion are the matrix metalloproteinases
rheumatoid arthritis, that they become un- (MMPs). These constitute a very broad
controlled and tissue destruction ensues. family of enzymes with a variety of sub-
However, the precise molecular and cellular strates and functions (Table 3). The cells that
mechanisms controlling the release and action release MMPs in periodontitis and rheuma-
of these molecules are still poorly understood. toid arthritis are polymorphonuclear leuko-
Cytokines released by lymphocytes, cytes (PMNs), monocytic phagocytes, and fi-
macrophages, and fibroblasts are different broblasts. Both interleukin 1 (IL-1) and
and are responsible for specific aspects of the tumor necrosis factor alpha (TNF-a) may
inflammatory reaction. Though involved in induce the production of collagenase and
the initiation of immune responses, these cy- other neutral proteases by most of these cells.
tokines have a wide range of effects on For both rheumatoid arthritis and peri-
many cells, leading to cell proliferation and odontitis, disease progression occurs as a
increased tissue destruction. result of very high tissue levels of IL-1b and
Tissue damage in periodontitis and TNF-a and low levels of cytokines such as
Figure 2. Histologic Appearance of Inflamed Gingival and Synovial Tissues
A B
C D
Histologic appearance of inflamed gingival (A) and synovial (B) tissues. Note heavy inflammatory cell infiltrates in
both specimens. Histologic appearance of bone resorption occurring in periodontal (C) and rheumatoid (D) tissues.
Note areas of active bone resorption associated with osteoclasts (arrows).
Table 2. Cytokines Involved in Periodontitis and Rheumatoid Arthritis

Cytokine Properties
Chemokines Produced by: macrophages, endothelium, fibroblasts, platelets, T cells
Functions:
Leukocyte chemotaxis, activation
IFN-a and Produced by: macrophages (a), fibroblasts (b)
IFN-b Enhanced by: bacterial endotoxin, TNF-a, Il-1
Functions:
All cells: antiviral state, increased class I MHC expression
NK cells: activation
IFN-g Produced by: NK cell, T cells
Enhanced by: IL-2
Functions:
Macrophages: activation of microbicidal function
Stimulation of some antibody responses
IL-1 Produced by: macrophage, endothelium, epithelium
Induced by: bacterial endotoxin, leukotrienes, C5a, TNF, Il-6
Functions:
Endothelial cell activation: inflammation, coagulation
PMN: activation
Hypothalamus: fever
IL-10 Produced by: macrophages, T cells
Functions:
Macrophages inhibition of IL-12 production
Reduced expression of co-stimulators and class II MHC molecules
IL-12 Produced by macrophages, dendritic cells
Functions:
NK and T cells: IFN-g synthesis, increased cytolytic activity
T cells: Th1 differentiation
IL-15 Produced by: macrophages
Functions:
NK cells: proliferation
T cells: proliferation
IL-18 Produced by: macrophages
Functions:
NK and T cells: synthesis of IFN-g
IL-6 Produced by: macrophages, endothelium, T cells

Induced by: bacterial endotoxin, leukotrienes, C5a, TNF, IL-6
Functions:
Liver: acute-phase proteins
B cells: proliferation of antibody-producing cells
TNF Produced by: macrophages, T cells
Induced by: bacterial endotoxin, viruses and protozoa, C5a, immune complexes,
substance P, Il-1, IL-2, TNF-a
Functions:
Endothelial cell activation: inflammation, coagulation
PMN: activation
Hypothalamus: fever
Liver: acute-phase proteins
Muscle, fat: catabolism
IL-10 and transforming growth factor b, concept of a monocytic hypersecretory state

which suppress the immunoinflammatory re- has also been described for patients with
sponse. In addition, an imbalance between rheumatoid arthritis.10
tissue inhibitors of metalloproteinases Many of the genes that regulate the cy-
(TIMPs) and MMPs secreted by tokine profiles and responses of monocytes
macrophages, fibroblasts, and other resident have been mapped to the HLA-DR region of
and inflammatory cells is characteristic of the chromosome 5 in the area of the TNF-b
active phases of both rheumatoid arthritis and genes.11 Because both rheumatoid arthritis
periodontitis. and periodontitis have been associated with
Bone destruction is a common finding this HLA complex, a common genetic basis
in periodontitis and rheumatoid arthritis. exists for the observed monocyte trait, linking
This occurs as a result of disruption to the rheumatoid arthritis and periodontitis.
normally balanced processes of bone resorp-
tion and bone formation. The major media- ENVIRONMENTAL FACTORS
tors of bone resorption are prostaglandin E2 For some time, the clinical manifestation of
(PGE2), IL-1, TNF-a, and IL-6. chronic diseases such as periodontitis and
In both periodontitis and rheumatoid rheumatoid arthritis have been recognized as
arthritis, the immune response is regulated being significantly influenced by environmen-
by genes that control T-cell responses to tal or “modifying” factors. These factors are
foreign antigens. In this way the nature of anything that might modify or alter the host
the protective antibody response as well as inflammatory response, such as demo-
the magnitude of tissue-destructive inflam- graphic, socioeconomic, lifestyle, diet, hor-
matory responses are determined. monal, and psychological variables. Since
genetic factors may account for up to 50%
ROLE OF GENETICS of the risk for both periodontitis and
The role of genetics in periodontitis and rheumatoid arthritis,8,12 other factors, includ-
rheumatoid arthritis is of considerable im- ing environmental influences and gene–envi-
portance. For both chronic periodontitis and ronment interactions, must explain the rest.
rheumatoid arthritis, there is considerable Of the environmental risk factors identi-
variation in clinical manifestation of the fied to date, smoking is probably the single
disease. Much of this can be accounted for most important environmental factor
by genetic factors.8 Many differences in making an impact on many chronic diseases.
disease manifestations can be related to the Through its adverse effects on the cardiovas-
overexpression or underexpression of numer- cular system, immune cell function, and
ous cytokines and other inflammatory medi- general tissue physiology, it is not surprising
ators. Of these, IL-1, TNF, and PGE2 have that smoking is considered a major risk
been found to be under strong genetic factor for the development of both rheuma-
control. Numerous studies have been pub- toid arthritis and periodontitis.13,14
lished concerning the so-called “hyper-re- Another environmental factor of inter-
sponsive monocyte genetic traits,” which est is socioeconomic status. This may be a
have common genetic regions that influence significant factor in the outcome of many
the susceptibility to inflammatory diseases. chronic diseases, including both rheumatoid
Typical of this trait is the overproduction of arthritis and periodontitis.15,16 The reasons
proinflammatory mediators such as IL-1b, are not entirely clear, although suggestions
TNF-a, and PGE2, and is typically seen in have been made that persons from lower so-
patients with aggressive periodontitis.9 The cioeconomic status may be less compliant
Table 3. Human Matrix Metalloproteases (MMPs) and Their Substrates (ECMs)*

Protein Collagenous Noncollagenous Nonstructural ECM
Substrates ECM Substrates Component Substrates
MMP-1 Collagen types I, II, Aggrecan, casein, nidogen, a1-antichymotrypsin, a 1-antitrypsin/a1-
III, VII, VIII, X, and serpins, versican, perlecan, pro- proteinase inhibitor, IGFBP-3, IGFBP-
gelatin teoglycan link protein, and 5, IL-1b, L-selectin, ovostatin, recombi-
tenascin C nant TNF-a peptide, and SDF-1
MMP-2 Collagen types I, IV, Aggrecan, elastin, fibronectin, Active MMP-9, active MMP-13, FGF
V, VII, X, XI, XIV, laminin, nidogen, proteoglycan R1, IGF-BP3, IGF-BP5, IL-1b, recombi-
and gelatin link protein, and versican nant TNF-a peptide, and TGF-b
MMP-3 Collagen types II, IV, Aggrecan, casein, decorin, elastin, a 1-antichymotrypsin, a1-proteinase fibrino-
IX, X, and gelatin fibronectin, laminin, nidogen, gen, IGF-BP3, L-selectin, ovostatin, pro-HB-
perlecan, proteoglycan, proteogly- EGF, pro-IL-b, pro-MMP-1, pro-MMP-8,
can link protein, and versican pro-MMP-9, pro-TNF a, and SDF-1
MMP-7 Collagen types I, II, Aggrecan, casein, elastin, enactin, b4 integrin, decorin, defensin, E-cadherin,
III, V, IV, and X laminin, and proteoglycan link Fas-L, plasminogen, pro-MMP-2, pro-
protein MMP-7, pro-TNF a, transferrin, and
syndecan
MMP-8 Collagen types I, II, Aggrecan, laminin, and nidogen a2-antiplasmin and pro-MMP-8
III, V, VII, VIII, X,
and gelatin
MMP-9 Collagen types IV, V, Fibronectin, laminin, nidogen, CXCL5, IL-1 b, IL2-R, plasminogen,
VII, X, and XIV proteoglycan link protein, and pro-TNF a, SDF-1, and TGF-b
versican
MMP-10 Collagen types III, Fibronectin, laminin, and Pro-MMP-1, pro-MMP-8, and pro-
IV, V, and gelatin nidogen MMP-10
MMP-11 Laminin a1-antitrypsin, a1-proteinase inhibitor,
and IGFBP-1
MMP-12 Elastin Plasminogen
MMP-13 Collagen types I, II, Aggrecan, fibronectin, laminin, Plasminogen activator 2, pro-MMP-9,
III, IV, V, IX, X, XI, perlecan, and tenascin pro-MMP-13, and SDF-1
and gelatin
MMP-14 Collagen types I, II, Aggrecan, dermatan sulphate av b3 integrin, CD44, gC1qR, pro-
III, and gelatin proteoglycan, fibrin, fibronectin, MMP-2, pro-MMP-13, pro-TNF a,
laminin, nidogen, perlecan, SDF-1, and tissue transglutaminase
tenascin, and vitronectin
MMP-15 Collagen types I, II, Aggrecan, fibronectin, laminin, Pro-MMP-2, pro-MMP-13, and tissue
III, and gelatin nidogen, perlecan, tenascin, and transglutaminase
vitronectin
MMP-16 Collagen types I, III, Aggrecan, casein, fibronectin, Pro-MMP-2 and pro-MMP-13
and gelatin laminin, perlecan, and vitronectin
MMP-17 Gelatin Fibrin and fibronectin
MMP-19 Collagen types I, IV, Aggrecan, casein, fibronectin,
and gelatin laminin, nidogen, and tenascin
MMP-20 Aggrecan, amelogenin, and cartilage
MMP-21 a1-antitrypsin
MMP-23 Gelatin
MMP-24 Gelatin Chondroitin sulfate, dermatin Pro-MMP2 and pro-MMP-13
sulfate, and fibronectin
MMP-25 Collagen type IV and gelatin Fibrin and fibronectin Pro-MMP-2
MMP-26 Collagen type IV and Casein, fibrinogen, and b1-proteinase inhibitor
gelatin fibronectin
MMP-28 Casein
*Many of these substrates are found in both the periodontium and the synovium.
Adapted from Somerville RPT, Oblander SA, Apte SS. Matrix metalloproteinases: old dogs with new tricks.
Genome Biol 2003;4:216–26.
with regard to their general healthcare and nant or single-gene recessive mendelian law
have less access to the full range of health- (Table 4). Since both inherited genetic varia-
care. However, these explanations do not tion and environmental factors such as
fully explain this relationship. In this regard, smoking, hygiene, and pathogenic bacteria in-
allostatic load has also been proposed to de- teract to determine a person’s risk for peri-
scribe dysregulation of physiologic adaptive odontitis and rheumatoid arthritis, these two
processes, including immune function, which diseases fit the definition of complex diseases.
in health maintain stability to stressors. It Hence, in response to an initiating event in
has been proposed that allostatic load may these diseases, environmental agents interact
follow a socioeconmic gradient that is in part with genetic factors to influence disease sus-
responsible for inequalities in chronic dis- ceptibility (Figure 3). Such interactions initiate
eases such as periodontitis and rheumatoid and regulate immunoinflammatory reactions
arthritis. In this model, low socioeconomic that ultimately manifest as the clinical signs of
status results in increased exposure to psy- rheumatoid arthritis or periodontitis. Al-
chosocial stress, which activates primary allo- though our understanding of the role of
static mediators, including a wide range of dental plaque as being pivotal in the initiating
inflammatory mediators. Under these condi- events for periodontal disease is well under-
tions, dysregulation of a range of im- stood, the initiating events for rheumatoid
munomodulatory functions occurs, which arthritis are less clear.
can lead to alterations in the extent and Interactions between environmental risk
severity of chronic diseases. factors and genetics are now providing us
with valuable clues as to the nature of
PERIODONTITIS AND RHEUMATOID complex diseases such as periodontitis and
ARTHRITIS—COMPLEX OR rheumatoid arthritis. One of the best-recog-
ECOGENETIC DISEASES nized environmental risk factors for both dis-
In recent times, periodontitis and rheumatoid eases is smoking. A relation between
arthritis have been considered “complex” or smoking and HLA-DR–shared epitope
“ecogenetic” diseases.17,18 A complex disease is genes, the main genetic risk factors for
a condition with a genetic component that rheumatoid arthritis and periodontitis, has
does not follow the simple single-gene domi- been shown to impart increased risk for
both rheumatoid arthritis and periodontitis.
Table 4. Features of Complex or From these types of studies, it is possible to
Ecogenetic Diseases define the various environmental risk factors
that, in certain genetic contexts, will initiate
• Interact with ecology, molecular genetics, toxicol-
ogy, public health medicine, and environmental adverse immune reactions, ultimately leading
epidemiology. to the clinical symptoms in various subsets
• Are common chronic diseases with adult onset of susceptible patients.
that show familial aggregation but do not follow In recent years there has been consider-
mendelian family patterns.
• Appear to be caused by an unknown number of able interest in identifying single nucleotide
multiple genes, which interact with environmental polymorphisms (SNPs) and statistical genetic
factors. strategies, such as haplotype mapping, to
• Only a small percentage (less than 1%–7%) of identify genes that may be important in
those affected show a single mutant gene transmit-
ted by mendelian inheritance with characteristic complex diseases such as rheumatoid arthri-
transmission. tis and periodontitis. Even though simple
• Often have an earlier age of onset and more one-to-one mapping between disease gene
severe clinical manifestations. and disease phenotype does not occur in
Figure 3. Disease Interactions Between Periodontitis and Rheumatoid Arthritis
HOST
ENVIRONMENT
RESPONSES
DISEASE
ETIOLOGY
GENETICS
The periodontal diseases and rheumatoid arthritis are classified as ecogenetic or complex diseases involving intricate
interactions among host responses, environmental factors, etiologic factors, and genetics.
complex disease, this should not reduce the preterm low-birth-weight infants, cardiovascu-
importance of trying to identify genes that lar disease, pulmonary disease, obesity, and
determine individual differences in disease osteoporosis. In the context of this chapter,
susceptibility for rheumatoid arthritis and considering the potential interaction between
periodontitis. An understanding and identifi- periodontitis and rheumatoid arthritis, it is of
cation of gene mutations in complex dis- interest that all these diseases have also been
eases, using genome-wide association studies, associated with persons suffering from
may account for genetic sources of variation rheumatoid arthritis (Table 5). Even after
in disease risk and should enable us to better
understand environmental effects. Table 5. Systemic Conditions Reported
to Be Associated with Both Periodontitis
and Rheumatoid Arthritis
SIGNIFICANT INTERRELATIONSHIPS
BETWEEN PERIODONTAL DISEASE Cardiovascular disease
Diabetes
AND RHEUMATOID ARTHRITIS AND Obesity
OTHER SYSTEMIC CONDITIONS Obstetric problems
The focus of this volume is the association of Pulmonary conditions
periodontal diseases with a large number of Renal conditions
Cancer
systemic conditions, including diabetes,
accounting for variable confounders, includ- flammatory mediators,56 HLA-DR anti-

ing various medications, many studies have gens,57–59 and hormones.60 All these studies
been able to demonstrate significant associa- have supported the notion that periodontitis
tions between rheumatoid arthritis and sys- and rheumatoid arthritis are interrelated,
temic conditions.19 The underlying feature which has led various authors to conclude
seems to be dysregulated chronic inflamma- that inflammation (and its dysregulation)
tion in both periodontitis and rheumatoid may be the central link between periodontitis
arthritis. and rheumatoid arthritis.23 Recent studies
have demonstrated that increased inflamma-
WHAT IS THE EVIDENCE FOR A tory mediator levels in rheumatoid arthritis
RELATIONSHIP BETWEEN patients, despite long-term use of anti-in-
PERIODONTITIS AND flammatory drugs, suggests a propensity in
RHEUMATOOID ARTHRITIS? these patents to overproduce a number of
For over 80 years, reports have existed in the inflammatory mediators.61,62 However, one
literature concerning a possible relation recent study has refuted such a conclusion.63
between rheumatoid arthritis and periodonti-
tis. A number of reviews and commentaries Does Periodontal Treatment Influence
on this topic have been published.20–25 Rheumatoid Arthritis?
As early as 1985, a case study was published
Clinical Reports reporting remission of rheumatoid arthritis
Several studies have reported little or no as- after periodontal treatment.64 This study re-
sociation between rheumatoid arthritis and mained largely forgotten until the publication
periodontal disease26–31; however, most of the of two additional studies that indicated that
literature on this topic supports such an as- periodontal treatment could reduce the
sociation. Although the least convincing in severity of rheumatoid arthritis.65,66 More re-
terms of scientific design, simple pilot studies cently, three studies indicate that periodontal
analyzing data obtained from self-reported therapy has the potential to reduce the sever-
illnesses have indicated a higher incidence of ity of active rheumatoid arthritis.67–69 This
self-reported rheumatoid arthritis in patients effect may be independent of any medica-
with periodontitis.32 tions used to control the arthritic condition.67
Many case-control studies have also Although these studies are interesting, they
been carried out.33 Since our last review in have involved relatively few subjects and
2008, 16 additional case reports have been highlight the need for larger well-controlled
published,34–49 14 of which supported a posi- randomized clinical trials to address this im-
tive relation between rheumatoid arthritis portant question.
and periodontal disease34–37,39–46,48,49 and two
did not support an association.38,47 For these Does Rheumatoid Arthritis Treatment
studies, periodontal conditions were vari- Influence Periodontal Disease?
ously measured as number of teeth missing, If the relation between rheumatoid arthritis
gingival bleeding, attachment loss, probing and periodontal disease is truly bidirectional,
pocket depth, and radiographic bone loss. then not only should periodontal treatment
Studies also have investigated several influence the outcomes of the clinical signs
clinical and laboratory parameters to further and symptoms of rheumatoid arthritis, but
ascertain whether a relation exists between the converse should also hold true. Several
periodontitis and rheumatoid arthritis. These studies have been published reporting the in-
parameters include cytokine profiles,50–55 influence of various rheumatoid therapies on
periodontal conditions in patients with both of this association to be carried out to es-
rheumatoid arthritis and periodontal disease. tablish the temporal sequence. Finally, from
Many of these studies have considered the the studies published to date, the influence
effect of medications used in the management of medications, which rheumatoid arthritis
of rheumatoid arthritis such as blockers of patients may be taking, on periodontitis is
TNF-a and IL-6. To date, data are limited to interesting. Many, if not all, of these med-
suggest that such agents can reduce local peri- ications are anti-inflammatory agents and,
odontal inflammation in rheumatoid arthritis as such, have the potential to suppress peri-
patients with periodontitis.70 odontal inflammation and affect periodon-
tal disease progression. Nonetheless, reports
Animal Models indicate that significant periodontal destruc-
Further support for a significant relation tion can still be seen in patients who may be
between periodontitis and rheumatoid arthri- taking anti-inflammatory medications for
tis has been highlighted in a number of rheumatoid arthritis.37,74 It has been pro-
animal studies. Of these studies, two have posed that before symptoms of rheumatoid
demonstrated the very intriguing finding that arthritis develop, periodontitis was most
induction of experimental arthritis can lead likely also developing and not detected.23
to alterations in the periodontal tissues. Con- Thus, in an analysis of the association
versely, one of these studies demonstrated between rheumatoid arthritis and periodon-
that induction of experimental periodontitis titis, consideration of disease duration (for
can lead to synovial joint changes consistent both periodontal and rheumatoid) is a criti-
with the development of arthritis.71,72 cal factor. Future studies concerning the re-
lation between periodontitis and rheumatoid
Significance of These Studies arthritis should address and document the
Careful assessment of the data reported disease with regard to the severity and dura-
from many of the previously mentioned tion of both diseases.
studies allows us to make some important
observations. First, few of these studies PROPOSED MECHANISMS FOR THE
support the commonly held tenet that pa- RELATION BETWEEN PERIODONTITIS
tients with rheumatoid arthritis have im- AND RHEUMATOID ARTHRITIS
paired oral hygiene (judged by plaque and Several mechanisms for a relation between
bleeding scores) because of their “disability.” periodontitis and rheumatoid arthritis have
It is variously reported that oral hygiene is been proposed. The principal mechanisms
no different between rheumatoid arthritis may involve either changes to blood vessels
patients with periodontitis and non-rheuma- or infection of host tissues.
toid arthritis patients with periodontitis.73,74
Another important observation from re- Vascular Alterations
cently published studies is that those with Recent investigations into the association
severe rheumatoid arthritis are more likely between osteoclast activation and vascular
to suffer from advanced periodontitis and damage suggest a common pathway in the de-
vice versa. However, the association seems velopment of periodontitis and rheumatoid
to be in favor of rheumatoid arthritis arthritis. It has been hypothesized that both
making an impact on periodontitis (RR: rheumatoid arthritis and periodontitis share
4.1) rather than periodontitis making an common molecular pathways within the
impact on rheumatoid arthritis (RR: 1.5).73 RANK/OPG/TRAIL (receptor activator of
Also, it is important for longitudinal studies NF-kappa B) axis whereby a decrease in os-
teoprotegerin (OPG) leads to reduced vascular Elevated antibodies and DNA for B.
protection.23 In addition, increases in RANKL forsythus, P. intermedia, P. gingivalis, and Fu-
and TRAIL levels within inflamed tissues may sobacterium nucleatum have also been found
result not only in the possible development of in synovial fluid.77–80 Taken together, these
vascular damage but also in activation of os- findings suggest the possibility that peri-
teoclasts and subsequent bone resorption. odontal pathogens (either whole or DNA)
Another vascular model proposes that may translocate from the periodontal tissues
microvascular involvement is one of the first to the synovium, where they could then ex-
stages of a number of chronic diseases, such acerbate the inflammatory processes occur-
as periodontitis and rheumatoid arthritis.75 ring within rheumatoid joints.
In this model, reduced caliber of capillaries
and greater number and elongated capillaries Citrullination—the Missing Link?
are noted in both periodontal tissues and A novel hypothesis for the development of
rheumatoid synovium. rheumatoid arthritis via the humoral re-
sponse to oral bacteria found in periodontitis
Bacterial Infection has been proposed.81 In this model, an au-
Data from several animal models demon- toimmune disease to proteins partially
strate that arthritis can develop secondarily altered by bacterial enzymes in genetically
to different stimuli and through different ef- susceptible individuals may develop (Figure
fector pathways, including exogenous infec- 4). Central to this hypothesis is the appear-
tions. If the observations in animal models ance of rheumatoid factors and anticyclic,
are also applicable to human rheumatoid citrullinated peptide autoantibodies during
arthritis, we might anticipate that different
types of infections as well as other environ- Figure 4. The Humoral Immune Response
mental exposures with capacity to induce ex- to Citrullination
cessive proinflammatory cytokines in geneti-
cally susceptible persons may contribute to Periodontal infection
disease either together with some autoim-
mune reaction or by themselves. Citrullination of proteins by P. gingivalis
Many periodontal pathogens exhibit or
characteristics similar to those of microor- inflammation
ganisms suspected to induce rheumatoid
arthritis in a genetically susceptible host. Pe- Production of autoantibodies to
riodontal pathogens incite a chronic continu- citrullinated proteins
ous inflammation within the periodontal
tissues and also serve as an abundant supply Cross-reactivity with
of lipopolysaccharides. Thus, the possibility cartilage components
that an ongoing periodontitis can trigger or
exacerbate rheumatoid arthritis in genetically
Autoimmunity to self-antigens
susceptible individuals is biologically plausi-
ble.76 A number of studies have reported ele-
vated serum antibodies to a number of peri- Rheumatoid arthritis
odontopathic bacteria including Porphy-
Citrullination occurring within the periodontal tissues
romonas gingivalis, Prevotella intermedia, Pre- may provide a stimulus for development of rheuma-
votella melaninogenica, Bacteroides forsythus, toid arthritis or exacerbation of the inflammatory
and Aggregatibacter actinomycetemcomitans. process in rheumatoid joints.
the development of rheumatoid arthritis. a full periodontal assessment. Because many

The production of deimination enzymes by of the signs and symptoms of periodontitis
periodontal pathogenic bacteria, such as P. are painless and subtle and may advance
gingivalis, can induce autoantibodies, allow- rapidly without the patient being aware of the
ing a link between periodontal infection and problem, this aspect of clinical assessment has
the development of rheumatoid arthritis. been overlooked. In light of current data,
Recently, two studies have identified cit- persons suffering from rheumatoid arthritis
rullinated proteins in inflamed periodontal seem to have a higher risk of developing peri-
tissues.82,83 These findings complement odontal problems. Furthermore, early evi-
another recent report detailing the autoanti- dence has suggested that treatment for peri-
body repertoire in periodontitis in which the odontitis can reduce the clinical symptoms of
induction of autoimmunity to citrullinated rheumatoid arthritis. Therefore, early interven-
proteins may be related to citrullination oc- tion to prevent periodontal destruction occur-
curring within the periodontal tissues.84 ring in those with rheumatoid arthritis should
These findings raised the intriguing question be considered to reduce the impact of
as to whether citrullination occurs in the pe- rheumatoid arthritis.
riodontium during the inflammatory process.
If this is the case, then the possibility exists CONCLUSIONS
that priming anti-CCP (anti-cyclic citrulli- For several decades it has been suspected that
nated peptide) antibodies may be produced because periodontitis and rheumatoid arthri-
during the development of periodontitis. If a tis share many common pathologic features,
later event such as joint inflammation results they may be clinically related or associated
in citrullination, then, in a primed individual, diseases. It is now becoming apparent, mainly
the subsequent antibody response could be from case-control and laboratory studies, that
very robust. This fits well with the so-called both disease severity and extent may be
two-hit model proposed for the development related among those suffering from both
of chronic inflammatory disorders such as rheumatoid arthritis and periodontitis. Al-
rheumatoid arthritis.85 Such a response is in though causality between the two diseases is
keeping with recent observations that experi- very unlikely, the fact that both diseases can
mental animals with a preexisting chronic in- make an impact on each other is becoming
fection or periodontitis develop experimental apparent. Indeed, emerging evidence suggests
arthritis at a faster and more pronounced that both diseases can have an impact on the
rate than nonprimed animals.71,72 other in a bidirectional manner.
CLINICAL RELEVANCE OF AN ASSOCIA- Supplemental Readings

TION BETWEEN PERIODONTITIS AND
RHEUMATOID ARTHRITIS Mercado FB, Marshall RI, Bartold PM. Inter-relation-
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cal protocols for rheumatoid arthritis patients systemic diseases co-induce (not just exacerbate) peri-
include an assessment for oral pathology, to odontitis? A hypothetical “two-hit” model. J Dent Res
date, these protocols do not routinely include 2006;85:102–5.
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CHAPTER 13
Periodontal Diseases and Cancer
INTRODUCTION persons.2 Indeed, tooth loss can be a result of

Periodontitis is a chronic immunoinflamma- either dental caries or periodontal diseases;
tory reaction to bacteria that reside within the however, age can also be a major contributing
subgingival plaque biofilm. In addition to factor in these two conditions. Thus, in early
pathogenic microorganisms in the biofilm, studies, tooth loss in older persons was
genetic and environmental factors contribute to assumed to be a more likely result of peri-
the pathogenesis of this disease, which results odontal disease than of caries. In more recent
in the destruction of the periodontal tissues times, such assertions would almost certainly
and alveolar bone supporting the teeth. During be challenged. Current understanding indicates
these responses, complications or other influ- that tooth loss in older persons may be a result
ences may impact systemic health via bac- of periodontal disease, but this association may
teremia or dissemination of locally produced not always be particularly strong. Therefore, it
inflammatory mediators. Also, bacteremia has is surprising that very few studies investigating
the potential to result in a general systemic in- the role of oral health and cancer have under-
flammatory response. Moreover, locally pro- taken specific periodontal assessments.
duced inflammatory mediators disseminated The potential interaction between cancer
into the circulation can result in increased levels and periodontal disease is important, and
of inflammatory mediators such as tumor many studies imply that a specific association
necrosis factor alpha (TNF-α), interleukins 1 between periodontitis and cancer (both oral
beta and 6 (IL-1β and IL-6), and and general) is feasible. However, larger, more
prostaglandin E2 (PGE2), as well as acute- defined studies are needed to determine
phase proteins such as C-reactive protein. This whether the association can be confirmed and
can result in a chronic inflammatory burden how this might impact our understanding of
on distant organ systems. the etiology of various cancers, their preven-
Recent studies have demonstrated association, and control.
tions between periodontal disease and several In this review, studies address the associa-
systemic diseases, including cardiovascular tion of general oral condition (e.g., oral
disease, diabetes mellitus, adverse pregnancy hygiene, restorations, prostheses, tooth brush-
outcomes, respiratory diseases, osteoporosis, ing), tooth loss, and periodontal disease with
and rheumatoid arthritis. both oral cancer and cancers of other organs.
With increasing attention focused on The educational objectives for this
oral/systemic interactions, studies have sug- chapter are:
gested that periodontal disease may be associ- 1. Understand the potential associations
ated with increased cancer risk.1 Interest for among oral health, periodontal disease,
such an association stemmed from early studies and various cancers.
that investigated the association of poor oral 2. Recognize the limitations of these
health and missing teeth on both oral cancer studies with regard to confounding
and cancer of other systemic organs. Although factors in risk assessment.
tooth loss may be a poor indicator of peri- 3. Explore the various hypotheses underly-
odontal disease, it has been used as a major ing the association among oral health,
surrogate marker for this disease in older periodontal disease, and cancer.
ORAL HEALTH, PERIODONTITIS, poor dental status have also been reported to
AND ORAL CANCER carry a significant risk for development of
Since one of the earliest case-control reports oral cancer.
on oral cancer was published more than 50
years ago,3 numerous studies have investi- Studies of the Relation Between General Oral
gated the role of oral health and oral cancer Health and Oral Cancer
(Table 1). Alcohol and smoking are consid- An early study investigating the role of den-
ered two of the most important risk factors tition, diet, tobacco, and alcohol on risk for
for oral cancer, but poor oral hygiene and oral cancer was a case study by Graham et
Table 1. Summary of Findings from Studies Published to Date Showing Relation

Between Oral Conditions and Oral Cancer
Irregular
Author(s) Study Tooth Poor Oral Gingival Poor Oral Check-ups Periodontal
Design Loss Hygiene Bleeding Condition Dental Condition
Graham et al., Case-control Yes Yes — — — —
19774
Zheng et al., Case-control Yes Yes — — — —
19905
Winn et al., Case-control No No No No — —
19916
Marshall et al., Case-control Yes Not — — — —
19927 significant
Bundgaard et al., Case-control Yes — — — Yes —
19958
Schildt et al., Case-control — — — Yes for — —
19989 recurrent
infections
Velly et al, Case-control — Yes — Yes for — —
199810 denture-
related
oral sores
Talamini et al., Case-control — — Yes Yes — —
200011
Moreno-López et al., Case-control — Yes — — No —
200012
Garrote et al., Case-control Yes — — Yes — —
200113
Campisi & Male Yes Yes — — — —
Margiotta, 200162 population
Balaram et al., Case-control Yes — Yes Yes — —
200214
Lissowska et al., Case-control Yes Yes — Yes Yes —
200315
Tezal et al., NHANES — — — — — Yes
200517
Rosenquist et al., Case-control Yes Yes — — — Yes
200518
Tezal et al., Case-control — — — — — Yes
200719
de Rezende et al., Case-control No — — — — Yes
200820
Divaris et al., Case-control Yes — — — Yes —
201016
CHAPTER 13 Periodontitis Diseases and Cancer 233
al.4 The case patients consisted of 584 men was assessed according to whether the teeth
with cancer of the oral cavity at the Roswell were brushed, men had an adjusted OR of
Park Memorial Institute, Buffalo, New York. 6.9 (CI: 2.5–19.4) and women an adjusted
Controls at the same institute consisted of OR of 2.5 (CI: 0.9–7.5) for increased risk of
1,222 males with no neoplastic diseases. In- oral cancer if they did not brush their teeth.
terviews were carried out to obtain informa- Interpretation of the findings indicated that
tion regarding dentition, diet, tobacco, and missing teeth and poor oral hygiene were risk
alcohol consumption. factors for oral cancer independent of the
From this study, a higher risk of devel- known risks associated with smoking and
oping cancer was reported in heavy smokers alcohol consumption.
and heavy drinkers. Poor oral hygiene was In a study aimed primarily at investigat-
also associated with increased risk for oral ing the effect of mouthwash use on oral
cancer. When controlled for other factors, cancer, Winn et al.6 studied 1,114 oral cancer
each of these three factors demonstrated a patients from four population-based registries
higher risk. When combined, heavy smokers in the United States. Control subjects (n =
and heavy drinkers with a poor dentition 1,268) were noncancerous individuals selected
had a risk for oral cancer 7.7 times higher by random dialing to select individuals of
than that of men with none of these fea- suitable age and gender-matched status. Inter-
tures. views were carried out to obtain information
In another case-control study carried regarding tobacco use, alcohol use, diet, oc-
out in Beijing, Zheng and colleagues5 investi- cupation, and oral health status. The oral
gated the dentition and oral hygiene status health parameters included number of teeth,
for risk of oral cancer. The subjects consisted use of dentures, tooth brushing frequency,
of 404 patients with histologically confirmed and the presence of bleeding gingiva. The
oral cancer and a similar number of control presence of other oral diseases as well as the
patients whose hospitalizations were for frequency, intensity, duration, and reason for
minor conditions. Subjects were interviewed use of mouthwashes were recorded. A highly
to obtain information regarding alcohol use, significant relation between mouthwashes of
tobacco use, dentition, and oral hygiene. Oral high alcohol content and oral cancer was
examination included recording the total noted for both males (OR: 1.5; CI: 1.1–2.1)
number of teeth, jagged teeth, filled teeth, and females (OR: 2.0; CI: 1.3–3.1). In con-
decayed teeth, and the presence of gingivitis trast to most other studies, this study found
or periodontal disease. After adjustment for no relation between oral/dental conditions
tobacco smoking, alcohol intake, years of and oral cancer.
education, gender, and age, males who had In another US investigation, Marshall
lost teeth had an increased risk for oral and colleagues7 carried out a case-control
cancer with an odds ratio (OR) of 2.4 (95% study in three western New York counties to
confidence interval [CI]: 1.3–4.5) for those investigate the contribution of alcohol, denti-
with replacement teeth and an OR of 3.7 tion, and diet to oral cancer. The cohort con-
(CI: 2.2–6.4) for those with no tooth replace- sisted of 290 pathologically confirmed cases
ment. The data for females showed an even of oral cancer selected from hospital records,
stronger effect of tooth loss on increased risk whereas matched controls were obtained
for oral cancer, with an OR of 5.6 (CI: 12.2– through neighborhood matching. Case pa-
14.5) for those with replacement teeth and tients and controls were interviewed to gather
an OR of 8.3 (CI: 3.5–19.6) for those with information concerning smoking and tobacco
no tooth replacement. When oral hygiene use, alcohol consumption, dental history (i.e.,
tooth loss, tooth replacement, oral hygiene, cancer including oral infections, dental pros-
and dental check-up practices), and diet. theses, radiographic exposure, restorations,
Compared with individuals who had lost no tooth loss, and presence of calculus. Recur-
teeth, an increased risk for oral cancer was rent oral infection was found to be associated
noted for those who had lost more than 11 with increased risk of oral cancer (OR: 3.8;
teeth (OR: 3.9; CI: 1.3–11.3). When further CI: 2.1–6.9). Other dental factors such as
analyzed, people who smoked cigarettes, restorations, dentures, and dental radiographs
drank alcohol, and had lost teeth without were of no significance.
having them replaced had an increased risk In a study investigating the association
for developing oral cancer (OR: 12.8; CI: 4.9– between dental factors and risk of upper di-
33.8). The effect of oral hygiene in this study gestive tract cancer, Velly and colleagues10
was determined to be insignificant. studied 717 patients from three centers in Sao
A population-based case-control study in Paulo who had newly diagnosed carcinomas
a Danish population has examined whether of the tongue, gingiva, floor of mouth, and
the risk of oral squamous cell carcinoma other parts of the oral cavity. Controls (non-
could be related to occupation, marital status, cancerous patients) were selected from the
dental status, and consumption of coffee, tea, same institutions, and data were collected
alcohol, and tobacco.8 In this study, the cases from two controls matched to each case on
consisted of 161 consecutively admitted pa- the basis of gender, 5-year age group,
tients with histologically verified intraoral trimester of hospital admission, and study
squamous cell carcinoma. Four-hundred age- site. Information collected by interview in-
and gender-matched controls were selected cluded information on socioeconomic vari-
from the neighborhood. Information was ables, health conditions, environmental and
gathered by interview, and no clinical dental occupational exposures, tobacco and alcohol
examination was carried out. After correcting consumption, and diet and oral hygiene. The
for alcohol and tobacco consumption, dental dental health information was obtained only
status was found to be a significant factor as- by interview and included information con-
sociated with oral squamous cell carcinoma cerning broken teeth, use of dentures and
manifestation. Those with fewer than five teeth sores caused by dentures, and frequency of
had an OR of 2.4 (CI: 1.3–4.1) compared tooth brushing. The association between
with that of those with 15 or more teeth. Fur- cancer and dental factors was assessed using
thermore, individuals who had irregular dental a number of adjustments for a priori and
check-ups had an OR of 2.1 (CI: 1.3–3.3) empirical confounders, including tobacco and
compared with that of those who had regular alcohol consumption, diet, and socioeco-
dental check-ups. Though significant, these nomic variables. The risk for all oral cancer
findings were determined to be less important in general was significantly associated with
than tobacco or alcohol use with regard to dentures (OR: 0.7; CI: 0.52–0.96), history of
risk for oral squamous cell carcinoma. oral sores caused by dentures (OR: 0.91; CI:
In a case-control study of a Swedish 0.6–1.3), broken teeth (OR: 1.42; CI: 1.1–1.9),
population, Schildt et al.9 investigated the as- and infrequent tooth brushing (OR: 2.2; CI:
sociation of oral infections and other dental 1.6–3.1). After adjustment of several con-
factors with risk of oral cancer. For this founders and for all dental factors, only the
study, 410 cases of oral cancer and 410 association with tooth brushing frequency
matched controls were sampled. All subjects was significant (OR: 1.8; CI: 1.2–2.8 and
received a mailed questionnaire concerning OR: 1.7; CI: 1.1–2.8, respectively). When as-
different exposure factors of interest for oral sessed on a subsite basis, only less-than-daily
tooth brushing was a risk for tongue cancer The role of tobacco, alcohol, and oral
(OR: 1.3; CI: 0.6–3.0) and other parts of the hygiene in the appearance of oral cancer was
mouth, including the gingiva (OR: 2.4; CI: investigated in a case-control study by
1.3–4.4). For laryngeal cancer, only broken Moreno-López et al.12 For this study, the cases
teeth (OR: 1.8; CI: 1.3–2.7) and infrequent consisted of 75 histologically confirmed oral
tooth brushing (OR: 1.9; CI: 1.2–2.9) were squamous cell carcinomas. The control group
significant risk markers. For pharyngeal consisted of age- and gender-matched individ-
cancer, only infrequent tooth brushing (OR: uals in the same healthcare center who did
1.5; CI: 1.0–2.2) was determined to be a sig- not suffer from cancer and did not have any
nificant risk factor. The authors concluded medical or oral disease or oral manifestation
that poor oral hygiene, due to infrequent of any systemic disease. An interview was
tooth brushing and denture-related oral sores, used to obtain information related to demo-
were significant risk factors for cancer of the graphic variables, tobacco use, alcohol con-
mouth and upper digestive tract, and that sumption, frequency of dental check-ups, and
these associations were not due to insufficient level of tooth brushing. No intraoral exami-
controlling for confounding factors. nation was carried out. Although no statistical
Talamini and colleagues11 carried out a significance could be found for dental visits, a
case-control study on an Italian population insignificant relation to tooth brushing fre-
vestigating the effect of oral hygiene and den- quency indicated this to be a protective factor
tition status on oral cancer risk. The cohort (OR: 0.31; CI: 0.18–0.56).
consisted of 132 first-incident persons with In a case-control study on a Cuban pop-
oral cancer identified in three northern Italy ulation, the effect of smoking, alcohol, food,
hospitals. One hundred and forty-eight hospi- oral hygiene, and sexually transmitted diseases
tal-based control subjects, who had been ad- on risk for oral cancer was evaluated. Garrote
mitted for acute conditions unrelated to et al.13 compared 200 patients with cancer of
smoking or drinking habits, were also re- the oral cavity and pharynx with 200 fre-
cruited for this study. Case patients and con- quency-matched age and gender controls
trols were interviewed to obtain information from the hospital. Interviews were held to
relating to sociodemographic characteristics, obtain information regarding sociodemo-
smoking and drinking habits, as well as dental graphic characteristics, smoking and alcohol
information related to oral hygiene, gingival use, prior occurrence of sexually transmitted
bleeding, mouthwash usage, wearing of den- infections, family history of cancer, and
tures, and dental check-up history. A visual dietary information. Indicators of oral hygiene
examination determined number of missing were self-reported via nine specific questions,
teeth, presence of calculus, decayed teeth, and whereas the number of missing teeth that had
mucosal condition. Gingival bleeding was not been replaced and the general oral condi-
found to be significant (OR: 3.9; CI: 1.2–12.6) tion with regard to presence of calculus,
when compared with those whose gingiva did decayed teeth, and mucosal irritation were
not bleed at all. When the general oral condi- evaluated visually by the interviewing dentist.
tion was assessed as being poor on the basis After allowance for confounding factors such
of calculus, decayed teeth, and mucosal irrita- as education, smoking, and drinking habits,
tion, the risk for oral cancer had an OR of those with more than 16 missing teeth had a
4.5 (CI: 1.8–10.9) compared with those who higher risk of having oral cancer (OR: 2.7:
had good oral condition. In contrast to previ- CI: 1.2–6.1). In addition, poor general oral
ous studies, the number of missing teeth was condition was more common among cancer
not found to be a significant factor. patients than controls (OR: 2.6; CI: 1.2–5.2).
In a population derived from three regions cluded that poor oral hygiene may be an in-
of India (Bangalore, Madras, and Trivandrum), dependent risk factor for oral and oropha-
Balaram et al.14 investigated the role of ryngeal cancer.
smoking, paan chewing, and oral hygiene on In a population-based case-control study
risk for oral cancer. In this study, 591 incident from the Carolina Head and Neck Cancer
cases of oral cancer and 582 hospital controls Study, the incidence of squamous cell carci-
that were frequency-matched by age and gender noma of the head and neck in 1,289 cases
were studied. Information regarding smoking was examined in subjects who were age, race,
habits, paan chewing, and oral hygiene habits and gender matched and compared with
was obtained by interview. Visual oral inspec- 1,361 controls.16 Oral health was assessed
tion allowed assessment of missing teeth and using tooth loss, tooth mobility, mouthwash
general oral condition based on the presence of use, and frequency of dental visits from an
calculus, decayed teeth, and mucosal irritation. interview of the subjects. After controlling for
Regular dental check-ups were found to be pro- covariates, tooth loss did not yield an associa-
tective for women but not for men (OR: 0.4; tion with squamous cell carcinoma of the
CI: 0.19–0.87). Significantly elevated risk for head and neck (16–28 versus 0–5 lost teeth:
oral cancer for both genders was noted among OR: 1.21; CI: 0.94–1.56), but routine dental
those with gingival bleeding (men = OR: 2.8; visits were associated with a 30% reduction in
CI: 1.7–4.7 and women = OR: 3.4; CI:1.8–6.1), the incidence of squamous cell carcinoma of
those with six or more missing teeth (men = the head and neck (OR: 0.68; CI: 0.53–0.87).
OR: 3.9; CI: 2.5–6.1 and women = OR: 7.6;
CI: 3.9–14.9), and those with interviewer-re- Studies of the Relation Between
ported poor general oral condition (men = OR: Periodontitis and Oral Cancer
4.9; CI: 3.1–7.8 and women = OR: 6.0; CI: In the first study in which the periodontium
3.00–12.00). was assessed, Tezal and colleagues17 used a
In a European case-control investigation, cross-sectional analysis of data extracted
Lissowska et al.15 studied a Polish population from the Third National Health and Nutri-
to investigate the effect of smoking, alcohol, tion Examination Survey (NHANES III;
diet, dentition, and sexual practices on risk National Center for Health Statistics 1994).
for oral cancer. The study population con- For this study, subjects who were 20 years
sisted of 122 patients with histologically con- and older with at least six natural teeth were
firmed cancer of the oral cavity and pharynx. included. Subjects requiring antibiotics before
The controls consisted of 124 age- and a dental examination were excluded. Peri-
gender-matched patients admitted to the hos- odontal measurements included assessment
pital for non-neoplastic conditions unrelated of clinical attachment loss, whereas other
to tobacco and alcohol. The subjects were in- oral assessments were number of missing
terviewed to obtain information regarding de- teeth, caries, restorations, and the presence of
mographics, smoking, alcohol consumption, partial or full prostheses. After adjustment
family history of cancer, and oral hygiene. for age, gender, race, ethnicity, education,
After adjusting for smoking and alcohol, and tobacco use, alcohol consumption, and occu-
poor dentition as assessed by number of pational hazard, clinical attachment loss was
missing teeth (OR: 9.8; CI: 2.3–42.8), the fre- significantly associated with the presence of
quency of dental check-ups (OR: 11.9; CI: oral tumors (OR: 4.6; CI: 2.3–9.3). Addi-
3.3–42.5) and of tooth brushing (OR: 3.2; tional analyses considering the interactions
CI: 1.2–8.5) were found to be the most signif- between clinical attachment levels (CAL) and
icant risk factors for oral cancer. It was con- smoking indicated that CAL was a signifi-
cant risk for tumor (OR: 21.76; CI: 3.6– more than five missing teeth also had signifi-
131.63) in current smokers, suggesting that it cant risk in both unadjusted (OR: 4.8; CI:
is a risk modifier. This concept is strength- 2.0–11.4) and adjusted (OR: 3.1; CI: 1.2– 8.2)
ened by the observation that CAL had no analyses. On radiographic assessment, a high
effect on tumor risk for former smokers or level of marginal bone was noted to be asso-
for people who never smoked; hence, CAL is ciated with an increased risk for oral cancer
probably not an independent risk factor. in unadjusted analyses (OR: 3.00; CI: 1.0–
Shortly after the Tezal et al.17 study, 8.7); however, this failed to reach significance
Rosenquist et al.18 published results from a in adjusted analyses. Regular dental check-
study that also used a comprehensive peri- ups were noted to be associated with a de-
odontal assessment. In this case-control study creased risk of oral cancer in adjusted analy-
of a Swedish population, alcohol consump- ses (OR: 0.4; CI: 0.2–0.6).
tion, tobacco use, oral hygiene, dental status, In a subsequent study, Tezal et al.19 carried
and dental radiographic status were evaluated out a case-control study of preexisting data for
for increasing risk for oral cancer. The case patients seen at the Roswell Park Cancer Center
subjects consisted of 132 oral and oropharyn- (1999–2005) to assess the role of periodontitis
geal cancer patients, who were selected from a in risk for tongue cancer. The subjects consisted
population residing in the southern healthcare of 54 non-Hispanic white males with primary
region of Sweden. Age- and gender-matched squamous cell carcinoma of the tongue. Age-
controls were selected from the same region and gender-matched non-Hispanic white men
with no previous cancer diagnosis (except for seen in the same hospital department but not
skin cancer). The oral condition was assessed diagnosed with any cancer or oral dysplasia
via interview for frequency of dental check- served as controls (n = 54). The periodontal as-
ups, visual assessment of plaque score, modi- sessment consisted of evaluation of alveolar
fied gingival bleeding index, number of bone loss from panoramic radiographs. Other
missing teeth, defective teeth, tooth mobility, dental information including caries, restorations,
furcation involvement, and presence of den- and endodontic treatment was determined from
tures. A radiographic examination of the den- the radiographs. Analyses after adjustments for
tition evaluated marginal bone levels, loss of the confounders of age, smoking habit, and
bone along root surfaces, angular bony number of missing teeth indicated that for
defects, and furcation defects. A mucosal as- every millimeter of alveolar bone loss, a 5.2-fold
sessment was also provided. In an unadjusted increase was found in the risk of tongue cancer
analysis, those with average oral hygiene (OR: (OR: 5.2; CI: 2.6–10.4). Other variables, includ-
3.0; CI: 1.7–5.1) or poor oral hygiene (OR: ing caries, restorations, and root canal treat-
10.0; CI: 5.1–20.1), as assessed by plaque ment, failed to show any significant association
scores, were significantly at risk for oral with tongue cancer.
cancer. After adjusting for smoking and The most recently published study assess-
alcohol use, individuals with an average ing the association among oral hygiene, peri-
plaque score had an OR of 2.0 (CI: 1.1–3.6), odontal disease, and oropharyngeal and oral
whereas those with a poor plaque score had cancer was a cross-sectional prospective case-
an OR of 5.3 (CI: 2.5–11.3). The number of control study.20 Fifty subjects with untreated
missing teeth was also found to be a signifi- oral and oropharyngeal squamous cell carci-
cant risk factor, with more than 20 missing noma were compared with 5,009 cancer-free
teeth being statistically significant in unad- subjects matched for age and gender. An oral
justed (OR: 6.1; CI: 2.7–14.0) and adjusted health questionnaire was used to assess tooth
analyses (OR: 3.4; CI: 1.4–8.5). Those with brushing as well as use of mouth rinses, dental
floss, and other oral hygiene aids. An oral ex- tion. When considered together (smoking,
amination was carried out to determine Com- alcohol, and oral conditions), risk for oral
munity Periodontal Index of Treatment Needs cancer seemed to increase significantly. When
(CPITN) scores, missing teeth, caries, restora- two of these confounders (smoking and
tions, and prostheses, but no consideration was alcohol) were removed, oral conditions re-
given to smoking status or alcohol consump- mained highly significant risk factors. The in-
tion. After very simplistic statistical analyses, terplay between oral condition and oral
the authors reported that advanced periodontal cancer, already induced by recognized risk
disease was greater in the subjects with oral factors such as alcohol and tobacco, needs to
and oropharyngeal cancer. Up to 76% of the be further investigated. It has only been in
cancer subjects had periodontal probing recent years that an evaluation of periodontal
pockets greater than 6 mm compared with condition has been assessed as a potential
20% of the patients without cancer. No statisti- risk factor. Although early data indicate a pu-
cally significant differences could be found for tative role for periodontal disease, there is
caries, missing teeth, restorations, or prostheses. considerable scope for further studies to inves-
In addition to clinical studies evaluating tigate in more detail specific periodontal pa-
the relation between periodontal diseases rameters, as well as types of periodontitis in
and oral cancers, other investigations have the periodontal diseases-oral cancer axis.
examined the effect of putative periodontal
pathogens on oral squamous carcinoma ORAL CONDITIONS AND VARIOUS
cells. In two in vitro studies, Porphyromonas TYPES OF CANCER
gingivalis was found to be intimately associ- Oral Conditions and Upper
ated with squamous carcinoma cells.21 More Gastrointestinal Cancer
specifically, P. gingivalis was found to be One of the first reports to suggest an associ-
abundantly present in malignant oral epithe- ation between oral condition and gastroin-
lium, and this species of bacteria was able to testinal (GI) cancer was a case-control study
induce the expression of B7-H1 and B7-DC carried out in Germany.23 The subjects in-
receptors in squamous carcinoma cells, cluded stomach cancer patients (n = 257)
thereby making them more evasive to the and healthy, noncancerous control subjects
immune system.22 (n = 766). Information was obtained from
patient interviews and 20 variables were
Summary of the Relation Between Oral found to be significantly associated with
Health and Oral Cancer gastric cancer. Of these, early tooth loss was
Many oral conditions, including tooth loss, identified as a prominent variable.
poor oral hygiene, poor oral condition, and During the 1990s, several case-control
general periodontal condition clearly are sig- studies were conducted to investigate the as-
nificant risk factors for oral cancer (Table 1). sociation of oral health and upper GI cancer.
Because of the great variability in statistical Demirer and associates24 studied a Turkish
analyses, it is difficult to determine the real population, principally to investigate the rela-
significance of many of these studies. tion between diet and stomach cancer, but
Nonetheless, investigators in several studies used some oral measurements as well. The
have tried to remove confounding influences patients with cancer (n = 100) had histologi-
and have been able to demonstrate that many cally proven adenocarcinoma of the stomach,
of these oral conditions remain significant and age-, gender-, and residential area-
risk factors. Perhaps the main confounding matched subjects with no GI disease were
factors are smoking and alcohol consump- used as controls (n = 100). Information was
obtained by interview with regard to food investigated the relation between tooth loss
and beverage intake, frequency of tooth and risk of developing esophageal squamous
brushing, and number of missing teeth. In cell carcinoma, gastric cardiac adenocarci-
this study, patients with gastric cancer noma, or gastric noncardiac adenocarci-
brushed their teeth less frequently (P <.0001) noma. The cases had been diagnosed previ-
and had more missing teeth (P <.0001). The ously through histologic confirmation of
relative risk and confidence intervals for these upper GI cancers (n = 2,204). The controls
data were not reported. (n = 27,715) were cancer-free, came from the
A case-control study on Chinese popu- Linxian area of China, and were part of the
lations from three areas in Shanxi province Linxian General Population Trial cohort in
(North-Central China) was carried out to 1985. Tooth loss was assessed from subject
determine the influence of diet, smoking, interview and also visual inspection. Tooth
drinking habits, sociopsychological factors, loss was high in this population, with 74% of
and family history on the etiology of participants having lost at least one perma-
esophageal cancer.25 As part of this study, in- nent tooth. The median number of teeth lost
formation concerning dental hygiene habits was six, and median age for first tooth loss
was obtained. The case patients (n = 326) was 39. Further analyses indicated that tooth
had been diagnosed previously with histolog- loss was significantly (P <.01) associated
ically confirmed esophageal cancer, and con- with each of the three cancer sites studied.
trols (n = 396) were matched by age, gender, When assessed for each cancer site, tooth
and residence location. Demographic, social, loss was associated with a relative risk (RR)
and medical information was gathered by in- of 1.3 (CI: 1.1–1.6) in the esophagus, an RR
terview and included dental hygiene habits. of 1.3 (CI: 1.0–1.6) for the gastric cardiac,
Of the parameters evaluated, frequency of and an RR of 1.8 (CI: 1.1–3.0) for the
tooth brushing was found to be associated gastric noncardiac. Additional analyses indi-
with reduced risk for esophageal cancer cated that the increased risk was strongest
(OR: 0.2; CI: 0.1–0.5). In another case- for the first teeth lost in younger persons.
control study, Watabe and associates26 In a similar study, Abnet et al.28 carried
studied a Japanese population to investigate out a prospective cohort study to determine
the etiologic relation between gastric cancer whether tooth loss was associated with in-
and lifestyle. The patients with gastric cancer creased risk of gastric noncardiac adenocarci-
(n = 242) and the control group (n = 484) noma in a cohort of Finnish smokers. The
were matched for age, gender, and place of study population comprised 29,124 subjects,
residence. Oral condition was determined ac- which included 49 esophageal squamous cell
cording to number of teeth present. The carcinomas, 66 esophageal/gastric cardiac ade-
results from this study indicated that tooth nocarcinomas, and 179 gastric noncardiac
number was inversely associated with a high adenocarcinomas. Interviews enabled informa-
OR for development of gastric cancer. After tion to be collected on general background
correcting for some confounders, the number characteristics, smoking, and dietary history.
of missing teeth was still found to be signifi- The dentition was assessed by interview and
cantly associated with gastric cancer. related to the number of missing teeth. Tooth
Several recent case-control, cohort, and loss was found to be significantly associated
cross-sectional studies have been carried out with an increased hazard ratio (HR) for
to ascertain the relation between oral health gastric noncardiac cancer, whereby the HR
and gastric cancer. In a large case-control for edentulous people versus those with less
study of a Chinese population, Abnet et al.27 than 10 teeth lost was 1.65 (CI: 1.1–2.5). For
esophageal squamous cell carcinoma and be associated with increased risk of

esophageal/gastric cardiac adenocarcinoma, esophageal cancer (OR: 1.58; CI: 1.0–2.7),
no statistically significant associations were and when adjusted for nonsignificant covari-
found with tooth loss. ates, OR was 1.59 (CI: 1.06–2.39). No associa-
In another cross-sectional study of a tions were noted when all covariates were con-
rural Chinese population, Wei and col- sidered. The authors interpreted this to indi-
leagues29 investigated the risk factors for cate that the extent and severity of poor oral
oropharyngeal squamous dysplasia. The health could be important contributing factors
study population (Linzhou, formerly Linxian, in the prevalence of esophageal cancer.
China) was chosen because of a very high in- Of the previous eight studies mentioned
cidence of esophageal squamous cell carci- in this section, four have been published by
noma and gastric cardiac adenocarcinoma. A the same group using essentially similar study
screening study of 724 adults who were ap- designs and similar population groups.
parently healthy was carried out. An inter- Nonetheless, from all of the studies published
view was conducted to obtain general infor- to date concerning oral conditions and upper
mation on personal characteristics, smoking GI cancer, evidence has accrued suggesting
and alcohol use, and living conditions. Dental that tooth loss may be an important risk
examinations followed the NHANES III pro- factor for GI cancer. How well tooth loss cor-
tocol and included a tooth count. Of the 720 relates with periodontal conditions is still
subjects, 230 people had a prevalent squa- open to question. It has, however, been used
mous dysplasia. Subjects who had lost as a surrogate marker for periodontal disease
between 12 and 31 teeth had higher odds for and poor oral health. With only one study se-
developing dysplasia (OR: 1.91; CI: 1.2–3.2). riously considering periodontal parameters, it
These findings were similar to those of the is too early to determine whether periodontal
earlier report by Abnet and colleagues.28 health is also a risk factor for this condition.
A cross-sectional study by Dye et al.30 in-
vestigated the oral health of a nonrepresenta- Oral Conditions and Lung Cancer
tive sample of adult participants in an Very few reports exist in the literature con-
esophageal cancer study. Subjects (n = 718) cerning the relation between oral disease and
were recruited from three regions within lung cancer. The most widely quoted study
Linzhou, China. They were examined by is population-based and derived from data
esophageal cytology and interviewed to obtain obtained from the NHANES I Epidemio-
information regarding health history and risk logic Follow-up Study.31 Data were gathered
behavior. A dental examination was also exe- from 11,328 adults between the ages of 25
cuted according to the NHANES III proto- and 74 who underwent a medical examina-
col, which included assessment of the number tion, a standardized medical history, and
of teeth present. The periodontal examination standardized dental examination in 1971 to
consisted of assessing gingival inflammation, 1975. The subjects were followed up, with a
CAL, and bleeding on probing. As noted pre- 96.2% success rate until 1992. Death certifi-
viously,27 tooth loss was prevalent, with 17% cates of the deceased were obtained, and the
of the study population being edentulous. In analysis considered those who had died from
an unadjusted model, those who had 12 to 31 malignant neoplasms, including lung and
teeth had an increased risk for esophageal bronchus; and pancreas; colon; gingiva; oral
cancer (OR: 1.7; CI: 1.03– 2.83). Poor oral cavity; and any other cancer. The dental ex-
health was derived from both periodontal aminations included measuring the extent of
status and caries experience and was found to gingival inflammation and the size of peri-
odontal pockets. A periodontal score was Similar to that found in other published
obtained using the Russell Index. Associa- reports, the relation of periodontitis to lung
tions between cancer types and periodontal cancer does not support a link. In this study,
status were examined controlling for age and associations between tooth loss and mortal-
gender. These associations were described ity patterns in a cohort from Glasgow were
using odds ratios and their 95% confidence studied33 in 223 subjects (median age at base-
intervals. More detailed analyses included line was 19 years) who were followed up for
using Cox proportional hazards models to up to 57 years. The cause of death was
determine whether individuals with gingivi- recorded and related to dental data including
tis, periodontitis, or edentulism at the com- missing teeth, decayed teeth, and restored
mencement of the study were at higher risk teeth. Missing teeth were used as the index
for developing fatal neoplasms during the of oral health. After extensive statistical
study period to 1992. Following these analy- analyses, the authors concluded that no as-
ses, it was determined that although peri- sociation existed between external causes of
odontitis patients had an elevated risk of death and tooth loss as a continuous (HR:
death from cancer, it was significant only for 0.97; CI: 0.92–1.03) or categorical variable
lung cancer (OR: 1.94; CI: 1.16–3.26). After for missing five to eight teeth (HR: 0.74; CI:
a Cox proportional hazards analysis adjust- 0.45–1.21) or missing nine or more teeth
ing for demographic factors, the HR was (HR: 0.89; CI: 0.42–1.88). In addition, no
determined to be 2.14 (CI: 1.30–3.53). With evidence of an association between lung
further adjustment for socioeconomic status, cancer and tooth loss was found, with or
smoking status, alcohol consumption, and without adjustment for smoking.
intake of vitamins A and C, the HR was Although the literature is scant on this
reduced to 1.73 (CI: 1.01–2.97). No associa- topic, to date it does not seem to support
tion between periodontitis and lung cancer any association between periodontal condi-
was detected if the analyses were limited to tion and lung cancer.
people who had never smoked. However, if
the analysis was restricted to smokers, then Oral Conditions and Pancreatic Cancer
periodontitis became significantly associated In light of earlier observations that oral
with lung cancer (HR: 1.94; CI: 1.14–3.30). hygiene and tooth loss could be associated
The authors interpreted these findings to with increased risk for upper GI cancers,
imply that an association between periodon- Stolzenberg-Solomon et al.34 hypothesized
titis and lung cancer, after adjustment for that tooth loss may be associated with pan-
known risk factors, could be demonstrated. creatic cancer. This was a cohort study of
However, they cautioned that this periodon- Finnish men, ages 50 to 69, who smoked
titis-cancer association could be spurious. more than five cigarettes per day and had no
In an analysis of the Health Profession- history of any malignancy apart from non-
als Follow-Up Study, US male health profes- melanoma of the skin or carcinoma in situ.
sionals responded to a questionnaire posted Baseline information obtained by interview
by the Harvard University School of Public included medical, dental (number of teeth),
Health.32 The principal analysis of 48,375 men smoking, and dietary history. Of the 29,104
showed a significant association for those with participants, 174 developed pancreatic cancer.
a history of periodontal disease and lung Cox proportional hazards models were used
cancers (HR: 1.36; CI: 1.15–1.60); however, to account for age, smoking, education,
no association between periodontal disease urban living, and height. In this study, tooth
and lung cancer was noted in never-smokers. loss, as accounted for by total edentulism,
was associated with pancreatic cancer when had never smoked (RR: 2.09; CI: 1.18–3.71).
compared with that for individuals missing 10 Furthermore, the influence of periodontal
or fewer teeth (HR: 1.63; CI: 1.09–2.46). disease was also stronger in those with a body
However, for people missing 11 to 31 teeth, mass index of less than 25 kg/m2 (RR: 2.2;
this association was not significant (HR: 1.23; CI: 1.34–3.61). The authors concluded that
CI: 0.82–1.85). The authors concluded that this indicated that smoking and obesity were
further studies were needed to fully evaluate unlikely to explain the association between
the association between tooth loss and pan- periodontal disease and pancreatic cancer.
creatic cancer. Nonetheless, they concluded that if the asso-
Hujoel et al.,31 in their study using the ciation is to be proved, additional studies are
NHANES I data to investigate the association required.
between periodontitis and various cancers, In an interesting follow-up to the
found no association with pancreatic cancer. Michaud et al.2 publication, Taguchi,35 in a
A subsequent study by Michaud et al.2 “Letter to the Editor,” commented that
investigated the association of periodontitis in Michaud and colleagues did not adjust for
216 males diagnosed with pancreatic cancer the effects of passive exposure to cigarette
from a larger cohort of 48,375 men partici- smoke, which could have negated their find-
pating in the Health Professionals Follow-up ings. In addition, Taguchi suggested that to
Study in the United States. The study period better understand the relation between peri-
was 16 years. At baseline, participants re- odontal disease and pancreatic cancer, it
ported the number of natural teeth; this was would be helpful to demonstrate an associa-
updated every two years. It was reported that tion between duration and grade of peri-
a periodontal disease analysis was carried out odontal disease and pancreatic cancer risk. In
at baseline and every two years thereafter. response to these comments Michaud et al.2
However, no details were provided as to the argued that notwithstanding the lack of data
nature of these analyses. Subjects who were concerning environmental tobacco smoke,
assessed to have periodontal disease at base- controlling for passive smoking in their study
line had an increased risk of pancreatic may have attenuated their findings but not
cancer (RR: 1.83; CI: 1.36–2.45). When ad- eliminated the association between periodon-
justed for age, smoking, profession, race, geo- tal disease and pancreatic cancer. It was
graphic location, physical activity, diabetes, noted that the twofold increase in risk for
body mass index, height, cholecystectomy, pancreatic cancer in people with periodontal
nonsteroidal anti-inflammatory drug use, disease who had never smoked is greater
multivitamin use, dietary factors, and total than the reported association between passive
calories, the RR was 1.64 (CI: 1.19–2.26). smoking and pancreatic cancer. Furthermore,
Most of this attenuation could be accounted it was pointed out this twofold increase in
for by smoking. The number of teeth present risk for pancreatic cancer among patients
at baseline was not significantly associated with periodontal disease who had never
with pancreatic cancer. However, in a joint smoked is of a similar magnitude to the as-
analysis, tooth loss in conjunction with peri- sociation between current smoking and pan-
odontal disease resulted in a 2.7-fold increase creatic cancer. With regard to the need for as-
(RR: 2.71; CI: 1.70–4.32) in pancreatic cancer sessment of duration and severity of peri-
when compared with either no periodontal odontal disease, Michaud was in agreement.
disease or no recent tooth loss. Additional Indeed, this should be a requirement for all
analyses indicated that the influence of peri- future studies investigating the association
odontal disease was stronger in people who between periodontal disease and any cancer.
Using the European Prospective Investi- odontal disease and prostate cancer in
gation into Cancer and Nutrition, Michaud 48,375 US male health professionals failed
and colleagues36 measured antibodies to to demonstrate an association between
various oral bacteria in 405 pancreatic cancer prostate cancer and periodontal disease.32
patients and 416 matched controls. From the A longitudinal prospective study was
data, individuals with antibodies to P. gingi- also used to examine periodontal disease in
valis were associated with a twofold higher relation to cancers that are predominant in
risk of pancreatic cancer than those with low women. Using a group of Finnish men and
levels (≤ 200 ng/mL) of these antibodies women, the association between breast
(OR: 2.14; CI: 1.05–4.36). Since P. gingivalis cancer and periodontal disease was examined
is a putative periodontal pathogen associated in 1,676 subjects.40 Although the number of
with chronic periodontitis, it was surmised, remaining teeth, gingival inflammation, oral
though not proved, that this species of bacte- hygiene status, calculus index, and probing
ria may have a direct effect on the pathogene- depths were recorded for a cohort of patients
sis of pancreatic cancer. in this study, the definition of periodontal
disease was not noted by the authors. The
ORAL CONDITIONS AND study reported that 1.75% of subjects with
REPRODUCTIVE ENDOCRINE periodontal disease and/or missing molars
CANCERS developed breast cancer compared with a
The relation between the periodontium and breast cancer incidence of 1% in the peri-
the reproductive systems of men and women odontally healthy patients. Furthermore, the
has been comprehensively documented,37,38 absence of any molar from the mandible was
whereas the possible effects of periodontal statistically associated with breast cancer in
diseases on the initiation and/or progression women (OR: 2.36; CI: 1.07–5.21).
of malignant diseases that affect the repro- Like most carcinomas, the etiology of
ductive systems of men and women have neoplasms associated with the male repro-
not been noted because of the relative ductive tract or the breast are not well un-
paucity of data. Only recently a few reported derstood. The addition of periodontal dis-
studies have suggested an association eases to a growing list of putative causes
between gender-related cancers and peri- does not clarify what, if any, relation de-
odontal diseases. Up to this time, most structive periodontal diseases have to disor-
studies have relied on collecting self-reported ders of the reproductive track or other
data from subjects to determine whether pu- hormone-sensitive tissues. Therefore, at this
tative links exist between diseases of the re- time, the relation between periodontal dis-
productive tract and the periodontium. For eases and sex hormone-sensitive malignan-
example, in a prospective co-twin study of cies cannot be established.
15,333 Swedish twins using data between
1963 and 2004, Arora et al.,39 using a ques- PERIODONTAL DISEASE, CANCER,
tionnaire, noted an association between AND MORTALITY
tooth mobility (i.e., a surrogate measure of To date, very few studies have investigated the
periodontal disease) and the incidence of association between periodontal disease and
prostate cancers. The analysis of their data cancer by assessment of the clinical parame-
suggested that periodontal disease was asso- ters of periodontal status. By far, most studies
ciated with prostate cancer (HR: 1.47; CI: have reported the association between tooth
1.04–2.07). In contrast to the previous study, loss and cancer risk. Such approaches may be
questionnaires regarding the relation of peri- flawed, since tooth loss may also result from
trauma or, more commonly, from caries. tion can be a significant risk factor for cancer
However, these studies claim that because and is also a possible risk factor for periodon-
teeth lost at an older age are more likely due titis. Thus, alcohol consumption must be ac-
to periodontal disease compared with those counted for when investigating the effect of
lost at younger ages (which may be due more tooth loss on cancer risk. In cancers of the
to dental caries), tooth loss in older persons oral cavity, this is particularly relevant, since
can be a good surrogate marker of periodon- alcohol is a significant risk factor for oral
tal disease. Therefore, assessment of tooth loss cancer. Many studies have adjusted for alcohol
may provide an insight into the overall role of intake and found that tooth loss persists as a
oral health and its effect on cancer risk. The significant risk factor for this cancer.15,17,18
cumulative influence of age on tooth loss and Socioeconomic status is also considered an im-
its relation to periodontal disease can be seen portant risk factor for periodontitis; hence,
in the study by Michaud et al.2 In this study, there is further potential for socioeconomic
which ran for more than 16 years, the number status to be a confounding issue in studies
of teeth lost at baseline was not related to risk considering the effect of tooth loss on cancer.
of pancreatic cancer. However, by the end of Most studies have included socioeconomic
the study, tooth loss within the previous four status in their questionnaires, but adjustment
years was noted to be a predictor of pancre- for this component has not always been a
atic cancer risk. When those with both peri- prominent feature of the statistical modeling.
odontal disease and recent tooth loss were as- Although smoking, alcohol consumption,
sessed jointly, the risk of pancreatic cancer in- and socioeconomic status may be the three
creased significantly compared with that of in- commonly recognized confounders for many
dividuals who did not have periodontal studies concerning cancer risk and periodontal
disease and had not experienced any recent disease, it is highly likely that many other pre-
tooth loss. These results suggest that in this viously unidentified confounding factors could
population, recent tooth loss may be a marker be at play and need to be identified before
for severity of periodontal disease, whereas these associations can be confidently accepted.
baseline tooth loss may reflect loss due to With these caveats in mind, several scien-
factors other than periodontitis. tific reports attempt to evaluate the relation
Another complicating factor in interpret- among periodontal disease, cancer, and mor-
ing many of the published studies is the influ- tality. One of the first to report that periodon-
ence of known risk factors, which include titis was positively associated with cancer was
smoking, alcohol consumption, and socio- Hujoel et al.31 in 2003. This study has been
economic status. Smoking is a well-recognized described in more detail in the previous
risk factor for oral and lung cancer, but it is section dealing with lung cancer. Briefly,
also a recognized risk factor for periodontal Hujoel and colleagues followed up 11,328 in-
disease and tooth loss. Thus, some authors dividuals over a 10-year period and compared
have questioned any reported association periodontal status with fatal cancer. Associa-
between tooth loss and cancer as being due to tions between cancer types and periodontal
confounding factors rather than a real risk status were examined, controlling for age and
factor.31,33 This may be true for lung cancer; gender. Of the six fatal cancers studied as the
however, other cancers appear to be less influ- main outcome measures, only lung cancer was
enced by smoking and indeed, tooth loss per- found to have a significant association with
sists as a significant risk factor for both gastric periodontitis. The association between peri-
and pancreatic cancer after adjusting for odontitis and lung cancer mortality could be
smoking status.2,30 Similarly, alcohol consump- found even after adjusting for known risk
factors for lung cancer such as smoking (OR: (HR: 1.01; CI: 1.00–1.02) or cancer mortality
1.94; CI: 1.16–3.26). (HR: 1.00; CI: 0.98–1.02). From this study, it
Further prospects for a relation between appeared that any relation between tooth loss
oral health and increased risk of total death and cancer mortality could be explained by
and death from cancer have been made from other causal or confounding mechanisms.
a cohort study on rural Chinese.41 This was a Tramini et al.43 investigated tooth loss
follow-up to the Abnet et al.27 study on a and associated factors in elderly patients in
Chinese population in Linxian, China, in France who had been institutionalized long
which 29,584 rural Chinese participated over a term. In this cross-sectional study of 321
10-year period. Tooth loss was used as the elderly patients, socioeconomic, behavioral,
measure of oral health, and mortality out- medical, and oral information was recorded.
comes were studied as well as total death, Multivariate logistic regression analyses were
upper GI cancer death, other cancer death, carried out to test the associations between
heart disease death, and fatal stroke. It was these covariates and tooth loss. The results
found that those with more than the age-spe- indicated that “cancerous disease” was the
cific median number of teeth lost had a statis- most significant condition associated with
tically increased risk of total death (RR: 1.13; partial tooth loss. The type of cancerous
CI: 1.09–1.18) and death from upper GI disease was not qualified. From these data,
cancer (RR: 1.35; CI: 1.14–1.59). After ac- the authors concluded that the number of re-
counting for the confounding effect of maining teeth has a strong effect on oral
smoking, these associations were generally still health-related quality of life.
significant. Risk of death at other cancer sites Söder et al.44 published the results of a
showed no significant associations with tooth 16-year longitudinal study investigating peri-
loss. Tooth loss was concluded to be signifi- odontitis and premature death. The causes of
cantly associated with increased risk of total death for 3,273 individuals were recorded
death from cancer and from upper GI cancer. and subsequently related to dental findings.
In contrast to the above findings, The dental assessment at baseline included
Cabrera et al.42 investigated the relation recording missing teeth, gingival inflamma-
between tooth loss and chronic disease and tion, oral hygiene status, calculus scores, and
found no associations between tooth loss and periodontal probing pocket depth. An indi-
total cancer mortality after adjusting for vidual was considered to have periodontitis if
known confounders (RR: 1.16; CI: 0.90– he or she had at least one tooth with a
1.49). This was a prospective study of females probing pocket depth of 5 mm or more.
residing in Gothenburg, Sweden, over 24 After logistic relation analysis of being dead
years. The dental examination consisted of (dependent variable) and several independent
determining tooth number; mortality out- variables including age, gender, education,
comes were death from cardiovascular disease income, smoking, dental visits, dental plaque,
and all-site cancer. Despite no association gingival inflammation, missing teeth, and
between tooth number and all-site cancer missing molars, the total number of people
mortality, no assessment of site-specific who died from neoplasms was significantly
cancers was made. Similar findings were higher in the periodontitis group who had
noted by Tu et al.33 in the previously de- missing molar teeth (OR: 3.62; CI: 1.28–
scribed Glasgow cohort study. Moreover, 10.16). It was concluded that young peri-
after adjusting for a variety of confounders, odontitis patients with missing molars were
no association was found between all-cause at higher risk for premature death by neo-
mortality for each additional missing tooth plasm than their more healthy counterparts.
In another case-control study, Hiraki et periodontal disease were compared with those
al.45 examined the relation between tooth loss with a self-reported history of periodontal
and the risk of 14 types of cancers in a disease. The latter demonstrated an increased
Japanese population. The cohort consisted of risk for total cancer (HR: 1.14; CI: 1.07–1.22).
5,240 cancer subjects and 10,480 noncancer For specific cancers, a history of periodontal
controls who were age- and gender-matched. disease was associated with increased risk for
Information on lifestyle, smoking, alcohol lung (HR: 1.36; CI: 1.15–1.60), kidney (HR:
consumption, diet, exercise, and number of 1.49; CI: 1.12–1.97), pancreas (HR: 1.54; CI:
teeth present was collected. Of the 14 cancers 1.16–2.04) and hematologic cancers (HR: 1.30;
studied, tooth loss was found to be associated CI: 1.11–1.53). These findings for lung and
with esophageal cancer (OR: 2.36; CI: 1.17– pancreas were in agreement with previously
4.75) and lung cancer (OR: 1.54; CI: 1.05– published studies. The findings for kidney and
2.27). After adjusting for age, these associa- hematologic cancers were new and have not
tions remained significant but were decreased. been reported previously. In contrast to that
These findings are in agreement with the found in previous studies, the association for
more focused studies on upper GI cancer and esophageal cancer, though increased, was not
lung cancer. significant after adjusting for smoking status.
In a detailed study, Michaud et al.32 ana- Missing teeth, which was also noted to be as-
lyzed periodontal disease, tooth loss, and sociated with smoking status, was found to be
cancer risk in a male health professional associated with increased risk for lung cancer
cohort. This prospective study was carried only (HR: 1.7; CI: 1.37–2.11). The associa-
out on the same Health Professionals Follow- tions were strongest for periodontal disease
up Study as described in the previous section and missing teeth when smoking was not con-
on pancreatic cancer. Commenced in 1986, sidered a covariate; this indicates that smoking
51,529 (97% male) participants answered a was a strong confounder for these associations.
questionnaire on lifestyle, smoking history, For pancreatic and kidney cancers, the associ-
alcohol consumption, physical activity, diet, ations remained strong even after controlling
and medical history. Follow-up questionnaires for smoking. For lung cancer, smoking was
were completed every two years until 2002. found to be a very strong confounder and was
Dental assessments were also carried out, probably largely responsible for risk of this
which consisted of self-reported experience of cancer. Removal of confounding factors for
periodontal disease and tooth loss. Cancer ex- kidney and pancreatic cancers such as diabetes
perience was recorded by the participants and obesity did not significantly change the
who were required to report any new cancer associations, indicating that these two known
diagnosis on the biennial questionnaires. risk factors were not likely to be responsible
The data were analyzed and multivariate for the noted association of periodontal
hazards ratios and 95% confidence intervals disease with pancreatic and kidney cancers.
were calculated by Cox proportional hazards Overall, the authors concluded that periodon-
models for periodontal disease experience and tal disease appeared to be associated with a
number of missing teeth at the baseline meas- small but nonetheless significant risk for
urement. From this study, the five main cancer in general. Some influence of smoking
cancers experienced by this cohort were col- was noted in smokers but the associations per-
orectal, melanoma of the skin, lung, bladder, sisted in people who had never smoked.
and prostate. After adjustment for known Whether some of these associations were due
cancer risk factors such as smoking history to direct effects of periodontal disease on
and diet, persons with no reported history of cancer or were the result of being more like a
surrogate marker requires further investigation. mechanical irritation, chronic infection, systemic
inflammation, and immune suppression, as well
PERIODONTITIS, VIRUSES, AND as increased exposure to carcinogens.1,41
ORAL CANCER
In recent years, several reports have suggested Diet and Mechanical Irritation
that viruses may be associated with various The role of poor oral condition and tooth
forms of periodontitis. In particular, Epstein- loss with trauma has been well discussed for
Barr Virus (EBV) has been implicated in the both oral and upper GI cancer. For decades,
pathogenesis of advanced and aggressive an association between poor restorative den-
forms of periodontitis.46 It has been hypothe- tistry and ill-fitting prostheses and oral cancer
sized that EBV proteins may lead to an up- has been recognized.54 However, more recently
regulation of growth factors and cytokines in- it has been proposed that tooth loss may alter
volved in cell transformation of EBV-associ- dietary patterns, which may be a contributing
ated oral malignancies.47 This is an interesting factor in the development of upper GI
theory; nevertheless, considerably more re- cancer.41 In addition, it has been suggested
search is needed to determine the exact role, if that tooth loss may result in inadequate masti-
any, that viruses play in periodontitis and oral cation and that the resulting poorly chewed
malignancies. food bolus could have an irritating effect on
the esophagus, leading to increased risk of
ORAL CONDITIONS, HELICOBACTER cancer through mechanical irritation.55 To
PYLORI, AND CANCER date, these hypotheses have not been proved.
Helicobacter pylori is associated with chronic In light of findings that tooth loss and
gastritis, duodenal ulcers, and an increased chewing efficiency are not related and that
risk of gastric adenocarcinoma.48,49 Since H. tooth loss is associated with increased risk for
pylori can be isolated in the oral cavity, espe- GI cancer, the fact that the GI system is a site
cially in those with periodontitis who have the that is unlikely to be affected by food bolus
bacterium in their GI tract,50 it has been pro- size mitigates against mechanical-trauma hy-
posed that the oral cavity may act as a reser- potheses.41
voir for H. pylori-associated gastric cancer. It
has been suggested that H. pylori cannot Inflammation
survive in the oral cavity, but there are studies Inflammation appears to play an important
that support the notion that H. pylori can be role in carcinogenesis, and the presence of in-
found in dental plaque and periodontal flammation may enhance cellular proliferation
pockets.51,52 Nonetheless, it is generally ac- and mutagenesis, reduce adaptation to oxida-
cepted that the presence of H. pylori in the tive stress, promote angiogenesis, inhibit apop-
oral cavity may be independent of infection tosis, and increase secretion of inflammatory
status of the stomach53 and no good evidence mediators.56 This is demonstrated with
exists for the presence of periodontal disease, chronic pancreatitis being associated with an
oral H. pylori, and gastric cancer.34 increased risk of pancreatic cancer.57 Indeed,
inflammation has been shown, at least in
POSSIBLE MECHANISMS FOR THE animal studies, to be associated with the pro-
ASSOCIATIONS BETWEEN gression of liver and colon cancer.58 Since pe-
ORAL CONDITIONS AND CANCER riodontal disease is an inflammatory disease
A number of hypotheses have been proposed to with elevated levels of circulating inflamma-
explain the observed associations between peri- tory cytokines, a suggestion has been made
odontal disease and cancer, including poor diet, that this could be a plausible link leading to
the breakdown of normal cell growth control chemokines, prostaglandins, growth factors,
and potential carcinogenesis.1 Thus, the host and enzymes that may have indirect effects
response in periodontal disease may lead to a on carcinogenesis by deregulating physio-
systemic exposure to proinflammatory cy- logic cell turnover and cell growth. Another
tokines, which in turn may lead to increased hypothesis proposes that periodontal
risk of neoplastic transformation at distant pathogens may increase the level of certain
sites. However, the situation may not be as carcinogens such as nitrosamines.41 The for-
simple as this, because most studies investigat- mation of endogenous nitrosamines in the
ing the link between cancer and inflammation oral cavity by nitrate-reducing bacteria is
consider the effect of local inflammation at promoted by poor oral hygiene as well as by
the site of the cancer rather than systemic ele- tobacco use and certain dietary factors.59 In-
vation of inflammatory mediators. It is possi- creased production of carcinogenic ni-
ble that elevated systemic levels of inflamma- trosamines by oral bacteria has been sug-
tory cytokines may encourage subthreshold gested as a possible mechanism for an in-
neoplastic states to become neoplastic, but creased risk of pancreatic cancer in individ-
local inflammation and local release of in- uals with reported periodontal disease.2
flammatory mediators at a site of potential
neoplastic transformation seems more likely. Immunity
Alternatively, it has been suggested that Periodontitis in susceptible patients may reflect
persons who suffer from both periodontal a failure in the interaction between the innate
disease and cancer may share similar gene and adaptive immune response to clear the
polymorphisms in genes encoding inflamma- bacterial challenge within the periodontal
tory cytokines. Thus, periodontitis may be pocket. Deregulation of the immune response
merely a marker of an underlying genetic pre- may also place a person at risk of inadequate
disposing factor rather than a true risk factor cellular surveillance for tumor growth. In par-
for cancer. ticular, the stable periodontal lesion consists of
a predominantly helper T cell 1 (Th1) re-
Infection sponse60 and is associated with high levels of
Chronic infections have been associated with interferon-gamma (IFN-γ), an important cy-
increased cancer risk. For example, bacterial tokine in cell-mediated immunity and tumor
infections such as H. pylori have been impli- surveillance.61 The progressive periodontitis
cated in gastric cancer as well as hepatitis B lesion consists predominantly of a Th2 re-
and C viral infections implicated in hepato- sponse with lower levels of IFN-γ and a poor
cellular carcinoma.48,49 Since periodontitis is a innate immune response.60 Hence, periodontitis
chronic infection, it has been postulated that could merely be a marker of immune dysfunc-
periodontal bacteria within the subgingival tion rather than a true risk factor for cancer.
plaque biofilm may be associated with car-
cinogenesis through the release of a multi- CONCLUSION
tude of toxic products (endotoxins, enzymes, To date, only a limited number of studies
hydrogen sulfide, ammonia), leading to cell have investigated the association between
mutations in tumor suppressor genes and periodontal disease and cancer risk, al-
proto-oncogenes or alter signaling pathways though many reports have been published
that affect cell proliferation or cell survival.19 concerning the association among cancer
In addition, chronic inflammation induced risk and oral condition, oral hygiene, and
by periodontal pathogens results in chronic tooth loss. Positive associations have been
release of proinflammatory cytokines, demonstrated even after controlling for
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CHAPTER 14
Dental and Medical Comanagement of
Patients with Diabetes
Evanthia Lalla, William Hsu, Ira B. Lamster
INTRODUCTION epidemiologic and clinical features. Both are

This chapter discusses the comanagement of very prevalent, easily screened, and intercon-
patients with diabetes mellitus by oral and nected by important pathophysiologic links.
medical healthcare providers. The need for The successful treatment for either condition
comanagement of patients becomes evident depends heavily on intensive intervention,
when one considers the prevalence and active maintenance, and lifestyle modifica-
chronic nature of diabetes and periodontitis tions. Managing issues such as acute hypo-
(its major oral complication) and the link glycemia, oral infection, and smoking cessa-
between the two diseases. Both topics are tion in diabetic patients is clinically relevant
briefly reviewed in the following text. The role for dental as well as medical professionals. As
of dental and medical professionals in this the incidence of diabetes continues to rise and
setting is then reviewed separately and in the understanding of the relation between
detail. This chapter concludes by summariz- diabetes and periodontitis deepens, the
ing the principles related to a patient-centered, comanagement of patients with diabetes is
team approach to diabetes care. expected to become the standard of care.
Educational Objectives Diabetes

After reading this chapter, the reader should Diabetes is one of the most common chronic
be able to do the following: illnesses, affecting approximately 26 million
• Appreciate the importance of dental and people in the United States and more than
medical comanagement of the patient 371 million throughout the world.1,2 In the
with diabetes decade from 1996 to 2006, the prevalence of
• Understand the responsibilities of oral diagnosed diabetes nearly doubled in the
healthcare professionals toward a patient United States,1 presenting significant chal-
with known diabetes and a patient who lenges for a wide range of healthcare profes-
may have diabetes (or prediabetes) but is sionals. The incidence of the disease is rapidly
unaware of it growing across all age and socioeconomic
• Describe specific procedures required to strata, but the highest expansion is seen
manage such patients in dental practice among the elderly and ethnic minority popu-
• Identify ways to prevent and treat emergen- lations.1 Despite being the leading cause of
cies related to diabetes in the dental office blindness, kidney failure, and lower limb
• Understand the ways in which medical amputations not related to accident or injury
and dental professionals can work in the United States, about 25% of those with
together to provide better care for their diabetes are unaware that they have the
mutual patients with diabetes disease.1,3 Because the symptoms are neither
specific to the disease nor accurately reflective
DIABETES AND PERIODONTITIS: of blood glucose concentration, the diagnosis
PREVALENT AND INTERRELATED of diabetes is frequently not made until severe
CHRONIC DISEASES symptoms or complications appear. Once dia-
Diabetes and periodontitis share many similar betes is diagnosed, its clinical sequelae can be
CHAPTER 14 Dental and Medical Comanagement of Patients with Diabetes 253
prevented or delayed with strict metabolic Gingivitis includes inflammatory disorders of

control. Thus, the patient can play a critical the nonmineralized tissues surrounding the
role in how the disease progresses by commit- teeth with no evidence of loss of support
ting to self-care; healthcare providers (beyond around the teeth (clinical attachment loss or
the treating physician) can contribute to the CAL) or loss of alveolar bone surrounding
better management of affected persons by the teeth. Periodontitis is associated with loss
reinforcing the need for good metabolic of attachment or loss of supporting alveolar
control. bone and loss of teeth. The persistent inflam-
mation and infection associated with peri-
Prediabetes odontitis has been linked to an increased risk
According to the 2013 Standards of Medical of many disorders, including cardiovascular
Care in Diabetes by the American Diabetes and cerebrovascular diseases, diabetes compli-
Association,4 the term prediabetes applies to cations, adverse pregnancy outcomes, respira-
those with glycemic levels too high to be tory disease, and kidney disease. Periodontitis
considered normal, but not meeting criteria generally takes many years to develop; more
for diabetes. These individuals are identified advanced disease is more common with
based on a hemoglobin A1c (HbA1c) result advancing age. Once periodontitis is diag-
between 5.7% and 6.4%, or a blood glucose nosed, attendant morbidity (abscess forma-
level following an overnight fast between 100 tion, alveolar bone and tooth loss) can be
and 125 mg/dL (impaired fasting glucose reduced by strict adherence to a rigorous self-
[IFG]), or a blood glucose level after a 2- administered and professional oral hygiene
hour oral glucose tolerance test between 140 regimen.
and 199 mg/dL (impaired glucose tolerance Defining the prevalence of periodontitis
[IGT]). Prediabetes is a condition that has has been challenging because there has not
received little medical attention in the past, been a generally accepted definition of peri-
but has important public health implications. odontitis. When the definition includes evi-
Prediabetes affects an estimated 79 million dence of periodontal destruction (e.g., 2 mm
Americans 20 years or older, more than CAL, generally considered the lower limit of
three times the number of diabetic cases, and detection, in at least one tooth surface), most
totaling 35% of the adult population. People adults are identified as affected.7 It is clear,
with prediabetes have a strong risk for devel- however, that this very mild form of peri-
oping type 2 diabetes and already have an odontitis does not affect function or place a
increased risk of developing heart disease, tooth at risk of being lost. In contrast,
stroke, and microvascular complications advanced forms of periodontitis affect 5% to
typical of those with fully developed dia- 15% of different populations.8
betes.5 Evidence is strong that people with An interesting trend observed over the
prediabetes who lose weight and increase last 30 years in developed countries is
their physical activity can prevent or delay increased tooth retention. Data from Sweden
diabetes and return their blood glucose levels indicate a reduction in the percentage of the
to normal.6 As with diabetes, the paramount population affected by gingivitis and mild-to-
challenge is early detection and intervention. moderate periodontitis and a corresponding
increase in the percentage of the population
Periodontal Diseases with a healthy periodontium.9 As examples,
In a similar sense, periodontal diseases are the percentages of periodontally healthy
common chronic disorders, and are broadly persons in 1983, 1993, and 2003 were 23%,
grouped into gingivitis and periodontitis. 22%, and 44%, respectively. However, the
percentage of those with severe disease diagnosis has been made over the last few
remained essentially unchanged during this years. Increased public attention and
time (13%, 13%, and 11%). enhanced public health measures have led to
In 2012, the prevalence of periodontitis a decrease in the percentage of undiagnosed
in the United States was evaluated using patients with diabetes from 30% in 2005 to
data from the 2009 and 2010 National 24% in 2007 and 27% in 2010.3 Further
Health and Nutrition Examination Survey improvement in the detection of diabetes can
(NHANES).10 Earlier surveys used a partial- be achieved by expanding the number of
mouth examination format, whereas the contact points that undiagnosed individuals
2009 and 2010 NHANES assessed six sites have with a wide range of healthcare
per tooth for both attachment level and providers. In the United States, there are
probing depth. Using the Centers for only 17,000 certified diabetes educators and
Disease Control and Prevention/American 4,000 endocrinologists12 whose primary focus
Academy of Periodontology case definition11 is providing clinical care. These numbers pale
for US adults age 30 years and older, 8.7% in comparison with the escalating disease
of the population had mild disease, 30% had burden. Therefore, the brunt of the responsi-
moderate disease, and 8.5% had severe bility for diabetes screening and management
disease. Thus, the periodontitis burden of has fallen on primary care physicians. A
United States adults was found to be greater decrease in the number of primary care
than estimated in earlier NHANES-based physicians in the workforce has generated
studies. Prevalence was greatest for men, new interest in enlisting more healthcare
Mexican Americans, current smokers, those providers, such as dentists, to expand the
with less than a high school education, and diabetes screening effort. National data
the poor. suggest that approximately 70% of Ameri-
Therefore, both diabetes and periodonti- cans have visited a dental office in the pre-
tis are common and present for years before ceding year,13,14 pointing to the potential for
clinical symptoms are evident. In addition, dental professionals to be involved in the
proper management of both disorders identification of persons unaware of their
requires affected persons to be involved in diabetic status.
their own care. For those with diabetes melli- Despite greater understanding of the
tus, this means careful control of carbohy- disease and the ever-expanding options for
drate consumption, weight control, and medical therapy, diabetes remains an incur-
adherence to other aspects of a healthy able and difficult-to-control disease. Land-
lifestyle. For those with periodontitis, this mark studies such as the Diabetes Control
means focus on performance of proper oral and Complications Trial (DCCT)15 and the
hygiene. Appropriate professional care is also United Kingdom Prospective Diabetes
critical, and patients play an active role by Study (UKPDS)16 have convincingly
keeping to their schedule of regular visits to demonstrated that lowering HbA1c levels
their physician or dentist. was associated with significant reductions in
risk for complications. In spite of the evi-
Underdiagnosis of Diabetes and Difficulties in dence, national data from 2007 to 2010
Achieving Optimal Metabolic Control suggest that only 52.5% of diabetic adults in
A significant percentage of patients with dia- the United States achieved the glycemic goal
betes remain undiagnosed, indicating the of an HbA1c level of less than 7%, and
desirability of screening at multiple health- almost 78% of diabetic adults met the less
care locations. Fortunately, some progress in stringent criteria of an HbA1c level of less
than 8%.17 The percentage of diabetic application of diabetes self-management

patients achieving the HbA1c goal of 7% skills and concrete lifestyle changes. Particu-
for the period 2007 to 2010 appears signifi- lar areas of lifestyle modification, such as
cantly increased compared with earlier maintaining oral hygiene and smoking ces-
national data, but remains an unsatisfactory sation, are beneficial for the management of
outcome (Figure 1). The underlying reasons periodontitis and diabetes, and provide
for the inability of so many patients to strong rationale for members of the various
achieve glycemic goals are not entirely clear, healthcare disciplines to work together to
but it is evident that the daily challenges of improve health outcomes for patients.
managing diabetes are inseparable from the Moreover, optimal diabetes manage-
complexities of life. Managing diabetes often ment requires a delicate balance. Theoreti-
becomes a daily struggle balancing glycemic cally, reaching glycemic target should not be
control with quality of life. Although the difficult as long as sufficient oral medication
adoption of advanced medical regimens and or insulin dosages are given. However, the
devices has opened up unprecedented possi- practical challenge is that intensive diabetes
bilities for improved diabetes care, successful therapy potentiates the risk of frequent and
outcomes can come about only by proficient serious hypoglycemic events that in turn limit
the intensity of treatment.18 Any interrup-
Figure 1. Percentage of Diabetic Adults with tions such as fasting or stress factors have a
HbA1c Levels Less Than 7.0% and Less significant impact on glycemic levels. All
Than 8.0%, from NHANES 1988–2010 healthcare providers who routinely take care
of diabetic patients should have a basic
" 1988-1994 " 1999-2002 " 2003-2006 " 2007-2010
understanding of diabetes medications and
the skills to manage acute hypo- and hyper-
90
glycemic emergencies.
80
Underdiagnosis of Periodontitis and
* Complexities in Achieving Optimal
70
Oral Hygiene Among Diabetic Patients
*
Unrecognized oral changes and difficulties of
60
diabetic patients in achieving optimal oral
hygiene and in receiving professional dental
Percentage (%)
!
50 *
care highlight the need for support by all
40
healthcare providers.
Important changes in the oral cavity
30
associated with diabetes mellitus19 may often
go unrecognized and therefore untreated.
20 Diabetes is an established risk factor for peri-
odontitis and the only disease shown to
10 independently and significantly increase this
risk.20 Other oral diseases and disorders that
0 may be linked to diabetes include Candida
A1c<7.0% A1c<8.0% infections, reduced salivary flow, dental
(<53mmol/mol) (<64mmol/mol)
caries, and certain oral mucosal disorders
*P <.01 and †P <.05, compared with 2007–2010 preva- (e.g., lichen planus, burning mouth syn-
lence. Adapted from: Diabetes Care 2013;26:2271–9.17 drome). Periodontitis does not always mani-
fest with symptoms that are obvious to the cytokines and other inflammatory mediators
patient. Furthermore, patients with diabetes produced in the highly vascular periodontal
are often unaware of their risk for periodon- tissue when periodontitis is present.23 Tumor
tal disease, medical professionals may not necrosis factor-alpha as well as interleukins 1
discuss the link between diabetes and peri- and -6 are three of the many inflammatory
odontitis with their patients, and oral care is mediators produced by the periodontal
often overlooked when trying to control tissues. If these mediators gain entry to the
other problems associated with diabetes. systemic circulation, important adverse
Thus, periodontal changes in diabetic effects may result when diabetes is present.
patients may often go undiagnosed for Of primary importance, these mediators
several years. may act as insulin antagonists.24,25
Periodontitis is a classic chronic disorder Older reports have indicated that peri-
and as such, once a patient is diagnosed, odontitis in patients with diabetes is associ-
management depends on patient compliance ated with subsequent development of clinical
for the most successful treatment outcomes. complications in these patients. Numerous
Patients are required to perform effective recent studies have defined these associations.
oral hygiene, which requires a daily commit- Saremi and colleagues26 examined a cohort of
ment. Furthermore, maintaining regular 628 members of the Gila River Indian Com-
appointments with their dentist for oral pro- munity in Arizona, a group with a very high
phylaxis and examinations to determine prevalence of type 2 diabetes. Following this
whether the periodontal condition is stable cohort for a minimum of 11 years revealed
requires a continuous decision to schedule that those with severe periodontitis at baseline
and keep appointments. As with those with (compared with those with a healthy peri-
diabetes, patients with periodontitis are chal- odontium or mild or moderate periodontitis)
lenged on a daily basis to adhere to these had a 3.2 times risk of dying from cardiac or
regimens.21 In both cases, most patients are renal disease. In addition, another report
unable to maintain this commitment and examining the same community found that
need the support of all health professionals compared with no disease or mild periodonti-
involved in their care. tits, individuals with moderate or severe peri-
odontitis or those who were edentulous had a
Effect of Periodontal Infections 2.0 to 2.6 times increased risk of developing
on the Diabetic State nephropathy.27 The chance of developing end-
The relation of diabetes mellitus and peri- stage renal disease was even higher for those
odontal disease is bidirectional. In addition to with moderate or severe periodontitis or those
the well-documented increased prevalence and who were edentulous. In both studies, the
severity of periodontal disease in patients with models were fully adjusted for potentially
diabetes, evidence suggests that periodontitis confounding variables.
may adversely affect metabolic control. A More recently, Demmer and colleagues28
recent report22 includes a review of how peri- asked an intriguing question: Could the pres-
odontal disease can affect metabolic manage- ence of periodontal disease predict the subse-
ment of diabetes, as well as the development quent development of diabetes mellitus?
of clinical complications of the disease. Nearly 9,300 persons were included in this
The effect of periodontal disease on study; specifically, those who were part of the
both metabolic control and ultimately on first United States National Health and
complications of diabetes is believed to be Nutrition Examination Survey (NHANES I,
due to the effect of proinflammatory 1971–1976), had received a dental examina-
tion, and were seen at least one other time (P = .003). These findings were observed in
(1982–1992). Periodontal status was deter- consideration of confounding variables and
mined by the Periodontal Index, and patients provide further evidence of the potential
were graded on a 0 to 5 scale, with zero being importance of periodontitis as a risk factor
periodontal health and all others grouped for dysglycemia.
into quintiles by severity of periodontal Other studies have examined the rela-
disease. Diabetes was determined by evaluation of periodontitis to the development of
tion of the death certificate (ICD-9 code for incident diabetes and dysglycemia. These
diabetes), use of diabetes medication as studies did not perform a complete peri-
reported by the patient, and/or a stay at a odontal examination; rather, they used
healthcare facility necessitated by diabetes as indices that categorized patients according to
determined by the discharge code. Odds the severity of the deepest probing depth in
ratios were calculated to assess the relation of a sextant (Community Periodontal Index,
periodontal disease to subsequent develop- CPI), or a partial-mouth examination with
ment of diabetes. Relative to periodontal stratification into three levels of disease
health (score of zero), the risk of developing severity. These approaches reduce the impact
diabetes mellitus was not increased for those of the reported findings. Examining the
with scores of 1 or 2. In contrast, the odds effect of baseline periodontal disease on sub-
ratios of developing diabetes were elevated in sequent glucose tolerance, persons with
groups with scores of 3 (2.26, confidence normal glucose tolerance at baseline but
interval [CI] 1.56 to 3.27); 4 (1.71, CI: 1.0 to with periodontitis displayed abnormal
2.69); and 5 (1.5, CI: 0.99 to 2.27). For indi- glucose tolerance 10 years later.30 Confirma-
viduals without teeth, the odds ratio was 1.3 tory results were reported by Morita and
(CI: 1.0 to 1.7). Since the investigators used colleagues31 in 2012. Following individuals
logistic modeling to account for the effect of with HbA1c below 6.5% for 5 years, those
other variables, these data suggest that peri- with periodontitis at baseline had an
odontitis is an independent risk factor for the increased risk of having an HbA1c of 6.5 or
development of diabetes. higher (relative risk 3.4; P = .037).
Furthermore, because infection is a risk In contrast, Ide and colleagues32 followed
factor for diabetes, the presence of periodon- patients with and without periodontitis for
titis has been assessed in relation to an the development of diabetes. After 7 years,
increase in HbA1c over time in nondiabetic moderate to severe periodontitis at baseline
persons.29 Individuals were categorized into was associated with an increased risk of inci-
four groups based on the percentage of sites dent diabetes in an unadjusted model.
with at least 5 mm of attachment loss at However, in a fully adjusted analysis, this
baseline. Over a 5-year period, the increase association was not observed.
in HbA1c levels was 0.023%, 0.023%, Another approach to examining the
0.065%, and 0.106% (P = .02) for the groups effect of periodontitis on the diabetic state is
with the lowest to highest severity of peri- via studies of the effect of periodontal
odontitis. Comparing individuals without therapy on metabolic control. As reviewed
periodontal disease at baseline who did not by Taylor and Borgnakke,22 20 studies were
evidence progression of periodontal destruc- identified that examined the effect of nonsur-
tion over 5 years with those with the greatest gical periodontal therapy on metabolic
severity of disease at baseline who experi- control. Seven of these studies were random-
enced further progression of disease, the ized controlled trials (RCTs) and 13 were not
change in HbA1c was 0.005% versus 0.143% (non-RCTs). Of the RCTs, four of seven
studies included the use of adjunctive antibi- guidelines alert physicians of the need to rec-
otics, and three of those studies demon- ognize periodontitis (and/or the risk for peri-
strated a positive effect of treatment on odontitis) in their patients with diabetes and
metabolic control. Of the 13 non-RCTs, advise them accordingly. They also review
eight reports were associated with an suggestions for managing the patient with
improvement in metabolic control. Five of known diabetes or at risk for diabetes in
the 13 reports included adjunctive antibi- dental settings. Finally, they include specific
otics, and three of these studies demon- recommendations for affected patients.
strated a positive effect. There is, however,
great heterogeneity in terms of the design of ROLE OF DENTAL PROFESSIONALS
the RCTs and the non-RCTs. It was con- There is a great need for dental professionals
cluded that the use of antibiotics as part of (e.g., general dentists, periodontists, and
periodontal therapy to improve metabolic hygienists) to assume a role in the manage-
management in patients with diabetes has ment of the patient with diabetes.
not been proved. Diagnosis and treatment of diabetes are
Subsequent systematic reviews examined clearly within the realm of the physician.
the effect of periodontal therapy on glycemic However, dental professionals can evaluate
control of patients with periodontal disease signs and symptoms indicative of poor meta-
and diabetes mellitus. The therapy provided bolic control in patients with known diabetes
was usually nonsurgical (root planing and and can seek to identify patients who may
scaling), possibly with adjunctive antibiotics, remain undiagnosed and refer these patients
but a few studies also included extraction of to physicians for proper evaluation and treat-
hopeless teeth and periodontal surgery. Two ment. A number of characteristics of dental
such reviews published in 2010 included five practice are consistent with dentists assuming
studies33 and seven studies,34 respectively. such a role: they treat large numbers of
Both concluded that the reduction in patients each year and often provide primary
HbA1c with periodontal therapy was 0.4% and preventive care. Dentists frequently see
for a period of at least 3 months. A 2013 patients on a regular basis, and most visits are
systematic review35 included studies pub- nonemergent in nature.
lished after the earlier meta-analyses. The Managing the needs of patients with
reduction in the level of HbA1c was deter- diabetes is not new to dentistry. The associa-
mined to be 0.36%. tion between diabetes and periodontal
All the previously mentioned studies disease, the possible other oral manifesta-
emphasize the importance and significant tions of this metabolic disorder, treatment
implications of the link between diabetes guidelines, and special considerations with
mellitus and periodontal diseases. An regard to the management of these patients
emphasis must be placed on increasing proin a dental setting all have been discussed in
fessional and patient awareness of this rela- the dental literature, promoted by profes-
tionship and of the need for medical-dental sional associations such as the American
comanagement of affected persons. Dental Association and the American
To this end, a joint European Federa- Academy of Periodontology, and taught in
tion of Periodontology (EFP) and American dental and dental hygiene schools for many
Academy of Periodontology (AAP) Work- decades. Similar to what has been shown
shop and subsequent consensus report pro- within the medical profession, however,
vided guidelines for both healthcare profes- efforts to translate research into primary care
sionals and patients with diabetes.36 These have been met with resistance,37 and such a
gap between knowledge and practice sional responsibility were influential. Variables
appears to exist in the dental profession. pertaining to patient relations, such as discus-
sion with patients, patient expectations, and
Are Dental Professionals Involved? the Medicaid status of their patients were
The first reports to document the extent of influential predictors for general dentists.
US dentists’ practice activities with respect to These findings provided a first step toward
the management of patients with diabetes38,39 identifying the components of targeted inter-
demonstrated that a clear majority of general ventions aimed at increasing the level of
dental practitioners did not feel they had involvement of specialists and general dentists
mastery of the knowledge involved, viewed in the management of the diabetic patient,
such activities as peripheral to their role as thereby contributing to the improvement of
caregivers, and did not believe that colleagues the dental patient’s oral and systemic health.
or patients expected them to perform such More recent surveys of dental profes-
activities. Although periodontists generally sionals and dental patients indicate support
performed risk identification and manage- for dental professionals to be more involved
ment for patients with diabetes more fre- in the management of patients with diabetes.
quently than general practitioners, both A national sample of dentists indicated that
groups tended to engage in activities that most respondents believe that it is very
inquire and discuss, and rates of proactive important or somewhat important to screen
patient management activities were low for for certain conditions, with nearly 80% believ-
both groups of clinicians. A subsequent study ing that assessment should include diabetes.42
of general dentists in New Zealand40 showed Furthermore, patients seen at an inner city
striking similarities in attitudes and orienta- dental clinic and those at private dental
tions compared with those identified in the offices were asked about their feelings regard-
US study. ing chairside testing for certain medical condi-
These data suggested a need to increase tions. The responses by clinic patients were
involvement of dentists in the active manage- overwhelmingly in support of such screen-
ment of the diabetic patient. Such actions can ings.43 The responses from patients seen in
be expected to result in improved periodontal private practice were also very supportive, but
and general health outcomes. The evidence not to the same degree as clinic patients. This
suggests, however, that approaches to chang- difference likely related to greater access to
ing dentists’ behavior should aim not only at medical services for private practice patients.
increasing knowledge, but also at overcoming A national/international survey specifically
attitudes and orientations associated with focused on a blood test for diabetes per-
actively managing patients who have diabetes. formed in the dental office and revealed that
Basic views of the dentist’s role as a primary more than 80% of dental professionals feel
and preventive care provider need to be that such screening is important; the primary
changed to facilitate the desired behavioral concern was about the time required to
changes. When looking at predictors of active perform the test (22% of respondents).44
management of patients with diabetes,41 these
appear different for general dentists versus How Can Dental Professionals
periodontists. For the latter, variables that Be More Involved?
reflected feelings of confidence, involvement For dental professionals to provide safe and
with colleagues and medical experts, and effective oral care to patients with diabetes,
viewing active management of the diabetic to be able to contribute to the patients’
patient as belonging in their sphere of profes- better overall management, and to help in
the identification of those with prediabetes • type of treatment/medications the patient

or even those with frank diabetes who remain is receiving
undiagnosed, it is essential to have a thorough • level of the patient’s metabolic control,
knowledge of certain aspects of this complex including recent HbA1c values
disorder. Dental professionals need to be • presence of any diabetic complications
aware of and appreciate the many risk factors or other diabetes-associated conditions
involved in the development of diabetes, the (e.g., obesity, hypertension, hypercholes-
types of treatments diabetic patients may be terolemia)
receiving, the risk for emergency episodes, the • frequency of prior hypoglycemic
difficulties and everyday challenges that dia- episodes and precipitating factors
betic patients are faced with, and the constant One very important next step is for the
support and reinforcement these patients need dentist to establish communication with the
to properly manage their chronic condition. treating physician. This allows the dentist to
Every dental care setting should have confirm answers to the latter questions, espe-
clinical protocols in place to provide for the cially when the patient is a poor historian.
dental needs of a patient with diabetes. These The dentist can then inform the physician
should include: about his/her dental treatment plan, discuss
• criteria assessed and risk factors consid- any concerns, and get advice about potential
ered when screening patients with poten- changes in the management of the patient if
tially unrecognized (pre) diabetes the plan includes any invasive and/or stressful
• evaluation of every new diabetic patient procedures. Communication should be
• routine care of a diabetic patient based ongoing, especially when the planned dental
on their level of metabolic control treatment is extensive and the patient is
• appropriate equipment, supplies, and poorly controlled.
training to prevent and/or manage a dia- An essential part of the oral disease risk
betic emergency during or after a dental assessment for patients with known diabetes
appointment is a detailed clinical evaluation. This should
In addition, guidelines should be in place include:
to determine: • a thorough intraoral exam for oral
• the need for a medical consultation, mucosal lesions (e.g., lichen planus, apht-
referral, or follow-up hous stomatitis)
• how to perform risk assessment for • identification of signs and/or symptoms
oral/periodontal diseases of opportunistic infections (e.g., oral
• the need for dental and/or periodontal candidiasis)
therapy and the frequency of follow-up • evaluation of salivary flow
care • assessment of taste disturbances and
• the need to refer to a dental specialist signs/symptoms of burning mouth syn-
Taking a complete medical history is drome
something that all dental practitioners are • dental caries assessment
required to do every time they see a new • a complete periodontal evaluation with
patient, and updates should be performed at whole-mouth probing depth and attach-
each maintenance/recall visit. However, once ment loss measurements, assessment of
a patient identifies as having diabetes, the the level of plaque and gingival inflam-
dentist should gather and record additional mation, and radiographic evaluation of
detailed information, including: bone levels, as needed
• time since diagnosis Managing the dental care of diabetic
patients should not be a significant challenge frequent recall appointments to prevent

in most cases. Any active infection must be and monitor bacterial recolonization,
immediately treated because it may also have reinforce proper oral hygiene, and treat
a significant adverse impact on the diabetic any disease reactivation.
state, especially the level of glycemic control. • There is no need for antibiotic premed-
The patient with diabetes who is under good ication, but antibiotics may be consid-
medical care and maintains good glycemic ered pre-/postoperatively or in conjunc-
control generally can receive any indicated tion with periodontal therapy, especially
dental treatment. if an overt infection is apparent.
Recommendations for proper home • Since diabetes affects the host response
care are very important for patients with dia- to infection, adjunct therapies such as
betes and must be discussed in detail before locally delivered antimicrobials, systemic
any therapy and reviewed at follow-up visits. antibiotics, or a subantimicrobial dose of
The oral hygiene regimen should include an doxycycline may be considered.
over-the-counter toothpaste and/or mouth • The patient’s physician should be con-
rinse with antibacterial properties to help sulted about dietary recommendations
manage supragingival plaque and gingival and any modification to the type and
inflammation. Patients must be encouraged dose of medications both pre- and post-
to brush and floss after each meal, conduct operatively.
self-examinations regularly, and contact the • Typically, diabetic patients should receive
dentist or hygienist if they see signs of infec- morning appointments when endoge-
tion, such as edematous, bleeding gingiva or nous corticosteroids are at high levels
other oral changes, such as ulcers, burning (better stress management).
mouth, or reduced salivary flow. • Vital signs, blood pressure, and blood
In patients with known diabetes, den- glucose levels should be assessed preop-
tists should not only aggressively screen for, eratively and as discussed in detail in the
but also carefully treat periodontal infections. text that follows.
Important points for consideration follow: • Appointments should be kept as non-
• If periodontal or other oral surgery is traumatic, short, and stress-free as possi-
needed, the level of glycemic control ble, because endogenous epinephrine
may determine healing and response to release in response to stress and pain
treatment. can antagonize insulin action and
• Elective therapy may be postponed until promote hyperglycemia.
the patient demonstrates improved • Epinephrine should be used in the dental
metabolic control. anesthetics to ensure long-lasting and
• The response to initial periodontal profound anesthesia.
therapy (scaling and root planing) • Postoperative analgesics should be pro-
should be closely monitored because it vided to ensure that the patient is pain-
may help the dentist to better assign free after tooth extraction, periodontal
prognosis and predict outcomes of surgery, or any other invasive procedure.
further treatment, including response to
and healing capacity after periodontal Prevention and Proper Management of
surgery, extractions, implant surgery, or Diabetes-Related Emergencies
regenerative procedures. Glycemic variability is one of the most fre-
• After active dental and/or periodontal quently encountered medical emergencies in
therapy, patients should be scheduled for dental offices. All dental professionals should
be trained to prevent, recognize, and prop- nomic responses eventually result in a state
erly manage both hypo- and hyperglycemic of hypoglycemia unawareness. At this stage,
episodes. the focus for the patient and office staff edu-
Hypoglycemia is defined as plasma cation should be on identifying a distinct set
glucose level below 70 mg/dL and confirmed of less obvious neuroglycopenic symptoms,
when symptoms are relieved after eating.45 It such as slow cognitive response, light-head-
is important to note that diabetic patients edness, sleepiness, confusion, difficulty speak-
may complain of symptoms suggestive of ing, and anxiety.
hypoglycemia at blood glucose levels higher The steps for intervention when hypo-
than 70 mg/dL if they have had chronically glycemia is suspected are outlined in Figure
elevated blood glucose. Hypoglycemia is 2. The immediate treatment for hypo-
commonly caused by missing or delaying glycemia is to give glucose or carbohydrates
meals while taking medication, consuming that easily break down to glucose, such as
alcohol, exercising, or doing a combination glucose tablets, fruit juice, nondiet soda, or
of these. Some of the important questions to honey. Complex carbohydrates and foods
ask patients at the beginning of the office that contain fat may delay the recovery
visit may include: “Did you miss or delay process and are not recommended as first-
your meal?” “Did you exercise without line treatment. A commonly recommended
snacking?” “Did you adjust your medication treatment algorithm for hypoglycemia, also
and how?” known as the 15-15 rule, includes (1)
The classic symptoms of hypoglycemia consume 15 g of simple carbohydrates; (2)
are hunger, shakiness, nervousness, sweating, wait 15 minutes to recheck blood glucose;
and weakness.45 However, as the duration of and (3) repeat 15 g of carbohydrates when
diabetes and the frequency of hypoglycemic glucose level is still below target (70 mg/dL).
events increase, individuals with diabetes If the initial glucose is below 50 mg/dL, con-
gradually lose these obvious adrenergic sumption of 30 g of simple carbohydrates is
symptoms. The deficient release of counter- indicated. Shortly after the immediate treat-
regulatory hormones and the blunted auto- ment, the patient should follow with a meal
Figure 2. Steps for Intervention When Suspecting Hypoglycemia
1. Check blood glucose to confirm hypoglycemia (blood glucose < 70 mg/dL).

2. If patient is conscious, give 15 g of simple carbohydrates orally as immediate
treatment.
Options include 4 oz of fruit juice, 5–6 oz regular soda, 1 tablespoon of table
sugar or honey, 7–8 Lifesaver candies, 3 tablespoons of jelly, 2 tablespoons of
raisins, or 4 –5 glucose tablets. If initial blood glucose is less than 50 mg/dL, give
30 g of simple carbohydrates.
3. Recheck blood glucose after 10–15 minutes. If blood glucose is less than
70 mg/dL repeat the treatment (step 2) until blood glucose returns to at least
90 mg/dL.
4. Follow with a meal or snack such as 6 saltine crackers, 3 graham cracker squares,
or 1⁄2 peanut butter sandwich. Further glucose monitoring may be necessary.
5. If patient is unconscious, activate 911. Inject glucagon intramuscularly.
6. When patient is alert enough to swallow, give fruit or soda immediately and fol-
low steps 2 to 4.
or snack. In practice, food such as ½ peanut diabetic patients early in the day can prevent
butter sandwich, six saltine crackers, or three hypoglycemic episodes associated with pro-
graham cracker squares provides complex longed fasting or delayed or skipped meals.
carbohydrates and protein to prevent further Not all diabetes medications cause
hypoglycemia. Occasionally, blood glucose severe hypoglycemia. For the purpose of
can plunge into the hypoglycemic range classifying drugs according to their risk for
again after the return to a normal level. hypoglycemia, diabetes medications can be
Therefore, further glucose monitoring may divided into either antihyperglycemic or
be necessary before leaving the dental office, hypoglycemic (Table 1). Technically, the anti-
especially before operating a motor vehicle. hyperglycemic class of medications includes
There always exists the temptation to agents that can lower glucose from the hyper-
overtreat hypoglycemia with a large amount glycemic range to near normal range without
of carbohydrates because of the urgency and the risk of driving the glucose concentration
discomfort associated with the symptoms. into the hypoglycemic range. Most of these
Yielding to this practice can lead to excessive agents work by mechanisms distinct from
rebound hyperglycemia, thereby generating direct stimulation of insulin production. For
vicious cycles of glycemic instability. In the others, the stimulation of insulin release
event of severe hypoglycemia in which the occurs in a glucose-dependent manner.
person is unconscious or too confused to Therefore these drugs have little potential to
ingest carbohydrates, trained personnel in cause hypoglycemia when used alone. In
addition to activating the emergency medical other words, the glucose-lowering effect of
service may use an intramuscular injection of these drugs moderates as glucose levels nor-
glucagon, which is packaged as a 1-mg malize. These drugs include biguanide, thia-
ampule of glucagon with diluent and a zoladinediones, alpha-glucosidase inhibitors,
syringe. The glucagon injection is expected to incretins, bile acid binders, and SGLT2 or
restore the patient to consciousness within 10 dopamine agonists. The hypoglycemic class
to 15 minutes, but the effect may be short- of medications lowers glucose levels either by
lived. Every dental office should have staff insulin replacement or direct insulin stimula-
capable of using a glucose monitor and tion. Sulfonylureas, short-acting insulin secre-
glucagon. In addition, care should be taken tagogues, and the various insulin formula-
to ensure that dental offices are equipped tions have the highest hypoglycemic poten-
with glucose monitors, unexpired glucose tial. Insulin-requiring patients are subject to
testing strips, glucagon kits, and appropriate hypoglycemic events and hypoglycemia
food/drink for treatment of a hypoglycemic unawareness, which can severely disrupt
episode. quality of life and compromise the ability to
Prevention and early recognition of tighten glucose control. A common miscon-
hypoglycemia is obviously best and an ception is that all patients on insulin have
important component in the planning for a type 1 diabetes. Although it is correct that
dental procedure. Most office-based dental individuals with type 1 diabetes must rely on
procedures do not necessitate an adjustment insulin for survival, many with type 2 dia-
of diabetes medications. When fasting or betes also require insulin at later stages of the
sedation is required, proper medication disease. It is important to recognize that the
adjustment should be made in advance to use of antihyperglycemic agents is associated
prevent an in-office diabetic emergency. with a profound risk of hypoglycemia when
Close communication among the healthcare combined with drugs from the hypoglycemic
providers should be a priority. Appointing class.
Generally, there is no need for adjust- the morning. If basal insulin is usually taken
ment of the medication or insulin regimen in the morning, either the same dose or no
before or on the day of the dental appoint- less than 75% of its usual dose should be
ment. If the patient is asked to fast overnight given. Those who are on NPH or premix
before the office visit and basal insulin is insulin in the morning should take only one
used, then either the same dose or no less third to one half of the usual dose. Glucose
than 75% of its dose should be given the levels should be monitored before the proce-
night before. If neutral protamine Hagedorn dure upon arrival in the office. During a pro-
(NPH) insulin or premix insulin is generally longed procedure, periodic glucose monitor-
taken at night, then no dose adjustment is ing may be necessary. The regular medication
required the night before the procedure. On regimen can be resumed upon returning to
the day of the dental visit, the fasted patient normal diet after the procedure is finished. In
should be instructed not to take any antidia- general, and especially for long and stressful
betic oral medications or fast-acting insulin in procedures, the dentist should consult with
Table 1. Classification of Diabetes Agents According to Their Potential to Lower

Glucose Below Physiologic Range
Hypoglycemic Agents Anti-Hyperglycemic Agents

Sulfonylureas Biguanide
Glyburide (Diabeta®, Micronase®) Metformin (Glucophage®)
Glipizide (Glucotrol®, Glucotrol XL®)
Glimepiride (Amaryl®) Thiazoladinediones
Pioglitazone (Actos®)
Short-acting secretagogues Rosiglitazone (Avandia®)
Repaglinide (Prandin®)
Nateglinide (Starlix®) Alpha-glucosidase Inhibitors
Acarbose (Precose®)
Insulin Miglitol (Glyset®)
Basal/intermediate to long-acting insulin
Detemir (Levemir®) Incretins
Glargine (Lantus®) Exenatide (Byetta®)
NPH (Novolin N®, Humulin N®) Sitagliptin (Januvia®)
Short-acting insulin Liraglutide (Victoza®)
Regular human insulin (Novolin R®, Humulin R®) Exenatide LAR (Bydureon®)
Ultra-short-acting insulin Saxagliptin (Onglyza®)
Aspart (NovoLog®) Linagliptin (Tradjenta®)
Lispro (Humalog®)
Glulisine (Apidra®) Amylin analog
Mixed insulin Amylin (Symlin®)
Aspart 70/30 (NovoLog mix 70/30)
Lispro 75/25 (Humalog mix 75/25) Bile acid binder
Lispro 50/50 (Humalog mix 50/50) Colesevelam (Welchol®)
Regular human mix 70/30
(Humulin 70/30, Novolin 70/30) SGLT2 inhibitor
Regular human mix 50/50 (Humulin 50/50) Canagliflozin (Invokana®)
Dopamine agonist
Bromocriptine mesylate (Cycloset®)
the treating physician regarding medication agnosed diabetes and prediabetes in asymp-
adjustments. tomatic patients, the American Diabetes
It is well known that chronically ele- Association currently recommends that such
vated glucose levels impair wound healing testing should be considered in adults of any
and predispose patients to infections.46 In age who are overweight or obese and who
contrast, transient hyperglycemia at levels have one or more additional risk factors for
lower than 300 mg/dL during an office diabetes. In those without risk factors, testing
appointment generally does not pose an should begin at 45 years of age (Figure 3).
immediate danger to most patients with type The increased risk is associated with certain
2 diabetes, nor does it necessitate cancellation demographic characteristics (minority race-
of the dental procedure as long as hyper- ethnicity status, family history of diabetes),
glycemia is corrected shortly. Acute hyper- clinical characteristics (physical inactivity,
glycemia can occur in the setting of pain, hypertension, dyslipidemia), and prior evi-
stress, or underdosing of diabetes medica- dence of abnormal glucose values (gesta-
tions related to the dental procedure. Review- tional diabetes, IFG, IGT).4
ing recent HbA1c test results can help deter- Historically, the primary method used to
mine the recent glycemic trends. However, for diagnose diabetes mellitus has been the
patients with type 1 diabetes, significant fasting plasma glucose test. Though valuable
ketoacidosis (also known as diabetic ketoaci- for making a diagnosis, this test tends to have
dosis or DKA) can occur at glucose concen- low sensitivity. The HbA1c assay is based on
trations usually above 250 mg/dL, in which the knowledge that blood glucose can bind to
additional insulin administration and hydra- hemoglobin molecules. This reaction is not
tion are urgently indicated.47 The telltale signs enzymatically driven and therefore is a
and symptoms of DKA include excessive measure of the exposure to glucose in the
thirst, fatigue, rapid breathing, fruity breath, blood. Based on the 2013 revisions of the
nausea, and vomiting. Most patients with Standards of Medical Care in Diabetes by
type 1 diabetes have the skills to manage the American Diabetes Association,4 the
hyperglycemia and mild DKA by aggressive HbA1c assay is also now accepted as a test to
rehydration and insulin administration; diagnose diabetes (with a cut point of ≥
however, a consultation with the patient’s 6.5%). In addition, this assay remains very
medical provider is necessary when the valuable for monitoring glycemic levels and
symptoms become severe. A patient who is response to treatment, and it can be an excel-
severely nauseated or unable to keep down lent screening tool that does not rely on
fluids and with blood glucose above 250 patient compliance, does not require fasting,
mg/dL should be transferred to a hospital and gives an indication of glucose levels over
emergency room for medical intervention. an extended period of time.
The importance of early diagnosis of
Screening for Undiagnosed Diabetes diabetes cannot be overstated and clearly
in the Dental Office cannot be the sole responsibility of the
Early identification of diabetes and, in diag- medical community or of any single group of
nosed patients, achieving and maintaining healthcare providers. Survey data from the
glycemic levels as close to normal as possible, American Dental Association published in
have been the focus of efforts from the 2008 show that 68.5% of adults had visited a
American Diabetes Association and the dentist in the previous year,14 and data from
medical and public health communities for the Behavioral Risk Factor Surveillance
many years. With respect to testing for undi- System suggest an even higher percentage.13
Figure 3. Criteria for Testing for Diabetes in Asymptomatic Adults
Test all adults who are overweight or obese (body mass index ≥ 25 kg/m2 for most, but
not all racial/ethnic groups) and have one or more of the following risk factors:
• Family history of diabetes (parent or sibling)
• High-risk race/ethnicity (African American, Hispanic/Latino, Alaska Native,
American Indian, Asian American, or Pacific Islander)
• Habitual physical inactivity
• Delivery of infant > 9 lb or history of gestational diabetes
• Polycystic ovarian syndrome
• Blood pressure ≥ 140/90 mm Hg or on therapy for hypertension
• High-density lipoprotein cholesterol < 35 mg/dL or triglycerides > 250 mg/dL
• HbA1c ≥ 5.7%, impaired glucose tolerance or impaired fasting glucose on
previous testing
• History of vascular disease or other diabetes-associated conditions
In the absence of the above risk factors, test starting at age 45 years. If normal,
repeat at least at 3-year intervals, or more frequently depending on risk status or initial
results (e.g., annually for those with prediabetes).
Adapted from the 2013 American Diabetes Association Standards of Medical Care in Diabetes. Diabetes
Care 2013;36(Suppl 1):S11–66.4
Insurance utilization patterns indicate that unaware of it) of between 27% and 53%,
individuals tend to seek routine and preven- with Mexican-American men exhibiting the
tive oral healthcare on a more frequent basis highest and white women the lowest.51 These
than routine and preventive medical care.48 probabilities increase among persons 60
These facts allow dentists and dental hygien- years of age to between approximately 48%
ists to be at the front line of screening inter- and 74%. These findings, combined with
ventions and risk-reduction strategies.49 Yet supportive data by subsequent NHANES-
can this happen in real world practice? based studies,52 demonstrate that simple
Previous studies have examined the per- pieces of information from a patient’s
formance of predictive models for diabetes medical history and an oral examination can
screening in medical settings using a mix of be used effectively to identify patients at risk
self-reported and objective characteristics.50 for undiagnosed diabetes in a dental care
The first report to explore a predictive model setting. The results of this novel approach
for undiagnosed diabetes51 that included afforded the opportunity to further test such
measures of periodontal disease used a model in the clinic.
national data from the third NHANES In a study published in 2011, individuals
study and was published in 2007. Findings who presented for care at a dental school
revealed that, for example, a 45-year-old clinic and had never been told they have pre-
person, with self-reported family history of diabetes or diabetes were recruited.53 To target
diabetes, self-reported hypertension, self- those at some level of risk for diabetes, the
reported high cholesterol levels, and clinical inclusion criteria included (a) being ≥ 40 years
evidence of periodontal disease bears a old if non-Hispanic white or ≥ 30 years old if
probability of having diabetes (and being Hispanic or non-white, and (b) self-report of
at least one diabetes risk factor (family history (Figure 4). A risk calculator is available from
of diabetes, hypertension, high cholesterol, or the American Diabetes Association, and
overweight). This resulted in 535 subjects who dental professionals can also use that to assess
then received a periodontal examination and (and discuss) levels of risk for diabetes in their
a point-of-care fingerstick HbA1c test, which patients.58 If they identify a patient at risk, they
provided additional variables to be used in can either use a screening blood test in the
the prediction models. Subjects were asked to office or refer to a physician for diagnostic
return fasted for an FPG test, the result of testing. Regardless of the strategy used and the
which was used as the study outcome to result of any testing, the concerns and findings
signify potential diabetes or prediabetes, per need to be discussed with the patient and, in
American Diabetes Association guidelines at the case of a medical referral, the dental pro-
the time. Of 506 subjects who returned for fessionals need to follow up on the outcome.
the FPG test, 21 (4.2%) were identified as Similarly, dental professionals should be
potentially diabetic (FPG ≥ 126 mg/dL), and involved in the ongoing efforts of patients with
161 (31.8%) as prediabetic (FPG = 100–125 known diabetes (or prediabetes) to achieve
mg/dL). Performance characteristics of simple appropriate glycemic control and modify
models to identify dysglycemia (FPG ≥ 100 behavior and habits, such as smoking, lack of
mg/dL) were evaluated, and optimal cut-offs physical activity, and unhealthy diet—all risk
for each variable in a given model were identi- factors that may exacerbate diabetes-associated
fied. The presence of ≥ 26% teeth with deep complications. Dentists and dental hygienists
periodontal pockets or ≥ 4 missing teeth cor- can help their patients by:
rectly identified 73% of true cases; the addi- • evaluating and managing risks for oral
tion of an HbA1c ≥ 5.7% increased correct complications
identification to 92%. Both predictive models • providing guidance in goal setting
presented in this study had sensitivity similar • helping with strategies to achieve goals
to what has been reported for diabetes risk and overcome barriers
assessment approaches tested in medical set- • providing continuous education, reinforce-
tings. A limitation is that the population ment, and support
under investigation was predominantly His- Dental practices should establish a system
panic, and thus further studies to assess exter- of referrals for routine preventive care as well
nal validity of these models in diverse patient as for urgent needs. A list of providers, with
populations is needed. phone numbers and other contact informa-
Recently, more studies exploring the tion, can be very useful for quick reference.
notion of screening for undiagnosed diabetes The dental team should also consider giving
in dental settings have been published, and handouts to patients with referral information,
work has provided evidence that implementa- or calling clinics directly. Multidisciplinary
tion of diabetes screening in dental settings is team care is key to both successful diabetes
feasible and that patients and dental providers recognition and management.
alike feel that the dental visit is a good oppor-
tunity for early diabetes identification.54–57 Patient Education
A report from the United Kingdom in 2008
Participation in the Management of Patients assessed the knowledge of diabetic patients
with Unrecognized or Known Diabetes regarding their risk for periodontal disease
Based on the above studies, the dentist or and their attitudes toward oral health.59 Only
dental hygienist should assess the presence of a third of the 101 patients who participated
risk factors for diabetes in their patients in the study were aware of their increased
268 Periodontal Disease
! and
! Overall
! Health:
! A! Clinician’s
! Guide
!
Figure 4. 5Dental-Medical!Collaboration! is! Key! to

! Both
! Successful
! Diabetes
!
Recognition and Management
! !
! ! ! ! ! ! ! ! ! ! ! ! ! ! !
Dental and medical professionals need to work beyond professional boundaries and strive for the best pos-
sible!care
! of! their mutual
! !
patients.! Dental professionals
! ! ! ! !
can contribute ! !
to the identification of! individuals
!
! ! ! ! ! ! ! ! ! ! ! ! !
with diabetes or prediabetes that remain undiagnosed, and medical professionals can screen for periodontal!
!
diseases ! promote
and ! ! oral! health in patients with diabetes.
risk for periodontitis as opposed to their Indeed, the American Diabetes Association
knowledge of the risk for other diabetic com- Standards of Medical Care in Diabetes rec-
plications, which ranged from 84% to 99%. ognize that every patient with diabetes needs
History of dental care was sporadic, with to see a dentist for appropriate evaluation
43% reporting seeing a dentist within the last and treatment of oral diseases.4 Patients need
year. An earlier study from Sweden60 had to be informed that proper control of peri-
reported that 83% of diabetic patients were odontal infections may even have a beneficial
unaware of the link between diabetes and effect on their level of metabolic control and
oral health, and that 48% believed that their systemic inflammation, as well as the risk for
dentist/dental hygienist was unaware that they vascular and kidney complications.22
even had diabetes. Oral health does not Patients must comprehend the overarch-
appear to be a priority for patients with dia- ing principle that medical and dental profes-
betes.13,61–63 Tomar and Lester13 reported that sionals have common goals: providing the
diabetic individuals were less likely to visit a best possible care to their patients and
dentist than a nondiabetic individual in the helping them avoid complications (Figure 5).
preceding 12 months, and the leading reason Multifactorial, complex diseases such as dia-
for not seeing a dentist was “lack of per- betes and periodontitis interrelate and can
ceived need.” Competing financial and time amplify one another, creating an imperative
commitments may explain the inadequacy of for a comanagement model that has the
routine dental care in patients with diabetes.64 potential to improve patient outcomes.
Dental professionals have an opportu-
nity and the responsibility to educate their ROLE OF MEDICAL PROFESSIONALS
patients about the diabetes-oral health link Members of the medical and dental aca-
and promote good oral and overall health demic communities, dentists, hygienists,
behaviors. They should play a supporting physicians, nurses, representatives from
role in modifying patient behavior and habits dental and diabetes professional societies, as
related to risk factors that may exacerbate well as representatives from dental/medical
diabetes-associated complications. Specifi- insurance carriers, have convened a number
cally, as part of oral health education, oral of workshops over the past years to address
health care providers can reinforce the need oral-systemic links and discuss issues related
for regular dental visits and proper oral to communication among different health-
hygiene, but also the need for proper nutri- care professionals and patients.
tion, exercise, smoking cessation, adherence As an example, two such symposia and
to medication regimens, regular monitoring their subsequent reports highlighted these
of blood glucose levels, and regular medical issues and offered recommendations. Follow-
follow-up, as indicated by the patient’s physi- ing the Scottsdale Project meeting in April
cian. Patients should be encouraged to 2007, a panel of experts presented a consen-
achieve the best glycemic control possible, sus report that stated, “it is appropriate to
since good control can improve oral health develop guidelines to assist medical providers
and lead to better and more predictable peri- in identifying patients who are at risk for peri-
odontal treatment outcomes. To this end, odontal disease or screening patients who
patients need to know that they are at may have undiagnosed periodontal disease.”65
greater risk for increased prevalence, severity, Similarly, the report following the July 2007
and progression of periodontitis and that Oral-Systemic Diseases: From Bench to
periodontitis has been recognized as a condi- Chair—Putting Information into Practice
tion often found in patients with diabetes. symposium stated, “there is a need for coor-
Figure 5. Key Messages All Healthcare Providers Can Reinforce
• Emphasize the importance of good control (HbA1c, blood pressure, cholesterol)

for complication prevention
• Promote a healthy lifestyle
• Reinforce self-exams
• Explain the benefits of comprehensive multidisciplinary care and emphasize the
importance of regular appointments with medical and oral healthcare providers
How Can a Busy Healthcare Provider Find the Time to Give Key Messages?
• Do not give every message at one appointment
• Customize and prioritize messages according to the patient’s needs
• Provide patient with a computer-generated reminder of key messages discussed
• Document what is accomplished at each appointment and the patient’s
response
• Create pamphlets for office or use materials available through national diabetes
or dental organizations and professional societies
• Include key messages in office newsletters
Source: Adapted from the 2007 National Diabetes Education Program publication Working Together to Manage
Diabetes: A Guide for Pharmacists. Podiatrists, Optometrists, and Dental Professionals. Atlanta, GA. US De-
partment of Health and Human Services, Public Health Service, Centers for Disease Control and Prevention,
National Center for Chronic Disease Prevention and Health Promotion, 2007.69
dination and cooperation between dental and have a dentist and when they last visited a
medical health professionals with regard to dentist, physicians can send a powerful
screening for and diagnosing diseases or con- message and play a significant role in pro-
ditions that affect patients who traditionally moting oral health and preventing oral com-
have been cared for by other healthcare plications in patients with diabetes. The
providers. Therefore, medical practitioners recent EFP-AAP Workshop and subse-
need to be aware of oral diseases and make quent consensus report mentioned earlier36
appropriate recommendations and referrals.”66 corroborated these concepts and provided
The concepts emphasized above are guidelines for healthcare professionals who
especially important for medical profession- care for patients with diabetes.
als who treat patients with diabetes (e.g.,
internists, diabetologists, nurses, diabetes Screening for Periodontal Changes
educators), since these patients are more and Key Questions to Ask
likely to have periodontal disease and more The guidelines for diagnosis of periodontal
likely to have less regular dental care. diseases include a detailed periodontal evalu-
Medical care providers need to discuss with ation, including probing depth measure-
their diabetic patients the importance of oral ments and intraoral radiographs, which are
health and its relation to the diabetic state, not feasible in most medical settings. Never-
and the potential sequelae of long-standing theless, medical providers can screen for peri-
and untreated oral infections and to provide odontal diseases (Figure 4) based on patient
educational brochures and other relevant history, symptoms (sore, bleeding gums, sen-
material. By simply asking whether they sitive teeth, history of abscesses), and a
visual assessment of the patient’s mouth for and beyond professional boundaries.
relevant signs, such as: The model of “working together” has
• food debris or plaque around teeth been extensively discussed in the diabetes lit-
• red, swollen, receding, or bleeding gums erature. In 2001, the National Diabetes Edu-
• loose teeth, separation of teeth cation Program (NDEP), a joint program of
• oral abscesses the National Institutes of Health and the
• missing teeth Centers for Disease Control and Prevention,
• halitosis published a report titled, Team Care: Com-
If diabetic patients tell a member of the prehensive Lifetime Management for Dia-
medical team that they have not seen a betes.68 This report was created to help orga-
dentist in the last year, they should be imme- nizational leaders of healthcare systems and
diately referred to one. If a patient has seen purchasers of healthcare to implement mul-
a dentist in the last year, but presents with tidisciplinary team care for people with dia-
detectable signs or symptoms of oral/peri- betes in all clinical settings and to set forth
odontal infections, he or she should also be an analysis of the evidence that supports
referred to a dentist. Finally, physicians team care as an effective method of chronic
should advise all poorly controlled diabetic disease management.
patients to see a dentist/periodontist for eval- The executive summary of this report
uation and treatment on a regular, ongoing stated that although primary care physicians
basis. Medical care providers should also currently provide 80% to 95% of diabetes
facilitate communication with treating dental care in the United States, they cannot do all
practitioners by offering information on the that is required and often are discouraged
patients’ medical background, level of that the current medical system does not
glycemic control, presence of complications, function well for people with diabetes.68 The
and comorbidities. Furthermore, physicians challenge is to find a way to meet the needs
should be available to offer advice on modi- of patients with diabetes by broadening the
fication of medical management that may be opportunities for delivery of care. Team care
necessary and should be open to a meaning- meets this challenge by integrating the skills
ful professional interaction to ensure that of different healthcare professionals with
patients receive the best possible care. those of the patient and family members to
create a comprehensive lifetime diabetes
PATIENT-CENTERED TEAM CARE management program. The report highlights
Finally, the concept of a “syndemic that if diabetes care is to achieve the health
approach to diabetes management,” as intro- benefits that modern science has made possi-
duced and discussed in the dental literature ble, it must be:
by Hein and Small,49 deserves some mention. • continuous, not episodic
Syndemic is a term originally used to • proactive, not reactive
describe a set of two or more linked health • planned, not sporadic
problems, which synergistically contribute to • patient-centered rather than provider-
excess burden in a population.67 A syndemic centered
orientation has the potential to provide a • population-based, as well as individual-
framework that can guide more efficient and based
effective initiatives because healthcare CONCLUSION
providers do not approach diseases such as Although the model of multidisciplinary,
diabetes and periodontitis as discrete prob- patient-centered care presents many chal-
lems and are prompted to collaborate across lenges, all healthcare providers should strive
to participate in it. There is no doubt that by States, 2010. Atlanta, GA: U.S. Department of
changing their thinking and trying to adopt Health and Human Services, Centers for Disease
Control and Prevention, 2011.
these concepts into everyday practice, health- 2. International Diabetes Federation. IDF diabetes atlas
care providers can render better health care update 2012. Available at: http://www.idf.org/ diabete-
and more predictable therapeutic outcomes, satlas/5e/Update2012. Accessed: July 31, 2013.
maximize their success in combating the dia- 3. American Diabetes Association. Diabetes statistics.
betes epidemic, and play a significant role in Available at: http://www.diabetes.org/diabetes-basics/
diabetes-statistics/. Accessed: July 31, 2013.
promoting the oral and overall health of 4. American Diabetes Association Position Statement.
patients. In the Working Together to Manage Standards of medical care in diabetes–2013. Dia-
Diabetes 2007 publication by the NDEP, all betes Care 2013;36(Suppl 1):S11–66.
healthcare providers are called on to play a 5. Diabetes Prevention Program Research Group. The
role in diabetes primary prevention and in prevalence of retinopathy in impaired glucose toler-
ance and recent-onset diabetes in the Diabetes Pre-
diabetes control.69 Among others, dentists and vention Program. Diabet Med 2007;24:137–44.
dental hygienists can make a difference in 6. Knowler WC, Barrett-Connor E, Fowler SE,
primary prevention and management because Hamman RF, Lachin JM, Walker EA, Nathan
patients are seen on a regular basis by them, DM; Diabetes Prevention Program Research Group.
patients trust them, and a few words from Reduction in the incidence of type 2 diabetes with
lifestyle intervention or metformin. N Engl J Med
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healthcare behavior. 7. Albandar JM. Periodontal Diseases in North
America. Periodontol 2000–2002;29:31–69.
Supplemental Readings 8. Papapanou PN. Periodontal diseases: epidemiology.
American Diabetes Association Position Statement. Ann Periodontol 1996;1:1–36.
Diagnosis and classification of diabetes mellitus. Dia- 9. Hugoson A, Sjodin B, Norderyd O. Trends over 30
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odontal disease. J Clin Periodontol 2008;35:405–14.
Chapple IL, Genco R, and working group 2 of the 10. Eke PI, Dye BA, Wei L, Thornton-Evans GO, Genco
joint EFP/AAP workshop. Diabetes and periodontal RJ. Prevalence of periodontitis in adults in the United
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12. National Certification Board for Diabetes Educa-
Lalla E, Kunzel C, Burkett S, Cheng B, Lamster IB. tors. Available at: http://www.ncbde.org/. Accessed
Identification of unrecognized diabetes and prediabetes August 6, 2013.
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Control and Prevention, National Center for Chronic betes mellitus. N Engl J Med 1993;329:977–86.
Disease Prevention and Health Promotion, 2007. 16. Turner RC, Cull CA, Frighi V, Holman RR.
Glycemic control with diet, sulfonylurea, metformin,
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CHAPTER 15
Dental and Medical Comanagement
of Cardiovascular Disease
Timothy C. Nichols, David W. Paquette
INTRODUCTION intervention by risk factor reduction.

Cardiovascular disease (CVD) accounts for 4. Understand commonly used medica-
29% of deaths worldwide, ranks as the tions for patients with CVD and their
leading cause of death, and is greatest in impact on the delivery of oral and
low-income and middle-income countries.1–3 dental care.
Atherosclerosis, a major component of
CVD, affects one in four persons and con- ATHEROSCLEROTIC
tributes to about 40% of deaths annually in CARDIOVASCULAR DISEASE
the United States.4 Between 2010 and 2030, Pathogenesis
the cost of medical care for heart disease (in Atherosclerosis has been defined as a pro-
2008 dollar values) is predicted to rise from gressive disease process that involves the
$273 billion to $818 billion (http://news- large- to medium-sized muscular and large
room.heart.org/news/1241). The pervasive- elastic arteries. Coronary atherosclerosis may
ness of CVD makes it a natural target for obstruct blood flow and result in ischemia to
prevention by all healthcare professionals. If the myocardium that is dependent on the
prevention programs could reduce the acute blood supply of the diseased artery. The
treatment costs and associated morbidity of lesions may also rupture, and the resulting
CVD by 20% per year, the savings would be thrombus may be clinically silent or cause a
at least $80 billion per year in healthcare fatal myocardial infarction (MI; i.e., heart
costs. By comparison, in 2010, the federal attack). About 40% of deaths in the United
government spent $62 billion on Part D, rep- States are attributed to complications of ath-
resenting 12% of total federal spending for erosclerosis; about half of these sequelae are
Medicare that year (https://www.cbo.gov/ represented by coronary atherosclerosis com-
sites/default/files/cbofiles/attachments/12-01- plicated by thrombosis and MI.6
MedicarePartD.pdf).5 This chapter reviews Atherosclerosis generally begins in child-
the known risk factors for CVD that are hood and manifests as a flat, fatty streak
current targets for disease prevention and usually detected only as an incidental finding
discusses a current and future rationale for at an autopsy performed for other reasons.7,8
oral, dental, and medical healthcare practi- The advanced, raised lesion is the atheroma,
tioners to work together to implement which consists of elevated focal intimal
optimal CVD risk factor reduction. plaques with a central core containing
The learning objectives for this chapter necrotic cells, cholesterol ester crystals, lipid-
are: laden foam cells, and plasma proteins includ-
1. Understand and define the pathogenesis ing fibrin and fibrinogen. This central core is
of coronary atherosclerosis and recog- also associated with a cellular infiltrate com-
nize its acute and chronic clinical pre- posed of hypertrophic smooth muscle cells,
sentations. macrophages, and sparse T lymphocytes.
2. Understand the scientific basis that One theory of atherogenesis is that the
identified risk factors for CVD. atherosclerotic plaque develops as a response
3. Understand the rationale that justifies to injury to the vascular endothelium and
that the endothelial injury is the primary Data from the Framingham Heart
event in atherogenesis. When the endothe- Study and from two other large prospective
lium is even minimally injured, platelets and cohort studies—the Chicago Heart Associa-
monocytes accumulate and attach to the tion Detection Project in Industry (N =
damaged wall. As platelets aggregate around 35,642) and the Multiple Risk Factor Inter-
the injury, they release thromboxane, pro- vention Trial (N = 347,978)—indicate that
moting further platelet aggregation and coro- most patients with fatal coronary artery ath-
nary vasoconstriction. Monocytes invade the erosclerosis or nonfatal MI present with at
intima and scavenge for lipids and other least one of four risk factors: cigarette
extracellular materials. These cells release smoking, diabetes mellitus, hyperlipidemia,
various growth factors that attract more and hypertension.12 With fatal MI due to
smooth muscle cells from the media of the coronary artery atherosclerosis, exposure to
artery with resultant intima hyperplasia. As at least one risk factor ranged from 87% to
the lesion progresses, fibrosis, lipid deposi- 100% for all three cohorts. For nonfatal MI
tion, necrosis, and calcification may ensue to in the Framingham Heart Study cohort,
yield the complicated plaque. Inflammation prior exposure to at least one risk factor was
and oxidative and mechanical stress by high found in 92% of men and 87% of women
blood pressure can induce primary injury of ages 40 to 59 years at baseline. Furthermore,
the arterial endothelium as well, by which another recent analysis involving 14 interna-
the pathogenesis of atherosclerosis can be tional randomized clinical trials (N =
initiated and propagated.9 122,458) showed that one of these four con-
ventional risk factors was present in 84.6%
Risk Factors of men and 80.6% of women with coronary
Traditional major risk factors for atheroscle- artery disease.13
rotic CVD include cigarette smoking, hyper- Recent attention has focused on ele-
tension (> 140/90 mm Hg), high levels of vated serum C-reactive protein (CRP) as a
low-density lipoprotein (LDL) cholesterol (> strong and independent risk factor or predic-
100 mg/dL), low levels of high-density tor of events due to coronary artery athero-
lipoprotein (HDL) cholesterol (< 40 mg/dL), sclerosis such as MI or sudden death.14 CRP
insulin resistance, diabetes mellitus, family is an acute-phase reactant produced prima-
history of premature coronary heart disease rily by the liver in response to infection or
(< age 45 years), age (men > 45 years, trauma. Other tissues may be involved in its
women > 55 years), obesity (body mass synthesis, including smooth muscle cells
index > 30 kg/m2), physical inactivity, and an from normal coronary arteries and diseased
atherogenic diet (Figure 1). It is also recog- coronary artery bypass grafts.15,16 CRP
nized that these factors can interact with appears to be directly involved in augment-
each other to increase risk of CVD.10 For ing the innate inflammatory response via
example, the Framingham Heart Study con- induction of prothrombotic factors (e.g.,
tained over 3,000 patients and showed that plasminogen activator inhibitor-1, proinflam-
for total cholesterol levels between 185 matory adhesion molecules, and monocyte
mg/dL and 335 mg/dL, cardiovascular risk chemoattractant protein-1) and interference
was elevated further with the addition of with endothelial nitric oxide synthase.17
each of the following risk factors: glucose In the Physicians’ Health Study, an epi-
intolerance, elevated systolic blood pressure, demiologic study of over 22,000 healthy
cigarette smoking, and left ventricular hyper- middle-aged men with no clinical evidence of
trophy on electrocardiography.11 disease, increasing levels of serum high-sensi-
CHAPTER 15 Dental and Medical Comanagement of Cardiovascular Disease 277
Figure 1. Cardiac Risk Factors for Coronary Atherosclerosis
Multiple risk factors are shown, many of which are known to increase risk in an additive fashion when present con-
currently. A cross-section of an artery is shown with a raised atherosclerotic plaque that obstructs a portion of the
lumen. From Netter’s Cardiology. Reproduced with permission.
tivity CRP at study entry were associated counterintuitive that death rates from CVD
with up to a threefold increase in the risk of overall have decreased by more than one
incident MI and a twofold increase in risk of third in the last two decades. The explana-
ischemic stroke.18 In the Women’s Health tions most often given for this apparent
Study (N = 28,263)19,20 of apparently healthy paradox include success of primary and sec-
participants, CRP proved to be the single ondary prevention strategies, improvements
strongest predictor of cardiovascular risk in patient care, and rehabilitation. These
when compared with other potential serum findings underscore the importance of recog-
biomarkers such as homocysteine, lipopro- nizing risk factors (see Figure 1) and opti-
tein(a), interleukin 6 (IL-6), intercellular mizing strategies for risk factor reduction
adhesion molecule 1 (ICAM–1), serum (Figure 2). These strategies constitute an
amyloid A, and standard lipid measures. opportunity for the medical and dental pro-
Accordingly, the relative risk ratio for the fessionals to work for a common goal of
highest versus lowest quartile of serum CRP continued improvement in cardiovascular
concentrations was 4.4 (95% CI: 1.7–11.3). health; nevertheless, there are formidable
Moreover, the addition of serum CRP to challenges to overcome to achieve this goal.
traditional cholesterol screening enhanced The first is to recognize that we are pro-
cardiovascular risk prediction and proved to viding encouragement for lifestyle changes
be independent of LDL cholesterol. The that patients may find very difficult, such as
poorest event-free survival in women was smoking cessation, weight reduction, dietary
among those with high LDL cholesterol and changes, regular exercise, and compliance
high CRP levels, and the best event-free sur- with prescribed medications for elevated cho-
vival was seen among those with low LDL lesterol, blood pressure, and diabetes mellitus.
cholesterol and low CRP levels. Notably, Although both dental and medical health-
persons with low LDL cholesterol levels but care providers can fairly encourage all of
high CRP levels were at higher risk than these, continued patient support over time is
those with high LDL cholesterol levels but essential. Second is to remember that athero-
low CRP levels. sclerosis may be present but not clinically
Recent data suggest that treatment with evident for years,23 underscoring the need for
HMG-CoA reductase inhibitors (statins) for sustained efforts at risk factor reduction even
asymptomatic individuals with elevated CRP in otherwise healthy persons.
levels but normal cholesterol levels reduces
risk for future cardiovascular events.14 These Clinical Presentation of
provocative findings have triggered consider- Cardiovascular Disease
able debate yet may fundamentally alter our Recognition of the symptoms of coronary
approach to primary prevention of coronary atherosclerosis is essential and not always
atherosclerosis. These data also reinforce straightforward. Three classic clinical presen-
applying the same logic for reducing sys- tations are possible. Angina pectoris or chest
temic inflammation by treating other dis- pain is usually retrosternal pressure, tight-
eases associated with systemic inflammation ness, heaviness, or discomfort that radiates to
such as periodontitis.21,22 the left arm, jaw, or back, and is often asso-
ciated with dyspnea, diaphoresis, nausea,
Prevention of Coronary Atherosclerosis by and a feeling of impending doom (Figure 3).
Risk Factor Modification Angina with exercise or exertion, large meals,
Because atherosclerosis continues to increase or emotional stress is usually predictable and
in prevalence in developed countries, it is relieved by rest, a pattern often called “stable
Figure 2. Non-Drug Therapy for Prevention of Coronary Atherosclerosis
Risk factors that can be addressed by all healthcare practitioners are shown. A standardized approach that provides
patient education about these risk factors and support for adhering to these lifestyle changes is the foundation of risk
factor reduction. Other risk factors are highly likely to be identified over time and this risk will be continually
updated. From Netter’s Cardiology. Reproduced with permission.
angina.” More ominous is chest pain at rest MEDICAL MANAGEMENT OF

or a sudden increase in frequency or ease of CORONARY ATHEROSCLEROSIS
onset of angina, a pattern often termed At present, 80 million Americans are
“unstable or accelerating angina.” thought to exhibit some form of CVD.2,3
Obtaining a history of angina requires Thus, many patients presenting to oral and
time and patience and the recognition that dental healthcare providers have coronary
there are several causes of chest pain. In addi- atherosclerosis and are receiving therapy. It is
tion, women and patients with diabetes melli- important, then, to understand the basic
tus may have a completely different pattern to classes of drugs that are used in patients
their angina or have anginal equivalents, such with heart disease, especially drugs that
as dyspnea alone or abdominal discomfort. A might have a direct impact on oral health or
high index of clinical suspicion in patients complicate oral and dental procedures.
with risk factors for coronary atherosclerosis
is of paramount importance for recognition Antiplatelet Therapy
of anginal equivalents. All patients with atherosclerosis should be
The second classic presentation of coro- on some form of antiplatelet therapy. The
nary atherosclerosis is MI or heart attack. minimal cost and relatively profound effec-
Patients experiencing an MI usually com- tiveness of aspirin makes it the treatment of
plain of prolonged (> 5 minutes) and sus- choice in all patients who can tolerate taking
tained chest pain not relieved by rest or this medication. Other currently available
nitroglycerin. Associated symptoms may also antiplatelet drugs are the thienopyridines:
be present, such as nausea and vomiting, ticlopidine, clopidogrel, prasugrel, and tica-
and palpitations signaling irregular heart grelor. Often, patients are on both aspirin
rhythms. Also alarming is the presence of and one of the thienopyridines; this is often
heart failure symptoms such as weakness referred to as “dual antiplatelet therapy” or
and dyspnea. The interval between treatment DAP. The rationale for DAP is to prevent
and long-term prognosis is directly propor- thrombosis on drug-eluting stents that have
tional; prompt recognition and early treat- been implanted inside one or more coronary
ment are associated with marked improve- arteries to open atherosclerotic obstructions.
ment in outcomes. Although the recommendations for
The third manifestation of coronary antiplatelet therapy are rapidly changing, it is
atherosclerosis is sudden cardiac death, in generally agreed that abrupt cessation of the
which the heart has an irregular rhythm that thienopyridines during the first year after
is unable to support blood pressure, usually placement of a drug-eluting stent can be
ventricular fibrillation. Tragically, coronary associated with acute thrombosis, resulting in
atherosclerosis first presents as sudden an otherwise preventable heart attack. The
cardiac death in approximately 25% of primary concern, however, for patients on
patients. The availability of personnel trained DAP is bleeding, especially with invasive or
to recognize and treat ventricular fibrillation surgical procedures. If the procedure requires
and administer cardiopulmonary resuscita- temporary cessation of either of these two
tion is the primary determinant of outcome. drugs, this should be done in consultation
Both community-based efforts and the pres- with the patient’s regular physician.24
ence of automatic external defibrillators
(AEDs) have been important factors in the New Oral Anticoagulant Therapy
improved survival rates for patients experi- The first new oral anticoagulants (NOACs)
encing sudden cardiac death. to be FDA-approved since the approval of
Figure 3. Angina Pectoris
Classic angina pectoris is retrosternal, radiates to the left arm or jaw, and feels like a heavy or constricting vise-like dis-
comfort. This illustration shows common precipitating factors. From Netter’s Cardiology. Reproduced with permission.
Coumadin (warfarin) over 35 years ago Angiotensin-Converting Enzyme and

include direct thrombin inhibitors (e.g., dabi- Angiotensin II Receptor Blockers
gatran) and factor Xa inhibitors (xabans: e.g., Patients with coronary atherosclerosis and
rivaroxaban). These drugs are approved for depressed heart function are generally
and being increasingly used therapeutically in encouraged to take angiotensin-converting
patients with deep venous thrombosis (dabi- enzyme (ACE) inhibitors. If they cannot tol-
gatran, rivaroxaban) and with atrial fibrilla- erate ACE inhibitors because of cough or
tion to prevent stroke (rivaroxaban). The other issues, they take angiotensin II receptor
challenge to all who deliver health care will be blockers (ARBs). Mortality rates have been
to maintain a current understanding of the shown repeatedly to be lower in post-MI
uses, potential for drug interactions, and side patients on ACE inhibitors. Both ACE
effects of these novel therapies. The practical inhibitors and ARBs are powerful antihyper-
issue is that bleeding is becoming an even tensive agents. For dental patients on stable
greater concern for patients on these drugs. doses, these drugs are not recognized to
As with the antiplatelet therapies, consultation interfere with oral procedures or dental care.
with the patient’s physician is paramount in
anticipating potential drug interactions if new Nitrates
drugs are being started and in planning for Both short-acting (less than 10 minutes) and
temporary interruption of oral anticoagulant long-acting (several hours) nitrates are fre-
therapy to achieve the balance between essen- quently used to relieve and prevent, respec-
tial hemostasis and undesired thrombosis.24,25 tively, myocardial ischemia. Nitrates may
also be used to treat heart failure, especially
Beta Blockade in African Americans, as well as hyperten-
As with aspirin, beta blockade is recom- sion. A nitrate-free interval is recommended
mended for all patients with CVD except on a daily basis to prevent tachyphylaxis. For
those with a contraindication, such as dental patients on stable doses, these drugs
untreated conduction disease in the heart are not recognized to interfere with oral pro-
with bradycardia, severe asthma, difficult to cedures or dental care.
control diabetes mellitus, and in some cases
severe atherosclerosis in arteries supplying Lipid-Lowering Therapy
the legs. In general, patients already receiving The current National Cholesterol Education
beta blockers should not experience any Program (NCEP) Guidelines recommend an
complications during dental procedures. In LDL-cholesterol level of less than 100 mg/dL
addition, cardiologists may recommend beta for patients with known CVD and a total
blockers for select patients with heart disease cholesterol of less than 200 mg/dL. Second-
undergoing general anesthesia for oral or ary causes of hyerlipidemia are diabetes mel-
dental procedures. The American Heart litus, liver disease, and renal failure. Regard-
Association provides guidelines for such situ- less of the cause, all patients who have values
ations.26 These issues are controversial, and higher than these levels should receive dietary
the guidelines are constantly being revised as counseling, suggestions for weight reduction,
new data become available. Updated guide- and encouragement to increase physical
lines are scheduled for publication in 2014. activity. The most common drugs used for
Consequently, considerable planning and dis- hyperlipidemia are HMG-CoA reductase
cussion between the cardiologist and the inhibitors or statins, which inhibit cholesterol
dentist would be required to start or stop synthesis. Pharmacologic intervention with
beta blocker therapy for a dental procedure. the statin class of drugs is used to further
reduce serum lipids and the likelihood of car- patients are likely to be taking medications
diovascular events even in those with average that can increase the likelihood of bleeding
LDL concentrations. Numerous clinical trials during dental procedures.
have consistently demonstrated that statin
drugs reduce cardiovascular events by at least CONCLUSIONS AND
25%.27 In contrast, the effect of statins and FUTURE DIRECTIONS
other lipid-lowering therapies on reducing the Dental and medical healthcare providers
size of atherosclerotic plaques is much need to work together closely to provide
smaller.28 This finding has been the basis for optimal care for their patients with estab-
seeking alternative explanations for why lished CVD. A basic understanding of the
statins improve outcomes so profoundly. For pathogenesis of CVD and commonly used
example, statins may have secondary anti- medications can provide a basis for prevent-
inflammatory effects. Indeed, CRP concen- ing complications during the delivery of
trations decrease 15%–50% with statin dental and oral health care in patients with
therapy.14 Thus, the pleotropic effects of these CVD.
drugs appear to improve outcomes and The role of the oral and dental health
markers of atherosclerotic CVD. Fibrates practitioner in prevention of heart disease has
reduce lipoprotein lipase activity, and nico- great potential. At present, he/she is uniquely
tinic acid reduces tissue lipase activity and poised to discuss risk factor reduction with
very-low density lipoprotein synthesis. Both patients, which is paramount for both oral
fibrates and nicotinic acid reduce triglyceride and cardiovascular health. Preventive interven-
levels effectively. A cholesterol absorption tions (primary or secondary) for coronary ath-
inhibitor (e.g., ezetimibe) and a bile acid erosclerosis focus on recognition and reduc-
reabsorption inhibitor (e.g., cholestyramine) tion of modifiable risk factors in patients (see
are often used in combination with other Figures 1 and 2). These approaches include
drugs to achieve target goals. Lipid-lowering blood pressure screening; weight reduction;
drugs should not have an impact on the exercise; smoking cessation; diet modification;
delivery of oral or dental care. medication compliance, especially with treat-
ments for blood pressure and diabetes; patient
LDL Apheresis counseling; and education. Initiating and
In rare cases, patients with familial hypercho- maintaining these lifestyle changes are not
lesterolemia do not respond to drug therapy easy tasks but are more likely to be adopted
and require apheresis. In this case, the by patients who receive consistent advice and
patient’s blood is perfused over a column encouragement from all of their healthcare
that binds and thereby reduces LDL levels. providers.
These patients develop coronary atheroscle- Currently, the future role of oral health
rosis by the second decade of life and should in atherosclerosis remains a consistent associ-
be carefully evaluated for all procedures. ation and not a causal risk factor.29 Human
trials that directly address the role of peri-
Coronary Angioplasty and Bypass Surgery odontitis and atherosclerosis have been
For patients with severe symptomatic coro- limited to the Periodontitis and Vascular
nary atherosclerosis, interventions involve Events (PAVE) study.30 This pilot study was
physically expanding stenotic vessels via designed to determine how many patients
angioplasty (with or without stenting) versus with combined symptomatic atherosclerosis
revascularization via coronary bypass and periodontitis would be needed to docu-
surgery. As previously discussed, these ment that successful treatment of periodonti-
tis reduces subsequent coronary and carotid MA, Stevenson LW, Yancy CW. 2009 focused update
events. The reader is also referred to Chapter incorporated into the ACC/AHA 2005 Guidelines for
the Diagnosis and Management of Heart Failure in
8 that has a discussion on what would be the Adults: a report of the American College of Cardiology
minimal criteria for definitively establishing Foundation/American Heart Association Task Force on
that periodontitis is a risk factor for heart Practice Guidelines: developed in collaboration with the
attacks and strokes. If periodontitis is proved International Society for Heart and Lung Transplanta-
to be a casual risk factor for CVD, cardiolo- tion. Circulation 2009;119:e391–479.
gists and oral and dental health practitioners Armstrong MJ, Gronseth G, Anderson DC, Biller J,
need to work even more closely to provide Cucchiara B, Dafer R, Goldstein LB, Schneck M,
optimal care of their patients. Messe SR. Summary of evidence-based guideline:
periprocedural management of antithrombotic medica-
Supplemental Readings tions in patients with ischemic cerebrovascular disease:
report of the Guideline Development Subcommittee of
Tricoci P, Allen JM, Kramer JM, Califf RM, Smith SC the American Academy of Neurology. Neurology
Jr. Scientific evidence underlying the ACC/AHA clinical 2013;80:2065–9. [PMID:23713086]
practice guidelines. JAMA 2009;301:831–41.
Runge MS, Stouffer G, Patterson C, eds. Netter’s Cardi-
Fleisher LA, Beckman JA, Brown KA, Calkins H, ology, 2nd ed. (Netter Clinical Sciences). Saunders,
Chaikof E, Fleischmann KE, Freeman WK, Froehlich Elsevier, 2010.
JB, Kasper EK, Kersten JR, Riegel B, Robb JF, Smith
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CHAPTER 16
of Pregnancy
Néstor J. López, Ricardo A. Gómez
INTRODUCTION 3. Enumerate the most common risk

Pregnancy involves complex physiologic, physi- factors for pregnancy complications.
cal, and psychological changes mediated by 4. Explain the considerations that have to
female sex hormones that have a profound be applied to provide dental treatment
impact even on healthy women. Physiologic to women with normal pregnancy.
changes during pregnancy can exacerbate 5. List strategies for the prevention of
already existing oral pathologic conditions, medical and dental complications in
such as gingivitis, periodontitis, and caries pregnant women.
lesions. Moreover, oral infections during preg- 6. Describe the initiatives that can be
nancy may be associated with adverse preg- taken by dentists and obstetricians in
nancy outcomes. Prenatal care is an essential comanaging patients with oral diseases
part of a successful pregnancy, and oral health and who are at risk for adverse preg-
assessment must be part of prenatal care. nancy outcomes.
Changes produced by pregnancy present a
number of unique management problems in PHYSIOLOGIC CHANGES IN
dental treatment. The best approach to avoid PREGNANCY AND THEIR RELATION
pregnancy complications and adverse preg- TO ORAL HEALTH
nancy outcomes is to apply preventive strate- Pregnancy is characterized by dramatic
gies. The most important objective in planning endocrine changes. Placental tissues produce a
dental care for the pregnant woman is estab- significant increase in progesterone and estrogen
lishing a healthy oral environment free of concentrations, which in turn influence physio-
inflammation and infection. logic changes in systemic and oral tissues. The
This chapter reviews the physiologic most important physiologic changes associated
changes that occur during normal gestation with pregnancy that have dental relevance are
and discusses the management of dental treat- addressed in the following text.
ment in women with normal pregnancy, as
well as women at risk for adverse pregnancy Gingival Hyperplasia and Edema
outcomes. The gingival vasculature appears to be sensi-
tive to sex steroid hormones. Vasodilation,
Educational Objectives increased vascular permeability, and cell pro-
By the end of this chapter, the reader should liferation by pregnancy hormones result in
be able to the swelling of gingival and descamation
1. Recognize the most important physio- cells, and a significant increase of gingival
logic, physical, and psychological crevicular fluid.1,2
changes mediated by female sex hor- Changes described in the microcircula-
mones that have an impact on healthy tion of pregnant women include swelling of
pregnant women. endothelial cells, adherence of granulocytes
2. Identify the effects that pregnancy’s to vessel walls, generation of microthrombi,
physiologic changes may have on oral disruption of perivascular mast cells, and
health. vascular proliferation.1,2 All the changes in
gingival tissues during pregnancy are associ- managing nausea and vomiting in the dental
ated with an exacerbated clinical inflamma- setting are provided in Pregnancy Complica-
tory response. However, the level of inflam- tions, found later in the chapter.
mation is not associated with an increase in
progesterone or estradiol levels in saliva or Cardiovascular Changes and Establishment of
with changes in PGE2 or IL-1beta levels in Uteroplacental Circulation
gingival crevicular fluid.3 Immune adapta- As the placenta and fetus develop, flow
tions that occur during pregnancy may through the uterine and placental arteries
further facilitate infections of oral tissues. increases notably. Changes in the microcircu-
For example, gingival fibroblasts exposed to lation and within the intervillous space (mim-
progesterone downregulate the production of icking an arteriovenous shunt) decrease arte-
interleukin 6 and a variety of matrix metal- rial resistance. Elevations in blood volume
loproteinases, making the gingiva more sus- (especially at the expense of maternal
ceptible to inflammatory challenges elicited plasma) and heart rate compensate for the
by bacteria.4,5 changes in vascular resistance. As a conse-
quence, cardiac output increases by 30% to
Upper Gastrointestinal Changes 40% throughout pregnancy. Maternal blood
Beginning in the first trimester, endocrine pressure tends to lower during the first and
changes induce a reduction in smooth muscle second trimester, reaching baseline levels
tissue tone and frequency of contractions. early in the third trimester. The growing
This affects gastric emptying and the function- uterus may compress the interior vena cava,
ality of the gastroesophageal sphincter, facili- impairing the venous return to the heart and
tating reflux of stomach content toward the therefore the stroke volume. Compensatory
esophagus and mouth. Psychological changes mechanisms are set in action, leading to
appear early in pregnancy and contribute to symptoms such as palpitations (due to tachy-
the nausea and vomiting syndrome called cardia), nausea, hypotension, and dizziness.
morning sickness. A small percentage (1% to This chain of events is frequently observed
3%) of these patients progress to hyperemesis during the second half of pregnancy when
gravidarum, which is associated with weight pregnant women are in the supine position.
loss, electrolyte imbalance, dehydration, and Dentists may reduce the likelihood of this
eventually ketonemia. Persistence of these supine hypotensive syndrome by elevating the
symptoms despite treatment obligates one to right hip of the patient with a pillow or
rule out other disorders, such as pancreatitis, folded sheet, or rolling the patient to the left
cholecystitis, hepatitis, psychiatric illness, and to alleviate vena cava obstruction.
hyperthyroidism.
Salivary changes during pregnancy Respiratory Changes
include an increase in volume that depends on The most important physiologic adaptations
oral-esophageal content delay rather than sali- at the respiratory level are derived from the
vary flow rate. Rarely, patients lose more than pressure that the pregnant uterus imposes on
1 liter of saliva per day, a disorder known as the abdominal side of the diaphragm, reduc-
ptyalism. Additional changes are a decreased ing the height and increasing the transverse
salivary pH and elevations of protein and diameter of the thorax. A progesterone-
estrogen concentrations. Estrogens act locally driven hyperventilation compensates for the
by increasing the proliferation and desquama- decreased residual capacity of the lungs.
tion of the oral mucosa, setting the conditions Dyspnea is not an uncommon sign during
for bacterial growth. Recommendations for the third trimester, especially in patients with
CHAPTER 16 Dental and Medical Comanagement of Pregnancy 289
twin gestation, large fetuses, or polihydram- DENTAL MANAGEMENT OF WOMEN

nios. As previously stated, avoiding the WITH NORMAL PREGNANCY
supine position is central to the management Dental care during pregnancy is less
of these patients. common than expected. Data from surveys
indicate that 30% to 50% of women do not
Hematologic Changes receive dental care during pregnancy.6,7
Red blood cells, leukocytes, and most coagu- Indeed, only about 10% of dentists provide
lation factors are increased during pregnancy. complete treatment for conditions considered
Plasma volume increases above that of red necessary during the gestation period, delay-
blood cells, leading to the condition known as ing most of them for the postpartum
physiologic anemia of pregnancy. Because of period.8 Pregnant women are also less likely
this hematologic adaptation, pregnant women to request dental treatment even in the
are diagnosed with anemia only when the context of free health services, such as those
hematocrit falls below 33%. On the other provided through the National Health
hand, leukocytosis during pregnancy is estab- Service in the United Kingdom.9 Moreover,
lished when the white blood cell count is only about 25% of patients are referred for a
above 15,000 cells/mm3. This is important to dental examination by healthcare providers
know when evaluating laboratory tests in the during pregnancy.9 Collectively, these data
setting of oral infections. Clotting factor pro- indicate that both health professionals and
duction by the liver is stimulated by gesta- patients tend to postpone dental treatments
tional hormones, leading to a hypercoagula- until after delivery.
ble state, which predisposes to thromboem-
bolism. Several disorders (e.g., antiphospho- Attitudes of Dentists, Physicians, and Patients
lipid syndrome) aggravate this condition and Toward Dental Treatment During Pregnancy
may require the use of aspirin or heparin. The reluctance of dental practitioners to
Such patients should receive close treatment provide dental care to pregnant women10
surveillance to determine whether dental pro- may explain, among other reasons, the low
cedures may be performed without the risk of percentage of women who receive dental
excessive bleeding. care during pregnancy. Lydon-Rochelle and
colleagues11 found that 58% of pregnant
Endocrine Changes women in Seattle, Washington, received no
Most of the physiologic adaptations previ- dental treatment during pregnancy. Only
ously described here are the result of 22% to 34% of women in the United States
primary endocrine changes during preg- consult a dentist during pregnancy. Even
nancy. Moreover, elevated levels of estrogens, when an oral problem occurs, only 50% of
progesterone, cortisol, and placental lactogen pregnant women attend to it.6
mobilize the patient’s metabolic resources to A common concern of dental practi-
secure fetal nutrition. As a result, a diabeto- tioners is the timing for necessary proce-
genic state develops, especially during the dures. The evaluation and management of
second half of pregnancy in which insulin pregnant women may require special consid-
resistance increases, eventually leading to ges- eration, but pregnancy does not preclude
tational diabetes in 4% to 10% of patients. them from necessary dental care. There is no
The resulting hyperglycemia state in women evidence that dental or periodontal treat-
with poorly controlled diabetes provides a ment is damaging to the pregnant woman or
suitable environment for the development of her developing fetus. However, the American
dental infections. Dental Association suggests that elective
dental care should be avoided, if possible, Safety of Dental Diagnostic and Therapeutic
during the first trimester and the last half of Procedures During Pregnancy
the third trimester.12 The recommendation Dental treatments are preferably performed
for not doing procedures during the first during the second trimester. Emergency
trimester is because the developing fetus is at dental procedures can be performed at any
greatest risk of teratogenicity during the gestational age. During the first and second
embryologic development (between the 2nd trimester, no specific positional requirement
and 8th weeks) after conception and because needs to be satisfied. On the contrary,
the highest rate of spontaneous abortion patients with a large uterus (such as those in
occurs during the first trimester. Thus, there the third trimester or those with twin gesta-
is concern that the patient may perceive that tion or polihydramnios) are at risk for supine
the cause of an eventual birth defect or hypotension due to vena cava compression.
spontaneous abortion is the dental proce- Therefore, propping patients on their left side
dure performed during that period. The last and frequent repositioning are necessary
weeks of the third trimester are associated during the dental procedure.
with greater discomfort and risk of supine A general principle used for all drugs
hypotension syndrome, because of the large and diagnostic tests during pregnancy is that
uterus and its content. the period before 12 weeks’ gestation is con-
Concern about the maternal and fetal sidered vulnerable for the embryo organogen-
effects of pharmacologic agents commonly esis. Specific drugs and tests may be adminis-
used in dentistry is another reason that may tered during the first trimester only when the
explain attitudes of dentists and women potential benefit surpasses the risks.
toward dental treatment during pregnancy.
However, most drugs used during dental Radiography
treatment are safe and listed likewise by the Dental radiographs can be undertaken safely
Food and Drug Administration (FDA) because they are associated with minimal
(Table 1). The recommendation is based fetal exposure to ionizing effects. The exami-
more on fear of litigation than on evidence nation should be performed with the patient
of harm. It is therefore remarkable that no using a lead apron and thyroid shield. The
evidence has emerged linking dental treat- limited x-ray exposure needed for dental diag-
ments and adverse pregnancy outcomes. On nosis poses no risk of congenital malforma-
the contrary, there is a growing body of evi- tions of the fetus.17,18 A study of a cohort of
dence, though controversial, that treatment 7,374 mothers did not find a significant asso-
of periodontal infections may reduce the rate ciation between the use of x-ray scans and
of certain pregnancy complications.13–15 low birth weight or preterm delivery.19
Another factor that prevents dentists
from performing treatment in pregnant Pharmacologic Agents
women is the belief that dental procedures Drugs used in dental treatment are fairly
may initiate an inflammatory cascade safe during pregnancy (see Table 1). Local
leading to uterine response, preterm labor, anesthetics such as lidocaine and prilocaine
and fetal loss. Although transient bacteremia are considered safe by the FDA (category
is recognized as part of the pathophysiology B). When possible, coadjuvant epinephrine
following dental invasive procedures, the spe- should be avoided, because it may impair
cific association between these procedures uterine blood flow through the placenta.
and pregnancy complications has not been Epinephrine is contraindicated in patients
demonstrated.14–16 with preeclampsia and chronic hypertension.
CHAPTER 16 Dental and Medical Comanagement
! ! ! of Pregnancy
! ! ! ! 291
Table !1. 6Drugs Frequently Used by the Dental Professional During Pregnancy
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!
Acetaminophen is !appropriate to ! treat ! !!
nature). Nitrous oxide! is a! sedative-analgesic
! !
patients with! ! dental ! pain! at any ! ! gestational
! ! and short-term
gas, ! ! use! is! considered
! ! safe
! ! B), as! well! as! ibuprofen
age (category ! ! in the during the ! !second and ! ! third
! trimesters !of
! and
first ! second ! ! trimesters ! (category ! B). The ! It ! is contraindicated
gestation. ! ! in patients
!
! drug
latter ! !
should ! be avoided ! ! during! the ! ! obstructive! pulmonary disease
with chronic !
! trimester
third ! owing! !to !known ! effects !on and drug-related dependencies.
both! fetal! ductus ! arteriosus ! and! renal ! func-
tion.! For severe
! ! pain, narcotics ! ! such
! ! as !oxy- Antibiotics ! ! ! ! !
codone! ! may! be ! ! used for ! a! limited ! !time Antibiotics ! used! for! oral
! infections
! ! are !gener-
! the first
during ! and second ! ! ! Avoid-
trimesters. ! !
ally safe for mother ! fetus.
and ! Penicillin ! family !
!
ing these !
drugs !during ! !
both the third! ! are frequently
agents ! ! ! used as ! coadjuvants
! in
trimester! and! women with ! impending ! deliv- !
the treatment of! periodontal! disease, ! dental
ery prevents breathing/withdrawal ! ! !
complica- ! ! ! Cephalosporins
abscesses, and cellulitis. ! ! fit!into
tions in the ! ! newborn.
! ! If a dental ! procedure ! the !same! category.
! ! Except for patients ! !!with!
! ! sedation,
requires ! a! safe
! choice is premedica- ! ! !
hypersensitivity, ! ! antimicrobial
both ! ! agents ! ! are
tion with an !antihistaminic ! ! such ! as doxy- ! !as safe
classified ! by the FDA! (category! B).
!
lamine !
(category ! ! B),! which also ! has! an Erythromycin!(with !the! exception !of ! the! esto-
antiemetic effect. ! ! !
Benzodiazepines ! should be late! form,! which! may! produce! cholestatic! hep-
!
avoided throughout ! ! pregnancy ! unless !a spe- ! clindamycin
atitis), and ! !
(category B) are! alter-
!
! !
cific indication !
arises (mostly of! a psychiatric! !natives for penicillin-allergic
! ! patients.! Metron-
idazole, an alternative for clindamycin in ampicillin or amoxicillin do not cover ente-

severe infections, may be administered as well rococcus. If enterococcus involvement is sus-
during the second and third trimester (cate- pected, vancomycin 1 g intravenously over 1
gory B). Tetracyclines are contraindicated hour is the choice. Table 2 summarizes the
during pregnancy. principles guiding dental treatment during
Antibiotic prophylaxis for infective pregnancy.21
endocarditis should be administered only to
women with cardiac conditions associated Table 2. Principles Guiding Dental
with a major risk for developing endocardi- Treatment During Pregnancy
tis. A recent committee opinion from the
1. Women should be advised to seek oral health care
American College of Obstetrics and Gyne-
prior to becoming pregnant and throughout gestation.
cology provided up-to-date indications for
2. Oral health care is safe and effective during pregnancy.
pregnant women with cardiac conditions
who require certain dental procedures.20 3. First trimester diagnosis (including necessary dental
x-rays with adequate shielding) is safe.
• Prosthetic cardiac valve or prosthetic
material used for cardiac valve repair 4. Acute infection, abscess, and conditions predisposing
to bacteremia and sepsis require prompt intervention
• Previous infective endocarditis regardless of the stage of pregnancy.
• Specific congenital heart diseases:
5. Necessary treatment can be provided throughout
Unrepaired dyanotic cardiac disease pregnancy. However, the period between the 12th
(including palliative shunts and con- and 22nd weeks represents the best time to provide
ducts), completely repaired cardiac oral services, especially scaling and root planing.
anomalies with prosthetic material or 6. Elective treatment for conditions considered not
progressive may be deferred until after delivery.
device (whether placed by surgery or
catheter intervention) during the first 6 7. Delay in necessary treatment could result in signif-
icant risk to the mother and the fetus.
months after procedure, and repaired
cardiac disease with residual defects at
the site or adjacent to the site of a Treatment of Specific Dental Conditions
prosthetic patch or prosthetic device During Pregnancy
(which inhibit endothelialization) During pregnancy, dental or periodontal care
Dental procedures eligible for prophy- may be modified according to the individual
laxis involve manipulation of the gingival characteristics of each patient and the condi-
tissue or periapical region of the teeth. No tions of the pregnancy, but there is no need to
prophylaxis is required in cases of general withhold treatment for any oral infectious
dental cleaning, cavity filling, taking of radi- condition. Extensive dental treatments, such
ographs, adjusting orthodontic appliances, or as crown placement and reconstructive proce-
injection of anesthetic into noninfected dures that need long appointments, should
tissue. Appropriate antibiotics for infective not be performed during pregnancy.
endocarditis prophylaxis should be adminis- The most important objective in plan-
tered 30 to 60 minutes before the dental pro- ning dental care for the pregnant woman is
cedure and include the following: establishing previous to pregnancy, or early
• Ampicillin 2 g intravenously during pregnancy, a healthy oral environ-
• Cefazolin or ceftriaxone 1 g intravenously ment, free of inflammation and infection.
• Amoxicillin 2 g oral There is evidence that oral health influ-
In patients allergic to penicillin, clin- ences systemic health and well-being.22
damycin 600 mg intravenously may be used. Maternal oral health has important implica-
It should be noted that drugs other than tions for birth outcomes and infant oral
health. The most prevalent oral diseases— oral flora, thus improving women’s oral
dental caries and periodontal disease—influ- health and reducing bacterial transmission to
ence maternal health status and may increase their children.33
the risk of other diseases. Periodontal disease
may increase the risk of atherosclerosis,23 dia- Pregnancy-Associated Gingivitis
betes,24 rheumatoid arthritis,25 and adverse Plaque-induced gingivitis is an inflammation
pregnancy outcomes.26 of the gingiva resulting from bacterial infec-
Maternal dental caries can also increase tion, and it is one of the most common oral
the risk of early development of caries in diseases in pregnant women.34,35 Pregnant
children.27 Dental caries and periodontal women have more gingivitis than nonpregnant
disease are both preventable conditions. women, with a prevalence ranging from 30%
However, these conditions are highly preva- to 75%.12,36 During pregnancy, the severity of
lent in women of childbearing age, especially gingivitis has been reported to be elevated, yet
among low socioeconomic level populations. unrelated to the amount of dental plaque
Both caries and periodontal disease are present.37,38 Approximately one of two women
chronic diseases with few or no symptoms, with preexisting gingivitis has significant exac-
making it difficult for the patient to be aware erbation during pregnancy.39 Gingivitis is
of the disease. The characteristics of both usually more evident during the second month
diseases, in addition to their high prevalence of pregnancy and reaches a maximal level
and insufficient treatment rates, induced the during the eighth month. The severity of gin-
US Surgeon General to characterize dental givitis is correlated with sex steroid hormone
and oral diseases as a “silent epidemic.”28 levels during pregnancy.38 The characteristics of
pregnancy-associated gingivitis are similar to
Dental Caries and Pregnancy plaque-induced gingivitis, but with a tendency
One-fourth of women of reproductive age in to more severe inflammation.37,38
the United States have dental caries,29 and The factors associated with higher gingi-
the prevalence of dental caries may reach val inflammation in pregnancy are increased
76% in young women of low socioeconomic levels of estrogen and progesterone,40 and a
status in developing countries.30 No definite decreased immune response.41 Aggravation of
data exist to indicate whether the incidence gingival inflammatory symptoms during preg-
of dental caries increases during pregnancy. nancy is also associated with low concentra-
Since dental caries usually takes more than tions of plasminogen activator inhibitor type-2
the 40 weeks of pregnancy to develop, it is (PAI-2) in gingival fluid. PAI-2, produced by
difficult to determine the pregnancy-related macrophages, is an important inhibitor of
incidence of caries. The main bacteria that tissue proteolysis and has multiple other func-
produce caries are Streptococcus mutans, tions. Women showing a low inflammatory
which is usually acquired by young children response to plaque have high concentrations of
from their mothers through direct salivary PAI-2, which probably protects connective
contact.31 Since maternal oral flora are the tissue from excessive breakdown.42
strongest predictor of infant oral flora,32 Changes in subgingival flora may occur
maternal health status is critical to children’s during pregnancy. Early evidence from cultiva-
oral health. Maternal dental educational and tion-based approaches indicated that hormonal
behavioral interventions such as use of fluo- surges during pregnancy may play a role in
rides, control of cariogenic diet, chlorhexi- increasing subgingival levels of black-pig-
dine mouthwashes, and varnishes can mented Bacteroides.43 However, more recent
decrease caries activity and the associated investigations using molecular methods did not
corroborate these findings.44 It is possible that isolated from amniotic fluid cultures obtained
the increased gingival inflammation in preg- from pregnant women with premature labor
nant women had a greater contribution in and intact placental membranes.49
altering the composition of the subgingival A study in pregnant mice showed that
microbiome than female sex steroids.44 F. nucleatum can cross the placenta and
Pregnancy epulis or pregnancy tumor is a spread to the amniotic fluid, producing pre-
pyogenic granuloma that appears in no more mature delivery and stillbirths.50 The associa-
than 5% of pregnant women. It is a peduncu- tion between pregnancy-associated gingivitis
lated, soft, erythematous lesion that grows with preterm birth was explored in a ran-
from an interdental papilla and is associated domized controlled trial.51 Women with gin-
with inflammation resulting from dental givitis who received periodontal therapy
plaque and calculus accumulation. The lesion before 28 weeks of gestation had a signifi-
usually arises during the second trimester, cantly lower incidence of preterm low birth
shows rapid growth, bleeds easily, and tends to weight than women who did not receive
diminish after pregnancy. The lesion can be periodontal therapy.
removed under local anesthesia and sometimes
carries a risk of excessive hemorrhage because Periodontitis and Pregnancy
of its high vascularity. Periodontitis, the destructive form of peri-
There is some basis to support the odontal disease, affects 15% of women of
hypothesis that gingivitis may be a potential childbearing-age in developed countries52 and
risk factor for the occurrence of preterm birth. 45% of women in undeveloped countries.53
One of the hypotheses that explains the associ- In the United States, up to 40% of pregnant
ation between periodontal disease and preterm women of low socioeconomic status have
birth is that periodontal infection is a source of some form of periodontal infection.54 In
bacteria and bacterial products that may some developing countries, such as Chile,
spread from the infected periodontium to the 76% of pregnant women of low socioeco-
systemic circulation and, eventually, to the nomic status have some form of periodontal
amniotic cavity. This is similar to transient disease (López NJ, unpublished data).
bacteremia occurring in patients with peri- Several studies have shown that mater-
odontitis.45 Bacteremia commonly occurs in nal periodontal infection is associated with
patients with gingivitis,46 and bacteria or their adverse pregnancy outcomes, such as
products may conceivably reach the placental preterm birth,26,55 preeclampsia,56 gestational
tissues, providing an inflammatory setting for diabetes,57 delivery of a small-for-gestational-
the onset of labor47 (Figure 1). There is evi- age infant,58 and fetal loss.59 A more com-
dence that some periodontal pathogens can plete critical review of the studies showing
cross the placental barrier and produce infec- association between oral infections and
tion in the fetal membranes. The prevalence of adverse pregnancy outcomes is presented in
P. intermedia has been found to be signifi- Chapter 9 of this book.
cantly higher in preterm than in full-term
neonates. The fetal antibody seropositivity for Preconception Oral Health
P. intermedia, as indexed by cord blood The American Academy of Periodontology
immunoglobulin M, suggests in utero expo- released the recommendation that “all women
sure of the fetus to this bacterium or its prod- who are pregnant or planning a pregnancy
ucts.45 Fusobacterium nucleatum is one of the should undergo periodontal examination, and
most commonly recovered microorganisms appropriate preventive or therapeutic services,
from sites with gingivitis,48 and is frequently if indicated, should be provided.”60 No defini-
CHAPTER 16 Dental and Medical Comanagement
! ! ! of Pregnancy
! ! ! ! 295
Figure !1. Proposed !Mechanisms! Involved! in! Preterm

! Birth
! Syndrome, Including
Periodontal
! Disease! !
tive evidence ! exists !that !the association ! ! ! ! ! !

outcome is! preconception
! ! !
preventive! oral
! ! ! ! ! ! ! ! ! ! ! ! ! ! !
between periodontal infection and adverse health care to ensure a healthy oral environ-
pregnancy outcomes is causal or is a surro- ment throughout pregnancy.
gate for! another maternal ! ! ! However,
factor. ! ! ! Patient ! education! about the ! effects
! of
! ! !
the strong evidence of an association between ! ! ! ! ! !
oral health on systemic health and preg-! ! !
! ! ! !
periodontal disease and systemic health ! ! ! !
nancy ! outcomes
! !
should be ! given ! before
! ! !
means that oral health care should be the aim ! ! ! ! !
pregnancy or early in pregnancy. The dentist !
of every ! person.
! ! This is especially
! ! important
! ! ! ! ! !
should inform the pregnant woman of the ! !
! ! ! ! !
for pregnant women, since no evidence sup- ! oral !changes she! may expect during preg-
! ! ! ! ! ! ! ! ! ! ! !
ports the concept that maternal oral health nancy and should discuss how to prevent
! ! ! ! ! ! ! ! ! ! ! !
influences pregnancy outcome. The obvious dental problems that may arise from these
and best cost-benefit strategy to reduce the changes. Pregnancy is a good time to obtain
effect of periodontal infections on pregnancy modifications in lifestyle behaviors because
women are more motivated to make healthy experience uterine bleeding during the first 5
changes during this time. months of gestation. This condition is
Although no oral diseases are directly known as threatened abortion and leads to
attributable to pregnancy, the physiologic spontaneous abortion in 10% to 20% of
and behavioral changes that occur during cases, with 80% to 90% of women continu-
pregnancy can aggravate preconceptional ing with their pregnancies uneventfully. A
existing gingivitis35 or periodontitis.61 Oral definitive prognostic factor is the presence of
hygiene instructions to control dental plaque a normal embryo/fetal ultrasound examina-
must be emphasized in pregnant women, tion.63 Dental treatments may be preferably
and treatment of gingivitis and periodontitis performed after bleeding stops, which
should be performed if needed. usually takes a few days after diagnosis.
PREGNANCY COMPLICATIONS Preterm Labor and Preterm Premature

Nausea and Vomiting Rupture of Membranes
Pregnant patients may experience varying Preterm delivery occurs in 3% to 12% of
degrees of nausea and vomiting, especially patients worldwide.64 Preterm labor and
during the first 3 months of gestation preterm premature rupture of membranes are
(morning sickness). Changes in the gingival the predecessors of preterm delivery in two
tissue elicited by the hormonal profile of ges- thirds of cases, accounting for most perinatal
tation, as well as a decreased use of oral mortality due to neonatal complications asso-
hygiene due to nausea, predispose patients to ciated with prematurity. Both conditions have
gingival inflammation. Therefore, dental been linked to a heterogeneous group of eti-
treatment is warranted for a percentage of ologies (the preterm delivery syndrome; see
these patients. Morning appointments Figure 1), including periodontal disease.
should be avoided. When needed, premed- Intrauterine infection is associated with both
ication with antihistaminic agents provides conditions, especially preterm premature
significant relief of symptoms along with a rupture of membranes.65–68
sedative effect that is desirable when per- Preterm labor is a disorder character-
forming dental procedures. Doxylamine 25 ized by regular uterine contractions and cer-
mg orally is an approved choice for patients vical changes occurring between 22 and 37
with nausea and vomiting during gestation, weeks of gestation. Of all patients diagnosed
including the first trimester.62 with preterm labor, only 50% actually deliver
Frequent vomiting may cause an acidic before 37 weeks. The clinical identification of
mouth environment, leading to growth of this group is difficult at the time of admis-
dental caries pathogens as well as acid dem- sion to the hospital.69 The most important
ineralization of the tooth enamel. Pregnant therapeutic measure is the administration of
women should be advised to mouth rinse intramuscular corticosteroids to reduce the
using a teaspoon of sodium bicarbonate in a risk of neonatal complications attributable to
cup of water after vomiting to counteract prematurity. Drugs aimed at reducing uterine
the demineralizing effect of stomach acid on contractions (tocolytics, such as nifedipine,
the teeth. A fluoride-containing mouth rinse betamimetics, atosiban) are also used to
carried out immediately before bedtime helps delay delivery for at least 48 hours. Antibi-
to remineralize teeth. otics are not used routinely in patients with
preterm labor.70
Threatened Abortion Preterm premature rupture of mem-
Approximately 10% of pregnant women branes is defined by the bursting of the
chorioamniotic membrane containing the tion, and newborn complications derived

fetus and the amniotic fluid, occurring from medically indicated premature delivery.
before labor begins, before 37 weeks of ges- Progression of the disease is interrupted
tation. Clinical presentation includes fluid only by delivering the fetus and placenta.
leaking from the vagina followed by uterine However, a significant percentage of patients
activity in the majority of patients. Manage- with preeclampsia are suitable to expectant
ment includes administration of both corti- management to advance in gestational age
costeroids and antibiotics to reduce the risk and decrease the risk of neonatal complica-
of neonatal complications, delay delivery, tions derived from early delivery.73 Drugs
and decrease the likelihood of maternal and commonly used for women with preeclamp-
neonatal infections. Antibiotics frequently sia are hypotensors such as labetalol, methyl-
used are ampicillin, erythromycin, clin- dopa, and hydralazine. Magnesium sulfate is
damycin, and metronidazole.71,72 Delivery is used in the prophylaxis and treatment of
indicated when the pregnancy has reached seizures, especially around labor and delivery.
32 to 34 weeks. Tocolytics are not routinely Patients at risk for preeclampsia may receive
used in patients with preterm premature aspirin starting in the second trimester of
rupture of membranes. pregnancy in an attempt to reduce the likeli-
For the two conditions described in the hood of developing the disorder.
previous text, essential dental procedures Emergency dental treatment should be
may be performed after the patient is admit- performed only after the preeclampsia
ted to the hospital or clinic, when treatment patient is stabilized and goals regarding
is established, and when uterine quiescence is blood pressure and neurologic status are
obtained. Elective treatment may be post- reached. The dentist should be aware that
poned until after delivery. patients with preeclampsia suffer from a
fragile neurologic condition. Informing ade-
Preeclampsia/Eclampsia quately about the procedure and premedica-
The development of both hypertension and tion with a sedative agent are to be consid-
significant amounts of protein in urine ered. Epinephrine is contraindicated; thus
occurring during the second half of preg- anesthetic drugs with vasoconstrictors must
nancy and puerperium is referred to as be avoided. If the patient is under aspirin
preeclampsia. The progression to seizures or prophylaxis, increased bleeding time is
coma characterizes eclampsia. The disorder expected. Elective procedures should be
is multisystemic and affects 3% to 7% of deferred after delivery until complete resolu-
pregnancies. The etiology of preeclampsia is tion of the disorder.
heterogeneous, but a common terminal
pathway characterized by endothelial dys- Fetal Growth Restriction
function is the key pathophysiologic land- Fetal growth restriction is a common diag-
mark of the disease.73 Patients with nosis during the second half of pregnancy.
preeclampsia have an increased risk for Diagnosis is made by ultrasound fetal biom-
maternal and perinatal mortality. Maternal etry when the estimated fetal weight falls
complications include persistent hypertensive below the 10th percentile for a specific gesta-
crisis, cerebral hemorrhage, liver/hematologic tional age. The disorder is associated with
dysfunction, and premature placental separa- increased perinatal morbidity and mortality,
tion (abruptio placentae). Fetal/neonatal although most fetuses diagnosed with the
complications are placental insufficiency condition are constitutionally small but oth-
(chronic fetal hypoxia), fetal growth retarda- erwise healthy.74 This distinction is usually
made by ultrasound velocimetry of placental DENTAL MANAGEMENT OF

vessels and a detailed examination of fetal WOMEN AT RISK FOR ADVERSE
anatomy. The mother is generally not PREGNANCY OUTCOMES
affected, unless she has evidence of maternal Risk Factors for Preterm Birth
disease predisposing to poor fetal growth Preterm birth is the most relevant adverse
(e.g., hypertension, diabetes, renal disease). A outcome for pregnant patients requiring
significant percentage of fetuses reach 37 dental treatment. Preterm birth should be
weeks of pregnancy under periodic ultra- thought of as a syndrome caused by multi-
sound surveillance. Recent investigations ple mechanisms, including infection, inflam-
have proposed that fetal growth restriction is mation, uteroplacental ischemia, choriode-
associated with adult disease (diabetes, cidual hemorrhage, uterine overdistention,
hypertension, and coronary heart disease).75 and stress (see Figure 1). A growing number
There are no specific medications for the of risk factors associated with these condi-
treatment of fetal growth restriction. Intra- tions have been described. The most impor-
muscular corticosteroids may be necessary tant risk factors for the development of
when preterm delivery is indicated. In spontaneous preterm delivery include:64
general, fetal growth restriction does not 1. Spontaneous preterm birth occurring in
alter dental treatment during pregnancy. a previous gestation
2. Intrauterine infection
Fetal Death 3. Short uterine cervical length as deter-
Fetal demise or stillbirth after 22 weeks mined by ultrasound in the mid-
occurs in 5 to 10 per 1,000 births. Diagnosis trimester
is reached by establishing the absence of 4. Inflammatory biomarkers in cervico-
cardiac activity by ultrasound. The most vaginal fluid or maternal urine (e.g.,
common causes of fetal death are maternal fibronectin)
diseases (preeclampsia, pregestational dia- 5. Low prepregnancy body mass index
betes, renal disorders), placental insufficiency 6. Systemic inflammation
(often associated with fetal growth restric- 7. Vaginal bleeding of uterine origin
tion), acute fetal hypoxia (due to placental during the second half of pregnancy
abruption, uterine rupture, or cord acci- 8. Multiple gestation
dents), congenital anomalies, chromosomal 9. Cigarette smoking
abnormalities, fetal infection, fetal anemia, 10. Social vulnerability (African-American
and conditions specific to multiple gestation. race, adolescent pregnancy, low socio-
A significant proportion (30% to 60%) of economic status)
fetal deaths have no evident cause.
Of significance for the dental profes- Dental Care in Women at Risk
sional is a rare hematologic condition that for Preterm Birth
develops when the deceased fetus remains in Several review studies76,77 have shown that it
utero for more than 3 weeks. In these cases, is safe to provide dental care for pregnant
fibrinogen levels may drop, leading to a sub- women, although clinical trials supporting
clinical coagulopathy that could progress to such evidence are scarce.13 The American
disseminated intravascular coagulation, char- Academy of Periodontology recommends
acterized by systemic spontaneous bleeding that pregnant women with periodontal
and multiple organ dysfunction. Any dental disease should receive periodontal treatment
procedure should be deferred until the con- during pregnancy.60 The notion that peri-
dition is completely resolved. odontal treatment and routine dental treat-
ment do not carry a special risk for the preg- A recent workshop on periodontitis and
nant patient is based on indirect observa- systemic diseases concluded that periodontal
tions derived mainly from clinical trials therapy has been shown to be safe and leads
aimed at determining the effect of periodon- to improved periodontal conditions in preg-
tal treatment on pregnancy outcomes. nant women.88
Twelve randomized controlled trials of
periodontal treatment in pregnant women Treatment Before and After 28 Weeks
have been published.14–16,51,78–85 The effect of of Gestation
periodontal treatment to reduce preterm birth López and colleagues14 performed a ran-
yield controversial results, but all the trials, domized trial with 200 pregnant women
with the exception of one,85 confirmed the with moderate to severe periodontitis. The
safety of providing dental treatment during study population showed several well-known
pregnancy, including oral prophylaxis, restora- risk factors for preterm birth. All the women
tions, extractions, and nonsurgical periodontal were of low socioeconomic level, 22% were
treatment. The study by Macones et al.85 sug- unmarried, 4.7% had a history of preterm
gested that treatment of periodontal disease birth, 15% smoked, 12% were underweight,
was associated with a trend toward an and 20% had begun prenatal care after 20
increase in indicated preterm delivery. weeks of gestation. In addition, 11% had
However, some methodologic flaws in the urinary infections and 18% had bacterial
study design of that trial raise reasonable vaginosis during pregnancy. All these infec-
doubts regarding the validity of its conclu- tions were medically treated. Two-hundred
sion. The investigators defined the periodon- women received periodontal treatment con-
tal status of the study participants as “early sisting of plaque control instructions, scaling,
localized chronic periodontitis,” and the only and root planing under local anesthesia
criterion that they used for the diagnosis of without vasoconstrictor before 28 weeks of
periodontal disease was periodontal attach- gestation. A control group of 200 women
ment loss of 3 mm or more on three or more received a periodontal examination at the
teeth. 85 Attachment loss is more a measure of time they were enrolled. Patients were moni-
past disease than of current periodontal tored every 4 to 6 weeks during the gesta-
disease86 and can also occur as a consequence tional period, and another complete peri-
of noninflammatory gingival recession. Peri- odontal examination was performed after 28
odontal variables that reflect current inflam- weeks of gestation. The control group
matory burden, such as bleeding on probing received periodontal treatment after delivery.
and pocket depths, are the more appropriate Carious lesions were treated, and all teeth
measures of periodontal disease as exposure indicated for extraction were extracted from
in the context of risk for systemic diseases.87 both groups. The incidence of spontaneous
Use of attachment loss alone as the only cri- abortions and of medically indicated
terion for diagnosing periodontitis can result preterm deliveries were similar in the treat-
in mistakenly including women who do not ment group and in the group who had not
have periodontal disease, as may have received treatment during pregnancy. No
occurred in the Macones et al. study.85 Unfor- other adverse events that could be ascribed
tunately, it is not possible to determine the to dental treatment were observed among
level of severity of the periodontal disease in the participants of the study.
the women included in the study because the
periodontal characteristics of the participants Treatment with Metronidazole
were not reported. Jeffcoat and colleagues16 did not report
safety outcomes for 366 women randomized No adverse events ascribed to dental treat-
into a group who received a prophylaxis or ment were identified in the treatment groups
scaling and root planing, with or without during pregnancy, and no significant differ-
systemic metronidazole therapy. Unexpect- ences were observed when women of the
edly, within this study, the lowest rate of treatment group were compared with the
preterm birth occurred in women who group who did not receive periodontal treat-
received scaling and root planing and ment. The results of this study show that
placebo, and not in the group who received periodontal treatment administered between
metronidazole. Metronidazole has been 7 and 28 weeks of gestation is not associated
shown to be effective in controlling peri- with an increased risk of serious adverse
odontal infection when given as an adjunc- events in women despite the presence of
tive of root planing. However, a later study other risk factors associated with adverse
by Carey and Klebanoff89 showed that oral pregnancy outcomes, such as low socioeco-
metronidazole therapy may produce changes nomic status, history of preterm birth,
in the vaginal flora leading to a heavy smoking, and genitourinary infections
growth of Escherichia coli and Klebsiella during pregnancy.
pneumoniae, which were associated with an
increased risk of preterm birth. Thus, oral Treatment of Periodontitis
metronidazole used as the only antimicrobial Offenbacher and colleagues78 randomized 74
for periodontal infection in pregnancy women with mild periodontitis, 40 of whom
should be used with caution. received periodontal treatment early in the
second trimester of pregnancy. Periodontal
Treatment of Extensive Pregnancy- treatment consisted of plaque control
Associated Gingivitis instructions, scaling and root planing, and
In another randomized trial,51 570 women crown polishing; 34 women received only
with extensive pregnancy-associated gingivitis supragingival debridement. This study popu-
received periodontal treatment before 28 lation represented a high-risk group of
weeks of gestation. Periodontal treatment preterm birth because 60% of the partici-
consisted of plaque-control instructions, sub- pants were African American and tended to
gingival scaling, crown polishing, and mouth be economically disadvantaged, and 75%
rinsing with 0.12% chlorhexidine once a day. had previously experienced preterm births.
Timing in which women received periodon- The findings of this study indicate that the
tal treatment is shown in Table 3. intervention was successful in treating peri-
The results of the study showed that odontal disease, and no serious adverse
treatment of gingivitis reduced preterm birth events occurred in terms of either obstetric
and low birth-weight infant rates by 68%. or periodontal outcomes that were attributed
Table 3. Timing in Which Pregnant to periodontal treatment. The authors
Women with Gingivitis Received reported two cases of fetal demise during the
Periodontal Treatment study; however, neither the timing nor the
group to which the women with these events
belonged was specified.
Tarannum and Faizuddin79 evaluated
the effect of periodontal therapy on preg-
nancy outcome in a randomized trial con-
sisting of 200 women with periodontitis. The
treatment group received plaque control
instructions and scaling and root planing during pregnancy if left untreated, and frac-
under local anesthesia, as well as mouth tured or decayed teeth that could adversely
rinse twice daily with 0.2% chlorhexidine. affect the health of adjacent teeth. Affected
The control group received tooth-brushing teeth were treated with temporary or perma-
instructions only. A significantly higher inci- nent restorations, endodontic therapy, or
dence of preterm birth was observed in the extraction at a time between 13 and 21
control group compared with that in the weeks of gestation. Four-hundred-eighty-
treatment group (76.4% vs 53.5%, P <.001). three women needed essential dental treat-
No adverse effects due to periodontal treatment, and 72.7% of these women completed
ment were reported. all recommended treatment. Serious adverse
effects were recorded, including spontaneous
Treatment of Slight-to-Moderate Periodontitis abortion, stillbirth, hospitalization for more
Michalowicz and colleagues15 conducted a than 24 hours because of labor pains or
multicenter, randomized trial to determine other reasons, fetal or congenital anomalies,
whether periodontal therapy reduces the risk or neonatal deaths. The adjusted odds ratios
of preterm delivery. They concluded that for all adverse outcomes related to essential
treatment of periodontitis in pregnant dental treatment were close to 1, showing
women improves periodontal disease and is that the dental treatments administered were
safe, but does not significantly alter rates of not associated with any significant increase
preterm birth. The data from this study were in risk for these outcomes.
also used to investigate safety outcomes Nonsignificant differences of adverse
related to the provision of dental care in events were found in women who received
pregnant women.13 Participants in the study essential dental treatment and who received
had generalized, slight-to-moderate peri- or who did not receive periodontal treat-
odontitis, and they belonged to minority and ment. The distribution of adverse events was
underserved groups who had an elevated not significantly different in women who
risk of adverse pregnancy outcomes. The received periodontal treatment nor in those
population study consisted of African- who did not receive treatment during preg-
American women (45%), Hispanic women nancy. Thus, in a population with a high risk
(42%), and women with a history of preterm of adverse pregnancy outcomes, periodontal
birth deliveries (9.3%). The authors random- and dental treatments administered between
ized 413 pregnant women with periodontitis 13 and 21 weeks of gestation did not
to a group who received scaling and root increase the risk of serious medical adverse
planing between 13 and 21 weeks of gesta- events, preterm deliveries, spontaneous abor-
tion. Dentists provided periodontal treat- tion or stillbirths, or fetal anomalies. This
ment over one to four visits, and topical or study confirms the predominant notion in
locally injected anesthetics were administered the obstetric community that few risks are
as needed. A control group of 410 women associated with routine dental care during
were monitored during pregnancy and pregnancy.90 Some experts advise deferring
treated after delivery. elective dental treatment during the first 12
Women of both groups were evaluated weeks of gestation because of the potential
for essential dental treatment. The necessity vulnerability of the fetus.78,91 However, there
for “essential” dental treatment was defined is no evidence that routine dental treatment
as the presence of one or more of the fol- or periodontal treatment may have adverse
lowing: odontogenic abscesses, decayed teeth effects on fetal development or induce mal-
judged likely to become asymptomatic formations.
This notion is confirmed by a retrospec- on the vaginal flora reported. López and col-
tive study92 that examined the records of leagues14 gave metronidazole and amoxicillin
23,441 pregnant women who delivered live to 29 pregnant women with severe aggressive
births from singleton pregnancies in the periodontitis as an adjunct to scaling and
United States. This study found that women root planing. The treatment was adminis-
who received preventive dental care during tered between 16 weeks and 28 weeks of
pregnancy had better birth outcomes than gestation; the administration of antibiotics
those who received no treatment (P <.001). began the day that scaling and root planing
No evidence of increased risk of adverse were initiated. No adverse effects that could
birth outcomes from dental or periodontal have been attributed to antibiotic treatment
treatment was found. were observed, and all the women had
normal-term parturition.
Treatment During Pregnancy and Risk of
Preterm Birth Managing Periodontal Infection in the
Ideally, women should begin their pregnancy Pregnant Adolescent Patient
without periodontal infections, and preven- Maternal age under 18 years is a risk factor
tive oral care services should be provided as for preterm birth,94 and pregnant adolescents
early in pregnancy as possible. However, if a are at an increased risk for medical compli-
periodontal or dental infection is diagnosed cations.95 In the United States, more than 6%
at any time during pregnancy, the treatment of adolescent females become pregnant
should be administered as soon as possible every year. Of these pregnancies, 51% end in
to reduce the risk of preterm birth. In live births, 35% in induced abortion, and
women with periodontal disease diagnosed 14% in miscarriages or stillbirth.96 Poor and
late in the second or in the third trimester of low-income adolescents make up 38% of all
pregnancy, and who have a high risk of women ages 15 to 19 in the United States;
preterm birth or symptoms of preterm labor, yet they account for 73% of all pregnancies
the administration of systemic antibiotics to in that age group. It is known that preva-
control periodontal infection is advisable. lence and severity of periodontal disease are
The combination of metronidazole (250 mg) also higher in disadvantaged populations.
plus amoxicillin (500 mg) three times a day Teenage mothers are much less likely than
for 7 days, in conjunction with root planing, older mothers to receive prenatal care and
has been shown to be effective to control are more likely to smoke during pregnancy.
periodontal infections in patients with As a result of these and other factors, babies
chronic periodontitis.93 Timing of the admin- born to teenagers are more likely to be
istration of antibiotics in relation to the preterm (<37 weeks’ gestation) and of low
scaling and root planing treatment is contro- birth weight (<2500 g) and have a greater
versial, and protocols to determine the best risk of serious and long-term illness, of
timing to administer antibiotics have not developmental delays, and of dying in the
been tested. first year of life compared with infants of
Apparently, the results of the adminis- older mothers.97 No studies exist about the
tration of metronidazole and amoxicillin oral health status in pregnant adolescents,
contrast with those of the administration of but by extrapolating the information on
metronidazole alone in relation to changes in prevalence of gingivitis and periodontitis
the vaginal microflora. This combination of from studies in nonpregnant adolescents, it
antibiotics has been widely used to treat peri- can be expected that these diseases have
odontal infection with no secondary effects similar prevalence. Gingivitis is common in
children, reaching a peak at puberty fol- legal issues when they are under the age of
lowed by a limited decline in adolescence. 18, make their overall management more
To determine the effect of periodontal complex.
treatment on pregnancy outcomes, a cohort of
164 pregnant adolescents at high risk of CONCLUDING PRINCIPLES
preterm birth was recruited by Mitchell-Lewis • Women’s healthcare providers should
and colleagues.98 The study population con- know the importance of protecting oral
sisted of pregnant adolescents, ages 14 to 19. health during pregnancy and educate
All were of low socioeconomic status; 60% their patients accordingly.
were African American and 39% Hispanic. • Pregnant women should be advised that
These sociodemographic characteristics— prevention, diagnosis, and treatment for
young age, minority ethnicity, and low socioe- oral disease, including needed dental x-
conomic status—are well-known risk factors rays and local anesthesia, are highly ben-
for preterm birth.94 Periodontal examinations eficial and can be undertaken without
were performed to assess dental plaque, calcu- additional fetal or maternal risk when
lus, bleeding on probing, and pocket depth. compared with not providing care.
Periodontal treatment consisted of oral • The safety and effectiveness of providing
hygiene instructions, scaling, and crown polish- oral health care during pregnancy,
ing. This treatment was given to 74 women; 90 including prophylaxis, restorations,
women with no treatment were used as con- extractions, and periodontal treatment
trols. Four plaque samples per subject were have been confirmed by many studies.
obtained during pregnancy and postpartum to • All women should receive at the beginning
study the prevalence of 12 bacterial species. of the pregnancy period an evaluation of
Preterm low birth weight occurred in 13.5% of their oral health status, which includes a
women who received periodontal treatment comprehensive periodontal examination,
and in 18.9% of women who did not receive assessment of gingival inflammation, peri-
treatment. The difference was not statistically odontal probing depth, and clinical attach-
significant. However, preterm birth mothers ment level measurements.
had significantly higher levels of Tannerella • Pregnant women with gingivitis or peri-
forsythia and Campylobacter rectus and consis- odontitis should receive periodontal treat-
tently higher levels of the other species studies. ment as soon as the periodontal condi-
The reduction of 28.6% in the incidence of tion is diagnosed. In women at risk for
preterm low birth weight, even though not sta- adverse pregnancy outcomes and peri-
tistically significant, shows that periodontal odontal infection, collaboration between
intervention may reduce adverse outcomes in the obstetrician and dentist is essential to
pregnant adolescents with periodontal infec- determine the timing and characteristics
tion. No adverse effects due to periodontal of periodontal treatment that should be
treatment were reported. administered.
Pregnant adolescents are at high risk for • No evidence links early spontaneous
adverse pregnancy outcomes; for those who abortion in the first trimester to oral
have gingivitis or periodontitis, the risk may health care or dental procedures.
increase. The principles for medical and
dental management of these patients are not Supplemental Readings
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group 3 of the joint EFP/AAP workshop. Peri- Available at http://www.cdc.gov/nchs/products/pubs/
odontitis and adverse pregnancy outcomes: consen- pubd/hestat/teenpreg1990-2002/teenpreg1990-
sus report of the Joint EFP/AAP Workshop on 2002.htm.
Periodontitis and Systemic Diseases. J Periodontol 98. Mitchell-Lewis D, Engebretson SP, Chen J,
2013; 84(4Suppl.):S164–9. Lamster IB, Papapanou PN. Periodontal infections
89. Carey JC, Klebanoff MA. Is a change in the and pre-term birth: early findings from a cohort of
vaginal flora associated with an increased risk of young minority women in New York. Eur J Oral
preterm birth? Am J Obstet Gynecol Sci 2001;109:34–9.
CHAPTER 17
of Osteoporosis, Kidney Disease,
and Cancer
Dawn J. Caster, James A. Kinane, Denis F. Kinane
INTRODUCTION of developing osteoporosis increases with

Before considering any therapeutic comanage, especially in women, because the loss of
agement issues, associations need to be con- ovarian function precipitates rapid bone
vincing, and mechanistic links and shared loss.3 About 300,000 hip fractures occur each
risk factors should be understood. This is year requiring hospital admission and, ulti-
particularly so for dental diseases and osteo- mately, surgical correction.3 Considering the
porosis, kidney disease, and cancer, since the increasing numbers of the elderly popula-
literature is relatively new and sparse. Fortu- tion, as the “baby boomers” rapidly
nately, these are addressed in previous chap- approach their sixth and seventh decades of
ters and in a recent workshop review.1 The life, it is easy to see how this disease process
goal of this chapter is to consider the man- can and will affect the healthcare system of
agement issues that may arise in dealing with the United States and worldwide.
the comorbid state. Can we modify treat- Osteoporosis is diagnosed on the basis of
ment? Do we need to prescribe the routine a low-impact or fragility fracture or low bone
drugs or are there alternatives? How should mineral density (BMD), which is best assessed
the dentist or physician treat patients pre- by central dual-energy x-ray absorptiometry
senting with both oral and systemic condi- (DEXA).4 By World Health Organization
tions? First, we need to consider the diseases guidelines, a diagnosis of osteoporosis is made
and the characteristics that might complicate by DEXA scan demonstration of a BMD
their dual management. Included in this con- that is 2.5 standard deviations below the
sideration are the new literature and findings young adult reference mean based on gender.
arising from the recent joint European and Classifications for osteoporosis are broken
American Periodontology Workshop. Each down into primary and secondary causes. Sec-
section concludes with suggestions for both ondary causes are many, and though less
the physician and the dentist for treating commonly seen in clinical practice, a few of
these patients. these causes, such as diabetes mellitus and
chronic obstructive pulmonary disease, are
OSTEOPOROSIS AND OTHER often seen in patients with osteoporosis.
BONE DISEASES
Osteoporosis Paget’s Disease
Osteoporosis is the most common bone Paget’s disease is a disorder characterized by
disease in humans. Disease prevalence has excessive resorption of bone. Subsequent to
been reported by some sources to be 3% to this resorption, new bone is deposited in a
6% in men and up to 13% to 18% in women haphazard fashion to compensate for the
(i.e., approximately 8 million women and 2 rapid bone loss. This creates the mosaic
million men), with a significantly higher pattern commonly associated with the
prevalence reported for those meeting the disease process that describes the disorgan-
diagnostic criteria for osteopenia.2 The risk ized trabecular bone formed rather than the
CHAPTER 17 Kidney Disease, and Cancer 309
normal pattern of lamellar bone. This disor- developed in the 1800s and have industrial
dered bone deposition is weak and prone to uses such as softening water for irrigation
deformities as well as fracture. The incidence systems. The compound’s ability to soften
of Paget’s disease is not well reported, and water is due to the inhibition of calcium car-
the current incidence of 3.0% to 3.7% is bonate crystal formation, and it was later
based on autopsies and radiographs of found that bisphosphonates can also inhibit
patients over 40 years of age.5 Etiology of calcium pyrophosphate crystal formation.
the disease is unknown, although there are Bisphosphonates are classified into two
several proposed theories, including viral and groups based on whether they contain an
genetic factors. Careful evaluation of history amino group. Mechanism of action differs
and physical examination help to delineate among the groups. Aminobisphosphonates
Paget’s disease from other possible diagnoses (zolendronate, alendronate, pamidronate,
(e.g., metastatic bone disease). Certain sero- ibandronate, and risedronate) disrupt the
logic and radiographic tests aid in making pathway involving metabolism of mevalonic
the diagnosis. There are several clinical mani- acid. They also promote abnormalities in
festations of Paget’s disease, including com- cytoskeleton production, inducing apoptosis
plaints of upper dentures no longer fitting; of osteoclasts that retard bone resorption.
however, the skeletal sequelae are most Bisphosphonates that do not contain amino
germane to the current discussion. groups (etidronate, clodronate, and tilu-
dronate) act by disrupting adenosine triphos-
Metastatic Bone Disease phate (ATP) formation after being metabo-
Metastatic bone disease is most commonly lized within osteoclasts, also promoting
associated with breast and prostate cancer, but apoptosis. Unfortunately, bisphosphonates
is frequently seen in advanced cases of malig- exhibit a secondary effect—their ability to
nancy. Tumor cells express several chemical inhibit bone mineralization, thereby causing
and genetic factors that make bone a pre- osteomalacia. Again we see a difference
ferred site for localization and growth. There among the classes. Whereas etidronate has
is much discussion in the medical literature been shown to inhibit resorption and miner-
regarding the propensity of certain malignan- alization at similar concentrations, alen-
cies to express osteoblastic versus osteolytic dronate has been shown to have a markedly
bone lesions. However, most patients with favorable therapeutic index (i.e., better
bone metastases have evidence of both lesions. resorption inhibition than defective mineral-
Clinical manifestations of metastatic bone ization) up to 36 months from initiation of
disease include pain, fracture, and possibly therapy.6 The overall higher potency and
spinal cord compression. Cord compression is lower toxicity of aminobisphosphonates are
a medical emergency requiring immediate likely the reasons they are used more often
intervention to prevent permanent neurologic in clinical practice than are other bisphos-
dysfunction. Although antineoplastic and phonates.
analgesic therapies are the mainstay of treat- Although less than 10% of orally
ment for most metastatic bone lesions, certain ingested doses of bisphosphonates are
alternative strategies have been gaining favor, absorbed, between 20% and 50% of the
such as bisphosphonate therapy. absorbed dose accumulates in bone, depend-
ing on the rate of bone turnover. The
Pharmacology of the Bisphosphonates remainder of the dose is excreted in urine.
Bisphosphonates are synthetic analogues of The half-life of these drugs varies consider-
inorganic pyrophosphate. They were initially ably, but in the case of alendronate (one of
! and
! Overall
! Health:
! A! Clinician’s
! Guide
!
the more common ! pharmaceutical

! ! ! ! agents Therefore, the! quality
! of
! evidence
! regarding
!
used
! in the !treatment ! ! of disorders ! ! of! bone ! the !true! incidence
! of ONJ
! ! is in ! !question,
! as
metabolism),
! ! ! it is ! as long ! !as 10 years.! One ! is !the! true
! causal ! relation! between! bisphos-
point of contention
! ! !is the ! time frame ! for phonates and ONJ. ! !Information ! presented
!
which !the ! compound ! !persists within ! ! the here is! based ! !on the! most ! ! current ! facts, ! but
bone, which ! !according ! ! to some ! ! sources, ! can this! is an! ! expanding
! field
! and ! the! !reader
be the ! !lifetime! of the ! patient. ! !7 This ! !is an should !update !regularly on ! this
! topic.
!
important ! factor to! bear in mind! when ! con- The ! known! epidemiologic !data !for !bis-
sidering! !interruption ! of therapy before surgi- phosphonate-associated !ONJ ! varies ! greatly
cal procedures. based !on! the! disease! processes !for !which !the
! ! ! drug! is! used (Figures
! 1–3).
! !Therefore, !this
Osteonecrosis of the! Jaw ! ! ! ! ! chapter ! considers
! the
! osteoporosis
! !and
Osteonecrosis! of the ! jaw (ONJ) ! ! has !attracted Paget’s ! disease ! patient! subsets! and ! those !
increased
! interest
! for both! medical ! and
! dental ! receiving! bisphosphonates ! for ! skeletal!! com-!
practitioners
! ! in! recent ! !years. ! In the early ! ! part plications of malignancy as separate entities.
of the last ! century, ! ! the ! term “phossy ! ! jaw” ! ! ! !
had! been used! to describe ! ! the condition
! that Figure 1. Clinical Photograph of an! Upper
! ! !
linked white ! phosphorus ! ! exposure
! with! !the !
Jaw Exhibiting ! ! !
Marked Osteonecrosis in! a
disease process ! of osteonecrosis. ! ! Radiation Patient on Bisphosphonate Therapy !
! !
and chemotherapy
! ! ! have also ! !been implicated !
as possible
! ! causes ! !of ONJ. ! The! most !recent !
debate !in the current ! ! literature! ! and !to! be
addressed ! in! this chapter is bisphosphonate- !
associated ONJ. Bisphosphonates ! ! ! ! !have! taken !
on !a vital role in !the! management ! of
! chronic
disease! !processes such ! as! osteoporosis ! and!
Paget’s! !disease, ! as well! as! the prevention ! of
skeletal! !complications ! !in patients ! with bone !
metastases. Bisphosphonate-associated ! ! ! ONJ !
was first ! reported
! ! in ! 2003; ! since! then !many
more cases! have
! come ! !to light, ! propelling !the Courtesy !of Dr.
! George
! M.! Kushner,
! !
University of !
American ! Society ! for! Bone ! ! !
! and ! Mineral ! Louisville Dental School.
Research ! (ASBMR) ! !to appoint ! ! a task ! force ! Figure 2.
! Orthopantomograph of!
to review ! the ! literature! and! make! recommen- Osteonecrosis in the Lower
! ! Border
! !
dations !for !future !diagnosis and ! !management. ! of$the Lower Jaw ! ! !
! !
The !case !definition !of ! bisphosphonate-
associated !ONJ! is! an! area! of ! exposed ! bone !
in the
! maxillofacial! region! that! does!not !heal
within ! 8 weeks ! after
! identification
! by
! !a
healthcare !provider, ! in! a! patient ! who ! was !
receiving! or! had! been! exposed! to! a! bisphos-
phonate !and! had! not! had ! radiation ! therapy !
to the
! craniofacial ! region.8 The! reporting !of
many !cases !involving !ONJ !associated !with
bisphosphonate !use ! was ! made! before ! !the Courtesy !of Dr.
! George
! M.! Kushner,
! University
! of !
accepted
! !ASBMR ! task! force! definition. Louisville Dental
! School.
! !
! ! ! ! ! !
! Dental! and Medical
! ! Comanagement of Osteoporosis,
! ! ! ! ! ! !
Figure !3. Computer-Assisted
! ! ! Tomographic
! ! disease !processes! requiring ! ! bisphosphonate
View of! the Subject
! Seen
! ! in Figure 2 therapy! have many ! areas ! of poor bone
!Demonstrating
! Extensive
! Osteonecrosis! of
! the health. These ! !areas are ! posited ! ! to carry ! a
Lower !Border of the
! Lower ! Jaw
! ! ! ! high risk ! for ONJ. ! The
! !antiangiogenic ! ! ! effects !
attributed
! ! to bisphosphonates ! ! ! are purported
to leave ! areas such ! ! as these in a relatively ! !
ischemic ! ! condition. ! !Ischemic ! ! regions ! ! ! with
infarcted! bone! do not !properly !remodel
because! of the! antiresorptive ! ! !properties! of
these medications.
! ! ! Areas ! such as these ! are
susceptible
! ! !to further necrosis ! !after! trauma !
such ! as oral surgery. ! ! Furthermore,
! ! these
areas are ! a perfect! ! nidus ! for infection, ! and a
wide !range !of bacterial ! ! infections
! ! is! found in
these ! !situations.! Again,
! ! these are ! only pro- !
posed! mechanisms,
! ! and! further ! clinical
!
! Dr.
Courtesy of ! George
! M.! Kushner,
! !
University of !
! ! !
research
! !is necessary ! to elicit the! pathophysi- !
Louisville Dental School.
ology of! the disorder, ! ! particularly ! ! regarding !
Patients! receiving
! bisphosphonate
! ! ! therapy the issue of predisposing ! ! ! factors !such as cor-
for osteoporosis
! ! and Paget’s disease ! !are ticosteroid! use! or alcohol ! ! abuse. !
mostly treated ! with ! oral ! agents, ! whereas
! !A ! currently investigated ! ! ! topic ! is the!
those with ! malignancy
! ! complications
! ! gener-
! early !identification ! of osteonecrotic ! ! bone !
ally receive intravenous
! therapy.! There! is con- before! the initiation ! ! of bisphosphonate !
flicting evidence ! regarding
! the
! incidence
! of therapy ! ! or oral surgery. ! ! This is extremely ! dif-
!ONJ in !patients receiving ! ! bisphosphonates
! ! ! ficult,
! however,
! !because ! ! most readily ! avail-
for osteoporosis.
! !One study estimated ! ! the! able radiographic! ! techniques
! ! cannot identify !
prevalence to! be less ! than 1 in! 250,000. ! 9 The defects of ! cancellous ! bone! until advanced !
incidence
! ! ! ! of! ONJ in patients ! receiving ! ! bis- stages.
! Current! recommendations ! ! by !the task
phosphonate
! ! therapy ! for complications ! of force call ! for development! of ! noninvasive
! !
malignancy
! ! ranges from ! ! 1% to 10%. ! 10 A diagnostic
! ! and imaging ! techniques
! to further
!
prospective ! study ! !by Bamias ! and colleagues ! 11 characterize
! ! the disorder. ! ! !
of ! cancer patients
! ! receiving ! bisphosphonate
! ! ! !
therapy estimated
! that the !risk of developing ! Management
ONJ! increased
! ! !with length !exposure ! to the Conditions requiring bisphosphonate
drug! and was ! dependent
! ! on! the! bisphospho-! ! therapy are common ! and! may (especially
nate used.! Although ! ! the data supporting ! ! osteoporosis)! ! become! more ! prevalent
! in !the
these claims
! ! are ! limited, ! it is! generally ! near future.! Morbidity ! secondary ! to !disease !
accepted! that ! ! the risk !of developing ! !ONJ ! is progression
! ! such as ONJ ! has a! negative!
higher
! in patients ! !receiving
! ! treatment
! !for impact on the ! healthcare
! ! ! system financially !
metastatic ! bone disease. ! ! Whether !this higher ! and! considerable ! emotional
! and ! physical !
incidence
! is secondary
! ! ! to !the higher ! doses ramifications! for the patient. ! ! Thus, ongoing !
received
! !by patients! with ! malignancy
! ! com-! preventive ! !measures! are necessary ! ! in manag-
pared with! ! those receiving ! ! therapy for !osteo- ing these! medical ! conditions.
! ! ! Until more
porosis ! or ! Paget’s ! disease !remains !to be ! seen. effective
! ! therapies! with fewer! adverse ! effects !
The ! ! pathogenesis ! of
! ONJ! !remains ! are available,
! the! use! of bisphosphonates ! !
unknown. Patients with the aforementioned will continue. The heightened awareness of
ONJ associated with these medications, priate nonsurgical treatment for periodontal
combined with stronger guidelines outlining disease (unless contraindicated by comorbid
case definitions and a call to responsible illness). Moderate bone recontouring is
reporting, has already resulted in an acceptable if necessary. There is currently no
increased number of cases reported over the contraindication to dental implant surgery
past 2 years. Management of bisphospho- in this patient subset. Endodontic treatment
nate-associated ONJ requires an interdisci- is the preferred mode of therapy over
plinary approach, with open communication extraction when at all possible. When inva-
between medical and dental practition- sive therapy is necessary, temporary discon-
ers and patients. Since the incidence and tinuation of bisphosphonate therapy is rec-
risks of developing this complication are dif- ommended; however, no evidence supports
ferent among patient subsets, this chapter improved dental outcomes when discontinu-
outlines the recommended management ing therapy. As previously mentioned, the
strategies separately for patients with osteo- long half-life of certain bisphosphonates
porosis/Paget’s disease versus those treated and the even longer retention of the medica-
for complications of malignancy. These rec- tion in bone call into question the validity of
ommendations for management are adapted such strategies. Once again, good quality
from the guidelines of the 2007 ASBMR communication between practitioners and
Task Force.8 patients is of the utmost importance in
As previously mentioned, free commu- making these decisions.
nication between medical and dental practi- For patients receiving medical therapy
tioners is necessary to ensure proper conti- for complications of malignancy, the risks of
nuity of care. Full disclosure concerning the developing ONJ are greater, and thus man-
risks and benefits of medical therapy is the agement strategies are more conservative.
responsibility of the medical practitioner for Dental evaluation by a qualified specialist
any patient initiating treatment with bispho- should be completed before the initiation of
sphonates. Reducing the risk of developing therapy, with follow-up evaluations at 6- to
ONJ includes observing strict maintenance 12-month intervals. If at all possible, invasive
of the patient’s oral hygiene and regular procedures with appropriate time allotted
follow-up visits with a dental practitioner, for healing should be performed before the
which should be an integral part of the start of medical therapy. If medical therapy
medical care for all patients taking bisphos- must be initiated sooner, then concomitant
phonates. Patients are to be instructed that surgical treatment is recommended with
any oral problems should be reported to close follow-up. Elective procedures such as
their physician and dentist promptly. implant placement and extraction of
The risk of developing ONJ in patients asymptomatic teeth are not recommended.
receiving oral therapy for osteoporosis or Symptomatic teeth should be treated by
Paget’s disease is fairly low. The risk also nonsurgical means when possible, unless the
seems to be related to length of exposure to tooth is excessively mobile and presents a
the medication. Therefore, it is not necessary risk for aspiration.
to have a dental evaluation before initiating Patients with established ONJ should
bisphosphonate therapy for these disorders. be referred to a qualified dental practitioner
For patients taking these medications for for management. For those with clinical evi-
longer than 3 years, there are more detailed dence of infection, appropriate antimicrobial
recommendations for management. Patients therapy is recommended. Surgical interven-
on long-term therapy should receive appro- tion for ONJ should be delayed unless the
necrotic bone has sharp edges that may KIDNEY DISEASE

cause continued trauma to adjacent soft The number of patients with chronic kidney
tissues. Segmental jaw resection may be nec- disease (CKD) is growing and is projected to
essary for large areas of necrosis. The deci- continue. As the incidence of CKD climbs,
sion to discontinue bisphosphonate therapy patients with CKD, including those with
for those with this complication depends on end-stage renal disease (ESRD), will repre-
the patient’s clinical condition, since this sent a larger portion of those seeking dental
strategy has not been established to improve treatment. With this in mind, it is important
outcome. Recommendations are to ensure to understand the complex interaction
maintenance of a high standard of oral between CKD and periodontal disease.
hygiene and ensure no active disease by CKD is associated with many physiologic
using nonsurgical and surgical therapy changes that may contribute to the develop-
where needed, as well as adjunctive antimi- ment of periodontal disease. Several docu-
crobial therapy. Anti-inflammatory drugs mented physiologic changes in oral tissues
should be avoided unless there is evidence have been associated with CKD. These
from research that such medications will not include xerostomia, decreased salivary pH
interfere or interact with medications used levels, decreased mineralization, and loss of
for osteoporosis. There is a possibility that the lamina dura.13 In addition, some of the
any dampening of normal inflammation medications commonly prescribed for CKD
may permit the bacteria in an infectious patients may increase the risk of developing
lesion to become more virulent, allowing periodontal disease.
greater destruction of bone. Alternatively, Both CKD and periodontal disease
dampening inflammation may be helpful in have been implicated as sources of chronic
certain cases of periodontal disease, but inflammation. Thus, periodontal disease may
until there is evidence one way or the other, represent a modifiable contributor to the
anti-inflammatory drugs should be avoided already high inflammatory burden in
in this comorbid situation. patients with CKD, especially those with
diabetes. Treatment of periodontal disease in
Case example: Patient has been treated with these patients could decrease the overall
bisphosphonates, with exposed maxillofacial chronic inflammatory burden and its seque-
bone present for more than 8 weeks. lae. A collaborative effort between dental
Risks: Potency and duration of bisphospho- and medical professionals is necessary to
nate use. ensure that patients get appropriate advice
Other risk factors: Age, genetics, additional and treatment.
systemic conditions, e.g., diabetes, obesity,
renal dialysis. Overview of Kidney Function
Management: Before use of cancer-related The principle function of the kidneys is to
bisphosphonate, a thorough dental examina- remove waste products of metabolism, as
tion is needed and optimal endodontic and well as to maintain fluid and electrolyte
periodontal health should be achieved. In balance. The kidneys also play a vital role in
addition, alternative dosing regimens that blood pressure regulation through the release
reduce bisphosphonate exposure should be of renin. Erythropoietin, a potent stimulator
considered. of red blood cell production, is also made by
(Modified from the 2009 BRONJ American the kidneys. Moreover, the kidneys play an
Association of Oral and Maxillofacial Sur- important role in bone health by providing
geons position paper.12) the final step in the conversion of vitamin D
! and
! Overall
! Health:
! A! Clinician’s
! Guide
!
Table 1. Classification of Chronic Kidney Disease

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'3F;7@F!I;F:!D;E=!835FADE!8AD!0"2 ! 34 )76G57!D;E=!835FADE
89!";6@7K!63?397!I;F:!@AD?3>!AD!;@5D73E76!>?) ! 34 2;39@AE7!3@6!FD73F
5A?AD4;6;F;7E!3@6
0-2!D;E=!D76G5F;A@
B9!";6@7K!63?397!I;F:!E>;9:F!>?)!675D73E7 C4ME3 FEF;?3F7!BDA9D7EE;A@
H9!";6@7K!63?397!I;F:!?A67D3F7!>?)!675D73E7 H4MI3 +D73F!5A?B>;53F;A@E
K9!";6@7K!63?397!I;F:!E7H7D7!>?)!675D73E7 ! 8IMB3 0A@E;67D!=;6@7K!D7B>357?7@F
I9!";6@7K!83;>GD7 M!8I!AD )7B>357!=;6@7K
6;3>KE;E
CKD! is! defined! as
! either
! kidney ! damage ! (pathologic
! abnormalities
! ! in blood,
! urine,
! ! or imaging)
! ! ! or a! GFR
!
less! than
! 60! for 3 months
! ! or !longer.! (Table modified
! ! from !K/DOQI 2002.14)
to
! its active ! form. Decreased! ! kidney
! function! Patients with CKD! and ESRD ! ! are ! at
can affect
! each of
! these
! ! areas and ! !has far- risk! for!!developing
! bone disease
! secondary
!
reaching consequences
! ! ! on overall ! health. ! ! to! the! electrolyte ! and endocrine ! ! derange- !
The
! waste
! ! products ! removed ! by the ments! that ! occur with ! decreased ! kidney
!
kidney ! include blood ! ! urea nitrogen,
! a function.! As kidney! disease ! progresses,
! phos-
byproduct of protein metabolism, and creati- phate excretion is impaired. ! ! There ! also
is
nine, a byproduct ! of ! muscle breakdown. ! ! decreased production ! of active ! vitamin D.
Blood !levels ! of ! ! compounds
these ! ! !are!!com-! Vitamin
! D !is either
! synthesized ! in the ! skin
monly used in lab testing ! to! measure! kidney! after exposure ! ! to! ultraviolet !! light or
function.
! ! ! More than 100 additional ! uremic absorbed! ! from dietary ! ! sources. ! However, !
solutes
! have ! been ! identified,
! many ! of which ! vitamin D !from ultraviolet ! ! light
! or dietary !
are thought ! to be toxic. As ! kidney ! function sources is not! active. It must undergo two
deteriorates,
! ! these ! solutes! can build ! !up, con- hydroxylation reactions to be activated in the
tributing to uremic ! syndrome.
! This
! !syn- body. The first hydroxylation ! ! reaction occurs
drome ! has been ! associated with
! an increase
! in the liver,! and ! ! the final
! hydroxylation
! ! ! reac-
in fatigue,! anorexia,
! and
! mental !status ! tion !occurs in! the !kidney. Decreased ! ! active
changes ! and has! been shown ! to ! ! cause ! leuko- ! vitamin! D levels ! in ! combination ! with
cyte !dysfunction, ! insulin
! resistance,
! and decreased
! ! phosphorus ! ! excretion ! ! lead to
decreased platelet ! !function. ! ! ! ! ! hypocalcemia,! ! hyperphosphatemia, ! ! and
! ! sec-
! Decreased !kidney ! perfusion ! causes the ! ondary !hyperparathyroidism. ! ! Long-standing
! !
release
! of renin! by granular ! cells
! in the juxta- !derangements
! ! in !calcium ! ! and ! phosphorus!
glomerular
! ! apparatus.
! This
! release
! con-! homeostasis
! ! eventually! lead to renal osteody- !
tributes ! to the ! renin-angiotensin
! ! system, strophy,
! which is! associated
! ! with impaired !
leading to! multiple ! local ! and systemic! effects, ! bone
! mineralization,
! ! increased ! risk of frac- !
such as vasoconstriction,
! ! ! sodium ! reabsorp- ! tures, and calcification. !
tion,
! and ! !fluid !! retention. ! There ! ! are! many ! ! ! ! !
antihypertensive
! ! ! agents targeting
! ! this! system, Overview of ! CKD ! ! ! !
such ! as angiotensin-converting
! ! ! enzyme ! CKD! is a! broad! term! used to encompass ! !
(ACE) ! inhibitors,
! ! angiotensin
! ! ! II receptor
! ! patients
! with !evidence ! of permanent ! ! kidney
!
blockers ! !(ARBs), ! and !a new ! class of direct ! damage
! ! and/or! progressive! decrease ! ! in
renin inhibitors
! ! ! (DRIs). ! ! ! ! ! kidney
! function
! as! defined by! glomerular ! fil-
tration rate (GFR).14 An estimated 31 Renal replacement therapies include

million Americans suffer from CKD, and hemodialysis, peritoneal dialysis, and kidney
millions of others are at risk (National transplantation. Dialysis provides a mecha-
Health and Nutrition Examination Survey nism for filtration of waste products,
data 1999–2006). The most common causes removal of excess fluid, and titration of elec-
of CKD are diabetes, hypertension, and trolytes. Dialysis does not replace the
glomerulonephritis. endocrine functions of the kidney. Therefore,
The National Kidney Foundation has many dialysis patients rely on exogenous
published staging guidelines for adult sources of erythropoietin and vitamin D as
patients with CKD. These guidelines are part of their treatment regimen. Patients
based on estimated GFR, which is calcu- undergoing transplantation recover complete
lated using the widely accepted Modification kidney function. However, they must remain
of Diet in Renal Disease (MDRD) equa- on lifelong imunosuppressive therapy to
tion. The equation uses serum creatinine prevent allograft rejection.
level combined with the variables of age, sex,
and race in the estimation of GFR. Medications Used for CKD
(MDRD equation: GFR [mL/min/1.73 m2] Antihypertensive Agents
= 186 × [Scr]-1.154 × [age]-0.203 × [0.742 if Many patients with CKD have hypertension
female] × [1.212 if African-American] [con- and require multiple medications to reach
ventional units]). This equation provides a adequate blood pressure control. Further-
much better estimate of kidney function more, the target blood pressure for patients
than does creatinine alone.14 Creatinine is a with CKD, at 130/80, is lower than for the
byproduct of muscle and thus creatinine general population (according to the Joint
levels vary with muscle mass. Two individu- National Committee on Hypertension 7).
als with the same creatinine can have striking Major classes of antihypertensive agents are
differences in GFR because of differences in diuretics, beta blockers, ACE inhibitors,
muscle mass. For example, an 80-year-old ARBs, and calcium channel blockers. Direct
white female with a creatinine of 1 mg/dL vasodilators, alpha blockers, and central-
has a decreased estimated GFR of 57 acting agents represent less frequently used
mL/min/1.73 m2, whereas a 30-year-old agents. Finally, the newest category of anti-
African-American male with a creatinine of hypertensives, DRIs, just became available.
1 mg/dL has a normal estimated GFR of Of these agents, calcium channel blockers
123 mL/min/1.73 m2. have been implicated as a source of gingival
hyperplasia.
Renal Replacement Therapy Calcium channel blockers consist of
CKD patients with a GFR of less than 15 dihydropyridines and nondihydropyridines.
mL/min/1.73 m2 are considered to be in The dihydropyridines include amlodipine,
kidney failure. Most patients at this level of felodipine, isradipine, nicardipine, nifedipine,
kidney function present with symptoms of and nisoldipine. The nondihydropyridines
uremia, and renal replacement therapy must include diltiazem and verapamil. Both
be initiated to sustain life. Occasionally, a classes of calcium channel blockers reduce
patient will have symptoms of uremia blood pressure by relaxing arteriole smooth
requiring renal replacement therapy prior to muscle and reducing systemic vascular resist-
reaching a calculated GFR of < 15. Any ance. The nondihydropyridines also have a
patient with a GFR of < 15 or who is on significant effect on heart rate through a
dialysis is considered to have Stage V CKD. direct negative chronotropic effect. In many
reports, calcium channel blockers have been plakia, and oral malignancies.18
documented to cause gingival hyperplasia Several drug-specific side effects are
(Figure 4), which is a potential adverse effect associated with immunsuppressive agents in
with all classes of calcium channel blockers, addition to the complications previously
but is thought to occur more often with listed. Corticosteroids continue to be used
dihydropyridine agents.13 Gingival hyperpla- frequently in transplantation and for the
sia usually occurs within months after the treatment of glomerulonephritis. Long-term
initiation of therapy and resolves within use can lead to steroid-induced diabetes and
months of discontinuing therapy.15 Clinicians poor wound healing.18 The calcineurin
may consider discontinuing these medica- inhibitors, cyclosporine and tacrolimus, are
tions in patients with calcium channel used frequently in transplantation and for
blocker–induced gingival hyperplasia. the treatment of glomerulonephritis.
! ! ! ! ! ! !
However, care should be made to find an Cyclosporine has been documented in many
alternative antihypertensive to help maintain studies to cause gingival hyperplasia in renal
adequate blood pressure control. transplantation patients.19 In addition, this
! ! ! ! effect is thought to be augmented ! when
Figure !4. Gross! Gingival
! Hyperplasia! in! the! !
cyclosporine is used in combination ! ! ! with! a
Upper !Anterior Region
! !of a Patient with
! calcium channel ! ! ! ! 20 Tacrolimus
blocker. ! ! has !
Hypertension
! on Treatment
! ! with
! a Calcium ! !
shown much lower rates of gingival hyper- ! ! !
!Antagonist
! (Dihydropyridine)
! plasia and ! ! may ! be !a safe alternative ! for ! a
! ! !
patient experiencing significant cyclosporine-! ! !
!
induced hyperplasia. ! ! 20,21 Any change in !
immunosuppressive ! !
medications ! should! ! be
! !
made by the patient’s physician to ensure ! ! ! !
efficacy and safety. Another approach! to
! ! ! !
treating! patients ! ! ! gingival hyperplasia
with ! !
! !
may be the combination of a standard oral ! ! !
hygiene program ! !and azithromycin ! ! therapy, !
! !
which has been shown in at least one study ! !
to reduce ! both! !symptoms ! ! and ! objective !
!
measures of cyclosporine-induced gingival! ! ! ! !
Immunosuppressive Therapy ! ! ! !
hyperplasia. In recent years, the mTOR
22 ! !
!
Immunosuppressive therapy ! ! is used ! in !inhibitors, ! sirolimus ! and ! !everolimus, ! ! !have
! !
patients with kidney transplantation and for ! ! !
been used more frequently in patients with ! !
! !
the treatment !
of glomerulonephritis. ! ! Com-
! ! ! !transplantation.
kidney ! ! ! They ! have ! been
monly used immunosuppressive drugs ! in
! ! ! associated with poor wound healing ! and
! ! ! ! !
!
transplantation are! corticosteroids, ! cal- oral mucositis.! ! 16 ! ! ! !
! ! !
cineurin inhibitors, mTOR (mammalian ! ! ! ! ! ! !
target! of rapamycin) ! !
inhibitors, !
belatacept, !Inflammatory ! State
! ! !
mycophenolate, and azathioprine. Many of ! !
16 The relation ! of kidney ! disease to ! periodontal
!
these! medications as ! well as alkylating ! !
agents ! !
disease is complex and requires further ! ! ! ! study.
! !
and rituximab are used for glomerulonephri- ! ! Periodontal disease contributes to a! chronic
! ! ! !
! ! !
tis. Significant immunosuppression can
17 ! ! !
inflammatory state ! that ! has ! been linked ! to
result ! in! numerous ! !
oral ! !
complications !
many systemic illnesses. Two recent cross-sec- ! ! !
including oral candidiasis, ! ! herpes
! ! tional! studies identified ! !
periodontal ! disease
simplex/zoster, aphthous! ulcers, hairy! leuko-
! ! ! ! ! ! !
as an independent risk factor for CKD. ! ! ! !
! ! ! ! ! ! ! ! ! !
! ! ! ! ! ! ! ! !
! ! ! ! ! ! ! ! ! ! !
However, the temporal relationship between of periodontal disease was shown to signifi-
the two is unknown, and no conclusions can cantly decrease CRP levels.30 A further pilot
be made on causality.23–25 study reported that surrogate measures of
Patients with CKD, especially those on glomerular filtration rates were affected
dialysis, have exceedingly high mortality adversely by periodontal disease such that
rates. Recent data from the US Renal Data periodontal treatment reduced these GFR
System (USRDS) show a mortality rate of surrogates (cystatin C).32 Measures that
84 deaths per 1,000 patient-years among decrease periodontal disease in the CKD
dialysis patients ages 20 to 44 and 174 deaths population may ultimately reduce the
per 1,000 patient-years among those 45 to 64 inflammatory burden of the CKD patient,
years of age. These rates represent an eight- thus decreasing the mortality from cardio-
fold increase from the rates of the general vascular disease, but no such study has been
population. The leading cause of morbidity performed.
and mortality in CKD patients is cardiovas- Another potential benefit associated
cular disease. with decreasing inflammatory markers in
The increased prevalence of cardiovas- CKD patients is decreased use of erythro-
cular disease among CKD patients is poietin-stimulating agents. Elevated CRP
thought to be multifactorial. Many of these levels in patients on dialysis are associated
CKD patients have well-known risk factors with higher doses of erythropoietin.29 Fur-
associated with cardiovascular disease, such thermore, the most recent information from
as hypertension and dyslipidemia. However, the USRDS shows that Medicare spent $1.9
chronic inflammation is a potential risk billion on erythropoietin-stimulating agents
factor for cardiovascular disease in CKD in 1 year alone. Decreasing CRP could result
patients. Reduction in kidney function is in lower erythropoietin doses and thus have
associated with increased serum levels of a large and positive financial impact.
inflammatory cytokines and C-reactive
protein (CRP) and decreased levels of Treatment of the CKD Patient with
albumin. This inflammatory state appears to Periodontal Disease
accelerate the progression of vascular The management of periodontal disease fre-
disease. quently requires significant instrumentation,
Furthermore, periodontal disease may pharmacotherapy, and sometimes surgery.
add to the inflammatory burden in patients Some clinicians recommend antibiotic pro-
with CKD. Periodontal disease is common phylaxis before dental procedures in patients
in CKD patients, often more severe than in with arterial venous grafts because of the
the general population, and it is frequently risk of infective endocarditis.33 Many antibi-
overlooked.26 Mortality from diabetic otic and analgesic regimens exist. For all
nephropathy and ESRD is significantly antibiotics, it is important to adjust the dose
greater in diabetic patients with periodontal based on GFR and to avoid nephrotoxic
disease compared with those with little or no agents in patients who are not yet on dialy-
periodontal disease.27,28 Many studies have sis. Nonsteroidal anti-inflammatory drugs
shown the association of inflammatory (NSAIDs) can decrease GFR and are best
markers to periodontal disease in dialysis avoided in patients with CKD. Patients with
patients.29,30 Treatment of periodontal disease CKD may have an increased bleeding risk
has been shown to reduce inflammatory secondary to platelet dysfunction as well as
markers in non-CKD patients.31 Further- to anticoagulants received on hemodialysis.
more, in a study of CKD patients, treatment One may try to implement a procedure on
the day after dialysis to decrease the risk.13 ing tooth loss, is associated with many estab-
Most renal transplant protocols include a lished risk factors for cancer as well as peri-
dental workup before transplantation to odontal disease and the incidence of cancer
treat potential problems once immunosup- itself.37 Many patients with cancer have pre-
pressive therapy is initiated. Extra caution is existing periodontal disease at the time of
necessary in renal transplantation patients cancer diagnosis. Michaud et al.38 reported
because they are more susceptible to infec- that although smoking was a major con-
tion. An interesting more recent study indi- founder in the potential association between
cates that CKD mediated by diabetes dura- cancer and periodontal disease, even when
tion was independently associated with peri- the analysis was limited to nonsmokers, the
odontal disease and further supports the association persisted for kidney, lung, pan-
infection susceptibility of both diabetics and creatic, and hematologic cancers. Arora and
CKD sufferers.34 The findings that periodon- coworkers,39 using a twin study design, found
tal treatment reduces inflammatory markers, a 15% increase in cancer risk related to peri-
improves diabetic condition, and reduces sur- odontal disease. Using NHANES III, Ahn
rogate measures of glomerular filtration et al.40 supported an association between
rates32 (i.e., inflammatory burden), underlines periodontal disease and orodigestive cancers.
the benefit of periodontal treatment and From a therapeutic standpoint, several
health when managing patients with CKD. cancer treatments are found to be toxic to
oral tissues and can worsen underlying oral
CANCER AND PERIODONTAL disease or result in the development of new
DISEASE periodontal disease. Cancer treatments
Almost 11 million people in the United include chemotherapy, radiation therapy,
States are living with cancer or have a surgery, hormone therapy, biologic therapy,
history of cancer, with approximately 1.4 and targeted therapy. Furthermore, some
million new cases occurring yearly.35 Cancer cancers may involve the oral cavity and have
is a broad term used to describe a group of a local effect on oral tissues.
illnesses defined by uncontrolled growth of In recent years, periodontal disease has
abnormal cells that can occur anywhere in been shown to have an association with
the body. Many environmental and intrinsic many chronic diseases, including cardiovas-
factors have been implicated in the develop- cular disease and diabetes. Much of this
ment of various forms of cancer. Environ- association is thought to be secondary to the
mental factors include tobacco, chemicals, chronic inflammatory state.41 Recent studies
radiation, and infection. Intrinsic factors have shown a small but significant increase
include gene mutations, hormones, and in cancer risk in patients with periodontal
immune conditions. Many cancers are likely disease.38,42
caused by a combination of environmental
and intrinsic factors.35 Chemotherapy
Patients with cancer represent a unique Chemotherapeutic regimens were developed
segment of the dental population. The to target rapidly dividing cells such as tumor
overall higher incidence of cancer in patients cells. With that concept in mind, it is logical
suffering from long-term inflammatory con- to draw an association between these thera-
ditions36 has encouraged researchers to con- pies and side effects impacting the gastroin-
sider possible links between chronic inflam- testinal tract. Oral toxicity associated with
matory periodontal disease and cancers.1 chemotherapy in cancer patients is a
Indeed, poor oral health in general, includ- common side effect of these medical regi-
CHAPTER 17 Kidney Disease, and !Cancer ! ! ! ! ! ! 319
mens,
! which
! ! can affect! the entire ! ! alimentary ! ications is not essential to this! discussion, but
tract.
! Symptoms ! ! are numerous, ! such as it is important ! ! to understand ! how they exert !
lesions of the oropharynx, dysphagia, gastri- their !effects on! tissues. Reactive ! ! ! oxygen !
tis, and diarrhea. species! cause! damage! to the! DNA ! ! of tumor !
Mucositis is a term ! used to! describe ! cells !as well! as healthy !tissue.! Damaged ! cells
!
inflammation ! ! of! the mucous ! membranes
! ! undergo ! apoptosis, ! setting ! into motion!! the!
lining
! the! oral cavity ! !and !digestive! tract. ! Oral ! body’s normal ! response! to cell death, ! which
mucositis
! !is commonly
! ! ! reported and ! is esti- includes
! increased activity ! of the ! immune !
mated! to be found ! ! in ! 35% to ! 40% of system. ! Activation
! of! the immune
! system
!
patients
! receiving !cytotoxic ! chemotherapy;
! ! increases
! the! concentration
! ! ! of proinflamma- !
the incidence ! ! is higher in !those ! undergoing ! tory! molecules
! ! ! in the! internal
! !milieu, ! such as
hematopoietic
! ! ! stem ! cell! !transplantation ! cytokines and ! ! biologically ! ! active
! proteins. !
(HCT).43 !Many !factors ! contribute ! ! to ! the Normal
! healing
! ! is !compromised ! ! by ! the per-
development ! ! of mucositis.
! ! Tissue ! sistence
! of the!offending ! agent.
! ! !
damage/cell ! death, ! ! stimulation
! of !a proin- ! ! ! ! !
flammatory
! !state,! and interference with Oral Mucositis:
! ! ! Ulcerative ! ! oral
! mucositis ! ! ! is
normal tissue healing ! ! ! are ! direct ! !and indirect ! one of !the more ! common ! side!! effects associ- !
effects of the ! medications.
! ! !This final chapter ! ated with
! chemotherapy.
! ! As
! previously
! ! men-
section
! ! focuses ! ! on complications ! ! ! of tioned, prevalence
! ! ! among ! cancer
! patients !
chemotherapeutic! ! regimens
! !and ! !HCT treated !with chemotherapeutic
! ! ! regimens
! ! can
involving ! ! the ! oropharynx, ! ! ! pretreatment
! ! ! con- be as high ! ! as !40% or even ! higher ! in patients !
siderations, ! and management ! of these
! ! issues.
! undergoing HCT. ! ! Intensive chemotherapy !
! ! ! ! can cause
! ! !ulcerative! mucositis ! !that! emerges
!Chemotherapeutic ! ! !Effects ! approximately
! 2 ! weeks ! after initiation ! of
Many chemotherapy ! ! regimens ! ! are! available, high-dose ! ! chemotherapy. ! 44 ! Risk ! factors for !
depending ! ! on the !type of! cancer. Some ! of development
! !of mucositis include younger
the more common ! ! ! agents associated ! with
! age, quality of dental hygiene, and level of
oral toxicity ! include ! !alkylating ! agents,
! immunosuppression! before the initiation of
anthracyclines,
! ! antimetabolites,
! ! ! ! antitumor therapy. The ulcerations ! ! associated ! ! with ! !oral
antibiotics,
! ! taxanes, ! and! topoisomerase ! ! mucositis
! can be ! extremely
! !painful and! may
inhibitors.! Many ! more anticancer ! drugs! are interfere with ! the! patient’s !capacity for
associated ! with !oral! toxicity; a more ! compre- required nutritional
! !intake. !Subsequent ! infec-
hensive list can be ! seen ! in Table 2. !The! indi- tion !is another noted problem ! associated
! ! with !
!vidual mechanism of action of these med- these! !lesions. ! ! Considering
! ! ! the level ! of!
Table 2. Chemotherapeutic Agents Associated with Oral Toxicity and Mucositis

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+3J3@7E 6A5F73J7>0!B35>;F3J7>
+ABA;EA?7D3E7!;@:;4;FADE 7FABAE;670!FABAF753@0!;D;@AF753@0!F7@;BAE;67
Adapted!from !UpToDate, 2010.
immunosuppression linked to chemotherapy, control trial, palifermin was shown to reduce

these are clinical findings that need to be the incidence of severe mucositis compared
identified and addressed in a timely fashion with the placebo group.47 Granulocyte-
by medical and dental practitioners. If symp- macrophage colony-stimulating factor
toms are severe, modification of the mouthwashes are also recommended for the
chemotherapeutic agents as well as dosing prevention of mucositis in this patient popu-
may be necessary. Mucositis is considered to lation. Low-level laser therapy has been rec-
be self-limited and usually resolves within 14 ommended in clinical guidelines as part of
days of cessation of chemotherapy. This may pretreatment for HCT patients. However,
coincide with the recovery of granulocytes, this therapy is expensive and not widely
but has not been shown to have a linear rela- available, and there is limited objective evi-
tionship. Other less common side effects are dence to support its efficacy. Cryotherapy is
xerostomia, hemorrhage, and neuropathy. also recommended for the prevention of oral
mucositis. It is important to remember that
Preventing Oral Mucositis: There are limited many of these guidelines are based on expert
objective data that support the concept of opinion; further clinical research is necessary
dental therapy prior to the initiation of treat- to validate such protocols.
ment for cancer. Many feel that aggressive
preventive dental care limits the extent of Treating Oral Mucositis: The treatment of
oral complications associated with such patients with established oral mucositis is
medical therapy. However, one study pro- supportive. Soft diets are a good choice to
posed that such measures had no impact on reduce the incidence of trauma to already
overall outcome.45 Practice guidelines con- friable tissue. Practitioners need to encourage
cerning oral prophylaxis for mucositis were sound oral hygiene practice because this
published in 2007 by the Mucositis Study reduces the incidence of secondary infection
Section of the Multinational Association of and promotes timely healing. Soft tooth-
Supportive Care in Cancer and the Interna- brushes, nonirritating oral rinses, and
tional Society for Oral Oncology removal of dentures should all be encour-
(MSSMA/SCCISO).46 For patients undergo- aged as part of routine care. Mucosal
ing standard chemotherapy, evaluation by a coating agents have been used, although
dental practitioner is encouraged before the data to support their efficacy are weak.
initiation of therapy. Interval assessment is Oral solutions including lidocaine,
recommended to evaluate oral cavity health, diphenhydramine, and morphine sulfate all
including the use of validated tools such as have been used as analgesic control for oral
the National Cancer Institute Common Tox- mucositis. The MSSMA/SCCISO panel rec-
icity Criteria or the University of Nebraska ommended systemic morphine as the treat-
Oral Assessment Score to ascertain the ment of choice for HCT patients with oral
severity and clinical course of mucositis. pain associated with severe oral mucositis.46
In patients undergoing high-dose Cautious evaluation of the neutropenic
chemotherapy plus HCT, preventive meas- patient is critical. These patients may present
ures have recently been developed and are with reduced signs and symptoms secondary
currently recommended for routine use. Pal- to myelosuppression. Antimicrobial therapy
ifermin is a keratinocyte growth factor-1 early in the course of infection is required to
stimulator. It accelerates growth of epider- avert potentially catastrophic complications.
mal cells including those of the gastrointesti- Studies have shown that oral and periodon-
nal tract. In a double-blinded randomized tal assessment and management reduce the
risk of infection and fever associated with leukemia. Within these main categories
oral conditions.36 Studies have also shown several subtypes exist. In addition, some less
that pretreatment oral care and oral care common forms of leukemia do not fit well
during therapy results in reduced oral com- into any of these categories.
plications with no increase in risk of fever or In all forms of leukemia, bone marrow
bacteremia.48 function is impaired. Anemia, thrombocy-
In summation, the complication of oral topenia, and impaired immunity often result.
mucositis has a very high incidence among These changes can result in gingival hemor-
cancer patients treated with chemotherapy. rhage, oral ulcerations, and increased oral
Clinical guidelines were published in 2007 out- infections.49,50 Treatment with chemotherapy
lining recommendations for the pretreatment and stem cell transplantation can contribute
of cancer patients at risk for developing oral further to this by causing increased bone
mucositis. Although preventive measures such marrow suppression as well as toxic effects
as palifermin and cryotherapy are recom- on oral tissues.
mended for high-dose chemotherapy patients, When evaluating a patient with leukemia
the basis of care is sound oral hygiene and who has gingival lesions, it is often difficult to
regular assessment by a dental practitioner. distinguish between changes due to the
Although oral mucositis is considered to be a disease process and those brought on by
self-limiting phenomenon, supportive care is treatment. To better characterize gingival
necessary to ameliorate the invasive symptoms lesions in patients with leukemia, a classifica-
associated with this complication. Special tion system has been proposed. This classifi-
attention needs to be given to the neutropenic cation system consists of four major cate-
patient because infection in this patient popu- gories: direct infiltration, direct drug toxicity,
lation is potentially life-threatening. graft-versus-host disease, and bone
marrow/lymphoid tissue suppression.51
Leukemia and the Oral Tissues It is important for dental practitioners to
Leukemia, a disease of the bone marrow recognize that a patient may present with oral
and blood, is characterized by the malignant lesions prior to the diagnosis of leukemia.
proliferation of white blood cells. Leukemias Case reports have described gingival hyperpla-
are further categorized according to the cell sia, rapidly progressive periodontal disease,
type that is involved: myelogenous and lym- prolonged postextraction hemorrhage, and
phocytic. Futhermore, leukemias are catego- gingival pain as presenting symptoms that led
rized as acute or chronic. Chronic leukemias to various leukemia diagnoses.49,52
occur more commonly in older persons and
are characterized by the excessive prolifera- Radiation Therapy in Head and Neck Cancer
tion of relatively mature, abnormal white Head and neck cancer comprises cancer of
blood cells. Typically, these leukemias the oral cavity, pharynx, larynx, salivary
progress over a period of months to years. glands, nasal cavity, paranasal sinuses, and
Acute leukemias are characterized by a rapid neck lymph nodes. Most head and neck
proliferation of immature white blood cells. cancers are squamous cell carcinomas.
Acute leukemias are the most common form Patients undergoing head and neck radiation
of leukemia in children, but they can also treatments are at risk for a variety of oral
affect adults. The four major classifications complications. These complications include
of leukemia are acute lymphocytic leukemia, mucositis, dysgeusia (altered sense of taste),
acute myelogenous leukemia, chronic lym- xerostomia (dry mouth), dental caries, peri-
phocytic leukemia, and chronic myelogenous odontal disease, and osteoradionecrosis. Col-
laboration among physicians and dental pro- tissue fibrosis of the salivary glands. The
fessionals is necessary to provide optimal care. result is both dose- and location-dependent.
Preradiation oral assessment and inter- Higher radiation doses and involvement of
vention, followed by the implementation of large areas of salivary tissue result in more
an oral care program before and during severe cases of xerostomia. Patients with sig-
radiation, is essential to improve outcomes in nificant xerostomia have a much higher risk
patients undergoing radiation. A recent of developing dental caries. For these
survey of healthcare professionals reported a patients, daily fluoride treatment and meticu-
75% referral rate for oral and dental assess- lous oral hygiene are recommended for the
ment before head and neck radiation. The prevention of dental decay.
same survey also reported that integrated Radiation can lead to alterations in vas-
dental and medical services were available at cularity of soft tissue and bone, reduced
only 25% of institutions.53 connective tissue cellularity, and increased
Mucositis is a common side effect of tissue fibrosis. The vascular changes result in
radiation therapy and has been reported in decreased blood flow to tissues, with con-
up to 80% of patients receiving radiation comitant tissue hypoxia and reduction in
therapy for head and neck cancer.54 Radiation tissue cellularity. This can have a deleterious
disrupts DNA replication in the basal layer of effect on bone and soft tissue in the oral
the oral epithelium. This leads to thinning of cavity. High-dose radiation has been shown
the epithelium and eventual ulceration of oral to contribute to tooth loss and greater peri-
tissues. The ulcerative phase is worsened by odontal attachment loss. Furthermore, peri-
local bacterial colonization.54 odontal attachment loss has the potential to
As in patients with chemotherapy- lead to osteoradionecrosis.55
induced mucositis, the cornerstone of Osteoradionecrosis is a less common
therapy in patients with radiation-induced but potentially devastating side effect of radi-
mucositis is adequate pain management and ation that primarily occurs in the mandible
maintenance of oral hygiene. Recent guide- and is a condition defined by exposed bone
lines specific to radiation-induced mucositis in areas of radiation injury. A recent retro-
support the use of midline radiation blocks spective study of 207 patients who received
and three-dimensional radiation therapy to radiation therapy showed osteoradionecrosis
minimize mucosal damage. The guidelines in 5.5% of patients.56 This complication
also recommend benzydamine, a locally occurs as a result of decreased wound
acting NSAID, for mucositis prevention in healing. It can occur spontaneously, but
patients exposed to moderate doses of radia- more frequently occurs after tissue trauma
tion. Because of a lack of clinical benefit, resulting in exposed bone, especially dental
the guidelines recommend against routine extraction. Preradiation assessment for
chlorhexidine rinses and antimicrobial potential problems and appropriate preradia-
lozenges to prevent radiation-induced oral tion extractions can help limit postradiation
mucositis. They also recommend against dental extractions and the potential develop-
sucralfate in the treatment for radiation- ment of osteoradionecrosis.
induced mucositis.46
Dysgeusia and xerostomia are common Surgery
side effects of radiation. Radiation therapy Surgical resection is an important treatment
can damage taste buds, and in some cases modality for head and neck cancers. Unfor-
lead to permanent taste loss. Radiation leads tunately, these surgeries are frequently disfig-
to atrophy, vascular damage, and connective uring and debilitating. Furthermore, infec-
tion of the oral cavity can lead to significant Recommendations for Cancer and Periodontal
setbacks in recovery and can delay adjunc- Disease Management
tive chemotherapy or radiation. Thorough Patients with cancer represent a unique
preoperative oral and dental evaluation can segment of the dental population. Many
help to improve outcomes. Patients who cancer treatments are toxic to oral tissues.
undergo significant resections often require On the other hand, chronic oral infectious
removable prostheses to maintain function and inflammatory conditions such as peri-
and may also undergo skin grafting as part odontal disease and endodontic lesions may
of the surgical procedure. Intraoral prosthe- contribute to cancer risk, and if they persist
ses can aid in speech and nutrition, whereas or exacerbate during cancer therapy, these
extraoral prostheses can help to reduce dis- conditions could be a source of life-threaten-
figuration. Regardless of the type of prosthe- ing infection. Pretreatment dental evaluation
sis, a preoperative meeting with the patient of the cancer patient is highly recommended
and family can help them know what to and can help identify potential problems and
anticipate postoperatively. Close postopera- facilitate the management of anticipated side
tive monitoring of the surgical site is essen- effects of therapy.
tial. When applicable, the skin graft site Dentists and physicians need to work
should be monitored for viability. During the together to plan care for their patients. In
initial postoperative evaluation, the patient particular, there should be a pretreatment
can be instructed in an oral care regimen, as oral evaluation for any existing periodontal,
well as oral opening exercises to aid in recov- carious, or endodontic problems that may be
ery of function. Several mechanical devices a future source of chronic infection or that
are commercially available that can aid in may be exacerbated by cancer treatment, or
oral opening exercises.57,58 if cancer therapy involves treatments that
reduce resistance to infection. Treatments
PERIODONTAL DISEASE AND that may induce xerostomia, such as radia-
CANCER RISK tion therapy, should be performed only with
This section has focused on the effect of the understanding that the reduced salivary
cancer treatments on oral tissues. A multidis- flow may result in rampant caries and oral
ciplinary approach, with involvement of mucosal problems that need to be prevented
medical and dental professionals, is necessary or regularly checked for and treated.
to optimize oral care in cancer patients.
However, note that poor oral health may be Supplemental Readings
a risk factor for the development of cancer.
Khosla S, Burr D, Cauley J, Dempster DW, Ebeling
Many studies have demonstrated the inflam- PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka
matory effects of periodontal disease, and S, McCauley LK, McGowan J, McKee MD, Mohla S,
this inflammatory state might have an effect Pendrys DG, Raisz LG, Ruggiero SL, Shafer DM,
on the development of cancer. A relation Shum L, Silverman SL, Van Poznak CH, Watts N,
appears to exist between tooth loss and head Woo SB, Shane E. Bisphosphonate-associated
osteonecrosis of the jaw: report of a task force of the
and neck cancer that is independent of American Society for Bone and Mineral Research. J
alcohol and tobacco use. Furthermore, tooth Bone Miner Res 2007;22:1479–91.
loss has been shown to be a risk factor for
the development of esophageal, gastric, and Craig RG. Interactions between chronic renal disease
pancreatic cancers. Also, periodontal disease and periodontal disease. Oral Dis 2008;14:1–7.
has been associated with a small, but signifi- Kadiroglu AK, Kadiroglu ET, Sit D, Dag A, Yilmaz
cant increase in overall cancer risk.38,42 ME. Periodontitis is an important and occult source of
inflammation in hemodialysis patients. Blood Purif Bone and Mineral Research. J Bone Miner Res
2006;24:400–4. 2007;22:1479–91.
9. Sambrook P, Olver I, Goss A. Bisphosphonates
Williams RC, Barnett AH, Claffey N, Davis M, Gadsby and osteonecrosis of the jaw. Aust Fam Physician
R, Kellett M, Lip GY, Thackray S. The potential 2006;35:801–3.
impact of periodontal disease on general health: a con- 10. Woo SB, Hellstein JW, Kalmar JR. Narrative [cor-
sensus view. Curr Med Res Opin 2008;24:1635–43. rected] review: bisphosphonates and osteonecrosis
of the jaws. Ann Intern Med 2006;144:753–61.
Epstein JB, Stevenson-Moore P. Periodontal disease and 11. Bamias A, Kastritis E, Bamia C, Moulopoulos
periodontal management in patients with cancer. Oral LA, Melakopoulos I, Bozas G, Koutsoukou W,
Oncol 2001;37:613–9. Gika D, Anagnostopoulos A, Papadimitriou C,
Terpos E, Dimopoulos MA. Osteonecrosis of the
Jham BC, Reis PM, Miranda EL, Lopes RC, Carvalho jaw in cancer after treatment with bisphosphonates:
AL, Scheper MA, Freire AR. Oral health status of 207 incidence and risk factors. J Clin Oncol
head and neck cancer patients before, during and after 2005;23:8580–7.
radiotherapy. Clin Oral Investig 2008;12:19–24. 12. Ruggiero SL, Dodson TB, Assael LA, Landesberg
R, Marx RE, Mehotra B. American Association of
Toth BB, Chambers MS, Fleming TJ, Lemon JC, Oral and Maxillofacial Surgeons position paper on
Martin JW. Minimizing oral complications of cancer bisphosphonate-related osteonecrosis of the jaws–
treatment. Oncology (Williston Park) 1995;9:851–8; dis- 2009 Update. J Oral Maxillofac Surg 2009;67:2–12.
cussion 858, 863–6. 13. Proctor R, Kumar N, Stein A, Moles D, Porter S.
Oral and dental aspects of chronic renal failure. J
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CHAPTER 18
Role of the Professional in Educating
the Public About the Importance of
Oral Health
Casey Hein
INTRODUCTION care practitioners to educate patients. Health

Health outcomes have long been recognized, outcomes—beyond the oral cavity—may be
in part, as a function of health literacy and positively influenced by effective patient edu-
education of the public.1 The level of health cation and health literacy campaigns target-
literacy, or level of knowledge necessary to ing oral health.
guide healthy living within a population, is Information about the relation between
one of the strongest social determinants of oral and systemic health started to be dissem-
health within a society. Limited healthcare inated to the public from a number of
literacy has been implicated in undermining sources beginning in the 1990s. Various public
the public’s ability to fully benefit from what relations campaigns have increased the aware-
healthcare systems have to offer. Lack of ness of the connection between oral and sys-
oral health knowledge presents an obstacle temic health among a broad audience of con-
to better oral health care in the United sumer-patients. Information from the lay
States.2,3 Almost 50% of all Americans lack press, mainstream radio and television, uni-
adequate oral health skills, which may versity- and government-sponsored public
account for billions of dollars in added health outreach to local communities, insur-
healthcare costs each year.2,3 It is important ance industry campaigns, and commercial
to consider whether a lack of adequate prac- advertising associated with oral care products
titioner-to-patient communication may be have provided highly visible and effective
implicated in the challenges we face regard- mechanisms for educating the public about
ing oral health literacy. the significance of oral health. However,
Oral diseases are often a source of over- nothing can be as powerful as practitioner-to-
looked infection and systemic inflammation patient education. The time dentists and
that has the potential to affect overall health. dental hygienists spend with individual
As such, oral diseases have been termed a patients presents a valuable opportunity to
“silent epidemic.”4 Given the strength of evi- communicate credible findings of research
dence that supports interrelationships related to systemic inflammation associated
between oral and overall health, educating with oral infections. In addition, as point-of-
consumer-patients about the threat that oral care providers, dentists and dental hygienists
infections may pose to general health can no are uniquely positioned to identify patients
longer be considered optional. Both dental who are at risk for chronic diseases such as
and nondental healthcare practitioners, such diabetes, cardiovascular disease (CVD), and
as physicians, nurses, and allied healthcare obesity—all of which share risk factors
providers, share in the responsibility to common to oral diseases.
educate the public regarding the significance As the depth and breadth of evidence
of oral health in achieving and sustaining supporting an association between periodon-
whole body health. Codes of professional tal diseases and several common systemic
conduct convey a responsibility of health- inflammatory diseases continue to expand, the
preponderance of evidence suggests that to emerging evidence of periodontal-sys-

dental providers have a responsibility to temic relationships with a number of articles
appropriately and effectively communicate this that call attention to the likelihood that peri-
information to patients. odontal disease is an often overlooked and
In the case of diabetes, 20 years of con- unrecognized source of infection with the
sistent evidence suggests that severe periodon- potential to evoke a systemic inflammatory
titis has an adverse effect on glycemic control response.16–18 As these kinds of evidence-
in diabetes, and a direct and dose-dependent based, authoritative statements are circulated
relation exists between the severity of peri- within the medical professions, it is reason-
odontitis and complications of diabetes.5–8 able to assume that more and more physi-
More recent evidence provides support for the cians and allied healthcare providers will
increased risk for diabetes in patients with acknowledge the significance of oral health
severe periodontitis.8 Some studies have shown in achieving and sustaining overall health.
that treatment of periodontal disease may As a result, they will begin to screen for oral
improve metabolic control of diabetes. Large- diseases, educate patients about oral-sys-
scale, definitive trials are needed to determine temic interrelationships, and pursue collabo-
whether periodontal treatment may alter rative relationships with dental practitioners
glycemic control. Similarly, in the case of preg- in the comanagement of inflammatory-
nancy outcomes, several pilot trials have shown driven disease states. Already, informally
a reduction of adverse pregnancy outcomes gathered information from physicians in spe-
associated with periodontal treatment.9–10 cialties such as endocrinology, cardiology,
However, a large study failed to show a reduc- obstetrics, rheumatology, pulmonology, and
tion in adverse pregnancy outcomes associ- nephrology, among others, substantiate that
ated with treatment of periodontal disease.11 medical practitioners are beginning to incor-
In a recent consensus opinion, researchers porate credible evidence of oral-systemic
suggested the possibility that different types of relationships into their practices. Simultane-
periodontal treatment (and timing and inten- ously, medical protocols that include peri-
sity of treatment), in specific populations of odontal screening and monitoring of clinical
women, might provide greater insight into the outcomes related to the oral care of patients
possibility that intervention of periodontal who may have a greater risk for CVD and
disease may decrease the risk for adverse preg- diabetes are beginning to emerge.18
nancy outcomes.12 Several studies have
assessed the effect of periodontal therapy on Educational Objectives
cardiovascular outcomes and have shown After reviewing the information presented in
improvement in endothelial function.13–15 this chapter, readers should be able to:
However, large, randomized, controlled trials • Discuss how the limitations in oral
are needed to look at the effects of periodon- health literacy present a barrier to
tal therapy on cardiovascular outcomes. Even effective prevention, diagnosis, and
though no definitive data are yet available on treatment of oral diseases.
the effects of periodontal treatment on several • Describe various sources of infor-
conditions linked to periodontal disease, asso- mation and statistics about the rela-
ciation data are strong. Accordingly, educating tion between oral and systemic health
patients about oral-systemic relationships is that suggest consumer-patients are
appropriate to ensure that their treatment aware of the importance of oral
decisions are well informed. health in achieving and maintaining
The medical profession has responded overall health.
CHAPTER 18 About the Importance of Oral Health 329
• Identify various hurdles that dental interrelationships at genetic and molecular

practitioners face in effectively educat- levels are changing the perceptions of non-
ing patients about oral-systemic dental healthcare providers regarding the
health and describe ways to address importance of oral health. Indeed, the shift
these obstacles. from an infection model to an inflammation
• Describe the responsibility of dental model relative to the threat that periodontal
professionals in ensuring that only sci- disease poses to overall health, has garnered
entifically supported evidence of oral- the attention of the medical community.
systemic relationships is communi- Medical journals—including some of the
cated to patients. most prestigious—are increasingly reporting
• Elaborate on the professional devel- evidence of oral-systemic relationships. In
opment process that will distinguish addition, governmental reports,4,21 educa-
individual dentists and dental hygien- tional institutions,22,23 and professional associ-
ists as authoritative experts in evi- ations24 have called for educational reform
dence of oral-systemic relationships. that would increase the knowledge of non-
• Identify ways in which dentists and dental healthcare providers regarding oral
dental hygienists can influence the health and collaborative models of care. This
public’s perception of the importance of would bring together dental and nondental
oral health outside the practice setting. healthcare providers to focus on interprofes-
sional, comprehensive chronic disease man-
THE PROCESS OF CHANGE IN agement that includes oral care.
INFLUENCING THE PUBLIC’S The insurance industry has investigated
PERCEPTION OF THE IMPORTANCE the potential cost savings associated with
OF ORAL HEALTH treatment of periodontal disease and found
“Because oral diseases in general are treat- that medical costs associated with chronic
able and usually not life threatening, they diseases such as CVD and diabetes may be
have been erroneously perceived as having significantly reduced when patients are
little relationship to other aspects of health, treated for periodontal disease.25,26 Although
often being viewed as of minor importance these studies do not prove cause and effect,
in the social and economic context.”19 This they are sufficient for insurance companies
opinion reflects the all-too-real disconnect to be more liberal in their coverage for peri-
between oral and overall health and there- odontal therapy and maintenance for their
fore has far-reaching implications. The his- clients with diabetes and CVD. In addition,
torical schism between dentistry and medi- various guidelines created by the health
cine, and consequently segregation of the departments of state agencies have begun to
oral cavity from the rest of the body, has address the importance of oral health in the
helped to contribute to the disparities that overall health of their citizenry.27,28
currently exist in oral health among Ameri- Changes in public policy, increased
cans.4 The failure to recognize oral health as insurance reimbursement, and improved
integral and essential to general health has medical/dental education undoubtedly will
also made an adverse impact on healthcare facilitate interdisciplinary collaboration
policy.20 between the healthcare professions; however,
Today, greater appreciation of the sig- this magnitude of change is unlikely to
nificance of inflammation in prevention and happen in the short term. In the interim,
management of chronic diseases and mount- educating the public through commercially
ing evidence in support of oral-systemic supported media campaigns, outreach from
professional organizations and universities, information have appeared in the main-

and individual practitioner-to-patient educa- stream media about the relation between
tion are essential in helping the public repri- oral and systemic health, including lay publi-
oritize the importance of oral health and its cations,29 television,30 and radio.31 In 2004,
implication to overall health. Time Magazine committed an entire issue,
The answers to the following five ques- “The Secret Killer,”32 to help readers explore
tions provide a reference point to guide practi- the link between inflammation and various
tioner-to-patient communication and articulate life-threatening conditions such as heart
messages that are essential to successful patient disease. The article introduced readers to
education in oral-systemic health: some fairly sophisticated scientific concepts
1. How much do consumer-patients that describe how the body’s efforts to heal
know about the threat inflammation the damage produced by infection and
poses to whole body health and oral- inflammation often end up causing perma-
systemic relationships? nent damage to certain organs and increas-
2. How important do consumer-patients ing the risk for various systemic diseases.
believe oral health is in achieving and The article specifically discussed the potential
sustaining overall health? for periodontal disease to elicit such a
3. How well are dental practitioners doing cascade of events: “It appears that some
regarding educating patients about people are more sensitive to plaques and
oral-systemic relationships, and what tangles than others. Perhaps they have a
are the hurdles involved in effectively genetic predisposition. Or perhaps a long-
communicating this information to running, low-grade bacterial infection, like
consumer-patients? gum disease, keeps the internal fires burning
4. What research should be credibly com- and tips the balance toward chronic infec-
municated to patients about the relation tion.”32 If readers can comprehend such
between periodontal disease and inflam- sophisticated information, it is reasonable to
matory-driven disease states, such as assume that the public is becoming increas-
coronary heart disease, stroke, diabetes, ingly aware of the relation between peri-
and adverse pregnancy outcomes? odontal disease and inflammatory-driven
5. In addition to individual practitioner- disease states.
to-patient communication, what types CNN News jump-started the year 2009
of activities could dental practitioners with a segment on “How to Live Longer,”
pursue to change the perception of which aired on January 2 and was hosted by
nondental healthcare providers regard- Dr. Sanjay Gupta, CNN’s Chief Medical
ing the importance of oral health, and Correspondent.30 Gupta discussed several
thereby increase the public’s awareness simple modifications to lifestyle that he pro-
of oral-systemic relationships? posed would net increased longevity. He
cited using dental floss as the number one
CONSUMER-PATIENTS’ recommendation, explaining that oral care
KNOWLEDGE ABOUT could reduce inflammation, a known con-
ORAL-SYSTEMIC LINKS, THE tributor to an increased risk for heart
SIGNIFICANCE OF ORAL HEALTH, disease.
AND THE THREAT INFLAMMATION These are only a few of the many
POSES TO GENERAL HEALTH examples of information on oral-systemic
Help from Mainstream Media health that have been generated through
Over the last decade, numerous sources of mainstream media sources.
Snapshot of What the Public Knows about the risk of systemic consequences
Piecing together data compiled by various related to periodontal disease, and asked
professional and nonprofit organizations and what kind of treatment they would prefer
the insurance industry provides a snapshot when they next visit the dentist, two of three
of how well the consumer-patient public consumer-patients from a nationally repre-
understands the importance of oral health in sentative sample opted for periodontal exam-
achieving and maintaining overall health. inations rather than routine prophylaxis.37
Findings of a survey conducted in the year The survey question and results of the con-
2000 by the American Dental Association sumer-patient responses are included in
indicated that the majority of consumer- Figure 1.
patients are aware of a link between peri-
odontal disease and systemic consequences, Strength of Patient Education Campaigns
and more than 99% recognize that preven- Various professional organizations, such as
tion of periodontal disease is an important the American Academy of Periodontology
step in maintaining oral health.33 (http://perio.org/consumer/index.html), the
Other data indicate that 85% of Ameri- oral care industry (http://www.colgate.com/
cans believe that a strong connection exists app/ColgateTotal/US/EN/MBHC.cvsp), and
between oral health and general health.34 nonprofit organizations such as the Ameri-
The majority (77%) of Americans believe can Diabetes Association (http://www.dia-
that personal maintenance of their oral betes.org) among others, have mounted
health is very important to their own overall impressive web-based patient education cam-
health,35 and 80% of Americans agree that paigns targeting oral-systemic health.
taking care of one’s mouth, teeth, and gums The contribution of medical providers
is “absolutely needed.”2 When asked whether in educating patients about the potential of
“you take dental health into account when periodontal disease to elicit systemic inflam-
rating your overall health,” 78% of respon- mation and increased risk for chronic disease
dents of a randomly selected nationally rep- states cannot be overlooked. In a February
resentative survey of US adults indicated 2008 issue of the Journal of the American
that they did.36 A correlational analysis of Medical Association,38 a patient education
the same data showed that the public’s page (Figure 2) was dedicated to a discus-
rating of oral and overall health were sion of periodontal disease and its potential
strongly related (r = .46; P <.001). These association to heart disease, stroke, and pre-
data suggest that oral health and general mature birth. The article briefly defined the
health status are clearly connected in the causes, signs and symptoms, prevention, and
consciousness of Americans.36 treatment of periodontal disease and offered
other resources for additional information.
Patients’ Concerns About Periodontal Disease
Of 1,000 subjects from a randomly selected, Summary Points
nationally representative survey of US 1. Consumer-patients are very aware of
adults, 85% reported that it was “very the connection between oral health
important” for dentists to examine their and general health.
mouths for periodontal disease.36 Other data 2. A number of publications from the
confirm that patients want to be evaluated lay press and mainstream radio and
for periodontal disease because they are con- television have done an excellent job
cerned about the systemic implication of of educating consumer-patients on
periodontal disease. When briefly educated the threat that inflammation poses to
Figure 1. Question on Consumer-Patient Survey Conducted in 2005
The survey question first provided a very brief overview of the risk that “gum disease”
may pose in increasing the risk for serious systemic diseases. Then consumer-patients were
asked to respond to how important it is to be examined for periodontal disease at their
next check-up. Results follow.
An estimated 50%–80% of adults have some level of gum disease. More important is that over
the last 10 years, evidence has been increasing that periodontal disease may be associated with
serious systemic consequences. This includes the potential for increased risk for heart disease and
stroke and, for pregnant women with periodontal disease, includes an increased risk of delivering
preterm, low-birth-weight infants. Persons with impaired immune systems and periodontal disease
may have an increased risk for developing certain respiratory diseases. In addition, diabetics have
an increased risk for developing periodontal disease, and periodontal disease in diabetics often
makes metabolic control of blood sugar levels very difficult. For this reason, it is very important
for diabetics to have thorough periodontal evaluations.
Question: Given the evidence that periodontal disease may be linked to these kinds of serious
whole body diseases/conditions, at your next visit to the dentist’s office, would you rather be exam-
ined for periodontal disease or have your teeth cleaned?
❑ Examined for periodontal disease ❑ Have teeth cleaned
Results: There were 1,415 responses to this question. Of these, 945 (66.78%) of consumer-patients
answered that given the evidence that periodontal disease may be linked to serious whole body dis-
eases/conditions, they would prefer to be examined for periodontal disease rather than to have their
teeth cleaned at their next visit to the dentist’s office.
Adapted from Hein C et al. Presented at 83rd Annual Session of the American Dental Hygienists’ Association;
Orlando, Florida; June 2006.37
whole body health and the potential ADVANCING PATIENT EDUCATION

of periodontal disease to incite an IN ORAL-SYSTEMIC HEALTH
inflammatory response. The American Dental Association Weighs in
3. Consumer-patients seem to be aware on Low Oral Health Literacy
that prevention of periodontal disease The American Dental Association (ADA)
is important in maintaining overall has defined oral health literacy as “the
health, and subsequently want to be degree to which individuals have the capacity
evaluated for periodontal disease to obtain, process, and understand basic
because they are concerned about the health information and services needed to
systemic implication of periodontal make appropriate oral health decisions.”3 It
disease. is recognized that people with low oral
4. Numerous sources of information are health literacy are often less likely to seek
available for educating patients in preventive care, comply with prescribed treat-
oral-systemic health, including web- ment, and maintain self-care regimens; as
sites designed for direct access of con- such, limited oral health literacy is a poten-
sumer-patients and printed materials tial barrier to effective prevention, diagnosis,
supplied by professional organizations and treatment of oral disease.3
that can be disseminated by health- People with limited literacy complain
care practitioners. that they are not given information about
! ! ! ! ! ! !
! ! ! ! ! ! ! ! ! !
Figure 2. Patient Education Article About Periodontal Disease
! ! ! ! !
As! a! public! service! of! JAMA,! the! organization! has! permitted! this
! article! to
! be! photocopied
! ! ! ! ! ! ! ! !
noncommercially by physicians and other healthcare professionals to share with patients. !
Reprinted! with! permission !from !Torpy JM,

! !Burke AE,
! Glass
! !
RM. !
JAMA !2008;299:5.38
! health! status
their ! in a format they! can com-
! those with! low! literacy! levels
! ! and tailor
!
! ! ! ! ! ! !
prehend, sending them off uninformed, frus- ! ! ! !
patient education communications accord-
! ! and
trated, ! !
distrustful. ! ! suggests
39 Research ! ! long-term
ingly, ! ! !
dental ! medical out-
and !
!
that when healthcare providers can identify ! ! ! ! !
comes may improve. The National Assess-
40 !
ment of Adult Literacy reported that over cans have difficulty obtaining, processing, and
90 million adults in the United States (2003 understanding basic health information and
data) were functionally or marginally illiter- services needed to make appropriate health
ate.41 Who are these individuals? decisions.1 This calls attention to the impor-
We know that children whose parents tance of healthcare providers improving their
have low literacy often have worse health communications skills and delivering patient
outcomes.42–44 Factors that may negatively education in such a way that it can be readily
influence oral health literacy include non- understood and acted on by patients.
white ethnicity, limited ability to speak Given such strong data that suggest that
English, and low level of education.45 People patients understand the correlation between
in disadvantaged populations often define oral and systemic health, it is reasonable to
oral health in terms of social aspects such as assume that dental providers are conveying
the appearance of their mouth and how the and reinforcing this information. However,
decline in their oral health may have a devas- evidence that dental practitioners are doing
tating impact on self-esteem, social interac- an adequate job in educating their patients is
tion, and employability. This research sug- not readily apparent when searching the pro-
gests that in this high-risk population, more fessional literature or reviewing survey data
emphasis should be placed on the systemic generated by professional organizations.
impact of periodontal disease.46 Although more than 75% of 1,000 subjects
It has been suggested that for people in a randomly selected, nationally representa-
with diabetes, information regarding the pos- tive survey of US adults believe oral health
sible effects that diabetes has on oral health is integral to overall health, it is disconcerting
would be beneficial, especially at the time to find that in the same survey, only 51%
that diabetes is diagnosed.47 Unfortunately, responded that their dentist discussed the
research suggests that some diabetes educa- relation between oral and overall health.36
tors do not routinely provide comprehensive An estimated 33% of dental patients
oral health education and that this is because may not know that periodontal disease
of lack of time and knowledge related to needs to be treated and should not be left
oral health. By integrating oral health educa- alone2; another 33% believe that a little
tion in the diabetes education curriculum, bleeding from brushing is normal.2 Although
perhaps future certified diabetes educators 83% of US adults may say their dentist is
can better serve patients.48 their primary source of information on oral
Another population that may benefit care practices, a significant percentage of
from customized patient education in oral- these adults also report that they have not
systemic health is pregnant women with discussed their oral health issues with a
certain ethnic backgrounds, especially in the dental professional.2 This is especially trou-
Hispanic population. The inclusion of oral bling when considering that more than 50%
health education materials that are specifically of adults living in the United States experi-
tailored to pregnant women with low literacy ence one or more oral health conditions.2
should become a part of prenatal care.49 These types of responses from con-
sumer-patients mirror the disturbing findings
ADDRESSING ORAL HEALTH reported by various researchers when they
LITERACY IN DENTISTRY AND studied dental providers’ track records in
DENTAL HYGIENE providing smoking cessation counseling. For
In a 2004 National Institutes of Medicine instance, it has been estimated that only
report, an estimated 90 million adult Ameri- 30%–50% of dentists and 25% of dental
hygienists in the United States ask their Lack of Training in Oral-Systemic Science
patients about smoking,50,51 and the cessation Oral-systemic science may not have been
advice provided in dental offices has been emphasized during a dentist’s or dental
described as “rather ad hoc and somewhat hygienist’s formal education and training.
superficial.”52 Another study found that Many are unclear about the credibility of
when comparing tobacco-use cessation serv- the science or strength of evidence; others
ices provided by various types of healthcare are uncertain about the etiologic mecha-
providers, interventions by dental providers nisms that have been implicated in many
ranked lowest (compared with physicians, oral-systemic relationships and are uncom-
mental health counselors, and social fortable with how these interrelationships
workers) in both quantity and quality of should be explained to patients.
services.53 Lack of training and incentives Results of a survey of North Carolina
were most often cited to explain the reluc- dental hygienists published in 2012 suggest
tance of dentists and dental hygienists to that although dental hygienists may have a
provide tobacco cessation interventions.54 high level of knowledge in some areas of
oral-systemic science, they need to improve
Dismantling Hurdles to their confidence levels and knowledge
Effectively Educate Patients About through expanded content in their educa-
Oral-Systemic Health tional programs and continuing education.55
By virtue of the frequency by which people Another study found that many adults with
visit dentists for check-ups and routine pro- diabetes are unaware of the importance of
phylaxis, dentists and dental hygienists are in oral care and receive inadequate counseling
a unique position to deliver a pivotally from healthcare providers. This suggests that
important message to patients about oral- both oral and nondental healthcare
systemic health. However, this opportunity providers need more education and training
is often forfeited. One of the greatest hurdles in oral health care in diabetes.56
in effectively communicating information Organized dentistry has recently taken
about issues related to oral-systemic health on the monumental task of planning for
is that dentists are often reluctant to discuss educational reform, much of which is related
issues that patients may perceive as unpopu- to revision of curricula to include more
lar. However, evidence that patients are con- comprehensive education in oral-systemic
cerned about periodontal disease suggests relationships, immunology, genetics, and
that the opposite may be true.36,37 Some den- molecular biology.23,57–59 For professionals
tists may believe that their involvement in already in practice, numerous opportunities
greater systemic sequelae of oral infections exist for continuing education in oral-sys-
and inflammation falls beyond their scope temic science. A routinely conducted litera-
of practice. However, data suggest a growing ture search of studies related to oral-systemic
trend in patients starting to view dentists as relationships, which includes both medical
overall healthcare providers.36 Accordingly, it and dental journals, will provide practition-
is crucial that dentists lead the charge in ers with the most up-to-date information.
conveying to patients the importance of
maintaining both oral and overall health.36 Ineffective Communication Skills
Other hurdles associated with effectively A dentist or dental hygienist may have inade-
communicating important information quate communication skills.
about oral-systemic health include the fol- Practitioner-to-patient counseling is the
lowing barriers: most effective way to increase a consumer-
patient’s understanding of the significance of dentists; delivering exceptional customer

oral health, assuming that practitioners have service, advocating patient education, and
adequate communication skills. It is unclear developing customized home care regimens
whether patients believe their dentists are as were cited as key in developing long-term
concerned with their overall health as they patient retention. The author concluded,
are with their oral health.36 As such, dentists “By demonstrating a strong commitment to
and dental hygienists must start to consider customer service, education, and home care,
the liability associated with a limited view of patients recognize that oral healthcare
their responsibility to ensure patients’ oral- providers are interested in their well-being
systemic health, must become proactive in rather than simply treating problems.”60 It
advocating for comprehensive education of seems clear that the public wants a different
patients, and should master effective commu- approach to dental care, and practitioners
nication skills. who provide effective patient education and
The first step in increasing patients’ under- risk-counseling services will be well posi-
standing of oral-systemic relationships is to tioned to grow their practices, even during
provide the right kind of training to ensure economically challenging times.
that all members of the dental team are able to
effectively communicate key messages related Summary Points
to oral-systemic health and to be prepared to 1. Because of a profound limitation in
appropriately answer patients’ questions. oral health literacy within the United
States, a large percentage of the
Scheduling Limitations public is not able to obtain, process,
Scheduling often does not allow for time to and make appropriate decisions
counsel patients; likewise, there are no incen- about their oral health. This disparity
tive or reimbursement mechanisms available contributes to avoidable healthcare
for patient education/counseling. spending in the magnitude of billions
Regardless of whether an incentive of dollars each year. The American
exists to educate and counsel patients, dental Dental Association recognizes the
providers are increasingly expected to severity of the lack of oral health lit-
perform these important services. A survey eracy in the United States and is
of the public’s perception of dentistry indi- taking steps to address this disparity.
cates that consumer-patients may see the 2. It is unclear whether the majority of
dentist’s role as much larger than the practic- dentists and dental hygienists are
ing dentist sees it and that patients may see proactively educating patients about
their dentist more as a physician than den- the relation between oral and sys-
tists see themselves.36 Patients expect dentists temic health; however, this is an
to discuss serious health issues they might be important factor to consider in deter-
confronting and not just discuss the tradi- mining why oral health literacy is so
tional expectations of dental services.36 A limited within the United States.
well-recognized practice management 3. A number of hurdles can prevent
expert60 noted that compared with previous dental practitioners from effectively
decades, more dental patients are “shopping communicating information about
around” for dental care and changing dental issues related to oral-systemic health.
practices. The availability of more compre- Dentists and dental hygienists must
hensive service offerings was cited as an address issues related to inadequate
important factor in patients’ selection of education in oral-systemic interrela-
tionships, philosophies of practice marketing oral care products. Note that the
that may be outdated or preclude source that patients often put the greatest
providing this level of patient educa- weight on is information coming from their
tion, and concerns related to the lack dentist or dental hygienist. Therefore, it is of
of compensation for providing prime importance that the dental commu-
patient education. Failure to provide nity and dental paraprofessionals stay
patient education services has both current with emerging research about oral-
ethical and legal implications. systemic connections. Oral health profession-
als are responsible for filtering second-hand
KEY AND CREDIBLE INFORMATION sources of information on oral-systemic
ABOUT THE LINK BETWEEN health (sources other than peer-reviewed sci-
PERIODONTAL DISEASE AND entific journals) to ensure that what is com-
SYSTEMIC DISEASES municated to patients is scientifically sound.
Information about the relation between oral The process of professional develop-
and systemic health originates from numer- ment that will prepare individual dentists
Figure 3. The Process of Ensuring Scientific Integrity of the Information We Communicate
to Patients
ous sources, including consumer publica- and dental hygienists to become authorita-
tions, television, radio, continuing education tive experts in the evidence of oral-systemic
programs, and insurance industry cam- relationships is illustrated in Figure 3. As
paigns. Other important sources of informa- practitioners proceed through this process—
tion include professional and not-for-profit from surveillance to clinical application and
organizations, such as the American public outreach—confidence in how to com-
Academy of Periodontology and the Ameri- municate this information to patients
can Diabetes Association, as well as sources becomes a natural by-product of the self-
from health professionals and industries learning that occurs throughout the process.
Sound Bites for Patient Education looked source of infection and inflam-
What evidence of oral-systemic relation- mation, and it is very important for
ships should we confidently communicate patients to be examined for this. If
to patients? The following statements, com- diagnosed, periodontal disease must be
municated in layman’s terms, are well sup- treated to reduce the risk of systemic
ported by scientific evidence, and easily inflammation associated with many of
understood by patients. These statements these diseases and conditions.
provide an explanation of the potential for
periodontal pathogens and their endotoxins Diabetes
to gain access to the vasculature and incite • Diabetes increases the risk of infec-
inflammation and a cascade of pathologic tion from any source. Periodontal
events in distant organs. This information disease is an infection and a compli-
is applicable when in distant organs and cation of diabetes that is often unrec-
when describing the etiologic mechanisms ognized.
that have been implicated in most of the • People with poorly controlled dia-
oral-systemic relationships under investiga- betes are much more susceptible to
tion. Each involve describing the interrela- periodontal disease and may be two
tionship between periodontal disease and to four times more likely to develop
the following: periodontal disease than people
without diabetes.
Systemic Inflammation • The presence of periodontal disease
• Today we know that infection from increases the risk of worsening
gum disease (periodontal disease) is not glycemic control over time.
contained simply within the oral cavity. • Research suggests that periodontal
• Bacteria and toxins from periodontal disease causes inflammation through-
disease can move through the ulcer- out the body, making it more difficult
ated lining of the gum pocket and for patients with diabetes to utilize
enter the blood vessels. insulin. This may cause hyper-
• Certain periodontal bacteria can glycemia and make it difficult for
evade the body’s defenses in the patients and their physicians to regu-
immune system and travel to distant late blood sugar levels.
sites, including the heart, kidneys, • Periodontal disease also increases the
lungs, brain, and developing fetuses in risk for coronary heart disease.
infected pregnant women. Simultane- • Good glycemic control, an HbA1c
ously, this causes inflammation value of less than 6% for most
throughout the body. patients, significantly reduces the risk
• This inflammatory process has been for the serious complications of dia-
linked to a number of serious diseases betes, including periodontal disease.
and conditions, such as heart disease, • Although more research needs to be
stroke, pneumonia, preterm birth of conducted, studies that have meas-
low-birth-weight babies, complications ured the difference in HbA1c values
of diabetes, and chronic kidney after treatment of periodontal disease
disease. It is therefore important that report improvements in blood glucose
any potential source of oral infection control over time.
and inflammation be treated. • Patients with poor blood sugar
• Periodontal disease is an often over- control may have more rapid recur-
rence of deep pockets in the gums late over a lifetime, increasing the
and less favorable long-term response cumulative risk for heart disease and
to treatment of periodontal disease. stroke.
• When periodontal disease goes • There is some early evidence suggest-
untreated in patients with diabetes, ing that treatment of periodontal
they are put at greater risk for devel- disease may improve the flow of
oping long-term complications associ- blood to the coronary arteries;
ated with diabetes, such as CVD and however, more research is needed
kidney disease. before it is known for certain how
• Patients should be counseled to periodontal treatment affects the
comply with their healthcare heart. In the meantime, the American
provider’s recommendations for Academy of Periodontology has
HbA1c testing at least every 3 months determined that treatment of peri-
and to request that physicians forward odontal disease may prevent the onset
copies of test results to their dentists. or progression of atherosclerosis-
This allows the dental provider to induced diseases.
monitor blood sugar levels and the
health of their patients’ gums. Increased Risk for Adverse
Pregnancy Outcomes
Increased Risk for CVD • Infection from any source increases
• Accumulated evidence suggests that the risk of complications during preg-
persons with periodontal disease may nancy. Periodontal disease may be
have a moderately increased risk for one of the infections that poses a
coronary heart disease and stroke. threat to healthy pregnancy.
• It is important to identify those who • An estimated 40% of pregnant women
may have a greater risk for heart have some form of periodontal disease.
disease or stroke and who have peri- • Evidence suggests that in some popu-
odontal disease. lations, pregnant women who have
• It is important to understand how periodontal disease may have a two
periodontal disease and increased risk to five times greater risk for develop-
for heart disease and stroke may be ing various pregnancy complications,
related. including preterm birth, preeclampsia,
• When inflammation is present within gestational diabetes, and delivery of
heart tissues, arteries become less low-birth-weight infants.
elastic and the lumen of affected • Now that oral healthcare providers
arteries become narrower and more and obstetricians recognize a possible
restricted. When arteries become link between inflammation in the
more narrowed, blood clots may body and problems during preg-
form and small particles of clots may nancy, the goal is to eliminate all oral
break off, accumulate, and clog arter- inflammation before and during
ies, impeding blood flow. This can pregnancy.
result in a heart attack, stroke, or pul- • Oral health before and during preg-
monary embolism, depending on the nancy may be important for prevent-
location of the blood clot. ing adverse pregnancy events; however,
• It is known that damage from infec- this has yet to be well established.
tion and inflammation can accumu- • Research has confirmed that periodon-
tal treatment during pregnancy is safe each dental appointment with an up-
and improves maternal oral health. to-date list of prescribed and over-
the-counter medications they are
Increased Risk for Respiratory Infection taking so that the dentist or dental
• Research suggests that institutional- hygienist can be aware of any agents
ized elderly people and patients in that may affect the oral cavity or be a
intensive care units who have poor contraindication for certain types of
oral hygiene may have a greater risk dental treatment.
for developing pneumonia and other • Up-to-date information regarding the
respiratory infections. status of the patient’s overall systemic
• Oral pharyngeal surfaces, including health needs to be related to the oral
the teeth, can serve as a reservoir for healthcare provider.
pathogenic bacteria known to cause • Patients need to be counseled to
pneumonia. These bacteria can be provide information about oral
aspirated into the lungs, where they health—especially when gum disease
can cause respiratory infections— has been diagnosed—to their other
many of which may be fatal. medical providers.
• Cytokines are a type of chemical nor- • Oral healthcare providers should con-
mally produced by the body to tinually reinforce good oral hygiene
defend itself against inflammation. and home care. Inclusion of an anti-
When produced in periodontal tissue bacterial toothpaste or mouth rinse in
as a result of infection, cytokines may the home care regimen can help reduce
cause inflammation of the lower res- dental plaque build-up and gingivitis.
piratory airway after aspiration of
bacteria known to cause pneumonia. Summary Points
This causes the lining of the airways Not only do oral healthcare providers have an
to become more vulnerable to invad- ethical obligation to educate patients about
ing bacteria. Therefore, it is important the relation between oral health and general
to identify elderly individuals who health, but dentists and dental hygienists are
may have a greater risk for respiratory also responsible for ensuring that what is com-
problems because of undiagnosed municated to patients and to the public at
and untreated periodontal disease. large is scientifically supported.
• Improved oral hygiene and frequent 1. Given the increasing preponderance of
care by an oral healthcare provider evidence about oral-systemic relation-
may reduce the risk for respiratory ships generated from second-hand
diseases in high-risk elderly patients sources, the task of ensuring scientific
living in nursing homes and patients integrity of information can be chal-
admitted to intensive care units.61 lenging. When practitioners systemize
the process of updating their knowl-
General Advice to Patients edge base through reading peer-
• It has become increasingly clear that reviewed articles on a routine basis, this
prevention, diagnosis, and treatment will provide an excellent screen through
of periodontal disease are very which to filter information from the
important in maintaining overall domain of second-hand, often unreli-
health during the aging process. able, sources of information.
• Patients should be advised to come to 2. Although much is still inconclusive
about certain oral-systemic relation- engage in novel outreach activities that have
ships, there does exist sufficient evi- the potential to increase awareness of peri-
dence of the relationship between odontal-systemic relationships. These types
periodontal disease and its role in of endeavors are valuable in bringing about
amplifying systemic inflammation improvement in oral health literacy, and they
and increased risk for heart disease, provide excellent opportunities for practition-
stroke, adverse pregnancy outcomes, ers to build interpersonal collaboration and
complications of diabetes, and enhance their practices.
increased risk for respiratory infec-
tions in institutionalized patients. CONCLUSIONS
Effective communication of this infor- Oral diseases are an often overlooked source
mation is a responsibility of all den- of infection that have the potential to com-
tists and dental hygienists. promise overall health, especially in those
who have an amplified inflammatory
OUTREACH ACTIVITIES TO response to bacterial infections such as peri-
INFLUENCE THE PUBLIC’S odontal disease. Evidence that supports a
PERCEPTION OF THE relationship between periodontal disease and
IMPORTANCE OF ORAL HEALTH increased risk for heart disease, stroke, wors-
The number of things that dentists and ened glycemic control in those with diabetes,
dental hygienists can do to reach out to the adverse pregnancy outcomes, respiratory
community to create greater awareness of conditions, chronic kidney disease, and com-
oral-systemic health is limited only by indi- plications of diabetes is emerging as a rela-
vidual initiative and a commitment to tively new body of knowledge that dental
change the perceptions of nondental health- and dental hygiene professionals are ethically
care providers and the public regarding the bound to share with their patients. Main-
importance of oral health. Table 1 lists a stream media, university- and governmental-
number of outreach activities that oral sponsored public health outreach, insurance
healthcare providers have reported as being industry campaigns, professional and non-
successful in increasing the awareness of profit organizations, nondental healthcare
oral-systemic relationships in physician com- practitioners and commercial advertising
munities and the public at large. associated with oral care products have con-
Beyond the practice setting, dentists and tributed greatly to increasing oral healthcare
dental hygienists have the opportunity to literacy. However, it must be recognized that
Table 1. Outreach Activities for Dental Professionals to Influence Nondental Healthcare

Providers and the Public About the Importance of Oral Health Outside the Practice Setting
• Volunteer to deliver a presentation at the local hospital’s rounds

• Take physicians and nurses to lunch to discuss building a collaborative relationship and systems of triage
• Routinely visit physicians’ offices to supply educational materials for patients
• Possibly partner with nursing organizations to conduct a health fair in which nurses screen for oral
diseases/conditions, and hygienists screen for CVD and diabetes
• Volunteer to present information at local meetings of civic organizations, hospital programs for the public,
churches, etc.
• Volunteer to write a column about oral-systemic relationships in community newspapers
• Invite medical colleagues to a study club when information on oral-systemic medicine is being presented
• Provide volunteer in-service training in oral healthcare for nursing assistants at nursing home facilities
• Use referral letters to simultaneously educate physicians about oral-systemic relationships
second-hand information about oral-sys- can Journal of Cardiology and Journal of Periodontology
temic health must be filtered by practitioners Editors’ Consensus: Periodontitis and Atherosclerotic Car-
diovascular Disease. J Periodontol 2009;80(7):1021–32.
to ensure that what is being communicated h t t p : / / w w w. j o p o n - l i n e. o rg / d o i / p d f / 1 0 . 1 9 0 2 /
to patients and the public at large is scientifi- jop.2009.097001?cook- ieSet=1.
cally supported.
Lack of health literacy has been cited as Hein C, Cobb C, Iacopino A. Report of the Independent
a significant factor in undermining the effec- Panel of Experts of ‘The Scottsdale Project’. Published as
a Special Supplement to Grand Rounds in Oral-Sys Med
tiveness of our current healthcare delivery 2007;3. Access through www.caseyhein.com.
system and may account for billions of
dollars in added healthcare costs each year. Hein C. Proceedings and consensus opinion from the
There are a number of reasons why dental global oral and systemic health summit; present evidence
providers may be reluctant to become and future directions. Grand Rounds in Oral-Sys Med
2007(Suppl):1. Access through www.caseyhein.com.
involved with counseling patients about oral-
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345
INDEX
Tables, figures, and boxes are indicated by an italic t, allostatic mediators, in RA, 221
f, or b. alpha blockers, in CKD treatment, 315
alpha-glucosidase inhibitors, 83t, 84, 263
A alveolar bone loss
A Treatise on the Disorders and Deformities of the in COPD, 186
Teeth and Gums (Berdmore), 50 vs coronary heart disease, 135, 136t
abscesses of periodontium, 11 early research on, 2
Acarbose (alpha-glucosidase inhibitor), 83t, 84 in osteoporosis, 60
acetaminophen, in pregnancy, 291, 291t in postmenopausal osteoporosis, 200
Acinetobacter sp., in lung disease, 182, 188 as risk factor for oral cancer, 237
acquired neutropenia, 11 vs skeletal bone loss, 200–201, 202t
Actinobacillus actinomycetemcomitans. See and teriparatide (PTH) treatment, 206
Aggregatibacter actinomycetemcomitans amalgam tattoos, 9
Actonel (risedronate), 204 Amaryl (glimepiride), 264t
acute coronary syndrome (ACS), 123 American Academy of Periodontology
acute leukemia, 321 patient education campaign, 331
acute necrotizing ulcerative gingivitis, 23 preconception recommendations, 294–295
acute-phase proteins pregnancy recommendations, 298
activity of, 36–37 American Academy of Periodontology (AAP),
in atherosclerotic disease, 276–278 periodontal diseases classification, 6–7, 7t
and cardiovascular disease, 39–40 American College of Obstetrics and Gynecology,
in inflammatory response, 34 cardiac conditions guidelines, 292
in pregnancy, 155 American Dental Association (ADA)
as systemic cellular markers, 38 on oral health literacy, 331
in systemic inflammation, 36 pregnancy guidelines, 289–290
See also C-reactive protein American Diabetes Association, patient education
addiction. See drug-related dependencies campaign, 331
Addison’s disease, in DM, 69 American Society of Bone and Mineral Research
adipokines, in insulin resistance, 70 (ASBMR)
adiponectin, in obesity, 125 ONJ lesions defined, 208
adipose tissue ONJ task force, 310
in DM, 65, 66t, 68 ampicillin/amoxicillin
and insulin resistance, 69–70 in periodontitis, 23
role in inflammation, 125–126 in pregnancy, 291t, 292, 302
adolescent patients, pregnancy in, 302–303 in premature rupture of membranes, 296–297
adult-onset diabetes mellitus (DM), 69, 71 amylin (Pramlintide), 88
advanced glycation end products (AGEs), 78, 79, 126 amyloid formation, in DM, 70
African-Americans analgesics, in pregnancy, 291, 291t
adolescent pregnancy, 303 anesthetics, in pre-eclampsia, 297
DM risk in, 265, 266b aneurysms, 123
gestational diabetes mellitus, 72 angina pectoris, 123, 278–280, 281f
glomerular filtration calculation, 315 angioplasty, 283
nitrate treatment, 282 angiotensin converting enzyme (ACE) inhibitors
periodontal disease prevalence, 13 in atherosclerotic disease, 282
preterm birth risk, 164, 301 in kidney disease, 314, 315
stroke risk, 136 anthracyclines, 319, 319t
Aggregatibacter actinomycetemcomitans antibiotic prophylaxis
in aggressive periodontitis, 10–11 in DM, 261
in connective tissue invasion, 33 for Enterococcus sp., 292
metronidazole/amoxicillin treatment, 23 in kidney disease, 317
in RA, 225 in pregnancy, 292
aggressive periodontitis, 10–11 antibiotics. See antibiotic prophylaxis; antimicrobial
alcohol use, as risk factor for oral cancer, 232–238 therapies; pharmacologic treatment; individual
alendronate, 309–310 names
alkylating agents, 319t antiemetics, in pregnancy, 291
346 INDEX
antihistamines, in pregnancy, 296 observational studies, 140

antihyperglycemic medications, 263–265, 264t PAVE study, 145–146, 147f
antihypertensive agents, in kidney disease, 315 population studies, 136–138, 139–140
anti-inflammatory drugs role of inflammation in, 131
in host-modulation therapy, 24 Western New York MI/Perio Studies, 138–139
in kidney disease, 317 atheromatous plaques
in ONJ, 313 vs clinical attachment loss, 137t
antimetabolites, 319, 319t CRP in, 39–40
antimicrobial therapies formation, 123–124, 276
anti-tumor antibiotics, 319t and periodontal disease, 58
for COPD, 186 role of inflammation in, 131
in DM, 114–115 and statin treatment, 282–283
effect on metabolic control, 258 atherosclerotic disease
in gingival disease, 8 epidemiology, 126–127
locally applied, 22–23 mechanisms, 123–124
lozenges in radiation therapy, 322 periodontal disease management in, 283
in oral mucositis treatment, 320–321 risk factors, 124–126
in osteonecrosis of the jaw, 313 Atridox (tetracycline), 22
in pregnancy, 291–292, 291t, 300 autoantibodies, in DM, 68
in preterm labor, 296–297, 302 azithromycin (Zithromax)
prophylaxis in DM, 261 in kidney disease, 316
prophylaxis in kidney disease, 317 in periodontitis, 23
rinses, 183
systemic vs locally applied, 22–23 B
in ventilator-associated pneumonia, 182–183 bacteremia
See also pharmacologic treatment animal studies, 140–141
antiplatelet therapy, in atherosclerotic disease, 280 following mechanical irritation, 35–36
antitumor antibiotics, 319t in inflammation, 36
aortic atherosclerosis, 123 in neutropenic patients, 321
Apidra (glulisine), 264t in pregnancy, 292t, 294, 295f
apoptosis in pulmonary infections, 180
bisphosphonates and, 309 sources of, 52
in bone remodeling, 196 transient, 290
in chemotherapy, 319 bacterial biofilm. See biofilms
in estrogen deficiency, 196, 205 bacterial burden, and atherosclerosis, 138
in inflammation, 41, 247 bacterial infections, as trigger for RA, 225
in preterm birth, 157 bacterial virulence
Arestin (minocycline), 22–23 effect on host cells, 32t
arterial plaque. See atheromatous plaques role in disease etiology, 50
ASBMR. See American Society of Bone and Mineral Bacteroides forsythus, in RA, 225
Research b-cell exhaustion, in DM, 69
aspart (NovoLog), 86, 86t, 264t benzodiazepines, in pregnancy, 291, 291t
aspiration pneumonia, 178 benzydamine, in radiation therapy, 322
aspirin Berdmore, Thomas, 50
in atherosclerotic disease, 280 beta blockers, 282, 315
in DM, 77, 80t BIC. See bone-to-implant contact
in preeclampsia, 297 bi-directional relationship, DM and periodontal
in pregnancy, 289, 291t, 297 disease, 256–258
in treatment of inflammation, 44, 46 biguanide, 83t, 84, 263
asthma, protectins effect on, 44, 45t bile acid binders, 263
atherogenesis, theory of, 276 Billings, Frank, 52
atheromatous diseases linked to periodontal disease biofilms
animal models, 140–144 in carcinogenesis, 248
case-controlled studies, 132, 133t composition of, 35
cohort studies, 132–135, 134t–135t early research on, 2
endothelial function studies, 146–148 in gingival inflammation, 31, 34f
meta-analyses of, 132 host response to, 13
INDEX 347
impact on systemic health, 2 comanagement, 323

in pregnancy, 153 epidemiology, 318
in RA, 214, 215 metastatic bone disease in, 309
in respiratory tract diseases, 179, 181f oral mucositis, 319–321
See also dental plaque and osteonecrosis of the jaw, 208
biomarkers radiation therapy, 321–322
in cardiovascular disease, 39–40, 276–278 surgery, 322–323
decreased with Arestin treatment, 22–23 cancer and periodontal disease
in DM, 40 Helicobacter pylori, 247, 248
in pregnancy, 298 lung cancer, 240–241
subantimicrobial-dose therapy and, 24 mechanisms of relationship, 247–248
types of, 19 mortality in, 243–247
bisphosphonates pancreatic cancer, 241–243
in host-modulation therapy, 24 periodontal disease association, 236–238, 323
and ONJ, 310–311 studies showing relationship, 232–238, 232t
in osteoporosis, 204–205, 204f upper GI cancer, 238–240
pharmacology of, 309–310 viruses, 247
blood urea nitrogen (BUN), 314 Candida sp., 8, 77, 255
blood-brain barrier CAP. See community acquired pneumonia
in pregnancy, 169 cardiac guidelines, American College of Obstetrics
BMD. See bone mineral density and Gynecology, 292
BMUs. See bone multicellular units cardiovascular abnormalities
bone disease in DM, 76
metastatic, 309 in pregnancy, 288
secondary to kidney disease, 314 cardiovascular disease (CVD)
See also alveolar bone loss; osteonecrosis of the biomarker reduction with subantimicrobial-dose
jaw (ONJ) therapy, 24
bone mineral density (BMD), 197–201, 198f, clinical presentation, 278–280, 281f
202t, 308 comanagement with periodontal disease, 283–284
bone morphogenetic proteins, 24–25 in DM, 75t
bone multicellular units (BMUs), 193, 194f epidemiology, 123–127, 275
bone remodeling global trends, 127
process of, 193–197, 194f, 195f inflammatory markers, 39–40, 276–278
role of OPG in, 43 management, 280
bone resorption/formation. See bone remodeling pathogenesis, 275–276
bone-sparing drugs, 204–206 patient education “sound bites,” 338
bone-to-implant contact (BIC) periodontal disease association, 19, 49, 57–58,
in osteoporosis, 203–204 135, 137
Boniva (ibandronate), 204 prevention, 278, 279f
brushing. See mechanical therapy prognostication, 107
BUN. See blood urea nitrogen related to kidney disease, 316
bypass surgery, 283 risk factors, 124–126, 276–278, 277f
and systemic inflammation, 30
C Type 2 DM as a risk factor, 77
calcineurin inhibitors, in kidney disease, 316 causal relationship
calcium Bradford Hill criteria, 170–171
in bone remodeling, 196, 196f of DM and periodontal disease, 58, 103–105
in periodontal disease, 203 of systemic and periodontal disease, 60
calcium channel blockers, in kidney disease, 315–316 See also risk factor assessment/reduction
Campylobacter rectus CD14, 34, 36–38
in animal studies, 165–169 cephalosporins, in pregnancy, 291–292, 291t
as indicator of atherosclerosis, 137 cerebrovascular disease
in pregnancy, 165 in atherosclerotic disease, 123, 126
in pregnant adolescents, 303 in DM, 75t
cancer linked to periodontal disease, 253
bisphosphonate therapy and ONJ in, 311 risk factors for, 124
chemotherapy, 318–319, 319t Charcot’s joints, 75t, 76
348 INDEX
chemotherapeutic agents Consumer-Patient Survey (2005), 331, 332f

in leukemia, 321 continuous glucose monitoring system (CGMS), 81
oral toxicity and, 319–321, 319t coronary artery disease (CAD), vs clinical attachment
in periodontal disease, 16, 21 loss, 135–136, 136t
Chicago Heart Association Detection Project in coronary atherosclerosis, 275, 278, 279f
Industry, risk factors for atherosclerotic disease, 276 coronary heart disease, 123–127
Chlamydia pneumoniae, in atherosclerosis, 131 corticosteroids
chlorhexidine (CHX) in pregnancy, 291t
in ventilator-associated pneumonia, 182–183 in premature rupture of membranes, 296–297
chlorhexidine gluconate (Peridex/PerioChip) in secondary osteoporosis, 199–200
in periodontal disease, 21 cortisol, in DM, 65
in pregnancy, 291t, 300 C-reactive protein (CRP)
in radiation therapy, 322 in atherosclerotic disease, 276–278
chronic kidney disease (CKD). See kidney disease as biomarker, 19
chronic leukemia, 321 in hypertension, 125
chronic obstructive pulmonary disease (COPD), 21, in inflammation, 3, 36–40
59, 184–187, 291 in kidney disease, 316–317
chronic periodontitis (CP), 10 in PAVE study, 146f
ciprofloxacin, in periodontitis, 23 in plaque formation, 124
citrullinated peptide autoantibodies, in RA, 216–217, as predictor of cardiovascular disease, 58
225–226, 225f in pregnancy, 155
CKD (chronic kidney disease). See kidney disease in RA, 215–216
clindamycin creatinine, 313, 315
in periodontitis, 23 critical nodes, in insulin signaling pathways, 67f
in pregnancy, 291–292, 291t crowns
in premature rupture of membranes, 296–297 in chronic periodontitis, 10
clinical attachment loss (CAL) implicated in systemic disease, 52
vs arterial plaque, 137t in pregnancy, 292
vs CAD, 135–136, 136t cryotherapy, in mucositis prevention, 320
in COPD, 187 CVD. See cardiovascular disease
in osteoporosis, 202t cyclosporine, in kidney disease, 316
in radiation therapy, 322 cystic fibrosis, lipoxins effect on, 43, 45t
as risk factor for oral cancer, 236–237 cytokines
as subjective measurement, 12 in bone remodeling, 193
clinical protocols for diabetic patients, 260–261, 266 in chemotherapy, 319
clodronate, 309 in DKA, 73
clotrimazole, in pregnancy, 291t early research on, 2
CNN News, 330 and EBV, 247
cocaine use, hemodynamic effects of, 126 in inflammatory response, 2–3
codeine, in pregnancy, 291t in insulin signaling pathways, 67f
Cohen syndrome, 11 in kidney disease, 317
Colgate-Palmolive Company, patient education, 331 and neoplastic formation, 247–248
colitis, resolvins effect on, 43, 45t in osteoporosis, 200
Colyer, J. F., 51 and periodontal disease, 9, 11, 12, 17–19
comanagement in plaque formation, 107, 124
of cancer, 308–322 in pregnancy, 154
of DM, 252–272 in RA, 217, 218t
of kidney disease, 308–322 in respiratory tract diseases, 180
of osteoporosis, 308–322 in systemic inflammation, 36, 38
of pregnancy complications, 298–303 cytomegalovirus, affecting atherosclerosis, 131
See also team-care
community acquired pneumonia (CAP), 177–178, D
179–180 d’Arcoli, Giovanni, 49–50
complement proteins, role in inflammation, 37 DCCT. See Diabetes Control and Complications
complex diseases, RA as, 221, 221t, 222f Trial
congenital heart disease, in pregnancy, 292 death, leading causes of, 1
connective tissue, in inflammatory response, 33 dementia, 123
INDEX 349
denosumab, 206 mechanisms of complications, 79–80

dental caries medications for, 263–265, 264t
maternal vs child, 293 pathophysiology, 64–70, 66f, 67f
in pregnancy, 293 patient education “sound bites,” 338–339
in radiation therapy, 321, 323 prevention of, 80t
reduction with fluoride, 21, 293 diabetes mellitus (DM) and periodontal disease
dental implants, and bisphosphonate therapy, 312 benefit of periodontal treatment, 23
dental plaque effect of hyperglycemia on periodontal health,
compared to respiratory tract pathogens, 182–183 100–107, 102t, 106f
composition of, 179, 188 effect of periodontitis on blood glucose levels,
in gingivitis, 7 107–115, 113t
as initiator of periodontal disease, 6, 16 periodontal disease as risk factor for DM,
and ventilator-associated pneumonia, 180, 181f 256–258
dental procedures periodontal disease association, 252–272
in preeclampsia, 297 periodontal disease in, 64, 75t
in pregnancy, 290, 292, 298–303 reciprocal link to periodontal disease, 79
in premature rupture of membranes, 297 two-way relationship of, 58–59, 99–100. See also
dental professionals hyperglycemia
attitudes toward treatment in pregnancy, 289–290 diabetes mellitus (DM) comanagement
role in DM management, 258–269 emergencies in dental offices, 261–265, 262f
dental prophylaxis guidelines available, 115–116
in DM, 256 role of dental professionals, 258–261, 267, 268f
in PAVE study, 145–146, 147t role of medical professionals, 269–272
in pregnancy, 300 screening in dental offices, 265–267, 266b
dental restorations treatment model, 268f
avoidance for hygiene, 51 underdiagnosis of DM, 254–255
Hunter on, 51 underdiagnosis of periodontitis, 255–256
dentifrices, success of, 21–22 diabetes self-management skills, 81
dentistry diabetic dermopathy, 78
American vs English, 52 diabetic foot, 79
role in risk factor assessment/reduction, 3 diabetic ketoacidosis (DKA)
dentition during dental procedure, 265
as risk factor for GI cancer, 238–240 vs HHS, 73–74
as risk factor for oral cancer, 232–236 pathogenesis, 73
dermatologic manifestations in DM, 78 in Type 1 DM, 71
detemir (Levemir), 86, 86t, 264t diabetic retinopathy, 74
DEXA. See dual-energy x-ray absorptiometry diabetogenic state, in pregnancy, 289
Diabeta/Micronase (glyburide), 264t diapedesis, in inflammatory response, 33
Diabetes Control and Complications Trial (DCCT), digital sclerosis, 78
74, 254 dihydropyridines, in kidney disease, 315–316
diabetes mellitus (DM) dipeptidyl peptidase IV inhibitors, 83t, 85
acute complications, 72–74 diphenhydramine, in oral mucositis, 320
and atherosclerotic disease, 125–126, 276, 277f, 280 direct renin inhibitors (DRIs), 314
classification, 64t disseminated intravascular coagulation (DIC)
clinical presentation, 71–74 in fetal death, 298
complications, 74–79, 75t, 110–111, 252–272, 313, in pregnancy, 298
316–317 diuretics, in kidney disease, 315
complications of treatment, 89–91 Down’s syndrome, 11
diagnosis, 72t, 73, 80–81 doxycycline
epidemiology, 63–64, 252–253 Atridox (tetracycline), 22
genetics of, 68–69, 70 subantimicrobial-dose therapy, 24
glycemic control in, 108–109 doxylamine, in pregnancy, 291, 291t, 296
HBA1c levels in, 102–103, 102t DRIs. See direct renin inhibitors
increasing incidence of, 100, 101f drug therapies
inflammation in, 30, 39, 40 causing secondary osteoporosis, 199–200
key points on, 63 for diabetes mellitus (DM), 82–84, 83t
management of, 81–88, 83t, 86t, 90t in host modulation therapy, 23–25
350 INDEX
in kidney disease, 317–318 in pregnancy, 291–292, 291t

in ONJ, 313 in premature rupture of membranes, 296–297
drug-related dependencies erythropoietin, 313, 315, 317
cocaine, 126 Escherichia coli
nitrous oxide use in, 291 in nosocomial pneumonia, 179
dual-energy x-ray absorptiometry (DEXA) in vaginal flora, 300
and dental implants, 203 ESRD (end-stage renal disease). See kidney disease
interpretation of, 198f, 200–201 estrogen
in osteoporosis, 308 in bone remodeling, 196, 196f
dysgeusia, in radiation therapy, 321 effect on periodontal health, 287, 288, 293
dyslipidemia in osteoporosis, 207
in DM screening, 265 in primary osteoporosis, 199
in macrovascular complications of DM, 77 etidronate, 309–310
in renal complications, 76 etiopathologic era of periodontal disease research, 1–2
as a risk factor for atherosclerotic disease, 125 Exenatide (GLP-receptor agonist), 83t, 85
dyspnea, in pregnancy, 288–289 eye disease. See ophthalmic complications
E F
ecogenetic diseases, RA as, 221, 221t, 222f fasting, in DM, 263
edema, in pregnancy, 287–288 fatty acid metabolism, 65–68, 69–70, 73
Ehlers-Danlos syndrome, 11 fatty streaks, 125, 131, 275–276
emphysema, 184–185 fibrinogen
enamel matrix proteins (Emdogain), in host- in atheromas, 275
modulation therapy, 24–25 in DM, 77, 126
endocarditis elevated in cardiovascular disease, 40
in kidney disease, 317 in fetal death, 298
in pregnancy, 292 formation of, 37
endocrine system in inflammation, 19, 36, 38
changes in pregnancy, 289 in periodontitis, 141
in secondary osteoporosis, 199–200 fibroblasts
endothelial injury, in atherosclerosis, 276 cytokines released from, 217, 218t, 219
end-stage renal disease (ESRD). See kidney disease gingival, 288
Enterobacter cloacae, in COPD, 188 in pregnancy, 288
Enterococcus sp., prophylaxis for, 292 fimbriae, in host response, 31, 32t
environmental risk factors flossing. See mechanical therapy
in DM, 68–69, 70 flow-mediated dilation therapy, 146–147, 147t
in RA, 219–221 fluconazole, in pregnancy, 291t
epidemiologic studies fluoride treatment
case-control for DM, 104 caries reduction with, 21, 293
cohort studies for DM, 104–105, 106f in radiation therapy, 322
cross-sectional for DM, 103–104, 105–106 fMLP. See formyl-methionyl-leucyl-phenyl-alanine
cross-sectional for hyperglycemia, 108 focal infection
longitudinal for DM, 106–107 Billings on, 52
longitudinal for hyperglycemia, 109 concept origins, 51
nonintervention for glycemic control, 108 original evidence for, 56
study design, 103 theory of, 56
epigenetic modification, in animal studies, 169–170 Food and Drug Administration (FDA), pregnancy
epinephrine guidelines, 290–292, 291t
as anesthetic in DM, 261 foreign objects, and abscesses, 11
contraindicated in preeclampsia, 290, 297 formyl-methionyl-leucyl-phenyl-alanine (fMLP), in
in hypoglycemia, 89 host response, 31, 32t
in insulin signaling pathways, 67f Forteo (parathyroid hormone), 206
Epstein-Barr virus (EBV) Fosamax (sodium alendronate), 204
in aggressive periodontitis, 247 Framingham Heart Study, risk factors for
in oral cancer, 247 atherosclerotic disease, 276
erythema multiforme, in gingival disease, 8 full-mouth extraction, effect on glycemic control, 114
erythromycin fungal infections, 8, 78, 255
INDEX 351
Fusobacterium nucleatum continuous glucose monitoring system (CGMS), 81

in pregnancy, 165, 294 during dental procedure, 264
supplies, 263
G glucose toxicity, in insulin resistance, 70
gastrointestinal (GI) tract Glucotrol (glipizide), 264t
cancer and oral health, 238–240 glulisine (Apidra), 86, 86t, 264t
chemotherapeutic toxicity, 318, 319t glyburide (Diabeta/Micronase), 83t, 84, 264t
Helicobacter pylori, 247 glycated hemoglobin. See hemoglobin A1c (HbA1c)
in pregnancy, 163, 288 glycemic control
GDM. See gestational diabetes mellitus affected by periodontal disease, 256–258
GEM 21S. See growth-factor enhanced matrix affected by periodontal treatment, 58–59,
genetic predisposition 112–115, 113t
for aggressive periodontitis, 10, 10f difficulty achieving, 254–255, 255f
for COPD, 185–186 in DM, 80t, 81
and periodontal disease, 57 effect of full-mouth extraction on, 114
in pregnancy, 154 effect of periodontitis on, 107–112
gentamicin/colistin/vancomycin, in ventilator- See also hemoglobin A1c (HbA1c)
associated pneumonia, 183 glycosylated hemoglobin. See advanced glycosylation
germ theory of disease causation, 50 end products (AGEs); hemoglobin A1c (HbA1c)
gestational diabetes mellitus, Tannerella forsythia Godlee, R. J., 51
and, 112 G-protein-coupled receptors (GPCRs), in host
gestational diabetes mellitus (GDM) response, 31, 32t
effect of periodontal health on, 111–112 granulocyte-macrophage colony-stimulating factor
effect on oral flora, 289 (GM-CSF)
epidemiology, 72 in mucositis prevention, 320
Gila River Indian Community, DM in, 256 growth factors, in host-modulation therapy, 24–25
gingival bleeding on probing (BOP), 12 growth hormone, in DM, 65
gingival diseases growth-factor enhanced matrix (GEM 21S), in host-
in DM, 64 modulation therapy, 25
hyperplasia, 315, 316, 316f gum disease. See periodontal disease
in leukemia, 321 Gupta, Sanjay, 330
non-plaque-induced, 8–9
plaque-induced, 7–8 H
in pregnancy, 153, 287–288, 293–294 Haemophilus influenzae
in pregnant adolescents, 302–303 in community-acquired pneumonia, 177, 179
treatment during pregnancy, 296, 300, 300t in COPD, 186
gingival inflammation Hashimoto’s thyroiditis, in DM, 69
bacteria in connective tissue, 33 HbA1c. See hemoglobin A1c (HbA1c)
bacterial components of, 31 HCT. See hematopoietic stem cell transplantation
bacterial/gastrointestinal equilibrium, 31–33 healthcare-associated pneumonia, 178–179
immune response, 34–35 hearing loss, in DM, 75t
inflammatory cascade, 33–34 heart disease, DM as a risk factor, 63
initiation of, 34f heat-shock proteins (HSPs), in host response, 31, 32t
gingivitis, epidemiology, 11–12 Helicobacter pylori
glargine (Lantus), 86, 86t, 264t affecting atherosclerosis, 131
glimepiride (Amaryl), 83t, 264t association with GI cancer, 247, 248
glipizide (Glucotrol), 83t, 84, 264t hematologic system
glomerular filtration rate (GFR) changes in pregnancy, 289
in antimicrobial prophylaxis, 317 and periodontal disease, 11
in kidney disease classification, 314t, 315 hematopoietic stem cell transplantation (HCT), 319, 321
glomerulonephritis, as cause of kidney disease, 315 hemodialysis, 315, 317
GLP-receptor agonists, 83t, 84 hemoglobin A1c (HbA1c)
glucagon, in glucose metabolism, 65, 66f in diabetes diagnosis/control, 102–103, 102t
glucagon injections, in hypoglycemic emergencies, as glycemic control monitor, 81
262–263 in prediabetes, 253
glucose metabolism, in DM, 64–65, 66f reduction with periodontal treatment, 23, 24,
glucose monitoring 58–59
352 INDEX
heparin therapy, in pregnancy, 289 in RA, 219

Hepatitis B See also immuno-inflammatory responses
in hepatocellular carcinoma, 248 hyperinflammatory traits, in pregnancy, 154
hereditary gingival fibromatosis, in gingival disease, 8 hyperlipidemia. See lipid dysregulation
herpes virus hyperosmolar/hyperglycemic state (HHS), 71, 73–74
affecting atherosclerosis, 131 hyperplasia/edema in pregnancy, 287–288
in gingival disease, 8 hypertension
HHS. See hyperosmolar/hyperglycemic state as atherosclerotic disease risk factor, 125, 276, 277f
high-density lipoprotein cholesterol (HDLC), 276, 277f comanagement of, 282
high-sensitivity CRP (hsCRP), 39 in DM, 77, 80t
Hispanics in kidney disease, 315
adolescent pregnancy, 303 in pregnancy, 290–291
DM risk in, 265, 266b hyperventilation, in pregnancy, 288–289
gestational diabetes mellitus, 72 hypoglycemia
preterm birth risk, 301 in DM, 89–90
hormone replacement therapy (HRT) emergencies in dental offices, 261–265, 262f
periodontal disease management in, 60 treatment, 90, 90t
and tooth retention, 208 hypoglycemic medications, 82–84, 83t, 263–265, 264t
hospital acquired pneumonia (HAP), 178–179 hypokalemia, in DKA, 73
host response hypophosphatasia, 11
acute-phase proteins, 36 hypotension, in pregnancy, 288
in chronic periodontitis, 10
in DM, 261 I
early research on, 2 ibandronate (Boniva), 204, 309–310
hyperinflammatory phenotype, 40 ibuprofen, in pregnancy, 291, 291t
to periodontal bacteria, 30, 31–34, 32t immune dysfunction, as risk factor for cancer, 248
in periodontal disease, 6–7, 11–13, 16, 18–19, 57 immunoinflammatory responses
See also hyper-inflammatory phenotype; immuno- in connective tissue, 33
inflammatory responses in gingivitis, 7
host modulation therapies, 20, 23–25, 24t and periodontal disease, 11, 17–19, 30
“How to Live Longer” (CNN News), 330 in pregnancy, 153, 293
HRT. See hormone replacement therapy immunosuppression, 11
HSPs. See heat-shock proteins immunosuppressive therapy, in kidney disease, 316
Humalog (lispro), 264t impaired glucose tolerance (IGT), 100
human immunodeficiency virus (HIV), 11 incretins, 263
human leukocyte antigens infant deaths. See pregnancy complications linked to
in DM, 68–69 periodontal disease
in RA, 219 infections
“Human Mouth as a Focus of Infection, The” and cancer, 248
(Miller), 50–51 in DM, 75t, 77
Hunter, William, 51–52 ectopic foci, 36
hydropyridines, in kidney disease, 316 inflammation
hypercholesterolemia, LDL apheresis in, 283 adipose tissue, 125
hypercoagulable state in atherosclerotic disease, 124
in pregnancy, 289 and cancer, 247–248, 319
hyperemesis gravidarum, 288 cocaine use and, 126
hyperglycemia gingival, 31–35, 34f
complications from, 74–77, 75t in kidney disease, 313, 316–317
diagnosis, 74 oral-systemic relationship, 1–2
in DM, 64, 65 in osteoporosis, 200, 203
effect on periodontal health, 100–107, 102t, 106f in pregnancy, 154, 162, 287–302, 295f
HHS state, 71 in RA, 223–224
HHS vs DKA, 73–74 resolution, 40–46, 42f, 44f, 45t
and inflammatory markers, 126 systemic, 19
hyperinflammatory phenotype systemic due to periodontal infections, 35–40
contribution to periodontal disease, 43 inflammatory markers
host response in, 40 in atherosclerotic disease, 276–278
INDEX 353
in kidney disease, 318 Legionella sp., in community-acquired pneumonia, 177

inflammatory response, in oral-systemic relationship, leptin
2–3 in insulin resistance, 70
influenza vaccination, in DM, 80t in insulin signaling pathways, 67f
insulin leukemias, 7, 11, 321
adjustment prior to dental appointment, 264 leukocytes, as systemic cellular markers, 38
signaling pathways, 67f leukocytosis, in pregnancy, 289
treatment for DM, 82–84, 85–87, 86t Levemir (detemir), 264t
types of, 264t lidocaine
insulin antagonists, 256–258 in oral mucositis, 320
insulin deficiency, absolute vs relative, 73–74 in pregnancy, 290, 291t
insulin resistance/sensitivity lifestyle modification
and adiponectin levels, 125 in DM, 72, 80t, 81–82
in DM, 64, 69–70 inactivity as a risk factor for atherosclerotic
in pregnancy, 72 disease, 276, 277f
as a risk factor for atherosclerotic disease, 276, 277f in pregnancy, 295–296
as a risk factor for cardiovascular disease, 71 lipid dysregulation, 80t, 282
role of inflammation in, 40 lipid mediators
interleukins in inflammation resolution, 42f
effect on metabolic control, 256–258 lipid-lowering therapies, 282
in inflammatory response, 2–3 lipoteichoic acids (LTAs)
in insulin signaling pathways, 67f in host response, 31, 32t
in pregnancy, 288 lipoxins, 43–44, 44f, 45t
International Diabetes Federation (IDF), 100, 116 lispro (Humalog), 86, 86t, 264t
Islets of Langerhans Löe, Harold
amyloid formation in, 70 periodontitis as complication of DM, 99–100
insulin secretion, 65 study of inflammation, 2, 30
transplantation of, 88 low birth weight (LBW). See pregnancy
isophane suspension (NPH), 86–87, 86t complications linked to periodontal disease
low-density lipoprotein cholesterol (LDLC), 124, 125,
J 276, 277f
Journal of the American Medical Association LPS binding protein (LBP), 34, 37, 38
(JAMA), patient education, 331, 333f LTAs. See lipoteichoic acids
juvenile diabetes, 71 lung cancer, related to oral health, 240–241
lupus erythematosus, in gingival disease, 8
K lymphocytic leukemia, 321
ketoacidosis, 71, 73
kidney disease M
classification, 314t macrophages
comanagement, 313, 317–318 in COPD, 185
in DM, 74–76, 75t early research on, 2
ESRD, 313 in pregnancy, 154
kidney function, 313–314 macrovascular complications, of DM, 77
medications, 315–316 malnutrition, 8
periodontal disease association, 59, 316–317 matrix metalloproteinases (MMPs)
replacement therapy, 315, 316 in COPD, 185
Kirk, Edward Cameron, 52 early research on, 2
Klebsiella pneumoniae, in vaginal flora, 300 MMP inhibitors, 24
Koch, Robert, 50 and periodontal disease, 12, 18
in pregnancy, 288
L in RA, 217
Lantus (glargine), 264t Mattila study, 55
LBP. See LPS binding protein (LBP) mechanical irritation, and oral cancer, 247
LBW (low birth weight). See pregnancy mechanical therapy, in periodontal disease, 16, 20–21
complications linked to periodontal disease medical nutrition therapy (MNT), in DM, 81
LDL apheresis, in atherosclerotic disease, 283 medical professionals, role in DM comanagement,
Leeuwenhoek, Antonie von, 50 269–272
354 INDEX
meglitinides, 83t, 84 neomycin sulfate, in ventilator-associated pneumonia,

mendelian inheritance, 221 183
meperidine, in pregnancy, 291t neurological complications, 75t, 76
mepivacaine, in pregnancy, 291t neutropenia
Merrit, Arthur H., 51–52 in oral mucositis, 320
metabolic control, affected by periodontal disease, and periodontal disease, 11
256–258 nitrates, in atherosclerotic disease, 282
metabolic syndrome, 71 nitrosamines, as carcinogens, 248
metastatic bone disease, 309, 311 nitrous oxide, in pregnancy, 291, 291t
Metformin (biguanide), 83t, 84 NovoLog (aspart), 264t
methicillin resistant Staphylococcus aureus (MRSA), 177 NPH (Novolin/Humulin), 86–87, 86t, 264, 264t
metronidazole NUG/NUP. See necrotizing periodontal disease
in NUG, 23 nursing-home associated pneumonia (NHAP), 179
in periodontitis, 23 nutrition
in pregnancy, 291t, 292, 296–297, 299–300, 302 and GI cancer, 247
microbiome analysis, 2 in gingivitis, 8
Microorganisms of the Human Mouth, The (Miller), 50 necrotizing periodontal disease and, 11
microvascular complications, 74, 126 in oral mucositis, 319
Miglitol (alpha-glucosidase inhibitor), 83t, 84 in pregnancy, 155
Miller, W. D., 50 as risk factor for oral cancer, 232–236
ministrokes, 123
minocycline (Arestin), 22–23, 147 O
MNT. See medical nutrition therapy obesity
Modification of Diet in Renal Disease (MDRD), effect on periodontal health, 100–102
kidney disease guidelines, 315 and insulin resistance, 69–70
Moraxella catarrhalis prevalence of, 101f
in COPD, 186 as a risk factor for atherosclerotic disease, 125,
morning sickness, in pregnancy, 288 276, 277f
morphine sulfate Offenbacher, S., 58
in oral mucositis, 320 ONJ. See osteonecrosis of the jaw
in pregnancy, 291t OPG. See osteoprotegerin
mosaic pattern, in Paget’s disease, 308–309 ophthalmic complications, 74, 75t
“Mouth Infection: The Cause of Systemic Disease” oral antiseptic mouthrinses
(Merrit), 51–52 effect on oral cancer risk, 237
MRSA. See methicillin resistant Staphylococcus in periodontal diseases, 21
aureus oral cancer, periodontal disease association, 231–249
mucositis oral flora
and chemotherapy, 319t equilibrium with host, 31–33
mucosal coating agents, 320 humoral immune response to in RA, 225–226, 225f
in radiation therapy, 321 in infants, 293
Mycoplasma pneumoniae, in community-acquired intrauterine exposure to, 165, 167
pneumonia, 177 as pathogens in respiratory tract diseases, 59,
myelogenous leukemia, 321 177–180
myelosuppression, in oral mucositis, 320–321 in pregnancy, 288, 293
myocardial infarction (MI), 55, 71, 123, 125, 280 oral health
in atherosclerotic disease, 283
N care of institutionalized patients, 183–184
nateglinide (Starlix), 83t, 84, 264t in COPD, 186–187
National Cholesterol Education Program, 282 historical improvements in, 21–22
National Health and Nutrition Examination Survey in pregnancy, 287–302
(NHANES III), 12 relationship to oral cancer, 238
National Kidney Foundation, kidney disease sulcular epithelium in, 35
guidelines, 315 oral health education
nausea and vomiting, in pregnancy, 296 consumer-patients’ knowledge, 331, 332f
necrobiosis lipoidica diabeticorum, 78 influencing public perception, 330–331
necrotizing periodontal disease, 6, 7t, 11, 23, 104 key information, 337, 337f
Neisseria gonorrhoeae, gingival lesions from, 8 key points on, 340–341
INDEX 355
oral health literacy, 327, 328, 334–336, 341 inflammation, 199f, 200
outreach activities, 341, 341t linked to periodontal disease, 60, 201, 202f
overcoming obstacles, 335–336 and metastatic bone disease, 309
physicians’ role in, 328 Paget’s disease, 308–309
responsibility for, 327, 329, 336 periodontal integrity, 199f, 203
“sound bites” for patient education, 338–340 therapies for, 204–207, 204f
oral hygiene osteoprotegerin (OPG), 195, 195f
in DM, 255–256 osteoradionecrosis
in institutionalized patients, 183–184 in radiation therapy, 321
in ONJ, 312–313 See also osteonecrosis of the jaw (ONJ)
as risk factor for oral cancer, 232–236 oxycodone, in pregnancy, 291, 291t
oral implants. See dental implants
Oral Infections and Vascular Disease Epidemiology P
Study (INVEST), 136, 138, 139t Paget’s disease, bisphosphonates and, 310–311
oral mucositis PAI. See plasminogen activator inhibitor
and chemotherapy, 319–321, 319t palifermin, in mucositis prevention, 320
and radiation therapy, 321 pamidronate, 309–310
oral opening exercises, in cancer resection, 323 pancreatic cancer, related to oral health, 241–243
“Oral Sepsis as a Cause of Disease” (Hunter), 51 Papillon-Lefevre syndrome, 11
oral sepsis as cause for disease, 51, 52 parathyroid hormone, in bone remodeling, 195–196, 196f
oral toxicity, and chemotherapy, 319, 319t parathyroid hormone (Forteo), 206
oral-systemic relationship pathogen-associated molecular patterns (PAMPs)
adverse pregnancy outcomes, 58 in host response, 31, 32t
cardiovascular disease, 57–58 patient education
current understanding, 55–56 diabetes self-management skills, 81–88, 253
dental professionals’ understanding of, 335 in DM, 255–256, 267–269
diabetes mellitus (DM), 58–59 key messages for medical professionals, 270–271, 270b
early understanding of, 49–50 maternal dental education, 293, 295–296
emerging recognition of importance, 1, 330–331 See also oral health education
historical era of research, 2–3 pattern recognition receptors (PRRs), in host
oral sepsis as cause for disease, 50–55 response, 31, 32t
osteoporosis, 60 PAVE. See Periodontitis and Vascular Events Study
patient education, 327–342 PDGF. See platelet-derived growth factors
periodontal disease as a risk factor, 56–57 pemphigoid, in gingival disease, 8
respiratory infections, 59 penicillin-family agents, in pregnancy, 291–292, 291t
osteoblasts, in bone remodeling, 193–194, 194f, 195f peptidoglycan (PGN), in host response, 31, 32t
osteoclasts Peptostreptococcus micros
in bone remodeling, 193, 194f in atherosclerosis, 137
in RA, 224–225 pericoronal abscess, 11
osteonecrosis of the jaw (ONJ) Peridex/Periochip (chlorhexidine gluconate), 21
bisphosphonate associated, 205, 310–311, 310f, 311f periodontal disease
comanagement of, 312–313 classification, 6–7, 7t
osteopenia epidemiology, 11–13
and alveolar bone loss, 201, 202f etiology and pathogenesis, 16–19, 18f
defined, 198 gingival diseases, 6–9
subantimicrobial-dose therapy and, 24 historical eras of research, 1–3
osteoporosis linked to systemic disease, 1–3, 9, 19
alveolar vs skeletal bone mineral density, 200–201 management of. See periodontal disease
bisphosphonate pharmacology, 309–310 management
BMD, 197–198 necrotizing, 11, 23
bone remodeling and skeletal integrity, 193–197 periodontal balance, 19f
calcium and, 203 periodontitis, 9–11, 9f
comanagement, 208–209 risk factors, 13–16, 16t
cortical/trabecular architecture in, 197f risk reduction strategies, 17t
dental implants in, 203–204 periodontal disease management
in DM, 75t, 78–79 antimicrobials, 22–23
etiology and classification, 199–200, 308 antiseptics/toothpastes, 21–22
356 INDEX
aspirin in, 44, 46 Socransky’s research on, 2

host-modulation therapy, 23–24 in spontaneous abortion, 58
locally administered agents, 24–25 postmenopausal osteoporosis, 196, 199, 200
mechanical therapy, 20–21 practitioner-to-patient communication, 327, 335–336
overview of, 19–20, 20f Pramlintide (amylin), 88
potential adjunctive approaches, 24f Prandin (repaglinide), 264t
systemically administered agents, 24 prediabetic state, 72t, 253
“Periodontal Infection as a Possible Risk Factor for preeclampsia
Preterm Low Birth Weight” (Offenbacher), 58 clinical presentation, 162
periodontal-systemic inflammation, 327–342 as distinct complication, 153–154
periodontitis epinephrine contraindicated in, 290–291
abscesses of periodontium, 11 etiology, 297
aggressive periodontitis, 10–11 as hyperinflammatory state, 154
chronic periodontitis (CP), 10 pathogenesis and risk factors, 162–163
as complication of diabetes, 99–100 periodontal disease association, 163–164
effect of systemic inflammation on, 107 pregnancy
effect on blood glucose levels, 107–115, 113t comanagement of adolescent pregnancy, 302–303
epidemiology, 12–13 comanagement of complications, 295f, 296–297
etiology/pathogenesis, 16–19, 18f comanagement of DM and GDM, 91
genetic/microbiologic risk factors, 9f comanagement of normal pregnancy, 289–290, 292t
increased risk with obesity, 100–102 dental caries, 293
management of, 19–25, 20f gingivitis, 7, 293–294
as manifestation of systemic disease, 11 inflammation in, 30, 40
necrotizing lesions, 11 patient education “sound bites,” 338–340
periodontal balance, 19f periodontal disease management in, 153, 164
risk factors, 13–16, 16t physiological changes in, 287–289
risk reduction strategies, 17t preconception recommendations, 294–295
simultaneous causal factors in, 9, 9f pregnancy epulis, 294
Periodontitis and Vascular Events Study (PAVE), pregnancy complications linked to periodontal
145–146, 147f, 283–284 disease
Periostat (doxycycline), 24 animal studies supporting, 165–170
peripheral artery complications, in DM, 75t association with periodontal disease, 157–162, 165
peritoneal dialysis, 315 clinical presentation, 154
peritonitis future research needs, 170–171
proresolution mediators’ effect on, 45t human studies supporting, 164–165
pernicious anemia, in DM, 69 infant deaths from, 157–158, 158f
PGN. See peptidoglycan intervention trials, 170
pharmacologic treatment pathogenesis, 153–154
in periodontal disease, 16, 17t periodontal disease connection, 19
in pregnancy, 290–291, 291t preeclampsia, 153–154, 162–163
“phossy jaw,” 310 preterm and low birth weight, 158, 160f, 161f
physiologic anemia of pregnancy, 289 types of complications, 153–154
Pioglitazone (thiazolidinedione), 83t, 84 premature rupture of membranes, 296–297
plaques. See atheromatous plaques; dental plaque preterm birth (PTB)
plasminogen activator inhibitor type-2 (PAI-2), in in adolescents, 302–303
pregnancy, 293 effect of dental care on, 298–303
platelet-derived growth factors (PDGF), 25 and periodontal disease, 294, 295f
pneumococcal vaccination, in DM, 80t periodontal disease management in, 298–303
pneumonia, 21, 59, 177–178, 182–184 risk factors for, 298
polymyxin B sulfate, in ventilator-associated risk from dental procedures, 290
pneumonia, 183 Prevotella intermedia
Porphyromonas gingivalis in pregnancy, 293–294
in animal studies, 165–169 in RA, 225
in connective tissue, 33 prilocaine, in pregnancy, 290, 291t
as indicator of atherosclerosis, 137 procoagulant factors, DKA, 73
in pregnancy, 157, 158, 164–169, 171 professional development, and patient education,
in RA, 225, 225f 337, 337f
INDEX 357
progesterone, effect on periodontal health, 287, 293 COPD, 184–188

proinflammatory mediators in hospitalized patients, 187–188
and cardiovascular disease, 39–40 mechanisms involved, 59, 179–180
DKA, 73 patient education “sound bites,” 340
effect on metabolic control, 256–258 and periodontal disease, 59
origins of, 44f pneumonia, 176–179
in RA, 217, 218t, 219 prevention of, 182–184
in systemic inflammation, 36 risk factors, 180, 181f
proresolution mediators, 42f, 43, 44–46, 44f retinopathy
prostaglandin E2 PKC inhibitors, 126
association with active disease, 12 prevention of, 81
early research on, 2 resolvins effect on, 44, 45t
prostheses rhBMP-2. See recombinant human bone
and oral cancer, 247, 323 morphogenetic protein-2
prosthetic cardiac valves, care during pregnancy, 292 rheumatoid arthritis (RA), periodontal disease
protamine hagedorn (NPH) insulin, 264 management in, 226
proteases rheumatoid arthritis (RA) and periodontal disease
in host response, 31, 32t clinical presentation, 214–216, 215f, 216t
protectins, 41, 42f, 44–46, 44f, 45t clinical relevance of association, 226
protein cell regulators, in plaque formation, 124 cytokines in, 217, 218t
protein kinase C (PKC), 126 as ecogenetic diseases, 221–222, 221t, 222f
Protelos (strontium ranelate), 205–206 environmental risk factors, 219–221
PRRs. See pattern recognition receptors genetic component, 219
Pseudomonas aeruginosa inflammation in, 216–219, 217f
in COPD, 188 matrix metalloproteinases in, 217, 220t
in nosocomial pneumonia, 179 mechanisms of relationship, 224–226
in ventilator-associated pneumonia, 182, 182f similarities, 214
PTB. See preterm birth studies concerning relationship, 222t, 223–224
ptyalism risedronate (Actonel), 204, 309–310
in pregnancy, 288 risk factor assessment/reduction
atherosclerotic disease, 57–58, 124–126, 278,
R 283–284
radiation therapy, in head and neck cancer, 321–322 common to oral and systemic disease, 1
radiography, in pregnancy, 290 defined, 57
receptor activator for nuclear factor kB ligand historical era of research, 2–3
(RANKL), 195, 195f oral cancer, 232–236, 232t, 238
receptor agonists, in inflammation resolution, 41 periodontal disease, 13–16, 16t, 56–57
receptor for AGEs (RAGE), 126 role of dentistry in, 3
recombinant human bone morphogenetic protein-2 “Role of Sepsis and Antisepsis in Medicine, The”
(rhBMP-2), 24, 25 (Hunter), 51–52
refractory periodontitis, 23 Rosiglitazone (thiazolidinedione), 83t, 84
renal disease. See kidney disease Rush, Benjamin, 50
renin, 313, 314 Ryff, Walter H., 50
repaglinide (Prandin), 83t, 84, 264t
“resolution deficit” phenotype, 44 S
resolution of inflammation, 42f, 44f, 45t Scottsdale Project (April 2007), 269–272
factors affecting resolution, 40–41 SDD. See subantimicrobial-dose therapy
mechanisms of, 41–43, 42f “Secret Killer, The” (Time Magazine), 330
origins of proresolution mediators, 44–46 sedation, in pregnancy, 291
process of, 41 selective estrogen receptor modulators (SERMs)
role of proresolution mediators, 43–44, 44f, 45t in osteoporosis, 205
resolvins, 41, 42f, 43–44, 44f, 45t self-monitoring of blood glucose (SMBG), 81
respiratory tract, changes in pregnancy, 288–289 short-acting insulin secretagogues, 263, 264t
respiratory tract diseases, periodontal disease “silent epidemic,” 293, 327
association, 179–183, 186, 188 single nucleotide polymorphisms (SNPs), in RA,
respiratory tract diseases associated with oral flora 221–222
bacterial strains involved, 182–183 Sitagliptin (dipeptidyl peptidase IV inhibitor), 83t, 85
358 INDEX
skeletal integrity inflammatory pathways, 35–36

vs alveolar bone loss, 200–201, 202t patient education “sound bites,” 338
in osteoporosis, 197 reduction with subantimicrobial-dose therapy, 24
SMBG. See self-monitoring of blood glucose role of in various disorders, 39–40
smoking. See tobacco use See also oral-systemic relationship
socioeconomic risk factors
in pregnancy, 293 T
in RA, 221 tacrolimus, in kidney disease, 316
Socransky, S. S., 2 Tannerella forsythensis
Socransky’s red/orange complex in preeclampsia, 164
contribution to periodontal disease, 35 in pregnant adolescents, 303
in pregnancy, 153 Socransky’s research on, 2
sodium alendronate (Fosamax), 204 Tannerella forsythia, in gestational diabetes, 112
sodium chloride/triclosan copolymer, 22 tartrate acid phosphatase, 193, 194f
“sound bites” for patient education, 338–340 taxanes, 319t
spontaneous abortion, 296 team-care
squamous cell carcinomas, 321 in DM, 271
SSA (serum amyloid A) proteins, role in See also comanagement
inflammation, 37 teriparatide (Forteo), 206
stannous fluoride/sodium hexametaphosphate, 22 tetracyclines
Staphylococcus aureus contraindication in pregnancy, 292
in community-acquired pneumonia, 177, 179 in host-modulation therapy, 24
in COPD, 188 in periodontal disease, 22
in nosocomial pneumonia, 179 thiazolidinediones, 83t, 84
in ventilator-associated pneumonia, 182 thienopyridine clopidogrel, 280
Starlix (nateglinide), 264t threatened abortion, 296
statins thromboembolism, in pregnancy, 289
and CRP, 124, 278 tiludronate, 309
in hyperlipidemia, 282–283 Time Magazine, “The Secret Killer,” 330
in inflammation, 46 tissue homeostasis
Streptococcus mutans, maternal vs child, 293 disruption of, 35
Streptococcus pneumoniae following inflammation resolution, 30
in community-acquired pneumonia, 177 TLRs. See Toll-like receptors
in COPD, 186 tobacco use
Streptococcus sanguis, 58 cessation, 20, 335
Streptococcus species, in pregnancy, 165 in chronic periodontitis, 10
stress, in chronic periodontitis, 10 passive exposure, 242
strokes risk factor for atherosclerotic disease, 126, 276, 277f
DM as a risk factor, 63 risk factor for COPD, 185
due to atherosclerotic disease, 123 risk factor for oral cancer, 232–236
strontium ranelate (Protelos), 205–206 risk factor for RA, 221
subantimicrobial-dose therapy (SDD), 24 tocolytics, in premature rupture of membranes,
sucralfate, in radiation therapy, 322 296–297
sudden cardiac death, in atherosclerotic disease, 280 Toll-like receptors (TLRs)
sulfonylureas, 83t, 84, 263, 264t in host response, 31, 32t
supine hypotension syndrome, 288, 290 role in inflammation, 37
syndemic approach, 271 tooth loss
synovial fluid, periodontopathic bacteria in, 225 effect of diabetes on, 105–107
systemic disease, metastasis from local infections, 51 and GI cancer, 247
systemic inflammation as indicator of periodontal disease, 242–246
acute-phase proteins, 36–37 topoisomerase inhibitors, 319t
biomarkers decreased with Arestin treatment, toxins, in host response, 31, 32t
22–23 transient ischemic attacks (TIAs), 123
caused by periodontal disease, 30, 40 transplantation, 88, 315
cellular and molecular markers of, 37–38 treatment model, for DM, 268f
effect of periodontitis on, 107 Treponema denticola, Socransky’s research on, 2
from focal infection, 49 Treponema pallidum, gingival lesions from, 8
INDEX 359
T-scores, 197–198, 198f found in connective tissue, 33

tumor necrosis factor-a (TNF-a) of periodontal bacteria, 30, 31
effect on metabolic control, 256–258 in remote tissues, 36
in inflammatory response, 3 viruses, cancer and oral health, 247
in insulin resistance, 70 vitamin D
in insulin signaling pathways, 67f activation of, 314
Type 1 vs Type 2 diabetes mellitus (DM), 63, 69 in bone remodeling, 195–196, 196f
in kidney disease, 314
U periodontal disease management in, 60
United Kingdom Prospective Diabetes Study in primary osteoporosis, 199
(UKPDS), 74, 254 in renal replacement therapy, 315
upper digestive tract cancer, 234–235 vitiligo, 69, 78
uremic syndrome, 314
Useful Instructions on the Way to Keep Healthy, to W
Strengthen and Re-invigorate the Eyes and the Sight weight control, comanagement of, 282
(Ryff), 50 weight loss, in DM, 81
uterine bleeding, in pregnancy, 296 Western New York MI/Perio Studies, 136, 138–139
Wilcox, Robert, 51
V Women’s Health Study, 278
vaginal flora, metronidazole treatment and, 302 World Health Organization (WHO), T-scores,
vancomycin hydrochloride, in ventilator-associated 197–198, 198f, 308
pneumonia, 183 wound healing, in DM, 265
vascular damage in RA, 225
vascular permeability, in pregnancy, 287–288 X
vasoconstrictors, in preeclampsia, 297 xerostomia
vasodilators, in kidney disease, 315 in chemotherapy, 320
ventilator-associated pneumonia (VAP), 178, 181f, in kidney disease, 313
182–184 periodontitis risk assessment, 16t
ventricular fibrillation, in atherosclerotic disease, 280 in radiation therapy, 321, 323
viral infections, in gingival disease, 8
virulence factors Z
effect on host cells, 32t Zometa (zoledronic acid), 204, 309–310

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ii

Periodontal Disease and Overall Health: A Clinician’s Guide

Copyright © 2014 by the Colgate-Palmolive Company. All rights reserved.

Professional Audience Communications, Inc.

Editorial Quality Control: Teri S. Siegel

Printed in the United States of America

Last digit is the print number: 6 5 4 3 2 1

Srividya Kidambi, MD, MS Angelo Mariotti, DDS, PhD

Hector F. Rios, DDS, PhD Thomas E. Van Dyke, DDS, PhD

Robert J. Genco, DDS, PhD Ray C. Williams, DMD

Fotinos S. Panagakos, DMD, PhD

—Former U.S. Surgeon General C. Everett Koop

INTRODUCTION Alzheimer’s disease (83,494), and diabetes

INTRODUCTION form of the disease and generally involves

Chronic Periodontitis and HIV infection can decrease host defenses

Genetic risk factors

Microbiological and lifestyle risk factors

old participants. Probing depths of ≥ 3 mm paradigm shift in our understanding of the

Table 2. Risk Assessment for Periodontitis

Table 3. Risk Reduction Strategies

Source: Dent Clin N Am 2005;49:611–36.

Figure 3. Schematic Illustration of the Pathogenesis of Periodontitis

Genetic risk factors

Antigens Host Prostanoids Connective Clinical

Environmental and acquired

Tissue breakdown products and ecological changes

Copyright © 2006 by Saunders, an imprint of Elsevier Inc.

Figure 4. The Periodontal Balance

Risk factors (e.g., genetics, Reduction of

Overproduction of proinflammatory or Expression of host-derived anti-inflammatory

Underactivity or overactivity Host modulatory Resolution of

Poor compliance Subgingival OHI, SRP, surgery, antiseptics, antibiotics

Copyright © 2006 by Saunders, an imprint of Elsevier Inc.

dental office (if the staff is appropriately for clinical

relies on an individual’s knowledge of the motivation and do not spend a sufficient

Figure 6. Potential Adjunctive Therapeutic Approaches

Bacterial + Host response component = Clinical

enamel matrix proteins (Emdogain®), bone Acknowledgments

19. Kinane DF. Periodontitis modified by systemic 1994;65:260–7.

2012;90:410–25. doi: 10.1016/ajhg.2011.12022. Thorsteinsdottir U, Kong A, Stefansson K. A

cyclooxygenase-2 and risk of severe chronic peri- 1992;63:118–30.

odontol 2004;75:1553–65. periodontitis in postmenopausal osteopenic

INTRODUCTION cancer5,6 are associated with oral organisms

Bacterial Components Bacteria and Gastrointestinal Equilibrium

Table 1. Summary of Main Effects of Bacterial Virulence Factors on Host Cells

Responses of Host Cells

among other events, to the synthesis of The Immune Response

TNF-! LBP Histamine

vated levels of circulating proinflammatory increase their concentration in the plasma.

Possible Role of Systemic Inflammation in important because increasing evidence sug-

tion does not follow a linear pattern with Returning to Homeostasis

Chronic Acute Class switching

Arachidonic EPA DHA

ATLa RvE1 PD1

Figure 3. Dual Anti-inflammatory and Proresolution Actions of Specific Lipoxins,

n CZjigde]^a 9jVa"VXi^c\ l BdcdXniZ

CVijgZ GZk^Zlh q >bbjcdad\n

enhanced mucosal clearance of bacteria Role of Proresolution Mediators

resolvins protected against neovasculariza- Origins of Proresolution Mediators

INTRODUCTION illness. One area of the body that has been

Cause of Systemic Disease.”13 He stated, rheumatic infections, kidney diseases, all

Table 1. Etiologic Classification of DM. In addition, DM is the leading cause

Feeding, satiety,! and! the! neurohumoral