The search for clues among systemic links
by Lynne Slim, RDH, MS, and Chris Lavelle, DDS, PhD, MBA
I’ve lived with asthma and an inappropriate inflammatory response since I was eight years old. My dad would put me in the shower so I could breathe more easily, and I spent many years on and off oral steroids. More than 10 years have passed since a paradigm shift in the pathogenesis of periodontal disease was proposed which emphasized patient susceptibility to gingivitis and periodontitis based on numerous risk factors. Unresolved and persistent periodontal inflammation that sometimes puzzles a conscientious hygienist and patient isn’t all about biofilm “infection.” This was a big “aha” moment for me, because I was frustrated with some of my patients over the years who did not respond well to conventional periodontal therapy. Once and for all, I could finally relate to a patient with a wonky oral inflammatory response because I’ve been troubled with one myself for many years.
Knowing who we are as oral health-care professionals is critical to our continued growth and success. Last night, I watched an episode of “American Idol.” I was struck by something Randy Jackson said to one of the contestants who was singing his heart out that night. He told the contestant after his performance that he was ready for the “BIG TIME” because this particular person had a strong sense of who he is! As we move forward in our professional journey, it’s important for us to understand that we are a lot more than oral health prevention therapists. As scientists continue to explore the various theories surrounding oral/systemic risks, progress in this particular discipline has been impressive and theories have either been strengthened or weakened by an accumulation of high-quality evidence. Will hygienists become recognized for their ability to detect inappropriate oral inflammation, and will this ability tie us more closely to the medical profession? Should we perhaps explore a future in primary medical care and work within primary care practices as oral and general health advocates?
In exploring the topic of oral/systemic links and in thinking about our new role as inflammation sleuths, I contacted someone who I thought could be objective about these growing links, and I asked him to discuss the strength of the evidence surrounding them.
Dr. Chris Lavelle resides in Canada and received his dental training in the United Kingdom. In addition, he has a PhD in anatomy and a DSc in pathology and is a Fellow in the Royal College of Pathologists in the U.K. He was a senior lecturer in pathology at the University of Birmingham, England. He is currently part of the dental faculty of Manitoba, University of Manitoba, Winnepeg, Canada.
Variable inflammatory responses
Gingivitis and periodontitis, together with most other forms of inflammation, are largely adaptive responses to microbial infections or, less commonly, tissue injuries. But whereas microbial infections of the biofilm on the tooth surfaces and gingival sulcus generally initiate these diseases, it is the variable inflammatory responses that drive the subsequent pathological changes of bleeding on probing and increased pocket depth. In fact, these acute and/or chronic inflammatory responses are well established, although much less is known about the dynamics of “systemic chronic inflammatory syndrome” or “para-inflammatory states” that characterize such diseases as obesity, type 2 diabetes, atherosclerosis, myocardial infarctions (heart attacks), cerebro-vascular accidents (strokes), asthma, preeclampsia (preterm births), rheumatoid arthritis, Alzheimer’s disease, erectile dysfunction, malignancies, and periodontal disease. Indeed, all such low-grade chronic inflammatory states are associated with common risk factors such as genetic mutations and/or environmental (e.g., gender, age, race, socioeconomic status, tobacco and alcohol abuse, infections, diabetes, dietary insufficiencies, obesity, periodontal disease, lack of exercise, etc.) factors. As these associations imply that patient education, scaling, and root planing provided by the dental hygienist improve both the oral health of patients and their overall well-being, the rationale for this caveat requires closer examination.
Gingivitis and periodontal disease
Triggered mainly by microbial infections, the acute inflammatory responses associated with gingivitis involve the coordinated delivery of blood components (plasma and leukocytes) to the site triggered by receptors of the immune system. When resident macrophages and mast cells recognize this initial microbial infection, they release a variety of mediators that elicit local inflammatory exudates of plasma proteins and leukocytes (mainly neutrophils) that are normally contained in the blood vessels. Activation of these cells by either direct microbial contact or through messengers (i.e., cytokines) secreted by the resident tissue cells, then leads to the release of such agents as reactive oxygen species [ROS] and nitrogen species [RNS] and enzymes. But whereas these highly potent agents attempt to kill the invading microbial organisms in the biofilm, they also cause collateral damage to the host tissues.1,2 If these acute inflammatory responses successfully eliminate the microbial infections or tissue damage, however, resident and recruited macrophages generally elicit complete resolution and promote repair (i.e., gingivitis is generally reversible with high standards of oral hygiene). In fact, the “switch” from inflammation to resolution is not merely a passive response to the elimination of microbial infections, since it requires antiinflammatory messengers (i.e., lipoxins, resolvins, protectins, and growth factors) derived from macrophages. If the acute inflammatory responses are slow or inadequate due to poor oral hygiene or virulent microbial infections, however, the neutrophil inflammatory infiltrate is replaced by macrophages and T lymphocytes. As these lead to subsequent scarring and fibrosis, they also predispose other or recurrent microbial infections and chronic gingivitis.
The exaggerated chronic inflammatory (granulomatous) responses may then attempt to wall off the microbial pathogens by layers of macrophages, although these may also attack and destroy the supporting tissues. Such reactions characterize the irreversible transition from chronic gingivitis to progressive periodontal attachment loss that affects about 10% of the adult population and about 30% of those over the age of 50. This transition is characterized by a shift in the dominant microbial strains in the biofilm from largely aerobic gram-positive to anaerobic gram-negative strains rather than a novel infectious strain. These can generally be controlled by such interventional procedures as scaling and root planing, augmented by systemic or local administration of chemically modified antibiotics, NSAIDs such as subantimicrobial dose doxycycline (SDD), or other antimicrobial agents, however, although they do not necessarily resolve the inflammatory changes required to restore tissue homeostasis.3 Again, this “switch from the inflammatory to the resolution and repair phase” requires the secretion of lipoxins, resolvins, protectins, and growth factors by macrophages prior to the restoration of periodontal attachment loss. This explains why intense research is currently centered on the synthetic development of these agents. However, they do not completely resolve the ravages of periodontal disease.
Chronic systemic inflammatory syndrome (para-inflammatory state)
Another form of chronic inflammation (termed “chronic systemic inflammatory syndrome” or “para-inflammatory state”) is a potentially more significant health-care threat. This is initiated by genetic mutations and/or environmental (e.g., gender, age, race, socioeconomic status, tobacco and alcohol abuse, infections, diabetes, dietary insufficiencies, obesity, periodontal disease, lack of exercise, etc.) factors rather than infections or injuries, although the relative significance of these parameters remains obscure. Nevertheless, these risk factors are integral with the increased prevalence of such a diverse range of systemic diseases as type 2 diabetes, atherosclerosis, asthma, preeclampsia, neurodegenerative diseases, malignancies, and periodontal disease. Moreover, these diseases are all characterized by increased serum C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL1β), - 6 (IL-6), and matrix metalloproteinases. In fact, these markers of systemic inflammation (especially CRP) are not only “markers” of these chronic systemic inflammatory or para-inflammatory states, but also with progressive reductions of insulin sensitivity and/or higher blood pressures that further exacerbate these disease states. The inference of these associations is then that individuals who abuse tobacco or who are obese have a greater prevalence for chronic periodontal attachment loss, cardiovascular diseases, preeclampsia, and many other diseases than those who do not. Such combined preventive measures as smoking cessation, weight control, dietary restrictions, and exercise are, therefore, logical strategies to control or reduce the diseases associated with such chronic systemic inflammatory states, especially when introduced at the time of adolescence. As these associations then raise the fundamental question whether treatment provided by the hygienist improves not only the oral health of patients but also their overall well-being, they warrant urgent consideration.
Do the therapeutic procedures of the hygienist improve the overall health of patients?
Dr. Lavelle: The answer to this question is, however, far more complex than traditionally envisaged. For example, complex interactions between both genetic and environmental risk factors (e.g., tobacco abuse, obesity, etc.) are associated with increases in the prevalence of loss of periodontal attachment and such other chronic diseases as myocardial infarctions (heart attacks), cerebrovascular accidents (strokes), preeclampsia (preterm births). These interactions then imply that some people are more susceptible to these lifestyle-related behaviors than others. Certainly, the elimination of a risk factor (e.g., smoking cessation) will improve pulmonary, cardiovascular, and oral mucosal functions depending on the duration and magnitude of prior smoking behaviors, although few would dispute that far greater health improvements will follow concomitant reductions of all other risk factors (e.g., obesity, exercise, etc.).
Unfortunately, periodontal disease, in common with all other chronic diseases, is characterized by periods of seeming latency that extend over years or even decades, during which the pathogenesis proceeds prior to the late-stage clinical presentation of characteristic signs and symptoms (e.g., tooth mobility and pain for periodontal disease or angina for cardiovascular disease). Although it is clearly preferable to prevent these diseases at the early reversible stages of their development (e.g., gingivitis), the early (e.g., adolescent) implementation of such effective preventive strategies as oral hygiene improvements, smoking cessation, weight control, etc., is impeded by the common misconception that people are “healthy” during these latent periods. Certainly all forms of tobacco abuse are dominant risk factors for periodontal disease, pulmonary, and cardiovascular disorders and malignancies, although the complex genetic and environmental interactions responsible for the greater susceptibility of some individuals to these lifestyle-related behaviors than others have yet to be defined. This dilemma is further compounded by the fact that few chronic diseases other than those at risk for cardiovascular disease have such reliable markers as differential serum cholesterol (i.e., high low-density lipoprotein [LDL] cholesterol and low high-density lipoprotein) levels and/or high blood pressure that can be delayed, arrested, or even reversed by the prompt prescription of statins, nonsteroidal antiinflammatory drugs (NSAIDs), dietary control, and exercise. For example, whereas such diagnostic techniques as bleeding on probing and assessment of periodontal attachment loss are generally used to assess gingivitis, they cannot assess the microbial infections or inflammatory responses that differentiate those at risk for further deterioration. Certainly, the pathological consequences of gingivitis may generally be delayed or arrested by improved oral hygiene education, scaling, and root planing. However, these benefits are likely to be transient without concomitant reductions in systemic (e.g., tobacco abuse, obesity, etc.) risk factors. For example, obesity contributes to the development of low-grade systemic chronic inflammatory or para-inflammatory states characterized by increases in such low-grade serum inflammatory markers as CRP, TNF-α, and IL-6, and thereby increases their susceptibilities for a diverse range of systemic diseases, including periodontal disease. Therapies provided by the dental hygienist are therefore unlikely to significantly improve the overall health of patients, without the concomitant reduction of other risk factors. The hygienist is, therefore, obligated to serve as a general health-care advocate and advise on both preventive oral and general health-care strategies.
These inherent obligations are emphasized by answers to the following questions:
1. Does periodontal treatment reduce the prevalence of preeclampsia?
Dr. Lavelle: The facts listed above can now be used to address the rhetorical headline in the U.S. News and World Report (dated 1/29/09), that proclaimed “treating gum disease does not decrease a pregnant woman’s risk for preterm births” (i.e., preeclampsia: a vascular disorder of pregnancy that complicates approximately 5% to10% of all pregnancies, and is a major cause for maternal and perinatal mortality and morbidity worldwide). Certainly preeclampsia is generally initiated by infections, vascular disease, and over-distension of the uterus, where the principal risk factors include advanced maternal age, multiple pregnancies, obesity, hypertension, kidney disease, diabetes mellitus, and tobacco abuse and periodontal disease are synonymous with those for low-grade systemic chronic inflammatory or para-inflammatory states.4 This was confirmed by the fact that women with severe periodontitis (15 tooth sites with pocket depths 4 mm) have more than twice the risk for preeclampsia than periodontally healthy women.5 However, a study of 1,800 pregnant women with periodontal disease, randomly assigned to those who received periodontal treatment before 23 weeks gestation and others who received no treatment, has reported no significant differences in obstetric or neonatal outcomes between these two groups.6 Thus, whereas all forms of treatment for periodontal disease during pregnancy is safe, conventional periodontal standards of care (i.e., oral hygiene instruction, scaling, root planing, etc.) are insufficient to reduce the risks for preterm births (preeclampsia) without concomitant reductions in such other risk factors as tobacco abuse and obesity that are also associated with increased serum levels of CRP.
2. What do we know about the relationship between periodontal disease and cardiovascular disease?
Dr. Lavelle: Based on recent meta-analyses involving nearly 150,000 subjects, the incidence and prevalence of cardiovascular disease (CVD) were 24% to 35% greater in subjects with periodontal disease than in those without, even after adjusting for such risk factors as smoking, blood lipids, race, gender, and obesity.7,8 In fact, two biological pathways may contribute to this association:
- (a) The chronic microbial infections that initiate periodontal disease may also contribute to low-grade, chronic, systemic inflammatory states denoted by such markers as CRP, TNF-α, and IL-6. But whereas periodontal therapy may lead to reductions in such markers, these benefits are likely to be transient without concomitant reductions in other risk factors (e.g., smoking cessation).
- (b) As microbial periodontal pathogens are capable of entering the systemic circulation, their subsequent invasion of the major elastic arteries may contribute to the formation of atheromatous plaques and subsequent blood clots (thrombi) and emboli that block arterioles in the heart (myocardial infarction), brain (cerebrovascular accident or stroke), and/or kidneys (renal failure).9
Thus, whereas such traditional cholesterol abnormalities as increased serum levels of low-density lipoprotein (LDL) cholesterol and decreased high-density lipoprotein comprise one of the causal pathways associated with CVD, an alternative or second inflammatory pathway may be linked to periodontal disease.10 However, in a randomized study of 303 subjects with both periodontal disease and severe CVD, scaling and root planing have been shown to be associated with significant reductions in mean probing depths after six months.9 However, although comparable reductions in their serum lipid abnormalities indicative of systemic inflammation were noted in nonobese patients, these reductions were not evident in obese patients.7 These findings not only explain why obese patients have higher prevalences for CVD and periodontal disease than nonobese patients, but also why periodontal therapy per se is unlikely to improve systemic health of such patients, without concomitant reductions in other (e.g., obesity) risk factors.
3. Does periodontal disease predispose the development of cancers?
Dr. Lavelle: The genetic mutations and/or environmental (e.g., gender, age, race, socioeconomic status, tobacco and alcohol abuse, infections, diabetes, dietary insufficiencies, obesity, periodontal disease, lack of exercise, etc.) risk factors for chronic systemic inflammatory syndrome or para-inflammatory states are analogous to those associated with the development of malignancies of the oral mucosa, upper gastrointestinal tract, pancreas, and lungs. As microbial infections of the oral flora and elsewhere are also associated with the development of malignancies, two pathways are involved: an extrinsic pathway, driven by inflammatory conditions that increase cancer risk, and an intrinsic pathway, driven by genetic alterations (oncogenes) that cause abnormal inflammatory responses that initiate neoplastic changes.11 As both pathways may be involved, the current “hot research topic” is associated with the development of chemical agents that reduce these inflammatory changes and thereby delay, arrest, or reverse the development of malignancies. As the development of these malignancies extends over periods up to two or more decades in duration prior to their initial clinical presentation and subsequent transformation to metastatic and invasive disease, the development of techniques to identify those at risk for malignancies is integral to the prescription of safe and effective prescription (i.e., they will have to be prescribed over long — very long — periods). One way to avoid the prescription of such agents is to ensure that patients reduce or even eliminate the risk factors, and the prevention of periodontal disease is integral to the achievement of this objective.
An index for chronic systemic inflammatory or para-inflammatory states:
In view of the significant similarities in risk factors (age, gender, tobacco abuse, obesity, lack of exercise, etc.) for cardiovascular, diabetes, preeclampsia, erectile dysfunction, periodontal disease, malignancies, etc., there is clearly a need for hygienists to devise some form of score card to evaluate the personal risks for their patients. An example is illustrated in Table 1.
Clearly, this score card needs refinement to define the relative significance of these parameters, yet the primary intent is to develop a “personalized index score” to educate patients on the imperative to reduce or hopefully eliminate the common risk factors (e.g., smoking cessation, exercise, etc.) for the diverse range of diseases listed above. Indeed, the need for development of such a “personalized index score” cannot be overstated, since this will ensure that hygienists become established as an integral component of the “total health-care workforce.”
- Van Dyke TE. The management of inflammation in periodontal disease. J Periodontol 2008; 79:1601-1608.
- Tanner AC et al. Clinical characteristics and microbiota of progressing slight chronic periodontitis in adults. J Clin Periodontol. 2007; 34:917-930.
- Allaker RP, Douglas CW. Novel antimicrobial therapies for dental plaque-related diseases. Int J Antimicrob Agents. 2009; 33:8-13.
- Cota LO et al. Association between maternal periodontitis and an increased risk of preeclampsia. J Periodontol. 2006; 77:2063-2069.
- Boggess KA et al. Maternal periodontal disease in early pregnancy and risk for a small-for-gestational-age infant. Am J Obstet Gynecol. 2006; 194:1316-1322.
- Ruma M et al. Maternal periodontal disease, systemic inflammation, and risk for preeclampsia. Am J Obstet Gynecol. 2008; 198:389.e1-5.
- Offenbacher S et al. Results from the Periodontitis and Vascular Events (PAVE) Study: a pilot multicentered, randomized, controlled trial to study effects of periodontal therapy in a secondary prevention model of cardiovascular disease. J Periodontol. 2009; 80:190-201.
- Bahekar AA et al. The prevalence and incidence of coronary heart disease is significantly increased in periodontitis: a meta-analysis. Am Heart J. 2007; 154:830-837.
- Humphrey LL et al. Periodontal disease and coronary heart disease incidence: a systematic review and meta-analysis. J Gen Intern Med. 2008; 23:2079-2086.
- Cairo F et al. Periodontal pathogens in atheromatous plaques. A controlled clinical and laboratory trial. J Periodontal Res. 2004; 39:442-446.
- Mantovani A et al. Cancer-related inflammation. Nature. 2008; 454:436-444.