Periodontal Medicine: Assessment of Risk Factors for Disease

The approach to the diagnosis and treatment of periodontal disease is changing. The disease has not changed, but dentistry's understanding of the pathogenesis and appreciation for the influence of host factors has improved. As a result, the approach to the management of the disease is evolving. This paper reviews some of the host risk factors that have been linked to an increased severity of periodontal disease and briefly highlights some of the evidence that has led to the current belief that periodontal disease may be a risk factor for adverse systemic health conditions.

During the past several decades, a great deal has been learned about the pathogenesis of periodontal disease and the bacterial pathogens that are responsible. The improved understanding of the pathogenesis has led to the development of many new diagnostic tools and therapies. Both diagnostic and therapeutic advances have been primarily directed at local factors (i.e., bacterial plaque). Specifically, they have focused on identifying the bacterial pathogens and decreasing or blocking the effects of their tissue-destructive enzymes. Although many new diagnostic tests have been developed, such as DNA probes for detecting known periodontal pathogens, they have not had the impact on diagnosis and therapy one might have hoped to achieve with such advances. More importantly, these advances in knowledge, understanding, and technology have not changed the routine periodontal examination nor the practitioner's ability to identify patients at increased risk of future disease.

Periodontics, like many other specialized areas of dentistry, is undergoing yet another change. The current era of change in periodontics is focusing on host factors. This evolution is being stimulated by new evidence that suggests a link between systemic factors and the severity of periodontal disease. At the World Workshop in Periodontics in 1996, a committee appointed by the American Academy of Periodontology to assess the current knowledge and summarize the status of periodontics concluded that assessment of risk was an integral part of diagnosing and treating periodontal disease. Page and Beck reported that evidence to support risk assessment in clinical decisions is substantial.¹ Evidence emerging from clinical research has shown that patients with systemic diseases (e.g., diabetes) as well as patients with other systemic factors (e.g., smoking) have an increased risk and severity of periodontal disease. As a result, these systemic "host" factors are now being recognized as significant contributors to development and progression of periodontal disease.

In addition to findings that support an increased risk relationship between systemic disease and periodontitis, evidence is also emerging to support the idea that periodontitis may have an adverse effect on systemic health.^2-8 Specifically, periodontal disease has been associated with an increased risk of coronary heart disease; poor glycemic control in diabetics; respiratory disease; and preterm, low-birth-weight babies. As a result of these new findings, much attention is being given to the interrelationship between periodontal disease and systemic health. Periodontal medicine is a term that has been used to describe this new era in periodontics. This paper reviews some of the host risk factors that have been linked to an increased severity of periodontal disease and briefly highlights some of the evidence that has led to the current belief that periodontal disease may be a risk factor for adverse systemic health conditions.

Local Risk Factors for Periodontal Disease

There is ample evidence to demonstrate a relationship between bacterial plaque and gingival inflammation.⁹ Poor compliance with oral hygiene and other local factors expose individuals (and specific periodontal sites) to increased bacterial plaque and the risk of periodontal disease. Anatomically difficult to clean or inaccessible areas such as deep periodontal pockets, calculus deposits, furcation defects, defective restorations, pontic spaces, and poor interproximal contact areas can serve as harbors for the undisturbed growth and maturation of bacterial plaque. These inaccessible areas (especially periodontal pockets of 5 mm or more) are more likely to harbor and promote the disproportionate growth of pathogenic microorganisms because they have decreased oxygen tension. As a result, they become sites for increased growth of anaerobic, gram-negative, putative pathogenic bacterial species. In an attempt to eliminate the pathogenic microorganisms, the host mounts an inflammatory response. Gingivitis results when the tissues become inflamed. Vascularity increases, which causes edema; and tissues become erythematous. The sulcular epithelium thins and bleeds easily. The inflammatory response includes the release of many cytokines, which act as chemoattractants for the recruitment of additional inflammatory cells and perpetuates inflammation. Some of these cytokines -- most notably IL-1B, TNF-a, and PGE2 -- directly contribute to gingival connective tissue and alveolar bone destruction. Periodontitis results when these pathogens and the inflammatory response begin to break down the periodontal attachment. Periodontal pocket depth increases and alveolar bone resorbs.

There is little debate about the fact that periodontal pathogens contribute to the pathogenesis of periodontal disease. However, the evidence to support a relationship between bacterial plaque and the progression of periodontitis is limited. Results from well-controlled clinical studies have found that the quantity of plaque was only weakly correlated with periodontitis.^10-12

Figure 1 Over the past several decades, our understanding of periodontitis has evolved from a simplistic model to a more complex interplay between bacterial infection and host response. In the simple model (top) we assumed that pathogenic bacteria were responsible for periodontitis and all individuals were equially susceptible to disease. The current more complex model (bottom) maintains a bacterial pathogenic etiology by also takes into consideration difference in individual susceptibility as well as environmental and host response influences.

However, it appears that the progression of periodontitis can be controlled with meticulous oral hygiene and professional cleanings (i.e., elimination of plaque can halt the progression of periodontitis).¹³ Studies using qualitative measures of plaque (i.e., specific periodontal pathogens) have offered mixed results. While periodontal pathogens are essential for periodontal disease destruction, these pathogenic microorganisms alone are not sufficient to explain the differences observed in periodontal disease severity. Recent studies on various factors that influence disease progression indicate that the putative bacteria associated with periodontal disease are only slightly significant. Factors in addition to bacterial plaque must also contribute to periodontal disease destruction. Periodontitis is now seen as resulting from complex interplay of bacterial infection and host response, often modified by behavioral factors¹⁴ (Figure 1). Perhaps the most fundamental change in our understanding of periodontal diseases is that not all individuals are equally susceptible to severe disease. Some individuals are more at risk for periodontitis than others. Several studies have led to the current understanding that only about 5 percent to 20 percent of the population is vulnerable to severe periodontitis.¹⁵

One of the best predictors of future disease progression appears to be past disease.¹⁵ An individual who has suffered from periodontitis previously is more likely to experience future disease destruction than an individual who has not had previous disease. On the one hand, an individual with increased pocket depth (past disease) is more likely to experience further disease destruction because the increased pocket depth is more likely to harbor and promote the growth of pathogenic bacteria. However, the other possibility is that systemic or environmental factors that originally predisposed that individual to periodontitis may continue to predispose him or her to future disease. Hence, the existence of previous disease is a positive indicator for that individual's "risk" of future disease. This latter view suggests a significant role of the host in the development and progression of periodontitis. Host factors that may have more influence on disease progression than periodontal pathogens include diabetes, smoking, stress, and genetic predisposition. Thus, it has become essential to identify systemic "host" factors that increase the risk of periodontal disease destruction.

Systemic 'Host' Risk Factors

Diabetes Mellitus

Diabetes is a systemic condition that has long been associated with an increased risk and severity of periodontal disease. The reasons for this relationship are many and relate to the pathogenesis and control of diabetes. Diabetes mellitus is a disorder that results in poor metabolic control of glucose levels in the blood. The hyperglycemia that results from poor control secondarily creates systemic changes that are commonly associated with the disease. Specifically, poor glucose control in diabetics results in complications such as retinopathy (blindness), atherosclerosis (cardiovascular disease), poor wound healing, infections, and nephropathy. Both Type I (insulin-dependent) and Type II (noninsulin-dependent) diabetes are risk factors for periodontitis. Those with poorer control have greater periodontal attachment loss and bone loss and progress more rapidly than diabetics with better metabolic control of their disease.

The mechanism(s) responsible for increasing the risk in diabetics is unclear but is likely to be related to an increased susceptibility to infections, an impaired immune response, poor wound healing, or a combination of these factors. An altered periodontal microflora has also been suggested as a possible cause for the increased periodontal disease seen in diabetics. However, a study of the quantitative and qualitative aspects of the microflora (i.e., the periodontal pathogens) in both Type I and Type II diabetics revealed no significant trends nor differences between diabetics and nondiabetics.¹⁶ Some specific mechanisms that have been proposed to contribute to periodontitis in diabetics include polymorphonuclear neutrophil leukocyte dysfunction, abnormal collagen metabolism, and genetic predisposition.^17,18 While the mechanism that exacerbates periodontitis in diabetics is not well-understood, the increased risk has been well-documented; and periodontitis can be considered a complication of diabetes, especially in the poorly controlled. Page and Beck reported that diabetics experience about a 2.8 to 3.4 times greater risk of developing destructive periodontitis as compared to nondiabetics in an adult population.¹

In many diabetic patients, especially those who are poorly controlled, the accumulation of glycosylated proteins and lipids increases as compared to well-controlled diabetics and nondiabetics. The glycosylation of proteins is a normal nonenzymatic occurence for all individuals, but it is significantly increased in those with hyperglycemia. The change permanently alters the structure of the protein and can be detected by laboratory assay. This is the basis for the latest and most accurate blood screening for diabetes -- the glycosylated hemoglobin test. It is an accurate diagnostic test used to measure how well-controlled a diabetic patient has been during the previous two to three months, which is equivalent to the half-life of a red blood cell (hemoglobin molecule).

The accumulation of advanced glycosylated end products in the tissues of diabetics alters the integrity and function of the affected tissues. This may be part of the underlying mechanism responsible for some or all of the complications observed in diabetics. In poorly controlled diabetics, the vessel walls show increased basement membrane thickness due to an accumulation of advanced glycosylated end products. In the vessel wall, these changes narrow the lumen and interfere with transport across to the connective tissues. These advanced glycosylated end-product related changes on the vessel walls are responsible for the microvascular complications of diabetes such as retinopathy, atherosclerosis, poor wound healing, infections, and nephropathy. In turn, advanced glycosylated end products may be related to the increased incidence and severity of periodontal disease observed in diabetics.

The effect of advanced glycolsylated end products on periodontal disease associated with diabetes is being studied.¹⁹ The accumulation of the end products in the periodontal tissues may contribute to periodontitis by changing the microvasculature, impairing membrane transport, and reducing the immune response as stated above. It has been suggested that advanced glycosylated end products induce an oxidant stress in the gingival vasculature that may be responsible for the accelerated injury and impaired healing seen in diabetics.²⁰ The accumulation of the end products may also make diabetics more suseptible to periodontitis by altering the collagen structure and function. In the case of collagen glycosylation, it increases cross-linking and results in diminished turnover.²¹ The normal repair and replacement of collagen in the periodontal tissues becomes impaired and more vulnerable to damage.

Well-controlled diabetics with good oral hygiene do not show an increased risk of developing severe periodontitis. In fact, well-controlled diabetics have fewer systemic complications than poorly controlled diabetics and have been shown to respond well to periodontal therapy.²² Perhaps more importantly with respect to systemic health, periodontal therapy has been shown to improve the ability of patients to metabolically control their diabetes.²³ They can more easily maintain normal blood sugar levels and, thus, require less insulin. There appears to be significant advantages for diabetic patients to be well-controlled and maintain good periodontal health. For this reason, awareness, improved diagnosis, and better communication between dentists and physicians have the potential to enhance the prognosis and therapy for diabetic patients. Coordinating the periodontal and medical management of diabetes benefits the patient by improving the control of hyperglycemia and enhancing the response to periodontal therapy.

Smoking and Tobacco

Smoking has long been associated with adverse systemic health effects such as respiratory disease and cancer. An analysis of data from the 1971-75 National Health and Nutritional Examination Survey in the United States showed a clear relationship between smoking and periodontitis.²⁴ Many studies since then have provided strong evidence to support an increased risk relationship between smoking and periodontal disease severity. In a comprehensive review, Salvi and colleagues reported that the increased risk for periodontitis in smokers was 2.5 to seven times greater than that of nonsmokers.²⁵

Proposed mechanisms include an altered immune response, decreased vascularity, impaired polymorphonuclear neutrophil leukocyte chemotaxis and phagocytosis, and decreased antibody production. Smoking also appears to decrease local oxygen levels. It has been suggested that the resulting decreased oxygen tension may encourage growth of anaerobic pathogens. However, experimental studies have shown that there is no difference between smokers and nonsmokers in the amount of plaque accumulation nor in the prevalence of periodontal pathogenic microorganisms.^26-28 On the other hand, Grossi and colleagues found that significantly fewer smokers became negative for periodontal pathogens (P. gingivalis and B. forsythus) than nonsmokers.²² This is consistent with a report by Zambon and colleagues that smoking increases the risk for subgingival infection.²⁹ The periodontal pathogens are re-established in the periodontal pockets of smokers much more rapidly than in nonsmokers following periodontal therapy. This finding is also consistent with previous reports in that the periodontal pathogens are the same and may account for the poorer response to periodontal therapy seen in smokers.

Bacterial plaque (periodontal pathogens) may not be the major contributor to bone loss in the periodontal destruction seen in smokers. To appreciate the effect of smoking on alveolar bone, Bergstrom and Eliasson evaluated 235 dental hygienists (a group thought to have very good oral hygiene habits).³⁰ Seventy-two were smokers. Alveolar bone height was significantly reduced in smokers as compared to nonsmokers. The degree of bone loss increased with years smoking and amount smoked. Presumably in this dental-hygiene-educated population, bacterial plaque did not play a contributory role in bone loss. Only 2 percent had light calculus. The amount of smoking in pack years is important to assess when determining an individual's risk for periodontitis.

Refractory periodontitis is characterized by low levels of plaque and a poor healing response to periodontal therapy. MacFarlane and colleagues evaluated a group of 31 patients with refractory periodontitis and found that there were no chemotactic defects, but phagocytosis was significantly impaired.31 Interestingly, they retrospectively discovered that a vast majority (28 of 31) of the refractory disease patients were smokers. The unusually high number of smokers (more than 90 percent) found in this group as compared to the percentage of smokers in Minnesota's general population (21 percent) appears to strongly implicate smoking as a major risk factor for refractory periodontal disease.

In some smokers, the appearance of the gingiva does not reflect the severity of the inflammation nor the degree of periodontal destruction. This lack of inflammation in the gingiva may be explained by decreased vascularity, increased vasoconstriction, an impaired immune response, or a combination of these factors. Smoking suppresses the vascular reaction normally observed with gingivitis and periodontitis.32,33 This may be due to decreased vascularity (fewer new vessels and/or vasoconstriction) in the gingiva of smokers. There are mixed reports about whether nicotine causes vasoconstriction or vasodilation in gingival tissues. In central tissues such as heart muscle, nicotine causes vasodilation, whereas in peripheral tissues such as the skin, nicotine causes vasoconstriction. Some reports suggest that nicotine causes vasoconstriction of gingival tissues. However, Baab and Oberg, using a microdoppler (flux = velocity x number cells), found that nicotine caused an increase in gingival blood flow.³⁴ It is possible that an increase in heart rate may have contributed to this finding by increasing the velocity.

In addition to the vascular effects, nicotine causes a decreased immune response. Both oral and peripheral neutrophils are effected by nicotine. They have decreased chemotactic response to antigen and decreased phagocytic ability. The immune system in smokers is decreased via impairing polymorphonuclear neutrophil leukocyte phagocytosis and decreasing antibody levels. The antibody production, specifically IgG and IgA, is suppressed in smokers.²⁵

Nicotine plays a role in periodontal destruction by up-regulating cytokine production. Payne and colleagues showed increased production of prostaglandin (PGE2) and cytokine (IL-1fl) in response to nicotine.³⁵ These immune regulatory mediators are known to increase periodontal destruction. The vasoconstrictive activity of nicotine along with the destructive effects of immune system up-regulation may explain the paradoxical findings in smokers, that is, less gingival inflammation and less gingival bleeding associated with more periodontal destruction as compared to observations in nonsmokers.

In addition to an increased prevalence and severity of periodontal disease, smokers have a decreased capacity to respond to surgical therapy. The healing response following periodontal therapy is decreased as compared to nonsmokers.36 However, individuals who quit smoking recover with a healing response that is comparable to nonsmokers.36 Smoking cessation has been shown to have beneficial effects on the periodontal tissues and the response to periodontal therapy.³⁷ The decreased capacity of smokers to respond well to surgical therapy appears to be true for implant therapy as well.38 Although the findings suggest that a perioperative smoking cessation program would improve implant success rates, it is important to note that the number of patients and duration of study are limited. More studies are needed to evaluate the benefits of a short-term smoking cessation program.

Psychosocial Stress

Psychosocial stress has been associated with periodontal disease. In World War II, soldiers on the battlefield presented with trench mouth, a condition also known as acute necrotizing ulcerative gingivitis. This form of periodontal disease is known to be stress-related.³⁹ The mechanism of stress-induced periodontal disease destruction is not well-defined. However, it has been known for many years that increases in corticosteroids, whether exogenous or endogenous, decrease the immune response. Psychosocial stress may predispose a susceptible host by decreasing the immune response to pathogenic bacteria and altering wound healing.

Genco and colleagues are studying the various aspects of psychosocial stress such as type, duration, and the patient's ability to cope as it relates to periodontal disease.⁴⁰ They believe that psychosocial stress without the ability to cope may be more detrimental than similar stresses experienced by individuals with good coping mechanisms.

The role of stress in aggravating systemic conditions (e.g., cardiovascular disease) has been well-documented. However, the evidence to support a relationship between psychosocial stress and periodontal disease is limited. In a case-controlled analysis of psychosocial factors and adult periodontitis, Moss and colleagues showed that individuals testing positive for antibody to the periodontal pathogen B. forsythus and rating high on the depression scale were 5.3 times more likely to have periodontitis than individuals testing negative for B. forsythus antibody and depression.⁴¹ Although these findings are suggestive, it is too early to make conclusive statements about the relationship of stress and periodontal disease destruction.

Genetic Predisposition

Genetics or familial inheritance of periodontal disease has long been suspected but difficult to prove. With their study of adult twins and periodontal disease, Michalowicz and colleagues were the first to demonstrate that, indeed, periodontal disease was linked to genetics.⁴² Several studies have subsequently shown a similar relationship between juvenile periodontitis and genetic predisposition. In 1997, Kornman and colleagues published the first evidence of a specific genetic marker for susceptibility to severe chronic adult periodontitis.⁴³ The basis of that work was the discovery of a relationship between specific polymorphisms of the IL-1 genotype and the expressed phenotype of severe adult periodontitis. Subsequently, the first commercial genetic test for susceptibility to periodontitis became available (PST, Medical Science Systems, Flagstaff, Ariz.). The degree of increased risk of severe periodontitis for genotype-positive patients is estimated to be about 6.8 times greater as compared to genotype-negative individuals. It is estimated that approximately 30 percent of the population may be positive for this genetic marker. No previous studies have shown a genetic relationship for chronic severe adult periodontitis. It is interesting to note that this relationship was only appreciated when smokers were removed from the data analysis. The effect of smoking on periodontitis had such a strong negative impact that it outweighed the effects of genetic predisposition.

An important distinction between genotype-positive individuals and patients with existing periodontal disease is that individuals who are genotype-positive do not necessarily have the disease. It is possible that these individuals have a genetic predisposition for severe periodontitis, but they have not yet been challenged by periodontal pathogens and they do not have signs of periodontitis. Theoretically, if these genotype-positive patients are not challenged by periodontal pathogens, they may remain periodontally healthy. Once identified, these patients (as well as other patients with known risk factors) may be able to be placed into high-risk preventive programs to prevent or reduce the future incidence of disease, that is, if an individual is known to be susceptible (genotype-positive, diabetic, smoker, etc.), then every effort should be made to prevent the exposure to the periodontal pathogens (i.e., excellent oral hygiene and prevention via a frequent recall program).

Periodontal Examination

Traditionally, the complete periodontal examination consisted of evaluating and documenting several findings (signs and symptoms of disease). It typically includes an evaluation and charting of probing pocket depth, attachment loss, gingival margins, inflammation, bleeding on probing, sulcular exudate, missing teeth, contacts, and occlusion. These findings are used to detect or diagnose existing periodontal disease. In practice, re-evaluations are used to "monitor" patients and to alter the course of their treatment based on clinical findings. Unfortunately, these clinical findings do not provide any prognostic information. Even those findings thought to be predictive of future periodontal disease breakdown, such as bleeding on probing and poor oral hygiene, have failed to correlate with future disease activity.⁴⁴ Only purulence, a relatively rare finding, has been associated with periodontal disease progression.⁴⁵ Conversely, lack of bleeding on probing and good oral hygiene are consistent with periodontal health.^13,46

An example of the poor prognostic ability of traditional clinical parameters was reported by McGuire and Nunn.^47,48 They classified each tooth into prognostic groups based on clinical findings at baseline and five and eight years later. Following 12 years, patients were examined and the prognostic values were compared to actual tooth retention. Except for those teeth given a good prognosis, the predictive value of these findings (with an experienced periodontist) was poor. Teeth given a good prognosis were retained and continued to have a good prognosis. However, those teeth given a less than good (i.e., fair, poor, questionable, hopeless) prognosis were often incorrectly predicted. The accuracy of prognostic factors following five years was 43 percent. The accuracy fell to 35 percent following eight years. Based on this study, the ability to predict tooth retention using traditional clinical parameters was less than 50 percent. Recognizing that this is only one study and that teeth are sometimes extracted for reasons other than periodontal disease, the findings suggest that prognosis requires more that just an evaluation of traditional clinical parameters.

This method of examination and documentation remains an important part of identification, prevention, and treatment of patients with periodontitis. However, the problem with this method of diagnosing periodontal disease is that it is limited to detecting disease after it has occurred, and it assumes that all individuals are equally susceptible. It does not have any predictive value nor does it take into consideration differences among individual patients (i.e., host factors). To identify the patients early (ideally prior to the onset of severe periodontitis), practitioners must place an emphasis on determining risk factors for each individual via better medical history (diabetes), family history (genetic predisposition), and social history (smoking), as well as an evaluation of other environmental factors (stress). Furthermore, since patients may present without knowledge of their own medical condition (50 percent of diabetics are undiagnosed), dentists must consider referral to a physician when severe disease or poor response to therapy cannot be explained by known factors.

Periodontal Disease as a Risk Factor for Systemic Disease

One study analyzed data from the 1971-75 National Health and Nutritional Examination Survey and correlated it with cardiovascular data. The report concluded that people with periodontitis at baseline had a 25 percent greater risk of subsequent coronary heart disease than those without periodontitis.⁷ The risk was especially high for men under age 50 (1.7 times greater). This analysis also found that periodontitis and poor oral hygiene were more strongly associated with total mortality than with coronary heart disease, which could indicate that neglect of oral health is more an indicator of poor health habits than an etiologic factor.

The mechanism(s) for the relationship between periodontitis and the systemic effects it may have are beginning to be understood. As an example, Beck and colleagues suggest that periodontitis, once established, represents a biologic burden of endotoxin and inflammatory cytokines that serves to initiate and exacerbate atherosclerotic and thrombogenic events.⁶ Herzberg and Meyers' study on the effects of oral flora on platelets supports this hypothesis.² They found that S. sauguis induced platelets to aggregate, and they propose a hypothesis that they may cause coronary thrombosis. Additional hypotheses are being studied to evaluate the effect of periodontitis on respiratory diseases and the incidence of preterm, low-birth-weight babies.3,5 Interested readers are referred to a comprehensive report from the 1997 Sunstar-Chapel Hill Symposium on Periodontal Disease and Human Health published in the Annals of Periodontology.⁸

It is interesting to note and important to remember that these hypotheses are reminiscent of the focal infection theories that fell out of favor in the 1950s and '60s because of a lack of evidence. The link between periodontitis and systemic disease requires further study with well-controlled clinical trials.

Conclusion

Once again, the approach to the diagnosis and treatment of periodontal disease is changing. The disease has not changed, but dentistry's understanding of the pathogenesis and appreciation for the influence of host factors has improved. As a result, the approach to the management of the disease is evolving. This article has highlighted some of the emerging evidence that links periodontal disease and systemic health. There is a rapidly growing body of data that supports a periodontal medicine interrelationship. Current evidence suggests that systemic factors contribute to the severity of periodontitis, and periodontitis may be a risk factor for systemic diseases. As part of a comprehensive examination of patients for periodontal disease, dental practitioners must act more like physicians to evaluate systemic illnesses and other conditions that may contribute to the risk and severity of periodontal disease. Conversely, physicians must understand the role of periodontitis in the health of their patients and become aware of the signs of severe periodontitis. This is the beginning of a new era in periodontics and provides an opportunity for dentists to develop new relationships with physician colleagues. Dentists should be encouraged to communicate with physicians about the health of their patients, and physicians should be alerted to the possible risks of severe periodontitis.

Author

Perry R. Klokkevold, DDS, MS, is an adjunct associate professor and clinical director in the Section of Periodontics at the University of California at Los Angeles School of Dentistry.

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To request a printed copy of this article, please contact: Perry R. Klokkevold, DDS, MS, UCLA School of Dentistry, Section of Periodontics, 63-022A CHS - Dental, Los Angeles, CA 90095-1668.