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In recent years, it has become apparent that the pathogenesis of periodontal diseases is more complex than the presence of virulent microorganisms. In fact, it is now widely accepted that susceptibility to periodontitis varies greatly between individuals who harbor the same, pathogenic microflora. To date, the bulk of evidence points to the host response to bacterial challenge as a major determinant of susceptibility. In this review, we will assess the data implicating various inherited and acquired risk factors for susceptibility to periodontal diseases.
Historically, it was believed that all individuals were uniformly susceptible to developing periodontal disease and that accumulation of plaque, poor oral hygiene and perhaps occlusal trauma were sufficient to initiate periodontitis. However during the past four decades it has become accepted that periodontal disease is caused by specific bacterial infections and that individuals are uniformly susceptible neither to these infections nor to the damage caused by them. With this understanding has come a concentration of effort into developing markers that will allow identification of susceptible individuals prior to them developing periodontitis and identifying risk factors that might be modified in order to prevent or alter the course of periodontal disease. With the knowledge of possible links between periodontal disease and systemic health that has emerged during the past decade, investigations into susceptibility to periodontal disease have taken on a wider significance.
A risk factor can be defined as an occurrence or characteristic that has been associated with the increased rate of a subsequently occurring disease. It is important to make the distinction that risk factors are associated with a disease but do not necessarily cause the disease. Risk factors may be modifiable or non-modifiable. Modifiable risk factors are usually environmental or behavioral in nature whereas non-modifiable risk factors are usually intrinsic to the individual and therefore not easily changed. Non-modifiable risk factors are also known as determinants. Evidence used to identify risk factors usually is derived from the following types of studies in order of increasing strength of evidence:case reports, case series, case-control study, cross-sectional studies, longitudinal cohort studies, and controlled clinical trials, also known as interventional studies. All of these studies can identify factors associated with a disease though they are not equal in strength. The longitudinal study may be capable of identifying a causal relationship. The interventional study gives the strongest evidence of a causal relationship and furthermore can provide evidence of the benefit of eliminating the risk factor. Associations identified through longitudinal and interventional studies are termed risk factors whereas associations, based on the observations of cross-sectional and case controlled studies are termed risk indicators. Thus the term risk factor denotes a greater weight of evidence supporting an association than does the term risk indicator.
Several different approaches to measuring periodontal disease have been developed by different individuals and groups. Indeed several indexes, each with its own strengths and weaknesses, have been designed and each incorporates subjective and objective assessments of differing weight into an ordinal scale. Examples are the periodontal index, the extent and severity index and the National Institute of Dental and Craniofacial Research (NICDR) periodontal disease index. More recently, Unell et al. have developed a periodontal disease index based upon patients answers to a questionnaire (Unell et al., 2000). According to Nunn the best and most pragmatic measures of periodontal destruction are alveolar bone level and clinical attachment level (Nunn, 2003). Perhaps more importantly, different studies have used different measures of periodontal disease, which has made the comparison of data between studies more complicated. Nonetheless, several risk factors have been identified where a relationship is suggested but not clearly established. This paper will review the evidence linking clearly established non-modifiable risk factors and modifiable risk factors to periodontal disease and also discuss more briefly some of the less well established risk factors that are the subject of ongoing research.
Smoking is the best established of the modifiable risk factors for developing periodontal disease. In addition to smoking, evidence exists which suggests a relationship between periodontal status and nutrition, alcohol consumption, socioeconomic status and stress levels, although these relationships have not been clearly established.
The relationship between smoking and periodontal health was investigated as early as the middle of the last century. More recently a wealth of epidemiological, clinical and in vitro studies have emerged that have provided irrefutable evidence that smoking negatively impacts periodontal health and propose mechanisms by which this may occur (Albandar et al., 2000). Cross-sectional and longitudinal data provide strong support for the statement that the risk of developing periodontal disease as measured by clinical attachment loss and alveolar bone loss increases with increased smoking. Although no long-term interventional studies exist, both cross sectional and longitudinal studies find that former smokers (clinically defined as two or more years since quitting smoking) experience less attachment loss than current smokers but more than never-smokers. Furthermore, the likelihood of developing increasing periodontal disease exhibits dose dependency (Tomar and Asma, 2000). Odds ratios for developing periodontal disease as a result of smoking range from 2.5 (Bergstrom, 1989), 3.97 for current smokers and 1.68 for former smokers (Tomar and Asma, 2000) and 3.25 for light smokers to 7.28 for heavy smokers (Grossi et al., 1995).
A number of studies have established that smoking is associated with reduced gingival bleeding (Bergstrom and Bostrom, 2001; Muller et al., 2001). Studies have shown that smoking does not reduce the amount of plaque present and in fact smokers may experience less gingival bleeding than non-smokers with lower plaque indexes (Bergstrom, 1999). It has been suggested that this reflects an alterations of the caliber of the blood vessels perfusing the gingival tissues (Mirbod et al., 2001). It has also been suggested that reduced bleeding reflects an underlying disruption of the immune response and that this may account for the increased loss of clinical attachment and alveolar bone. These findings suggest a reduced reliance on the use of gingival bleeding as an indicator of gingival inflammation when assessing a smoker’s periodontal health.
Periodontal treatment tends to be less likely to be successful in smokers than in non-smokers (Bostram et al., 1998; Ah, et al., 1994). Studies evaluating the efficacy of periodontal disease control and specific periodontal procedures including regenerative procedures, soft tissue grafting procedures and implant procedures have consistently demonstrated a negative effect from smoking on success rates.
In vitro studies have shown altered gingival crevicular fluid inflammatory cytokine profiles, immune cell function (Ryder et al., 1998a; Ryder et al., 1998b) and altered proteolylic regulation in smokers. More recently, Chang et al. have demonstrated altered Cox-2 mRNA expression in gingival fibroblasts in response to nicotine (Guzman et al., 2003). Nonetheless, the results of these studies are not consistent and to date no clear mechanism has emerged to explain how smoking may affect periodontal disease. A new area of study that has emerged is the relationship between smoking and genetic polymorphisms (see below). However the results of investigations carried out to date cannot be considered definitive.
Diabetes is a modifiable factor in the sense that though it cannot be cured, it can be controlled. Studies that have examined the relationship between diabetes and periodontitis are heterogenous in design and aim. Thus, both positive and negative conclusions have been drawn with respect to the relationship between the two diseases. In general no difference in impact has been determined between type 1 and type 2 diabetes mellitus. Diabetic parameters examined include glycemic control, duration of disease, presence of other diabetes-associated complications and population studied. Periodontal parameters examined have included gingivitis, clinical attachment loss, and alveolar bone loss (Tomar and Asma, 2000). A review of the literature by Kinane found considerable evidence to suggest that diabetes and periodontitis have a direct relationship (Kinane and Chestnutt, 1997). Studies have shown a relationship between poor glycemic control and periodontal disease parameters (Guzman et al., 2003; Tsai et al., 2002; Tervonen et al., 1994, Cutler et al., 1999). Taylor et al. have suggested a bi-directional relationship between periodontal disease and glycemic control (Nishimura et al., 2003; Taylor, 2001) with each disease having a potential impact on the other. Cross sectional studies on Pima Indians, a group displaying the highest prevalence of type 2 diabetes in the world, show an odds ratio of 2.8 to 3.4 for developing periodontal disease in type 2 diabetics compared to non-diabetics (Emrich et al., 1991). Similarly, longitudinal studies have shown increased risk of ongoing periodontal destruction in diabetics as compared to non-diabetics with an odds ratio of 4.2. Finally, studies have been done which suggest that poorly controlled diabetics respond less successfully to periodontal therapy relative to well-controlled and non-diabetics (Westfelt et al., 1996; Tervonan and Karjalainen, 1997)
Of all of the various microorganisms that colonize the mouth, there are three, Porphyromonas gingivalis, Tannerella forsythia (formerly Bacteroides forsythus), and Actinobacillus actinomycetemcomitans have been implicated as etiologic agents in periodontitis. As stated above, the presence of periodontal pathogens, though necessary to cause disease, is not sufficient. Indeed the odds ratio of developing periodontal disease in an individual who harbors one of the putative periodontal pathogens is not high enough to consider them a risk factor (Ezzo and Cutler, 2003). The presence of A. actinomycetemcomitans confers no additional risk of developing localized aggressive periodontitis in adults despite the fact its presence is necessary for the disease to develop (Buchmann, et al., 2000). It has been shown that Prevotella intermedia, P gingivalis, and Fusobacterium nucleatum may be risk indicators for periodontal disease in a diverse population, though they are not risk factors (Alpagot et al., 1996).
Studies have demonstrated that individuals under psychological stress are more likely to develop clinical attachment loss and loss of alveolar bone (Hugoson et al., 2002; Mawhorter and Lauer, 2001; Pistorius et al., 2002; Wimmer et al., 2002). One possible link in this regard may be increases in production of IL-6 in response to increased psychological stress (Kiecolt-Glaser et al., 2003). Another study suggests that host response to P. gingivalis infection may be compromised in psychologically stressed individuals (Houri-Haddad et al., 2003). Despite existing evidence from case control and cross sectional studies, no longitudinal or interventional studies have been published that confirm psychological stress as a risk factor for periodontal disease. Perhaps the relationship is simply due to the fact that individuals under stress are less likely to perform regular good oral hygiene and prophylaxis (Croucher et al., 1997).
Although bacterial infection is the etiologic agent in periodontal disease, studies of identical twins suggest 50% of susceptibility to periodontal disease is due to host factors (Michalowicz et al., 2000). Similarly, indigenous and relatively isolated populations have been shown to develop distinct periodontal of periodontal disease that differ from group to group (Dowsett et al., 2001; Ronderos et al., 2001).
A currently widely held view based upon a great deal of evidence is that the destruction observed in periodontal disease is the result of an improperly regulated immune response to bacterial infection rather than the directly destructive effect of the bacterial pathogens themselves (Van Dyke and Serhan, 2003). In the case of localized aggressive periodontitis, it has been suggested that overly active or “primed” neutrophils may be responsible for mediating much the tissue destruction that is observe in that disease (Van Dyke and Serhan, 2003). IL-1 gene polymorphisms have been linked to periodontal disease. Thus specific Il-1 genotypes have been linked to the presence of pathogenic microorganisms (Socransky et al., 2000), and to an increased risk of periodontal diseases in non-smokers (Kornman et al., 1997) and smokers (Meisel et al., 2002; Meisel et al., 2003). In a population studied by Kornman et al. 1997 an odds ration of 18.9 was associated with a specific IL-1 genotype. It also determined that this genotype and smoking accounted for as much as 80% of the periodontal disease observed in that population. Recently Meisel et al. 2002 have shown results that demonstrate no effect of Il-1 genotype in non-smokers. Guzman et al. 2003 have shown a possible relationship between Il-1 genotype and periodontal status in diabetics. At this point no definitive Il-1 genotype exists that puts individuals in any given population at risk for periodontal disease. Furthermore, the evidence suggesting possible interactions between Il-1 and smoking and diabetes suggest that there is interplay between genetic an environmental factors that results in periodontal disease.
Evidence also suggests possible relationships between periodontal disease and fMLP and Fc receptor polymorphisms. These, however, are less well documented at the present time. Similarly, relationships between HLA genetics and periodontal disease have also been suggested though they are not clearly established.
Several cross-sectional studies have shown that alveolar bone density is altered in osteoporotic individuals. Fewer studies have demonstrated a relationship with clinical attachment levels. However, these results have also been contradicted by several other studies. In longitudinal studies a relationship has been shown between osteoporosis and alveolar bone loss, but not between osteoporosis and clinical attachment levels.
Several deficiencies of neutrophil function have been related to periodontal disease. These include Chediak-Higashi syndrome, cyclic neutropenias, lazy leukocyte syndrome, agranulocytosis and leukocyte adhesion deficiency and Down syndrome and Papillon Lefevre syndrome. Except for Downs syndrome, these diseases are exceedingly rare, so probable though not definitive relationships to periodontal disease have not been established (Deas et al., 2003).
Ageing is associated with an increased incidence of periodontal disease (Grossi et al., 1994; Grossi et al., 1995). However it has been suggested that the increased level of periodontal destruction observed with aging is the result of cumulative destruction rather than a result of increased rates of destruction. Thus aging is not a risk factor per se (Genco, 1996).
Smoking and types 1 and 2 diabetes are well-established risk factors for periodontal disease, whereas the etiologic microorganisms P. gingivalis, T. forsythia and A. actinomycetemcomitans are risk indicators. Genetic polymorphisms, especially with regard to IL1 but also tumor necrosis factor (TNF), human leukocyte antigen (HLA) and others have also been investigated, although strictly speaking they cannot be generally considered risk markers or risk indicators. Similarly, susceptibility to periodontal disease may be the result of defects in neutrophil function. In the case of localized aggressive periodontitis the defect may be relatively benign. In more severe conditions of neutrophil dysfunction, the incidence may be so low or the disease so debilitating as to preclude rigorous analysis of periodontal relationships. Future studies will likely be focused on understanding the relationship between genetic and environmental factors and also on the rapid and practical identification of at-risk individuals, and will allow us to tailor therapy to more closely suit the needs of our patients as individuals and thus achieve better results.
Supported in part by USPHS Grant DE13499
Presented at the 9th International Meeting of the International Academy of Periodontology, Cape Town, South Africa, 25–27 October, 2003