Genetic and Hereditary Factors

Periodontitis is a complex disease, with multiple causative factors. Immune-mediated inflammatory conditions, such as periodontitis, are complex due to the interplay of several causal components (genetic and environmental factors) which simultaneously interact with each other in an unpredictable manner. Furthermore, due to the nonlinear nature of these complex interactions, the presentation of disease in some individuals may be disproportionately greater than in other individuals with the same causal factors.

When there is a dysbiosis between host and oral microbiome, an atypical response manifesting in altered inflammatory reactions may lead to changes in the subgingival environment which elicit further periodontal inflammation and disease progression.

Periodontal diseases have been shown to be affected by genetic factors (Page and Kornman 1997). A number of genetic disorders, such as Down syndrome, leukocyte adhesion deficiency syndrome (LADS), Papillon-Lefevre syndrome, Chediak-Higashi syndrome, chronic neutrophil defects, or cyclic neutropenia are associated with more or less severe periodontal conditions.

The hereditary aggregation was demonstrated in a twin study for periodontitis (Michalowicz et al. 1991) and an epidemiological trial on aggressive periodontitis in a Dutch population (van der Velden et al. 1993). Following the adjustment for environmental factors such as tobacco use, it was estimated that 50% of the variance in disease may be attributed to a genetic background (Michalowicz et al. 2000) in younger patients, with a much lower percentage (<25%) attributed to genetic background in older populations.

Gender

Hormonal changes in women during menstruation, pregnancy, menopause, or therapy with pharmaceutical supplements have an impact on periodontal health. Disease susceptibility may be increased due to hormone-related alterations of the gingival blood flow (Kovar et al. 1985), the composition and flow rate of saliva (Laine 2002), or the bone metabolism (Lerner 2006). Additionally, data from epidemiological studies interestingly reveal that men may be at greater risk for periodontal diseases: in most clinical trials men are often found with worse periodontal health (Albandar 2002; Meisel et al. 2008). Most often, however, these deteriorations may be explained by an increased prevalence of male tobacco use and men’s increased tendency to neglect oral hygiene (Meisel et al. 2008).

Age

The aging process itself is suggested to be an independent risk factor for periodontal diseases (Papapanou et al. 1989). In contrast, a longitudinal study involving an elderly Scandinavian population (age 75 or older) demonstrated stable periodontal conditions for five years, suggesting a limited impact of the aging process itself in otherwise relatively healthy individuals (Ajwani and Ainamo 2001). However, the extent and severity of periodontal diseases are shown to increase with age (Albandar 2002) as a consequence of the cumulative burden from various risk factors such as tobacco use or plaque accumulation (Albandar 2002; Albandar et al. 1999). Additionally, metabolic disorders, including diabetes mellitus, osteoporosis, rheumatoid arthritis, or vascular diseases, are more likely to develop in the elderly and thus affect periodontal conditions (Persson 2006).

Insufficient Oral Hygiene

Today, accumulated plaque is considered to be a dental biofilm briefly defined as a complex bacterial structure adherent to wet surfaces (Socransky and Haffajee 2002). For the therapy of periodontal diseases, it is important to consider that biofilms can protect their microorganisms, either from the host immune response or antimicrobial agents, and thus become difficult therapeutic targets (Socransky and Haffajee 2002). So far, only mechanical debridement was shown to be a predictable approach to successfully destruct the dental biofilm. Therefore, mechanical plaque control should be performed supragingivally by the individual on a regular basis and subgingivally, if needed, by the oral health professional.

Any factors that facilitate biofilm formation, such as plaque retention or insufficient supragingival plaque control, are common risk factors for periodontal breakdown due to their causality with gingival inflammation and possibly the onset of periodontitis. This includes several anatomic conditions, such as enamel pearls, tongues, grooves, root furcations, and concavities, as well as root proximities (Roussa 1998; Vermylen et al. 2005). Calculus and acquired iatrogenic factors, such as insufficient restorations, additionally contribute to plaque accumulation (Lang et al. 1983; Oliver et al. 1998).

It was proven some 40 years ago by classical experiments conducted by the work group Löe and Theilade that oral microorganisms are relevant for the development of inflammable periodontal diseases (Theilade et al. 1966). In a longitudinal study of more than 26 years, a further research group examined the influence of plaque-induced gingival inflammation on the subsequent loss of clinical attachment in a periodontally well-maintained Scandinavian population (Schatzle et al. 2003). The supragingival plaque accumulation correlated with the degree of gingival inflammation. However, sites with bleeding on probing at every visit demonstrated about 70% more attachment loss than sites without inflammation for the duration of the study. Moreover, it was shown that the susceptibility of gingivitis seems to be higher among males suffering from periodontitis (Dietrich et al. 2006).

It should therefore come as no surprise that the recent EFP S3 level practice guideline (Sanz et al. 2020) makes several strong recommendations aiming at achieving adequate oral hygiene in patients with periodontitis. These recommendations include continued enforcement of oral hygiene advice throughout all phases of periodontal therapy, engaging the periodontitis patient in behavioral change for oral hygiene improvement, and the performance of supragingival professional mechanical plaque removal and control of retentive factors as part of the first step of therapy (Sanz et al. 2020).

Tobacco Use

Over the past 40 years, robust epidemiologic oral health research has identified cigarette smoking as the most important environmental risk factor, second only to poor oral hygiene. Cigarette smoking has consistently been demonstrated to have a dose- and time-dependent association with periodontitis and tooth loss (Dietrich and Hoffmann 2004; Dietrich et al. 2015), with smokers showing increased clinical attachment loss, deeper periodontal probing depths, and more recession. Paradoxically, the clinical characteristics of gingival inflammation or bleeding on periodontal probing are suppressed in smokers (Dietrich et al. 2004). Smokers show less favorable results after conventional, surgical, and regenerative periodontal therapy. Periodontal plastic surgery has poorer outcomes in smokers (Erley et al. 2006). Moreover, smoking impairs the osseointegration of oral implants and is at least partly responsible for a majority of biological complications in implant dentistry, such as peri-implantitis (Strietzel et al. 2007). A common clinical observation is delayed wound healing after therapeutic interventions (Figure 3.2) (Silverstein 1992).

The unequivocal evidence for the importance of cigarette smoking as a cause of periodontitis and a factor associated with disease occurrence and treatment outcomes has led to cigarette smoking being included as a “grade modifier” in the current classification of periodontal diseases. Specifically, periodontitis patients who are not classified as grade B or C based on disease progression or bone loss relative to age will be “upgraded” to grades B or C if they are light (<10 cigarettes per day) or heavy (10+ cigarettes per day) smokers, respectively (Tonetti et al. 2018).

There are various potentially significant pathogenic effects of tobacco-related substances on the periodontal tissues, immune response system, or composition of the oral flora. Periodontal destruction associated with tobacco use is caused by a wide multidimensional range of effects on different functions in cells, tissues, and organ systems. Some of these effects are diametric in nature, due to the effects of different tobacco constituents. However, when summarizing the properties of the tobacco-induced alterations in the metabolism of vasculature, connective-tissue, and bone, as well as on cell-mediated and humoral immunity, it is more than likely that tobacco use shifts the physiological balance between anabolic and catabolic mechanisms in a more destructive direction, due to an alteration of protective immune and tissue mechanisms (Johnson and Guthmiller 2007; Palmer 2005; Ryder 2007). Moreover, there is evidence that tobacco consumption may change the genetically determined susceptibility for periodontal diseases (Meisel et al. 2004).

Diabetes Mellitus

Diabetes mellitus is a metabolic disorder categorized by a hyperglycemia due to impaired insulin production or insulin resistance. Insulin is a pancreatic-hormone-maintaining glucose metabolism. At least two major groups of diabetes mellitus (type 1 and type 2) are differentiated based on their pathogenesis. In addition, some diseases such as hormone-secreting tumors, conditions such as pregnancy (gestational diabetes), or drugs such as corticosteroids can lead to diabetes mellitus. Treatment of diabetes mellitus primarily aims to keep blood sugar levels within a target range. Treatment may include an interview for behavioral change for dietary adjustment, reducing physical inactivity and sedentary time, or several drugs. They usually include oral antihyperglycemic drugs or insulin replacement therapy, as well as drugs for prevention and/or treatment of diabetes complications such as hypertension. If left untreated, serious long-term complications may occur, affecting small and large blood vessels, eyes, kidneys, nerves, or the immune system.

Diabetes mellitus has been associated with increased prevalence and severity of periodontal disease (Figure 3.3) (Emrich et al. 1991; Shlossman et al. 1990). The majority of studies demonstrate a more severe periodontal condition in diabetic adults than in adults without diabetes (Papapanou 1996; Verma and Bhat 2004). The type of diabetes does not affect the extent of periodontitis when the duration of diabetes is similar. However, those living with type 1 diabetes develop the disease at an earlier age, and, hence, have it for longer periods, and may therefore develop a greater extent and severity of periodontitis (Oliver and Tervonen 1994; Thorstensson and Hugoson 1993). Individuals who have optimal time in range (i.e., well-managed diabetes) are more likely to be similar to non-diabetics in their periodontal status (Westfelt et al. 1996).

Diabetes status is also considered in the diagnosis and classification of periodontal disease as a grade modifier. Periodontitis patients who also live with diabetes may be upgraded to grade B or—if exhibiting increased time out of range (HbA1c ≥7.0%)—grade C (Tonetti et al. 2018).

A common complication of diabetes mellitus is the increased susceptibility for microbial infections due to an impaired function of the host immune response. Diabetes mellitus may contribute to periodontal inflammation via specific mechanisms. The hyperglycemia may promote the formation of advanced glycation end products (AGE), i.e., glycated body proteins (Wautier and Guillausseau 1998). Accumulation of AGE may have an impact on periodontal micro-vascularization or may lead to an increased number of monocytes within the site of inflammation (Katz et al. 2005). A modification of physiologic cell functions of certain subtypes of granulocytes is also reported (Manouchehr-Pour et al. 1981a, 1981b). Moreover, some studies suggest an alteration of pro-inflammatory mediators in gingival crevicular fluid, including tumor necrosis factor-α, prostaglandin-E2, and interleukin-1 β (S. P. Engebretson et al. 2004; Salvi et al. 1997a, 1997b). A further research group reported a decreased gene expression of anti-inflammatory and antibone-resorptive molecules such as interleukin-10 and osteo-protegerin (Duarte et al. 2007). Collagen is produced by fibroblasts and is an important molecule of the periodontium. In vitro findings indicate a reduction of collagen synthesis in a dose-dependent fashion of glucose concentration (Willershausen-Zonnchen et al. 1991).

Interestingly, there is some evidence for periodontitis as a contributing factor in the pathogenesis of diabetes mellitus (Taylor et al. 1998). Inflammatory markers, including tumor necrosis factor-α, increase with periodontal severity and thus affect the insulin metabolism in in those with diabetes (S. Engebretson et al. 2007). In contrast, their reduction occurs following antimicrobial periodontal therapy, leading to an improvement of glycemic control (Iwamoto et al. 2001).

The evidence-based perspective: Evidence from a systematic review, including meta-analysis, suggests a significantly higher severity but the same extent of periodontal disease in individuals living with diabetes compared with non-diabetics (Khader et al. 2006).

Stress

Stress may be caused by acute or chronic stressors. A stressor can be intrinsic or extrinsic in origin and is frequently defined as anything that causes an adaptive and nonspecific neurological and physiological response in an individual. Chronic stressors are of relatively longer duration and include several “life events” such as the loss of a family member, splitting of a relationship, long-term illness, miscarriage, or “daily hassles.” Events of a relative short duration, such as traffic jams, surgical interventions, dental visits, or unpleasant questions in a medical exam, on the other hand, may act as acute stressors to an individual. The physiologic response is mediated by several immune-to-brain-to-immune regulatory pathways (Breivik et al. 2006). The individual stress coping behavior depends on genetic susceptibility and environmental and developmental factors as well as gathered experiences during the course of life.

Several studies indicated an association of negative stress, depression, anxiety, or poor coping behavior with periodontal diseases (Genco et al. 1999; Hugoson et al. 2002; Wimmer et al. 2002). Negative stress may lead to an increased susceptibility to periodontitis mediated through different pathways.

As one mechanism, it was suggested that due to stress, the oral hygiene may be limited (Deinzer et al. 2001). Additionally, academic stress was shown to cause an enhancement of interleukin-1 secretion detected in gingival crevicular fluid in a study by Deinzer and coworkers (Deinzer et al. 1999). This cytokine is a strong stimulator of osteoclasts leading to destructive bone metabolism. Interleukin-6, another inflammatory cytokine, was found to be elevated in the gingival fluid of depressed women (Johannsen et al. 2006). In addition, a prolonged reduction of the secretion of immunoglobulin A, an important salivary antibody, was observed in students participating in a major medical exam (Deinzer et al. 2000).

Cortisol and the catecholamines adrenaline and noradrenaline are the major stress hormones produced by the cortex of the suprarenal gland in response to stimulation by hypothalamus-releasing hormones. Increased levels of stress-mediated cortisol were found in the gingival crevicular fluid and in saliva (Hugo et al. 2006; Ishisaka et al. 2007; Nakajima et al. 2006). Additionally, stress-induced hypercortisolemia was linked to elevated levels of plaque and gingivitis (Hugo et al. 2006). Moreover, evidence from animal experiments reveals changes in the periodontal tissues following stress exposure (Nakajima et al. 2006). Restraint stress was able to enhance attachment loss after challenge with the putative periodontal pathogen Porphyromonas gingivalis. Findings from in vitro experiments suggest an effect of catecholamines on the growth of certain oral bacteria (Roberts et al. 2002). Thus, a stress-induced increase of catecholamine levels in the gingival crevicular fluid may be able to mediate the composition of the subgingival biofilm.

HIV/AIDS

The acquired immunodeficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV), leading to a destruction of the immune system of the affected host. The CD4⁺