Periodontal disease and systemic health: current status

Abstract

The relationship between poor oral health and systemic diseases has been increasingly recognized over the past two decades. Indeed, the clichés “You cannot have good general health without good oral health”, “The mouth is part of the body” and “Floss or die”, are gaining an increasing momentum. A large number of epidemiological studies have now linked poor oral health with cardiovascular diseases, poor glycaemic control in diabetics, low birthweight preterm babies and a variety of other conditions. The majority have shown an association, although not always strong. As a result, a number of meta-analyses have been conducted and have confirmed the associations and at the same time cautioned that further studies are required, particularly with regard to the effect of periodontal treatment in reducing risk. A number of biologically plausible mechanisms have been put forward to explain the association and there is accumulating evidence in support of them, although at this stage, insufficient to establish causality. Nevertheless, the relationship between poor oral health and systemic diseases has become a significant issue, such that adult oral health can no longer be ignored in overall health strategies. This review provides an update on current understanding of the contribution of poor oral health to systemic diseases, the possible mechanisms involved and the relevance of this for general dental practitioners.

Abbreviations and acronyms

AGEs

advanced glycation end products

BMI

body mass index

CAPS

Cardiovascular and Periodontal Study

CHD

coronary heart disease

COPD

chronic obstructive pulmonary disease

CRP

C-reactive protein

CVD

cardiovascular disease

HSP

heat-shock proteins

PLBW

preterm low birthweight

Introduction

The effect of oral health on general health has been revisited over the last two decades with a number of epidemiological studies showing a link between poor oral health and a range of medical conditions including cardiovascular diseases,¹ type 2 diabetes,² adverse pregnancy outcome,³ osteoporosis,⁴ aspiration pneumonia⁵ and rheumatoid arthritis.⁶ The focus more recently has been on identifying possible mechanisms that underlie these associations and whether treating oral diseases leads to an improvement in markers of systemic disease. Cardiovascular disease, obesity and diabetes, in particular, are significant public health problems worldwide and governments are well aware that, unless action is taken, the cost of managing these diseases is capable of bankrupting health budgets in the not-too-distant future. As a result, public awareness has been raised quite dramatically by encouraging individuals to make lifestyle changes regarding diet and exercise. Poor oral health is also a public health problem, with gingivitis and chronic periodontitis being among the most common human infections. Current evidence suggests that improved oral health should be encouraged as part of the healthy lifestyle message to reduce the burden of chronic disease. The objective of this review, therefore, is to provide an update on current understanding of the contribution of poor oral health to systemic diseases, the possible mechanisms involved and the relevance of this for general dental practitioners.

Cardiovascular disease

Cardiovascular disease (CVD) is the leading cause of death in many societies. However, up to 50 per cent of patients with cardiovascular disease have none of the traditional risk factors. Yet, if morbidity and mortality from this disease are to be reduced, it is necessary to understand all possible risk factors. Individuals with severe chronic periodontitis have been reported to have an increased risk of developing CVD after adjusting for many of the traditional risk factors, such as age, gender, diabetes, smoking and family history. However, some studies have been contradictory and this is not surprising when considering the different populations studied, the study designs and analyses used. In this situation a meta-analysis can be helpful in giving insight into the strength of the relationship between these two diseases as, in effect, it combines all the data across a number of studies that may have used different measures in different populations, into one large study with many participants. The studies have to meet certain quality criteria for inclusion and so not all studies are included. There are now a number of meta-analyses all showing that periodontitis patients are at increased risk for developing CVD.^7–11 One of the most recent analyses⁹ examined five prospective cohort studies involving over 86 000 patients who were followed for more than six years, five cross-sectional studies (17 724 patients) and five case-control studies (1423 patients) and found a statistically significant increase in both the prevalence and incidence of coronary heart disease (CHD) in patients with periodontitis. Patients with chronic periodontitis had a 1.14 times higher risk of developing CHD than the controls. Of interest was the fact that patients with less than 10 teeth had a slightly higher risk (1.24 times) of developing CHD and there appeared to be an inverse relationship between the number of teeth and the relative risk of CHD. This is also supported by further meta-analysis¹¹ showing that periodontitis and/or ≤ 10 teeth was associated with a 25–30 per cent increased risk of CHD. There has been some discussion in the literature regarding the use of tooth loss as a surrogate marker of periodontal disease, as not all teeth are lost for periodontal reasons. Nevertheless, tooth loss does appear to be an indicator of risk for CHD.

Epidemiologic studies, however, have their limitations and cannot establish causality, especially in this case, when both diseases share common risk factors, such as smoking. As a result, the focus now is on understanding the biology behind the association and several possible mechanisms have been put forward to provide a framework for assessing the biological plausibility of such an association.

Mechanisms underlying the association

The simplest explanation is the “common susceptibility model” where an individual has a genetically determined phenotype that puts them at risk for atherosclerosis and infection. In this case periodontal infection does not cause the atherosclerosis, even though both diseases are present in the individual.

Direct effect of oral infections

It is now widely accepted that infection and inflammation play an important role in the initiation and progression of atherosclerosis and there are several studies supporting a role for oral infections in this regard. Oral bacteria have been identified in atherosclerotic plaques, demonstrating that they invade blood vessel walls. Porphyromonas gingivalis was found in 100 per cent of atherosclerotic plaques from carotid endarterectomy samples, with Fusobacterium nucleatum and Tannerella forsythia found in up to 80 per cent.¹² Other oral organisms have also been detected.^13,14 However, there is still some uncertainty about whether they cause the atherosclerosis or invade an already damaged artery. Even so, it is likely that their presence will contribute to further damage with platelet aggregation and thrombosis.^15–17 A recent study has shown that increasing bacterial load of oral bacteria, rather than any specific bacterial species, was associated with myocardial infarction and this was independent of other cardiovascular risk factors.¹⁸ Similarly, a mixed infection with high levels of P. gingivalis, T. forsythia and F. nucleatum was found in the majority of a group of cardiovascular patients in the ongoing longitudinal Brisbane Cardiovascular and Periodontal Study (CAPS).¹⁹ The fact that this association with periodontopathic bacteria was independent of actual periodontal disease status emphasizes the importance of the role dentists play in assisting and encouraging their patients to achieve good plaque control, irrespective of their periodontal status.

Cross-reactivity/molecular mimicry

In recent years, the concept of immune cross-reactivity or “molecular mimicry” has gained a lot of support as a fundamental mechanism in atherogenesis.²⁰ In this hypothesis it is proposed that the immune response to bacterial heat-shock proteins (HSPs) may result in antibodies that cross-react with self heat shock proteins expressed on damaged arterial cells, and that this may lead to the progression of atherosclerosis. Indeed, a correlation was found between high antibody titres to self heat shock proteins (HSP60) and mortality due to atherosclerosis.²¹ All cells express HSPs as a protective mechanism when stressed and endothelial cells may become stressed on exposure to bacterial lipopolysaccharide, cytokines or mechanical stress from high blood pressure. One does not normally make an immune response to self antigens, however, in periodontal disease the immune response to P. gingivalis HSPs, the so-called GroEL antigens, could cross-react with the self antigens expressed on endothelial cells (Fig 1). In support of this, anti-P. gingivalis GroEL antibodies have been shown to cross-react with human HSPs.^12,22 Further, T cells that react with both P. gingivalis GroEL and human HSPs have been shown to exist in the peripheral blood of patients with cardiovascular disease and in the atherosclerotic plaques themselves,²³ as well as in diseased periodontal tissues.²⁴ This strongly suggests a role for immune cross-reactivity in linking periodontal disease with the pathogenesis of cardiovascular disease. Interestingly, the systemic antibody response to oral organisms also appears to be associated with coronary heart disease and stroke, further suggesting involvement of the immune response.^18,25–27 Indeed, a recent meta-analysis¹⁰ concluded that there was a stronger association with CHD in periodontitis patients with an elevated antibody response to periodontal pathogens than with the clinical periodontal parameters alone.

Figure 1.  Molecular mimicry. The immune response to bacterial heat-shock proteins (HSPs) may cross-react with self heat shock proteins expressed on damaged endothelial cells, leading to the progression of atherosclerosis.

Inflammation

Another mechanism linking these two diseases is that periodontal inflammation leads to an increase in circulating cytokines and inflammatory mediators that in turn damage the vascular endothelium, leading to atherosclerosis. Periodontal inflammation can indeed lead to elevated levels of cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumour necrosis factor-α (TnF-α) which trigger the release of C-reactive protein (CRP) from the liver, thus contributing to systemic inflammation and atherosclerosis. High CRP levels are considered a significant risk factor for myocardial infarction, particularly in conjunction with the ratio of total cholesterol to high-density lipid.²⁸ There are now a number of studies showing an association between elevated CRP levels and the severity of periodontitis.^29–32 Severe chronic periodontitis has also been associated with increased blood pressure, raised cholesterol levels,³² carotid intima thickening³³ and reduced arterial elasticity in association with high CRP levels.^34,35 A reduction in CRP and IL-6 levels has been observed following periodontal treatment in otherwise healthy individuals with chronic periodontitis.³⁶ Interestingly though, a decline in arterial elasticity along with an increase in CRP and IL-6 levels was observed 24 hours after intensive periodontal treatment when compared with patients receiving regular periodontal treatment.³⁷ However, some two months later the intensive treatment group showed a greater improvement in arterial elasticity which was associated with a significant improvement in periodontal health and this was sustained until six months. Several other studies have also shown that treating periodontal disease can lead to improvements in serum biomarker levels and endothelial dysfunction.^38,39 Thus, chronic periodontitis may have a direct effect on endothelial dysfunction as well as an indirect effect via stimulation of CRP synthesis in the liver. Although these treatment studies have led to an improvement in these markers, it is not known whether this will translate into a reduced risk for myocardial infarction or stroke. This will require larger, longitudinal studies over many years. Meanwhile, however, dentists should be aware of the consistent association between periodontal infection/inflammation and CVD and of the potential preventive benefits that periodontal treatment may have in reducing risk. Periodontitis may contribute quite significantly to the overall burden of both systemic infection and systemic inflammation in some individuals and so could be a modifiable risk factor.

The National Heart Foundation of Australia has recently released guidelines for assessing absolute CVD risk in Australian adults for use by primary care health professionals.⁴⁰ They are designed to help clinicians assess patients before they show any symptoms of CVD. Absolute CVD risk assessment to predict risk of a cardiovascular event over the next five years is now recommended for all adults aged 47–74 years and not already known to be at increased risk for CVD. A web-based calculator is available at http://www.cvdcheck.org.au. Adults with known risk factors such as hypercholesterolaemia, systolic blood pressure ≥ 180 mmHg, serum total cholesterol > 7.5 mmol/L, moderate or severe chronic kidney disease and diabetics aged over 60, or with microalbuminaria are already considered to be at increased absolute risk. The cumulative effect of multiple risk factors may be synergistic over time, therefore, absolute risk, that is, the probability that an individual will develop CVD within a given period of time, based on the combination and intensity of risk factors is considered more important than any single risk factor. Preventive strategies should, therefore, be aimed at reducing all modifiable risk factors rather than targeting individual risk factors. In this context, until there is evidence from periodontal treatment studies that show otherwise, it would be a prudent preventive strategy, at this stage, to address periodontitis as a modifiable risk factor along with smoking, blood pressure, serum lipids, waist circumference and body mass index, nutrition, physical activity level and alcohol in those found to have moderate or high absolute CVD risk (10–15 per cent and > 15 per cent risk of CVD within the next five years, respectively).

Obesity

In most industrialized countries there is an “obesity epidemic”, one of the consequences of which is an overwhelming increase in type 2 diabetes mellitus (DM), not only in adults, but also in children and adolescents, and Australia is no exception. Obesity is also a risk factor for hypertension, dyslipidaemia, CHD and stroke, and there is now evidence that obesity is also associated with periodontitis.⁴¹ The most commonly used indicator of obesity is body mass index (BMI) (weight in kg/(height in m²)), with a BMI ≥ 25 kg/m² considered overweight and ≥ 30 kg/m² considered obese. Indeed, BMI together with extensive periodontal disease has been related to increased CRP levels in otherwise healthy middle-aged adults.²⁹ However, BMI has its limitations as it does not assess body fat distribution and so abdominal obesity is generally regarded as a better indicator of disease risk. This is assessed by waist circumference, which should be less than 102 cm for men and 88 cm for women.⁴² In this context, it is interesting to note that high waist circumference was associated with periodontitis in young adults aged 18–34 years, but not in older adults.⁴³ Abdominal obesity in conjunction with glucose intolerance, hypertension and dyslipidaemia has been termed metabolic syndrome or insulin resistance syndrome and is an indicator of increased risk for cardiovascular disease.⁴⁴ The cause of metabolic syndrome is not known, however, it is now recognized that adipose tissue can produce a number of hormones and cytokines that contribute to systemic inflammation and insulin resistance, which in turn can lead to the development of type 2 diabetes and cardiovascular disease.^45,46 Of particular interest in recent years is the adipocytokine, leptin, which controls appetite on the one hand, and has immune regulatory functions on the other, such as the production of inflammatory cytokines. Obesity is associated with reduced sensitivity to the appetite suppressing effects of leptin, leading in turn to higher levels.⁴⁷ Infection and inflammation can also lead to higher leptin levels.⁴¹ As raised serum leptin concentration can enhance atherosclerosis it is, therefore, a potential risk factor for CVD.⁴⁸ However, whether periodontal inflammation has any effect on leptin levels, or vice versa, remains to be determined, especially in view of the epidemiological association between obesity and periodontitis. Nevertheless, a recent study suggests that overweight and obese individuals who are periodontally healthy may be at risk for initiation and progression of periodontal disease due to an overgrowth of Tannerella forsythia in subgingival plaque.⁴⁹ Thus, clinicians need to be aware that patients with abdominal obesity, as well as carrying a greater burden of systemic inflammation, may also have a greater burden of infection, placing them, not only at greater risk for periodontitis, but also compounding their risk for CVD.

The National Heart Foundation Guidelines⁴⁰ recommend that overweight or obese adults without known CVD or who are not known to be at high risk for CVD should be assessed for absolute CVD risk using the Framingham Risk Equation, even though the predictive value has not been specifically assessed in this population. In this situation, the Framingham Risk Equation may underestimate CVD risk as it does not take into account obesity or overweight status, especially abdominal or central obesity. Notwithstanding the influence of obesity, as discussed above, until there is evidence to the contrary, periodontitis should be regarded as a modifiable risk factor in those found to have high absolute CVD risk.

Diabetes

The literature on the relationship between periodontal disease and diabetes mellitus, both type 1 and 2, is also steadily increasing and it is generally accepted that the relationship is a bidirectional one. On the one hand, it has been known for over 60 years that diabetes is a modifying factor for periodontal disease. This has been confirmed in more recent studies,^50–53 such that periodontal disease is now called the sixth complication of diabetes⁵⁴ along with retinopathy, nephropathy, neuropathy, macrovascular disease and poor wound healing. Indeed, a recent meta-analysis of 23 studies concluded that the prevalence and severity of periodontal disease is greater in diabetics than non-diabetics.⁵⁵ On the other hand, periodontitis contributes to poor metabolic control in people with diabetes⁵⁶ which can place them at risk for diabetic complications. A long-term study that followed 628 patients with type 2 diabetes for 11 years indicated that those with severe periodontitis had three times the risk of death from ischaemic heart disease or diabetic nephropathy than those with no, mild or moderate periodontitis and that this was additional to the effects of traditional risk factors for these diseases.⁵⁷ A more recent study that followed 500 type 2 diabetics over 22 years found that those with periodontitis were at increased risk (up to 3.5 times the risk) for end-stage renal disease.⁵⁸

Glycosylated haemoglobin (HbA1c) levels are an accurate representation of the degree of diabetic control over the previous 2–3 months and correlate well with diabetic complications. As a result of chronic hyperglycaemia, glucose becomes attached to haemoglobin and remains so for the lifespan of the erythrocyte (120 days). HbA1c levels in diabetics should be around 7 per cent and, in non-diabetics, ≤ 6%. An HbA1c of 6 per cent approximately equates with a mean plasma glucose level of 7.5 mmol/L and an HbA1c of 7 per cent with 9.5 mmol/L. Poorly controlled diabetics generally should have their HbA1c levels checked every three months.

Diabetics are considered to be more prone to infection due to the effect of chronic hyperglycaemia on macrophage and neutrophil function, by reducing their ability to produce reactive oxygen species required for oxidative burst. Many of the complications of diabetes are thought to be due to the accumulation of advanced glycation end products (AGEs) as a result of glycation of proteins such as haemoglobin, as discussed above, and collagen, which can affect the vasculature, including the periodontal vasculature. However, it is thought that periodontal inflammation can influence glycaemic control via inflammatory cytokines such as IL-1, IL-6 and TnF-α, with IL-6 and TnF-α in particular leading to increased insulin resistance.⁵⁹

The majority of periodontal treatment studies have shown some improvement in diabetic control as measured by a reduction in HbA1c levels, but some of these studies only had small numbers of patients. A recent meta-analysis of 456 patients has shown that the reductions in HbA1c were small (< 1%), and not statistically significant.⁶⁰ Hence, further studies with larger sample sizes and including only type 2 diabetics are needed before definite conclusions can be drawn. Even so, HbA1c levels tend to increase over time in diabetics, and so even a small reduction may be of clinical significance for individual patients, especially as the studies do seem to show a lot of inter-individual variation.

The beneficial effect of periodontal treatment in reducing inflammatory mediators and hence systemic inflammation, as discussed above, also has to be considered. However, irrespective of any effect of periodontal treatment on diabetic control, from the dentist’s perspective the most important issue is treating periodontal infection to improve the oral health of diabetic patients that would otherwise be compromised by poorly controlled diabetes. As many diabetics are undiagnosed, dentists are well placed for helping identify these patients. A recent study has shown that the probability of having diabetes is increased in patients with periodontitis who are older than 45 years and who have a family history of diabetes together with a history of hypertension and hypercholesterolaemia, and that this probability increases with age.⁶¹ With the ageing population this suggests that dentists should become more proactive in working with medical colleagues in diagnosing and managing diabetic patients. In this regard, a relatively inexpensive blood glucose monitor could be a useful addition to the dental surgery. A casual blood glucose of ≥ 11.1 mmol/L, especially if accompanied by any of the classic symptoms of polyuria, polydypsia or unexplained weight loss, would require further investigation by the patient’s medical practitioner.

The Heart Foundation guidelines⁴⁰ recommend that diabetics up to the age of 60 years, who are not known to have CVD or to be at high risk, have their absolute risk over the next five years calculated using the Framingham Risk Equation, recognizing that this may be an underestimate of risk in this population and, therefore, should be regarded as an estimate of their minimum CVD risk. As mentioned previously, diabetics over 60 years and those with microalbuminuria (> 20 mcg/min or urinary albumin:creatinine ratio > 2.5 mg/mmol for males and > 3.5 mg/mmol for females) are already known to be at increased absolute risk for CVD. Once again, until there is more evidence available, periodontitis should be regarded as a modifiable risk factor in diabetics found to have high absolute CVD risk.

Adverse pregnancy outcomes

Preterm birth rates have not reduced significantly despite advances in antenatal care and almost 50 per cent of mothers delivering preterm babies have none of the known risk factors such as smoking, alcohol consumption, previous low birthweight baby, stress, illness, low socio-economic status or poor nutrition.⁶² Infection, particularly maternal genito-urinary tract infection, is implicated in a large number of cases.⁶³ However, it is hypothesized that maternal infection and inflammation elsewhere may also play a role in these cases. Hence, infection with periodontal bacteria and the ensuing cascade of immuno-inflammatory mediators, including IL-1, IL-6, TNF-α and prostaglandins, especially PGE₂, has also been implicated. Higher cytokine levels have been found in women who deliver preterm⁶⁴ and it is thought that they affect the viability of the placenta leading to low birthweight and initiate premature contractions of the uterus.⁶⁵

Numerous studies have investigated the association between periodontal disease and preterm low birthweight (PLBW), with the majority finding an association, however, once again, some have been contradictory. It is interesting to note that many of the studies showing a positive association involve Black and Hispanic Americans from low socio-economic backgrounds whereas those showing no association are UK based. This suggests that ethnic or environmental factors may also be involved. A contributing factor to the conflicting results is the variability in definitions used for periodontal disease and adverse pregnancy outcome. Nevertheless, a meta-analysis of five studies (three cohort and two case control) conducted between 1996 and 2002 concluded that there was indeed a positive association and that pregnant women with periodontal disease had 4.28 times greater risk of preterm birth than periodontally healthy women.⁶⁶ Of note is the fact that 40 articles were identified and only five met the inclusion criteria for the meta-analysis. It was also concluded that there was no convincing evidence that periodontal treatment would reduce the risk. A later systematic review of 25 studies reported that 18 of them showed an association and that periodontal treatment did lead to a reduction in PTLBW and preterm birth.⁶⁷ However, both reviews concluded that more rigorous studies are required. Two further meta-analyses^68,69 concluded that there probably was an association and a further review in 2008⁷⁰ agreed that there are “indications” of an association but that there is a lack of conclusive evidence supporting improved pregnancy outcome following periodontal treatment. These authors also highlighted the need for larger, more rigorous studies to assess the risk of adverse pregnancy outcomes in mothers with periodontitis as well as the effect of prevention or treatment of periodontitis on these outcomes, if substantiated.

Respiratory disease

Over the last 15 years, a number of studies have investigated the relationship between periodontitis and respiratory disease with aspiration of anaerobic periodontal pathogens thought to be responsible. Poor oral hygiene has been associated with increased risk for chronic obstructive pulmonary disease (COPD)⁷¹ and patients with COPD were found to have more periodontal attachment loss than healthy controls.⁷² To date there have been two systematic reviews, both of which concluded that there was evidence of an association between oral health and COPD and pneumonia.^73,74 The oral cavity, including dental plaque, can act as a reservoir of respiratory pathogens in patients in intensive care units, hospitalized patients with chronic lung diseases and nursing home residents.⁷⁵ Interventions aimed at de-contaminating the oral environment by chlorhexidene gel, mechanical debridement or toothbrushing reduced the prevalence of respiratory pathogens in dental plaque and reduced the rate of pneumonia by approximately 40 per cent.⁷⁵ It has also been suggested that aspiration of saliva containing cytokines and proteases from inflamed periodontal tissues could alter the respiratory environment and facilitate colonization of respiratory pathogens, but evidence for this is lacking.

Conclusions

There are now many studies linking periodontal disease with systemic disease. Substantial variations in study design, patient populations, definitions of disease and statistical analysis have contributed to the difficulties in interpretation of the findings of these studies. In addition, periodontitis and chronic diseases such as cardiovascular disease share many risk factors. Despite this, there is strong evidence that a small but significant relationship exists. However, large, well-designed prospective studies are now required to determine whether these diseases are linked simply because they have risk factors in common or whether a true causal relationship exists. Meanwhile, a recent consensus review by physicians and dentists recommended that education to encourage improved oral health should be part of efforts to improve general health, as this is likely to reduce the burden of cardiovascular disease and diabetes.⁷⁶ If oral health is considered as part of general health, it follows that dental and medical care should be more closely integrated and that health education to encourage improved oral health should be included with the current healthy lifestyle messages, alongside smoking cessation, diet and exercise. The current evidence is such that prevention and treatment of periodontal disease may reduce chronic systemic disease risk at both the individual and community level. The dental profession, therefore, has an important role in ensuring that oral disease does not contribute to systemic disease in any individual.