Periodontitis and Systemic Conditions − Is There a Link?

The possibility that periodontal diseases have an effect on systemic health is being widely investigated. This paper reviews the potential links and the mechanism of these effects.

Although the effects of periodontitis on systemic health do not yet have an effect on clinical decisions, knowledge and understanding of the link, effects and mechanism are important.

Over the past 20 years, an ever increasing number of studies have investigated a possible role for periodontal disease as a risk factor for systemic conditions. Most studies have focused on the atherosclerotic conditions, cardiovascular disease and stroke.

More recently, studies have also investigated a possible link with adverse pregnancy outcome, diabetes and respiratory disease.

This paper reviews current knowledge in each of these areas.

Cardiovascular disease:

Atherosclerosis is now considered to be an inflammatory process, leading to a potential role for infectious agents in initiating or modulating the process. Chlamydia pneumoniae, Helicobacter pylori and the Herpes viruses have been linked to the development of cardiovascular disease.

As periodontal lesions are recognized as reservoirs for the systemic spread of bacterial pathogens and their products, there has been considerable interest in an association between periodontitis and cardiovascular disease.

Epidemiological studies

There have been numerous studies investigating a potential association between periodontal disease and cardiovascular disease (reviewed by Scannapieco et al1). Initial case-control trials compared the oral health of patients with cardiac disease with age- and gendermatched healthy controls. 

The majority of these studies reported a positive association between poor oral health and the prevalence of cardiovascular disease. Subsequently, a number of cross-sectional studies have been undertaken.

Results from longitudinal studies have been less clear, the majority showing the presence of periodontitis as a

risk factor for cardiovascular disease, but a significant minority finding no association between the conditions. Two major factors have been highlighted for the difficulties in the interpretation of these studies.

 First,the level of assessment of both periodontal disease and cardiovascular outcome vary greatly amongst the different studies. Many of the earlier reports used data from large epidemiologic studies, not specifically

designed to record levels of periodontal disease.

Hence, the markers of disease were relatively crude, concentrating on general oral health rather than specifically periodontitis.

Secondly, the role of confounding variables is significant when looking for a causal link between the two conditions. As periodontitis and cardiovascular disease share common risk factors, in particular smoking, the potential for confounding is high2 − some authors have suggested that the apparent causal link is simply an artefact resulting from these other shared risk factors. Scannapieco et al1 carried

out a systematic review of studies into the associations between periodontal disease and risk for cardiovascular disease. These authors concluded that a moderate association existed between the two conditions, but insufficient evidence was currently available to justify periodontal intervention to prevent the onset or progression of atherosclerotic conditions.

 They also concluded that there was a need for randomized controlled intervention trials to establish definitively a role for periodontal disease in the aetiology of atherosclerosis.

Proposed biological mechanisms

It has been argued that persistent local infections, such as periodontal disease, could promote atherosclerosis at a distant site through systemic dissemination of bacteria or their products via bacteraemia or endotoxaemia, directly affecting endothelial cell function, or resulting in increased levels of circulating inflammatory mediators which in turn can induce atherosclerosis.

Bacterial LPS and inflammatory cytokines can directly affect endothelial cell function, increasing expression of adhesion molecules and chemokines, thereby increasing the risk of atheroma formation.

 LPS also initiates platelet aggregation and adhesion and promotes the formation of foam cells and

the deposition of cholesterol within the intima of the artery.

CRP levels are elevated in patients with unstable angina and recent acute myocardial infarction and are also an independent predictor of future myocardial infarct and stroke. The effects of CRP on the cardiovascular system have yet to be fully elucidated, but it is thought to activate the complement system and be involved in foam cell formation in atheromas. 
CRP levels are also elevated in patients with periodontitis, while recent studies have shown that successful non-surgical therapy significantly decreased serum IL-6 and CRP levels. Elevated serum fibrinogen and IL-6 are also predictors of cardiac events.

Stroke

Studies investigating a link between periodontal disease and stroke are much less common. Early case control studies indicated an association between the two conditions. 
More recent cross-sectional studies have also reported a small increased risk for stroke in patients with periodontitis, particularly for non-haemorrhagic stroke, ie stroke caused by atheroma formation.

When the vessel wall thickness and lumen diameter of the common carotid artery was used as the outcome measure, a more significant association with periodontal disease was recorded.
 The same biological mechanisms linking periodontitis and atheroma formation have been suggested to underlie this proposed link.

Proposed biological mechanisms:

As discussed for cardiovascular disease, the biological mechanisms proposed to explain the link between maternal periodontitis and PLBW involve translocation of inflammatory mediators (such as IL-1β, TNFα and PGE2), or periodontal bacteria and their products, from the periodontal tissues to the foetal-placental unit via the systemic circulation, subsequently inducing premature labour. Initial studies in experimental animals have provided support for this hypothesis. Various low-grade, localized, nondisseminating subcutaneous challenges of pregnant hamsters with P gingivalis, a Gram negative microbe frequently associated with periodontal disease, resulted in increases in amniotic PGE2 and TNFα levels, which were associated with a significant reduction of foetal weight by up to as much as 25%.

A similar study in a pregnant mouse model found that local maternal infection with P gingivalis compromised normal foetal development by systemic dissemination and direct targeting of the foetal-placental unit.

Maternal infection with Campylobacter rectus resulted in a similar, significant reduction in litter birthweight. Interestingly, Madianos et al reported that increased maternal IgG levels to known periodontal pathogens

appeared to confer protection for the foetus against preterm birth. In contrast, high levels of foetal IgM to C rectus were associated with an increased risk of preterm delivery, supporting the hypothesis that blood-borne bacteria can reach the foetus and induce an immunologic response.

Diabetes:

Diabetes is a well characterized risk factor for periodontitis (Figure 2). In recent years, it has been suggested that the link between these two conditions is bidirectional, the presence of periodontal disease also acting as a risk factor for poor glycaemic control. In 1996, Taylor and colleagues reported a longitudinal trial in which diabetic patients with significant periodontal disease had an increased risk of worsening glycaemic control over a 2-year period, compared to diabetics with healthy periodontal tissues.

Conversely, in other studies, patients receiving periodontal treatment, with or without antibiotic therapy,

have shown no significant change in glycated haemoglobin levels. A recent met-analysis of  intervention studies reported an overall reduction in glycated haemaglobin levels of 0.4% following periodontal therapy, and 0.7% when treatment included systemic antibiotics, both improvements below the level of statistical significance.

 A number of problems with such studies have been pointed out, in particular the small sample sizes, but also confounding variables such as smoking and body mass.

Respiratory disease:

Bacterial contamination of the lung is primarily caused by aspiration of colonized secretions from the oropharnyx into the lower airways. Pathogens most commonly associated with communityacquired pneumonia include Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus. Anaerobic periodontal bacteria have been suggested as potential pathogens in aspiration pneumonia.

 In an ageing mouse model, mixed infections of P gingivalis and T denticola caused severe pneumonia. In addition, cytokines and enzymes released into gingival crevicular fluid and, subsequently, saliva can also be aspirated, subtly affecting the respiratory environment, upregulating adhesion receptors on the mucosal surface and thus increasing respiratory pathogen colonization.

A small number of crosssectional studies have investigated a possible association between poor oral health and chronic obstructive pulmonary disease (COPD). Results indicated that patients with poor oral hygiene levels had an increased risk of developing COPD, while patients with COPD had more periodontal attachment loss than healthy controls, particularly patients who were previous smokers. Two recent systematic reviews concluded that there was evidence of an association between oral health and both pneumonia and COPD, with the evidence for the link to pneumonia being stronger. Studies have also investigated the effect of improved oral hygiene on pulmonary function. These studies were carried out both in ICU wards and in nursing homes, while the level of oral care varied from the use of chlorhexidine gels to non-surgical mechanical therapy by a hygienist. Again, the results indicated that improving oral hygiene significantly reduced the occurrence of respiratory disease in both settings.