Periodontitis (Gum Disease) & its Risk Association in Diabetes, Pregnancy & Cardiovascular Disease

The Global Burden of Disease (GBD) study [1990-2010] states that oral diseases have high prevalence rate affecting almost 3.9 billion people worldwide. Severe periodontitis and tooth loss being the 6th and 36th most prevalent conditions respectively.¹ “Their impact on individuals and communities is considerable in terms of pain and suffering, impairment of function and reduced quality of life and cost of treatment (FDI, World Dental Parliament, 2012).” World Health Organization (WHO)¹ has identified periodontal disease, including gingivitis and destructive periodontitis, as one of the three important dental diseases and one of the major causes of adult tooth loss.² Periodontitis is a chronic multifactorial infectious and inflammatory disease characterized by progressive destruction of the tooth supporting tissues which leads to tooth loss.³

The focal-infection theory, based on the principles of infectious disease established by Koch and Pasteur, put forth the notion that the invasion of the bloodstream by bacteria from a localised infection (such as periodontal diseases) could spread to distant organs and tissues to cause disease. The criteria for establishing a causal association between the two diseases have been further defined and is principally based on the Bradford Hill criteria which include biological plausibility, epidemiological association, and the impact of intervention on one disease affecting the second.⁴ In recent years there has been keen interest in potential associations between periodontal disease and various chronic systemic diseases and conditions e.g. cardiovascular disease (CVD) , diabetes , adverse pregnancy outcomes (APO), respiratory disease, chronic kidney disease etc. Predominantly CVD, diabetes and APO (preterm low birth weight, preeclampsia) have been frequently documented in scientific literature. Three possible mechanisms have been postulated to play a role in the distant non-oral manifestations of oral diseases: dissemination of bacterial toxins, metastatic infections, and immunological injury. The word “metastasis is not limited only to cancer cells but infections and inflammation also have the potential to metastasize.⁵ Periodontitis produces inflammatory responses beyond the periodontium. This oral inflammation triggered by the periodontal infection releases inflammatory mediators and increases the systemic inflammation.

Mechanism of association between periodontitis and cardiovascular disease

Atherosclerosis is an inflammatory condition.⁶ Association between periodontitis and CVD is based on the inflammatory mechanisms triggered by periodontal microbes, locally or systemically, which then influence the initiation and propagation of the atherosclerotic lesions. Inflammatory stimuli as triggered by the inflammatory cytokines and chemotactic agents lead to changes in the endothelium. Lipid streaks, comprised of modified low-density lipoproteins (LDL) within macrophages and dendritic cells (DCs) in the intimal layer, can initiate and propagate this inflammatory response. These changes initiate interactions with monocytes that promote leucocyte migration into the intimal layer of the artery and release of chemotactic cytokines such as monocyte chemotactic protein-1 (MCP-1). MCP-1 attract additional monocytes or other cells that can transport bacteria into the lesion. The dendritic cells transform into foam cells, which release inflammatory cytokines and matrix metalloproteinase (MMPs), further amplifying the inflammatory response within the lesion. This further elevates the levels of the inflammatory mediators contributing to systemic inflammation. (Figure 1)⁷

Figure 1: Pathways of association between gum disease and cardiovascular disease⁷

Abbreviations: LPS-Lipopolysaccharide, Th cells-T helper cells, Ab-Antibody, CVD-Cardiovascular Disease

Mechanisms of association between periodontitis and diabetes

Dysregulation of the immune system is central in the pathogenesis of diabetes. The hyperglycaemic state in diabetes results in various proinflammatory effects that leave an impact on multiple body systems, including the periodontal tissues. The hyperglycaemic state results in deposition of AGEs (advanced glycation end products) in the periodontal tissues (as well as elsewhere in the body), and binding of the receptor for AGE (RAGE) results in local cytokine release and altered inflammatory responses. Neutrophil function is also altered that leads to enhancement of the respiratory burst and delayed apoptosis (leading to increased periodontal tissue destruction). Co- factors combine leading to dysregulated inflammatory responses in the periodontal tissues secondary the chronic challenge by periodontal bacteria (Figure 2).⁸

Figure 2: Possible pathways of association between gum disease and diabetes.⁸

Abbreviations: RANKL-Receptor Activator of Nuclear Factor Kappa-Β Ligand, OPG-Osteoprotegerin, AGE-Advanced Glycation End-product, RAGE-Receptor for Advanced Glycation End-products, TNFα-Tumor Necrosis Factor Alpha, IL-Interleukin

Mechanisms of association between periodontitis and adverse pregnancy outcomes (APO)

Chronic periodontal infections produce local and systemic host responses leading to transient bacteraemia. Bacterial endotoxins and other bacterial substances gain an access to the gingival tissue, initiate and trigger the local inflammatory reactions that produce high levels of pro-inflammatory cytokines. Activation of maternal inflammatory cell response and cytokine cascades predominantly cause the pathophysiological processes of preterm labour, low birth weight, and pre-eclampsia (Figure 3)⁹

Figure 3: Possible pathways of association between periodontitis and adverse pregnancy outcomes⁹

Conclusion

A growing body of evidence through epidemiological, clinical, and interventional studies have revealed the often-overlooked relationship between oral bacteraemia or inflammation due to periodontitis and systemic disease. This complex interplay is important for developing improved therapeutic interventions, which establish the foundation for studying, diagnosing, and treating this complex oro-systemic interconnection within an integrative framework.¹⁰