Role of C-Reactive protein and periodontal disease in systemic health: A review

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1 J. Adv Dental Research REVIEW ARTICLE All Right Res Role of C-Reactive protein and periodontal disease in systemic health: A review Smitha CN * Sweta Soni ** Basu SK *** *M.D.S, Associate Professor, **M.D.S, Senior Lecturer, Department of Periodontics, ***M.D.S, Associate Professor, Department of Oral Pathology & Microbiology, Vyas Dental College & Hospital, Jodhpur, Rajasthan, India. smita_cn@yahoo.co.in Abstract: Periodontitis is a destructive inflammatory disease of the supporting tissues of the teeth. This condition is caused by a chronic, mixed infection of gram-negative bacteria. Periodontal pathogens affect local and systemic immune and inflammatory responses. A number of scientific evidence has shown that individuals with periodontitis have a significantly increased risk of developing coronary heart disease. In addition to conventional risk factors, chronic infection and subsequent production of systemic inflammatory markers, C-reactive protein (CRP) may be associated with this increased risk. This review appraises the available evidence to determine the influence of chronic periodontitis on the serum levels of C-reactive protein (CRP) and its effects on systemic health of an individual. However, considerable work is still needed to confirm the relationship between periodontitis and CRP. Keywords: Periodontitis, Periodontal Therapy, Coronary Heart Disease, Atherosclerosis, Atherothrombosis, preterm low birth weight, C - reactive protein. Introduction: Periodontitis is a chronic, tissue destructive inflammatory state that is predominantly induced by gram-negative bacteria that colonize the gingival crevice. Periodontal pathogens affect local and systemic immune and inflammatory responses. Serial Listing: Print ISSN( ) Online-ISSN ( ) Bibliographic Listing: Indian National Medical Library, Index Copernicus, EBSCO Publishing Database, Proquest., Open J-Gate. The local inflammatory response to these bacteria or bacterial products is characterized by infiltration of the periodontal tissues by inflammatory cells including polymorphonuclear neutrophils (PMNs), macrophages, lymphocytes and plasma cells. Activated macrophages release cytokines and some individuals respond to microbial challenge with an abnormally high delivery of such inflammatory mediators as PGE 2, interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFα). These cytokines are involved in the destruction of both the periodontal connective tissue and alveolar bone. [1] Subgingival biofilms constitute an enormous and continuing bacterial load. They present continually renewing reservoirs of lipopolysaccharide (LPS) and other gram-negative bacteria with ready access to the periodontal tissues and the circulation. Systemic challenge with gram-negative bacteria or LPS induces major vascular responses, including an inflammatory cell infiltrate in the vessel walls, vascular smooth muscle proliferation, vascular fatty degeneration, and intravascular coagulation. LPS upregulates expression of endothelial cell adhesion molecules and secretion of IL-1, TNFα and thromboxane, which results in platelet aggregation and adhesion, formation of lipid-laden foam cells, and deposits of cholesterol and cholesterol esters. [1] Among the environmental risk factors and indicators shared by periodontitis and systemic diseases, such as cardiovascular disease, are tobacco smoking, stress, aging, race or ethnicity, and male gender. Studies demonstrating genetic factors shared by periodontitis, cardiovascular disease, preterm labor, and osteoporosis have not yet been performed but may be fruitful. Several reports have implicated long standing periodontal disease in the development of cardiovascular disease, cerebrovascular accidents and preterm low birth weight infants. [2] Periodontal disease may lead to atherogenesis by two different pathways:

2 2 1. A direct invasion of the arterial wall as evidenced for chlamydial organisms and P. gingivalis and some other periodontal pathogens. [2,3] 2. The release of some systemic inflammatory mediators and acute phase reactants with atherogenic effects. Eg. : TNFα, IL-1, IL-6, CRP, and serum amyloid- A. [1] Acute phase response: The acute phase response is triggered subsequent to infection, trauma, necrosis or malignancy and the function of acute phase response is the removal of the inciting agent and promotion of healing. Acute phase proteins are defined as proteins whose concentrations are altered atleast 25% in response to inflammation. Most acute phase proteins are synthesized primarily by the liver in response to proinflammatory cytokines including IL-1α, IL-1β, IL-6, tumor necrosis factor-α, transforming growth factor β and interferon-γ. The major acute phase proteins include C- reactive protein, serum amyloid-a and fibrinogen whose concentrations increase with inflammation whereas concentrations of albumin and transferrin is decreased. [4] The existence of CRP was first reported in 1930 by Tillet and Frances [5] who identified a substance in the sera of patients acutely infected with pneumococcal pneumonia that formed a precipitate when combined with C-polysaccharide of the cell wall of streptococcus pneumoniae and found that when serum from febrile patients was mixed with a cell-wall component of pneumococci called Fraction C, formed a precipitate. Subsequently, nomenclated as C-reactive protein. C-reactive protein (CRP) is a type I acute phase protein which can increase upto 1000 fold after the onset of a stimulus. CRP levels reflect the burden of inflammation within atherosclerotic lesions, thus reflecting the instability of the plaques. For this reason, an increased level of the protein may be a prelude to rupture of the plaque and thus, to occlusive arterial disease. [4] Structure: C-reactive protein is a non-glycosylated circulating plasma protein which together with the distinct but closely related protein, serum amyloid P component (SAP), comprises the pentraxin family of proteins [4] which belong to the lectin fold superfamily. The human CRP molecule (Mr 115,135) is composed of five identical non-glycosylated polypeptide subunits (Mr 23,027), each containing 206 amino acid residues. The protomers are noncovalently associated in an annular configuration with cyclic pentameric symmetry. Each protomer has the characteristic "lectin fold," composed of a two-layered β sheet with flattened jellyroll topology. The ligand binding site, composed of loops with two calcium ions bound 4 Å apart by protein side-chains, is located on the concave face. The other face carries a single α helix. The pentraxin family is named for its electron micrographic appearance from the Greek penta (five) ragos. [4] Ligands: The most well characterized ligand of CRP is phosphocholine (PC). This interaction requires calcium and is responsible for studies showed that CRP bound chromatin through interactions with the histones and does not bind naked DNA. CRP binds the histones H1 and H2A most strongly, with considerably less binding to H2B, H3 and H4. The binding of CRP to chromatin has been reported to cause its solubilization in the presence of complement. [6] CRP and periodontal disease: C-reactive protein was traditionally thought to be produced by the liver in response to inflammatory cytokines. Several recent studies, however, clearly showed that C-reactive protein can be produced by non hepatic tissues. [7] In healthy young adult volunteer blood donors, the median concentration of CRP is 0.8 mg/l, the 90 th centile is 3.0 mg/l, and the 99th centile is 10 mg/l, but, following an acute-phase stimulus values may increase from less than 50 mg/l to more than 500 mg/l, that is, 10,000-fold. This effect is mainly seen as periodontal pathogens do not induce only local inflammation and tissue destruction but they are also involved in systemic increase in inflammatory and immune response. Low levels of bacteremia, LPS, and other bacterial components may provide a stimulus for systemic inflammatory responses such as increased production of CRP due to activation of the cascade of inflammatory cytokines production by monocytes and other cells in periodontal tissues. [8] Denovo hepatic synthesis starts very rapidly after a single stimulus, serum concentrations rising above 5 mg/l by about 6 hours and peaking around 48 hours. The plasma half-life of CRP is about 19 hours and is constant under all conditions of health and disease, so that the sole determinant of circulating CRP concentration is the synthesis rate, which thus directly reflects the intensity of the pathological process stimulating CRP production. [7] Properties and functions: [2,9] 1. C-reactive protein when bound to bacteria, can activate the complement to enhance opsonisation and clearance of the bacteria prior to the production of specific IgM or IgG. This process of protein coating to

3 3 enhance phagocytosis is similar to opsonization by antibodies. 2. C-reactive protein bound to bacteria or cells can interact with the natural killer cells and with the monocytes and may increase the tumoricidal activity of these cells. 3. Modulates macrophage function, since macrophages possess C-reactive protein receptors and C-reactive proteins can potently upregulate proinflammatory cytokine production. 4. C-reactive protein has been shown to induce the synthesis of IL-1α, IL-1β, TNFα and IL-6 in human peripheral blood mononuclear cells and alveolar macrophages, suggesting that one of its physiological roles may be the amplification of inflammatory responses. CRP & cardiovascular disease: Several studies have reported that periodontitis patients are at higher risk for cardiovascular diseases including coronary artery diseases and stroke. The association is hypothesized to be linked to direct effects of periodontal pathogens or indirect host mediated effects triggered by infection. Systemic inflammatory host responses in periodontitis are suggested to be one of the possible underlying mechanisms of this relationship. CRP and other acute phase molecules possess a wide variety of functions, including pro-inflammatory properties, activation of complement factors, neutralization of invasive pathogens, stimulation of repair, and regeneration of a variety of tissues. CRP represents an emerging and reliable marker of acute phase response to infectious burdens and/or inflammation. [10,11] A systematic review and meta-analysis [12] on the prevalence and incidence of coronary heart disease has shown significant increase in periodontitis. Meta-analysis of the 5 prospective cohort studies indicated that individuals with periodontal disease had a 1.14 times higher risk of developing coronary heart disease (CHD) than the controls. The prevalence of CHD in the crosssectional studies was significantly greater among individuals with periodontal disease (PD) than in those without PD. This indicates that both the prevalence and incidence of CHD are significantly increased in PD. Therefore, PD may be a risk factor for CHD. Prospective studies are required to prove this assumption and evaluate risk reduction with the treatment of PD. Role of CRP in the pathogenesis of atherosclerosis and atherothrombosis: Direct biological activity of CRP on vascular cells and monocytes/ macrophages: CRP could directly activate endothelial cells to express adhesion molecules, chemokines, and cytokines. CRP was also shown to inhibit nitric oxide (NO) production and stimulation of NO release via downregulation of endothelial NO synthase. CRP unregulated angiotensin receptor-1 (AT1-R) protein expression, increased AT1-R number on vascular smooth muscle cells, and promoted vascular smooth muscle migration and proliferation in vitro. CRP functioned as a chemo-attractant for monocytes and was able to induce tissue factor expression in macrophages. Furthermore, soluble CRP and immobilized CRP have been demonstrated to mediate uptake of native low density lipoprotein (LDL) into macrophages. [13] CRP & preterm low birth weight: C-reactive protein (CRP) is an acute phase reactant produced by liver in response to diverse inflammatory stimuli, including heat, trauma, infection, and hypoxia. CRP has been associated with adverse pregnancy outcomes, including preterm delivery, [14] preeclampsia, and intrauterine growth restriction. [15] Furthermore, periodontal disease has been associated with increased risk of preterm low birth weight, low birth weight, and preterm birth. [16] Preterm birth is a major medical, social, and economic problem accounting for large proportion of maternal and especially, neonatal mortality and morbidity. Preterm infants are at elevated risk for death, neuro-development disabilities, cognitive impairment, and behavioral disorders. Therefore, CRP might be a plausible mediator of the association between periodontitis and adverse pregnancy outcomes. Elevated CRP could amplify the inflammatory response through complement activation, tissue damage, and induction of inflammatory cytokines in the monocytes and therefore may mediate the relationship between periodontitis and adverse pregnancy outcomes. [17] Potential mechanisms that were put forward to explain the relationship between periodontal disease (PD) and preterm low birth weight (PTLBW) infant delivery was that periodontal infection serves as a chronic reservoir of lipopolysaccharide (LPS) which are responsible for the production of interleukin-1beta (1L- 1β), prostaglandin E 2 (PGE 2 ) and tumour necrosis factoralpha (TNFα) and CRP that are in turn associated with preterm parturition and fetotoxicity [18,19] Effect of periodontal therapy on serum CRP level: Destructive periodontal diseases in the general population have been associated with both an increased prevalence of atherosclerotic complications and an elevation in serum CRP values. Several short term intervention studies reported that treatment of

4 4 periodontitis reduces the serum concentrations of inflammatory markers which are thought to be initiating factors for cardiovascular disease. Periodontitis is an infection caused by gramnegative bacteria that are organized in a biofilm in a subgingival location between the diseased root surface of the tooth and the junctional epithelium. Low levels of bacteremia, endotoxins derived from gram-negative microorganisms and other bacterial components may provide a stimulus for systemic inflammatory responses. [1] As such, it is relatively insensitive to the effects of systemic antibiotics, and its treatment requires, in the first instance, the removal of the biofilm by mechanical professional instrumentation. Following successful treatment, bacterial load is significantly reduced, while antibody titers and avidity to the specific pathogens are improved. As a result of these changes, local inflammation significantly decreases, and there is a significant improvement of the clinical parameters (probing pocket depths, bleeding on probing). Decrease in serum CRP was significantly associated with the periodontal treatment in terms of decrease in the infection burden and the associated periodontal inflammation as assessed by clinical parameters. [10,11] Various studies have assessed the systemic effects of treating severe widespread periodontitis in a population of otherwise healthy individuals by examining treatment associated changes in markers of inflammation that are also implicated in cardiovascular atherosclerotic diseases. These were accompanied with significant reductions in serum IL-6 and CRP concentrations. In a multivariate model, serum CRP levels were significantly associated with the outcome of periodontal treatment after correcting for potential covariates (age, body mass index, gender, and smoking) and polymorphisms in the IL-6 (174 C/G) and IL-1A (889) genes. [20] Conclusion: In conclusion, this review provides evidence that periodontitis elicits a mild acute-phase response with elevation of CRP levels. C-reactive protein is a nonspecific marker of inflammation. Elevated levels are found in subjects with cardiovascular diseases. CRP has been associated with adverse pregnancy outcomes, including preterm delivery, pre-eclampsia and intrauterine growth restriction. Periodontitis influence levels of C- reactive protein. Periodontal treatment results in lowered CRP levels; however, the treatment studies available are scarce. Further research should investigate whether the changes in cellular and molecular markers in peripheral blood in periodontitis are indeed causally related to cardiovascular events and whether periodontal therapy and maintenance of periodontal health will reduce the risk for such events. References: 1. Williams RC, Offenbacher S. Periodontal medicine. Periodontol 2000; 23: Patel P, Mendell MA, Carrington D. Association of Helicobacter pylori and Chlamydia pneumoniae infections with coronary heart disease and cardiovascular risks factors. Br Med J 1995; 311: Deshpande RG, Khan MB, Genco RJ. Invasion of aortic and heart endothelial cell by P.gingivalis. Infect Immun 1998; 66: Pepys MB, Baltz ML. Acute phase proteins with special reference to C-reactive protein and related proteins (pentaxins) and serum amyloid-a protein. Adv Immunol 1983; 34: Tillett, WS, Francis T. Serological reactions in pneumonia with a non-protein somatic fraction of pneumococcus. J Exp Med 1930; 52: Thompson D, Pepys MB, Wood SP. The physiological structure of human C-reactive protein and its complex with phosphocholine. Structure 1999; 7: Richard FM, Henry G. Effects of C-reactive protein on the lymphoid system. J of Experimental Med 1975; 141: Hans C. Ablij, Arend E. Meinders. C-reactive protein: history and revival. European Journal of Internal Medicine 2002; 13: Noack B, Genco RJ, Trevisan M, Grossi S. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol 2001; 72: Wu T, Trevisan M, Genco RJ, Falkner KL, Dorn JP, Sempos CT. Examination of relation between periodontal health status and cardiovascular risk factors: Total and high density lipoprotein, cholesterol, C-reactive protein and plasma fibrinogen. Am J Epidemiol 2000; 151: Ioannidou E, Malekzadeh T, Dongari-Bagtzoglou A. Effect of periodontal treatment on serum C-reactive protein levels: A systematic review and meta analysis. J Periodontol 2006; 77: Amol Ashok Bahekar, Sarabjeet Singh, Sandeep Saha. The prevalence and incidence of coronary heart disease is significantly increased in periodontitis: A meta-analysis. Am Heart J 2007; 154: Verma S, Yeh ET. C-reactive protein and atherothrombosis beyond a biomarker: an actual partaker of lesion formation. Am J Physiol Regul Integr Comp Physiol 2003; 285: R1253 R1256; discussion R1257 R Pitiphat W, Gillman MW, Joshipura KJ, Williams PL, Douglass CW, Rich-Edwards JW. Plasma C-reactive protein in early pregnancy and preterm delivery. Am J Epidemiol 2005; 162: Tjoa ML, Van Vugt JM, Go AT, Blankenstein MA, Oudejans CB, Van Wijk IJ. Elevated C-reactive protein levels during first trimester of pregnancy are indicative of

5 5 preeclampsia and intrauterine growth restriction. J Reprod Immunol 2003; 59: Jeffcoat MK, Geurs NC, Reddy MS, Cliver S, Goldenberg RL, Hauth JC. Periodontal infection and preterm birth: Results of a prospective study. J Am Dent Assoc 2001; 132: Cermak J, Key NS, Bach RR, Balla J, Jacob HS, Vercellotti GM. C-reactive protein induces human peripheral blood monocytes to synthesize tissue factor. Blood 1993; 82: Offenbacher S, Beck JD, Lieff S, Slade G. Role of periodontitis in systemic health: spontaneous preterm birth. J Dent Edu 1998; 62: Konopka T, Rutkowska M, Hirnle L, Kopec W, Karolewska E. The secretion of prostaglandin E 2 and interleukin IL-1β in women with periodontal diseases and preterm low birth weight. Bill Group. Int Rech Sci Stomatol odontol 2003; 45(1): D Aiuto F, Parkar M, Andreaou G, Brett PM, Ready D, Tonetti MS. Periodontitis and atherogenesis: causal association or simple coincidence? J Clin Periodontol 2004; 31: Source of Support: Nil Conflict of Interest: Not Declared Received: October 2010 Accepted: December 2010

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Focal Infection Theory

Paradigm Shift Focal Infection Theory 1900, British physician William Hunter first developed the idea that oral microorganisms were responsible for a wide range of systemic conditions that were not easily