THE ORAL BLOODSTREAM AS A POWERFUL BIOMARKER OF DENTAL CARIES - AN OVERVIEW

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1 Review Article Hegde et al THE ORAL BLOODSTREAM AS A POWERFUL BIOMARKER OF DENTAL CARIES - AN OVERVIEW Authors: Mitra Hegde*, Divya Tahiliani** Prof. (Dr) Nidarsh D. Hegde*** ABSTRACT Dental Caries is one of the most common oral diseases confronted by every practitioner and saliva plays a dynamic role in providing an effective defense system for the oral environment. It is the nature's phenomenal oral fluid with several organic and inorganic constituents, which partakes in various functions striking a balance to maintain a healthy milieu. This paper will take through the cause-effect relationship of salivary factors like flow, ph, buffering capacity, immunoglobulins and antioxidants with dental caries. It will also give a brief description of effect of systemic conditions on dental caries. KEYWORD : Saliva, Dental Caries, Salivary ph, Buffering Capacity, Hypertension Introduction Saliva is an oral biofluid which emulates body's general health. In the oral cavity it bathes and mimics the role of bloodstream as it contains serum constituents, measured in standard blood tests to 1 monitor health and diseases. It is nature's primary defense mechanism for the oral environment and particularly important for protecting exposed tooth surfaces. While internal protection for dentin comes from odontoblasts and the dental pulp, the body's external protection for enamel comes from 2 saliva. As a diagnostic fluid, it offers distinctive advantages over serum.whole saliva is preferred for diagnosis of systemic conditions, because it contains serum constituents. These constituents are derived from the local vasculature of the salivary glands and gingival 3 crevicular fluid. It can be collected non-invasively, and by individuals with limited training, including the patient. No special equipment is needed for 4 collection of fluid. It is most valuable for children and patients with fewer compliance problems and a NAME & ADDRESS OF CORRESPONDING Prof.(Dr) Mithra N Hegde Senior Professor & Head of the Department Department of Conservative Dentistry & Endodontics A.B.Shetty Memorial Institute of Dental Sciences address: drhegdedentist@gmail.com cost effective approach for screening large 1 populations. Early detection using salivary biomarkers minimizes the need for more invasive treatment. It prevents oral health disease at an early stage and provides a good oral health in rejuvenated state. 5 This complex fluid has a myriad of functions which, when combined plays a vital role in maintaining a healthy oral milieu. However patients strive to 2 maintain a healthy dentition throughout their lives. Saliva's principal function is lubrication to protect the oral mucosa. It also aids in food digestion, cleansing oral cavity and antimicrobial activity, facilitate speech, buffering action by neutralizing unwanted effect of acid on oral tissue and most importantly striking a balance of calcium phosphate concentrations which is the first step in dental 3 caries initiation. Saliva Collection Kauffmann et al stated that saliva can be considered as gland specific saliva and whole saliva. Each type of salivary gland secretes a characteristic type of saliva. Differences in the concentration of salt/ions 6,7 and total proteins among glands can be observed. Evaluation of secretions from the individual salivary glands is primarily useful for the detection of glandspecific pathology; infection and obstruction. Gland-specific saliva can be collected directly from individual salivary glands: parotid, submandibular, *Senior Professor & Head of the Department, Department of Conservative Dentistry & Endodontics A.B.Shetty Memorial Institute of Dental Sciences **Post Graduate Student, Department of Conservative Dentistry & Endodontics A.B.Shetty Memorial Institute of Dental Sciences **Professor, Department of Oral & Maxillofacial Surgery A.B.Shetty Memorial Institute of Dental Sciences 51

2 sublingual, and minor salivary glands. Secretions from both the submandibular and sublingual salivary glands enter the oral cavity through Wharton's duct, and thus the separate collection of saliva from each of these two glands is difficult 4 (Navazesh, 1993). However, wholesaliva is most frequently studied when salivary analysis is used for evaluation of 1,3,8,9 systemic disorders. There are two main aspects of saliva, quantity and quality. When oursalivary glands fail to produce adequate quantity of saliva, our mouths become dry and unable to self- cleanse. Improper quality affects saliva's buffering capacity. This protective balance gets altered and leads to manifestation of caries, halitosis or gingivitis. Systemic diseases change various factors like salivary flow, consistency and affect the oral 10 balance. Saliva and Dental Caries: LenanderLumikarai et al studied that in healthy situation, there is no correlation between saliva secretion rate and dental caries. However when the salivary secretion rate drops below a certain minimum, the rate of dental caries increases dramatically. Low buffering capacity is a risk factor for dental caries and also is indicative for low saliva 11 secretion. Salivary factors affecting dental caries 1. Salivary flow Salivary flow enhances saliva's self-cleansing property. It is dependent on sensory stimulation, stress, body positioning, degree of hydration, food ingestion, drugs and smoking etc. The most dramatic effect on salivary flow is seen in radiation therapy patients for head and neck diseases. 2. ph of saliva The ph of saliva is another important component to maintain the integrity of oral cavity, ph increases the remineralization of tooth surface because of the increased degree of super saturation.the acidic ph can cause maximum incidence of dental caries by dissolution of enamel that occurs when the ph falls below critical ph i.e Buffering capacity The determination of buffering capacity of saliva helps to establish the role of buffer system in tooth integrity. A study done by Hegde and Shetty et al on adult South Indian population showed a positive correlation between dental caries with salivary flow, ph and buffering capacity. The study stated an increase in salivary flow rate which resulted in decreased caries incidence.a study done by 13 Johansson et al and SaelbtromA-K et al stated that decreased buffering capacity caused the demineralization of tooth structure which caused dental caries. 4. Salivary Protein Salivary mucin protects oral tissues and takes part in enamel pellicle formation, enhancing its protective feature. A highrisk of caries prevails if mucin is absent.hence keeping a constant check on salivary protein can identify high risk patients at an e a r l y s t a g e b e f o r e e n a m e l d e n t i n e demineralization sets in and progressing to frank carries. 5. Organic &Inorganic elements The organic and inorganic elements of saliva are significant factors in caries. A large number of salivary substances have direct or indirect role in caries onset. Oral environment has a constant supply of concentrated nitrates, the metabolic product of nitric oxide(no). NO is involved in several inflammatory disorders. Virtually, every cell and many immunological parameters are modulated by NO.Hegde et al's evaluation of nitric oxideas biomarkers in dental caries concluded that nitric oxide levels in saliva acts as a potential biomarker of caries risk in adults. The anti microbial activity of NO show that it is a modulator of bacterial proliferation and suggests a lower caries incidence in adults with increased NO production. The low ph value in oral cavity makes nitrite conversion possible, resulting in autoinhibition of acidogenic bacteria i.e S.mutans. NO expresses its antibacterial effect in two ways- by inhibition of bacterial growth and/or by increase of macrophages-mediated cytotoxicity from saliva. Being a highly reactive radical, it plays a role in nonspecific natural defense mechanism, hence preventing bacterial growth and development. 16 Torell P studied the correlation between Iron and dental caries. Iron ions even in small amounts, when 52

3 Hegde et al brought to the mouth, precipitate on the enamel surface as thin acid resistant coatings containing gels and crystals of hydrous iron oxides. They alsoadsorb salivary calcium and phosphate ions and nucleate to form apatites, thus mediating a replacement of minerals, which have been dissolved 17 during the acid phases of the caries process. 18 Moreover, Shara K et al unveiled in their study that glucosyl transferase (GTF) enzyme from mutans streptococci plays a pivotal role in dental caries and catalyzes the conversion of sucrose. Hydrogen peroxide is bactericidal for oral micro-organisms. In high concentration, hydrogen peroxide inhibits GTF and oral microbes. But, infact, it is very difficult to exclude peroxide in the oral cavity without an inhibitor such as catalase. With the help of iron from supplement which contain ferroussulphate, h y d r o g e n p e r o x i d e c a n b e p r o d u c e d. So, iron are strong inhibitor of the GTF enzyme because can role in inactivating the enzyme that actively participates in dental caries by taking advantage of a Fenton reaction which requires metal ion such as iron or copper and peroxide. Hence it concludes that higher iron levels in saliva fights against mutans streptococci and also has an additive effect on promoting remineralizationof enamel. 6. Immunoglobulins in saliva A largeamount of salivary compounds are produced directly by salivary glands and can hardly be detected in plasma.secretary IgA and lysozyme are present in great amounts in saliva, but less in blood, so they can be considered as originating from saliva. 1 9 A studydone by Hegde et al on salivary immunoglobulins and dental caries concluded that salivary IgA increases with decrease in caries activity and salivary IgG does not show any correlation with dental caries. Major secretory immunoglobulin is salivary IgA. It is the first line of defense of the host against pathogens which invade mucosal surfaces. Oral immunity is improved by salivary IgA antibodies.the infectious nature of dental caries assumes the hypothesis that some form of host immunity can regulate caries activity.if immunity could regulate the caries activity, then salivary IgA might give a clear correlation. 20 Bagherian et al found higher levels of salivary IgA in the saliva of children who were having a low DMFT score. Hence it emphasizes the importance of immunoglobulins in controlling the caries activity 21 in the oral environment. 7. Antioxidants insaliva Free radicals are continuously produced in vivo and there are a number of protective antioxidant enzymes for dealing with these toxic substances. Glutathione peroxidase is one of the free radical 22 scavenger enzymes. Layan et al studied and concluded that glutathione peroxidase catalyzes the reduction of hydro peroxides including hydrogen peroxides by reduced glutathione and functions to protect the cell from oxidative damage. Amerongen 23 et al identified it as body's natural oral defences that may protect against or prevent caries 24 development. Similarly Hegde et al concluded in a study that enzymatic antioxidants increase with caries activity. Myeloperoxidase enzyme activity increased with caries activity in both saliva and serum. Increase inglutathione peroxidase activity with caries has been observed in saliva. Hence saliva can give not only the same information as serum testing, but also additional or new information that cannot be obtained from serum. 25 Hegde et al also studied the effect of total anti oxidants and its correlation with dental caries and concluded that total antioxidant level in saliva increases with caries activity. Oxidative stress which occurs as a result of an imbalance between free radical/reactive oxygen species and antioxidant system has been implicated as one of the important contributory etiologic factors in many of oral 26 inflammatory pathologies and dental caries. Systemic conditions altering Caries balance The above mentioned factors have been found to have significant correlation with dental caries and the alteration in these parameters has been a 3 subject of great interest.mittal et al reviewed thatthe salivary factors like decrease in ph, flow rate, consistency, volume and buffering capacity led to increase dental caries in systemic diseases like diabetes, acquired immunodeficiency syndrome, immunosuppressive patients and patients on radiation therapy. However, the same results were not obtained in children with chronic end stage renal disease patients (Arora et al, Andrade et 27 al) possibly due to their higher salivary urea level in these patients, which buffered the bacterial biofilm in oral cavity before caries initiation and progressive cavitation took place. MAHARAJA KRISHNAKUMARSINHJI BHAVNAGAR UNIVERSITY Vol. 4 Issue-2 May

4 Dental Caries and Renal diseases Several studies show that uremic patients have higher rates of decayed, missing, and filled teeth, loss of attachment, and periapical and mucosal lesions than the general population. The consequences of poor oral health may be more severe in Chronic Kidney Disorder (CKD) patients because of advanced age, common co-morbidities such as diabetes, concurrent medications, and a state of immune dysfunction that may increase the risk for systemic consequences of periodontitis and 28 other oral and dental pathologic conditions. Poor dentition and other signs of poor oral health should be an alarm clock also at early stages of chronic kidney disease. Increased dental calculus has been observed, perhaps as a consequence of a high salivary urea and phosphate levels. Interestingly, however, the antibacterial effect of urea may also be responsible for a lower caries rate as reported in 29 hemodialysis patients (Akar et al) Several studies have shown a significantly worse dental health in uremic patients compared to healthy controls regarding the DMFT index (decayed, missing, filled teeth; Bayraktar et al, 2007; Borawski et al, 2007; Bayraktar et al, 2009). On the other hand, no significant differences in DMFT index have been found among CKD patients in some studies (Bots et al, 2006; Bots et al, 2007; Sobrado Marinho et al, ) Dental Caries and Hypertension 36 Al Samarrai et al reviewed the severity of dental caries among hypertensive patients being similar to healthy adults. However they had lowest value of ph and flow rate with highly significant difference for ph. Patients with high blood pressure experience xerostomia. Overtime if left untreated, Xerostomia will lower the ph within the oral cavity, which will increase the development of plaque and therefore dental caries (Bartels C, 2000). Autoimmune diseasesand Dental Caries 1,2,3 Iwasaki etal showed that autoimmune disease l i ke S j o g re n Sy n d ro m e s h ow i n c re a s e d concentration of sodium and chloride, IgA, IgG, lactoferrin and albumin and a decreased concentration of salivary phosphate levels. The most clinically significant marker in such patients which led to oral symptoms like dental caries, fungal infections, oral pain and dysphagia was due to reduced salivary flow- hyposalivationaka Xerostomia where the oral micro-environment host immunity is altered. Hence acomprehensive salivary evaluation and artificial salivary substitutes is the main stay of their oral health regime. HIV and Dental Caries 37 Hegdeetal'sextensive study on oral health status in acquired immunodeficiency syndrome patients revealed the importance of in-office saliva biomarkers showed significant correlation between the CD4 count with dental caries and salivary parameters like reduced flow, ph and buffering capacity. This also offered distinctive advantage of using safernon-invasive collection method for diagnosis when compared with serum collection and evaluation in sero positive patients. Periodontal Disease and DentalCaries Genetic susceptibility for aggressive periodontal disease can be screened for at an early stage. During active periods of the disease increased levels of inflammatory markers like interleukins, can be demonstrated in saliva. Gornowiczet al studied proinflammatory cytokines like IL-6, IL-8 and TNF-αin saliva of adolescents with dental caries disease and its prevalence had a significant relevance with inflammation in oral cavity which is one of the very 38 first responses of the host to a pathological insult. Conclusion To conclude, although blood is the gold standard for diagnosis of diseases, saliva offers an alternative to serum as a biologic fluid for diagnostic purposes.it is almost certain that next few years will witness an evolving spectrum of salivary screening. Several home andin-office testing kits will begin to appear and saliva will out perform other bio-media in the diagnosis of diseases.by doing so, the dental practice can benefit from enhanced diagnosis, early detection of problems, improved patient communication and motivation and an increased dental awareness for patients. References 1. Deepa T, Thirrunavukkarasu N. Saliva as a potential diagnostic tool. Indian journal of Medical Sciences, v0l 64, no 7, July Ranganath LM, Shet RGK, Rajesh AG. Saliva: A 54

5 Hegde et al powerful diagnostic tool for minimal invasive dentistry. The journal of contemporary dental practice; March-April 20; 13(2): Sanjeev M, Vikram B, Sushant G, Gaurav A, Sanjay B. The diagnostic role of Saliva A Review. J ClinExp Dent. 2011;3 (4):e Eliaz Kaufman, Ira B. Lamster. The diagnostic applications of saliva A review. Crit Rev Oral Biol Med. 13(2):197-2 (2002). 5. Cynthia P, Trajtenberg, Juliana A et al. Salivary flow rates, per se, may not serve as consistent predictors for dental caries. Open Journal of Stomatology, 2013, 3, Walsh NP, Laing SJ, Oliver SJ, Montague JC, Walters R, Bilzon JLJ. Saliva parameters as potential indices of hydration status during acute dehydration. Med Sci Sports Exerc 2004: Hu S, Denny P. differentially expressed protein markers in human submandibular and s u b l i n g u a l s e c re t i o n s. I n t J O n c o l 2004;25: Edgar WM. Saliva: its secretion, composition and functions. Br Dent J 1992; 172: Chiappin S, Antonelli G, Gatti R, Elio F et al. Saliva specimen:a new laboratory tool for diagnostic and basic investigation. ClinicaChimica Act 383 (2007) Gopinath V.K, Arzreanne A.R. Saliva as a diagnostic tool for assessment of dental caries. Archives of Orofacial Sciences 2006; 1: Lenander-Lumikari M, Loimaranta V. Saliva and dental caries.adv Dent Res Dec;14:40-7. Chitharanjan Shetty, Mithra N Hegde, DarshanaDevadiga. Correlation between dental caries with salivary flow, ph and buffering capacity in adult South Indian Population.Int. J.Res.Ayurveda Pharm. 4 (2) March-April Johansson I, Saellstrom AK, Rajan BP, Parameswaram A. Salivary flow and dental caries in Indian children suffering from chronic malnutrition. Caries Research,1992, 26: Mithra N. Hegde, Suchetha Kumari, Nidarsh Hegde, Shilpa Shetty, Nireeksha. Evaluation of the status of salivary nitric oxide in patients with dental caries.nitte University Journal of Health Science. NUJHS Vol. 2, No.2, June 20, ISSN Bayindis Y.Z, Polat M.F, Seven N. Nitric Oxide Concentrations in Saliva and Dental Plaque in relation to caries experience and oral hygiene. Caries research 2005; 39: Torell P. Iron and Dental Caries. Swed Dent J. 1988(3) F l i n k H, t e g e l b e r g A, S o r e n s e n S. Hyposalivation and iron stores among individuals with and without active dental caries. ActaOdontol Scand Dec; 58(6): Shara Ket al. The Role of Iron on Initiation of Dental Caries.Feb 20MediaShara. 19. M i t h ra H e g d e, D a r s h a n a D eva d i ga, Chitharanjan Shetty, Aditya Shetty. Correlation between dental caries and salivary immunoglobulin in adult Indian population :an in vitro study. Journal of Restorative Dentistry.Vol 1. Issue 1. Jan-April Bagheran A, Jafarzadeh A, Rezaeian M, Ahmedi S, Razaity MT. Comparison of the salivary immunoglobulin concentration levels between children with early childhood caries and caries-free children. Iran J Immunol 2008;5: Everhart D.L, Grigsby W R, Carter W.H. Evaluation of Dental Caries Experience and Salivary Immunoglobulins in Whole Saliva. J Dent Res September-October Layan, Miloglu O., Altun O., Erel O., Yılmaz A.b., Oxidative Stress and Myeloperoxidase Levels in Saliva of Patients With Recurrent Aphthous Stomatitis. Oral Diseases. 14, Amerongen AVN, Bolscher JGM, Veerman ECI. Caries Research 2004; 38: Mithra N Hegde, Suchetha Kumari, Nidarsh D. 55

6 Hegde, Shilpa. S. Shetty. Myeloperoxidase and Glutathione Peroxidase Activity of Saliva and Serum in Adults with Dental Caries: A Comparative Study. The Journal of Free Radicals and Antioxidants. Photon 139 (2013) Mithra N Hegde, Suchetha Kumari, Nidarsh Hegde, AnuMoany. Correlation between Total Antioxidant Level and Dental Caries in Adults - an In vivo Study. RJPBCS. Volume 2 Issue 4 Page No October December Dipanshu kumar, Ramesh Pandey, Deepti Agrawal, Deepa Agrawal. An estimation and evaluation of total antioxidant capacity of saliva in children with severe early childhood caries.internal Journal of Paediatric Dentistry 2011, Ruchi Arora and Bhumi Sarvaiya. Estimation of Salivary urea levels and its relation with dental caries in children with chronic renal failure. Journal of Oral Health Research, Volume 1, Issue 2, April Silvia Martí Álamo, Carmen Gavaldá Esteve, M Gracia Sarrión Pérez. Dental considerations for the patient with renal disease. J ClinExp Dent. 2011;3(2):e HarunAkar, Gulcan Coskun Akar, Juan Jesu s Carrero, Peter Stenvinkel, and Bengt Lindholm. Systemic Consequences of poor oral health in chronic kidney disease patients.clin J Am SocNephrol 6: , Bayraktar G, Kurtulus I, Duraduryan A, Cintan S, Kazaneioglu R, Yildiz A, Bural C, Bazfakioglu S, Besler M, Trablu S, Issever H. Dental and periodontal finding in hemodialysis patients. Oral Dis 2001; 13: Borawski J, Wilczynska-Borawska M, Stokowska W, Mysliwiec M. The periodontal status of pre-dialysis chronic kidney disease and maintenance dialysis patients.nephrol Dial Transplant 2007;22: Bayraktar G, Kurtulur I, Kazancioglu R, Bayramgurler I, Cintan S, Bural C, Bozfakioglu S, Issever H, Yildiz A. Oral health and inflammation in patients with end stage renal failure. Perit Dial Int 2009;29: Bots CP, Poorterman JH, Brand HS, Kalsbeek H, v a n A m e r o n g e n B M, Ve e r m a n E C, NieuwAmerongen AV. The oral health status of dentate patients with chronic renal failure undergoing dialysis therapy. Oral Dis 2006;: Bots CP, Brand HS, Poorterman JH, van Amerongen BM, Valentijn-Benz M, Veerman EC, ter Wee PM, NieuwAmerongen AV. Oral and salivary changes in patients with end stage renal disease (ESRD): a two year followup study. Br Dent J 2007;27:202:E Sobrado Marinho JS, Tomás Carmona I, Loureiro A, Limeres Posse J, García Caballero L, Diz Dios P. Oral health status in patients with moderate, severe and terminal renal failure. Med Oral Patol Oral Cir Bucal 2007;: Sulafa Al-Samarrai. Dental caries in relation to salivary parameters among hypertensive p a t i e n t s i n c o m p a r i s o n to h e a l t hy individuals.j Bagh College Dentistry. Vol , Mithra N. Hegde,Nidarsh D. Hegde, Amit Malhotra. Prevalence of oral lesions in HIV infected adult population of Mangalore, Karnataka, India. Journal of BioDiscovery, October 20 Issue Gornowicz A, Bielawska A, Bielawski K, Grabowska Z S, Wojcicka A, Zalewska M, Macriokowska E. Pro-inflammatory cytokines in saliva of adolescents with dental caries disease. Annals of Agricultural and Environmental Medicine 20, Vol 19, No 4, ) Source of Support : Conflict of Interest : Date of Submission : Review Completed : NIL NOT DECLARED