Early detection of disease plays a crucial role for treatment planning and prognosis. Saliva has great potential as a diagnostic fluid and offers advantage over serum and other biological fluids by an economic and noninvasive collection method for monitoring of systemic health and disease progression. The plethora of components in this fluid can act as biomarkers for diagnosis of various systemic and local diseases. In this review paper, we have emphasized the role of salivary biomarkers as diagnostic tools. 1. Introduction Human diseases having global impact include cancer, cardiovascular, metabolic, and neurological diseases. Diagnosing these disease conditions is becoming challenging and thus requires supplementing clinical evaluation with laboratory testing [1]. Salivary diagnostics holds great promise as an effective modality for the early diagnosis, prognostication, and monitoring posttherapy status. Whole saliva is a mixture of the secretions of the major and minor salivary glands, mucosal transudations, gingival crevicular fluid, serum and blood derivatives from oral wounds, desquamated epithelial cells, expectorated bronchial and nasal secretions, bacteria and bacterial products, viruses and fungi,other cellular components, and food debris. It is a complex fluid containing an entire library of hormones, proteins, enzymes, antibodies, antimicrobial constituents, and cytokines [2]. The mechanism of entry of these constituents from the blood into the saliva is by transcellular, passive intracellular diffusion and active transport, or paracellular routes by extracellular ultrafiltration within the salivary glands or through the gingival crevice [3, 4]. The many advantages of saliva as a clinical tool over serum and tissues are noninvasive collection of sample, smaller sample aliquots, good cooperation with patients, cost effectiveness, easy storage and transportation, greater sensitivity, and correlation with levels in blood. Promising new technologies have unveiled large numbers of medically valuable salivary biomarkers for different disease conditions including cancer, autoimmune, viral, bacterial, cardiovascular, and metabolic diseases [2]. 2. Potential Biomarkers in Saliva The wide spectrum of molecules present in saliva provides valuable information for clinical diagnostic applications (Figure 1). Whole saliva is most frequently used for diagnosis of systemic diseases, because it can be easily collected and it contains most of the serum constituents. Salivary diagnostics can be used for the following diseases/conditions (Figure 2) [4]. Figure
References
[1]
Y.-H. Lee and D. T. Wong, “Saliva: an emerging biofluid for early detection of diseases,” American Journal of Dentistry, vol. 22, no. 4, pp. 241–248, 2009.
[2]
T. Pfaffe, J. Cooper-White, P. Beyerlein, K. Kostner, and C. Punyadeera, “Diagnostic potential of saliva: current state and future applications,” Clinical Chemistry, vol. 57, no. 5, pp. 675–687, 2011.
[3]
J. M. Lee, E. Garon, and D. T. Wong, “Salivary diagnostics,” Orthodontics and Craniofacial Research, vol. 12, no. 3, pp. 206–211, 2009.
[4]
S. Mittal, V. Bansal, S. Garg, G. Atreja, and S. Bansal, “The diagnostic role of Saliva—a review,” Journal of Clinical and Experimental Dentistry, vol. 3, no. 4, pp. e314–e320, 2011.
[5]
D. Malamud, “Saliva as a diagnostic fluid,” Dental Clinics of North America, vol. 55, no. 1, pp. 159–178, 2011.
[6]
M. Greabu, M. Battino, M. Mohora et al., “Saliva—a diagnostic window to the body, both in health and in disease,” Journal of Medicine and Life, vol. 2, no. 2, pp. 124–132, 2009.
[7]
F. Ahmadi Motamayel, P. Davoodi, M. Dalband, and S. S. Hendi, “Saliva as a mirror of the body health,” DJH Journal, vol. 1, no. 2, pp. 1–15, 2010.
[8]
K. D. Bhoola, M. W. McNicol, S. Oliver, and J. Foran, “Changes in salivary enzymes in patients with sarcoidosis,” The New England Journal of Medicine, vol. 281, no. 16, pp. 877–879, 1969.
[9]
J. W. McGehee Jr. and R. B. Johnson, “Biomarkers of bone turnover can be assayed from human Saliva,” Journals of Gerontology A, vol. 59, no. 3, pp. 196–200, 2004.
[10]
F. A. Scannapieco, P. Ng, K. Hovey, E. Hausmann, A. Hutson, and J. Wactawski-Wende, “Salivary biomarkers associated with alveolar bone loss,” Annals of the New York Academy of Sciences, vol. 1098, pp. 496–497, 2007.
[11]
P. N. Floriano, N. Christodoulides, C. S. Miller et al., “Use of saliva-based nano-biochip tests for acute myocardial infarction at the point of care: a feasibility study,” Clinical Chemistry, vol. 55, no. 8, pp. 1530–1538, 2009.
[12]
C. S. Miller, J. D. Foley, A. L. Bailey et al., “Current developments in salivary diagnostics,” Biomarkers in Medicine, vol. 4, no. 1, pp. 171–189, 2010.
[13]
M. Qvarnstrom, S. Janket, J. A. Jones et al., “Salivary lysozyme and prevalent hypertension,” Journal of Dental Research, vol. 87, no. 5, pp. 480–484, 2008.
[14]
S.-J. Janket, J. H. Meurman, P. Nuutinen et al., “Salivary lysozyme and prevalent coronary heart disease: possible effects of oral health on endothelial dysfunction,” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 26, no. 2, pp. 433–434, 2006.
[15]
A. Totan, M. Greabu, C. Totan, and T. Spinu, “Salivary aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase: possible markers in periodontal diseases?” Clinical Chemistry and Laboratory Medicine, vol. 44, no. 5, pp. 612–615, 2006.
[16]
H. H. Chan, Z. H. A. Rahim, K. Jessie, O. H. Hashim, and T. B. Taiyeb-Ali, “Salivary proteins associated with periodontitis in patients with type 2 diabetes mellitus,” International Journal of Molecular Sciences, vol. 13, no. 4, pp. 4652–4654, 2012.
[17]
H. Raff, “Utility of salivary cortisol measurements in Cushing's syndrome and adrenal insufficiency,” Journal of Clinical Endocrinology and Metabolism, vol. 94, no. 10, pp. 3647–3655, 2009.
[18]
O. H. Drummer, “Drug testing in oral fluid,” The Clinical Biochemist Reviews, vol. 27, no. 3, pp. 147–159, 2006.
[19]
E. J. Cone and M. A. Huestis, “Interpretation of oral fluid tests for drugs of abuse,” Annals of the New York Academy of Sciences, vol. 1098, pp. 51–103, 2007.
[20]
V. C. Figueiredo, M. Szklo, A. S. Szklo et al., “Determinants of salivary cotinine level: a population-based study in Brazil,” Revista de Saude Publica, vol. 41, no. 6, pp. 954–962, 2007.
[21]
T. Guinan, M. Ronci, H. Kobus, and N. H. Voelcker, “Rapid detection of illicit drugs in neat saliva using desorption/ionization on porous silicon,” Talanta, vol. 99, pp. 791–798, 2012.
[22]
G. de Paoli, K. M. Walker, and D. J. Pounder, “Endogenous γ-hydroxybutyric acid concentrations in saliva determined by gas chromatography-mass spectrometry,” Journal of Analytical Toxicology, vol. 35, no. 3, pp. 148–152, 2011.
[23]
D. Sweet and D. Hildebrand, “Saliva from cheese bite yields DNA profile of burglar: a case report,” International Journal of Legal Medicine, vol. 112, no. 3, pp. 201–203, 1999.
[24]
N. Kamodyova, J. Durdiakova, P. Celec et al., “Prevalence and persistence of male DNA identified in mixed saliva samples after intense kissing,” Forensic Science International, vol. 7, no. 1, pp. 124–128, 2013.
[25]
A. Minarowska, “The activity of cathepsin D in saliva of cystic fibrosis patients,” Folia Histochemica et Cytobiologica, vol. 45, no. 3, pp. 165–168, 2007.
[26]
A. C. Gon？alves, F. A. Marson, R. M. Mendon？a et al., “Saliva as a potential tool for cystic fibrosis diagnosis,” Diagnostic Pathology, vol. 8, p. 46, 2013.
[27]
M. O. Lexner, A. Bardow, J. Michael Hertz, L. Almer, B. Nauntofte, and S. Kreiborg, “Whole saliva in X-linked hypohidrotic ectodermal dysplasia,” International Journal of Paediatric Dentistry, vol. 17, no. 3, pp. 155–162, 2007.
[28]
S. A. Oliveira, M. M. Siqueira, D. W. G. Brown, L. A. B. Camacho, T. Faillace, and B. J. Cohen, “Salivary diagnosis of measles for surveillance: A clinic-based study in Niteroi, state of Rio de Janeiro, Brazil,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 92, no. 6, pp. 636–638, 1998.
[29]
K. P. Delaney, B. M. Branson, A. Uniyal et al., “Evaluation of the performance characteristics of 6 rapid HIV antibody tests,” Clinical Infectious Diseases, vol. 52, no. 2, pp. 257–263, 2011.
[30]
P. L. Corstjens, W. R. Abrams, and D. Malamud, “Detecting viruses by using salivary diagnostics,” The Journal of the American Dental Association, vol. 143, no. 1012S, 18S pages, 2012.
[31]
J. Eguchi, K. Ishihara, A. Watanabe, Y. Fukumoto, and K. Okuda, “PCR method is essential for detecting Mycobacterium tuberculosis in oral cavity samples,” Oral Microbiology and Immunology, vol. 18, no. 3, pp. 156–159, 2003.
[32]
D. G. Silva, R. H. Stevens, J. M. B. Macedo et al., “Higher levels of salivary MUC5B and MUC7 in individuals with gastric diseases who harbor Helicobacter pylori,” Archives of Oral Biology, vol. 54, no. 1, pp. 86–90, 2009.
[33]
S. Kabir, “Detection of helicobacter pylori DNA in feces and Saliva by polymerase chain reaction: a review,” Helicobacter, vol. 9, no. 2, pp. 115–123, 2004.
[34]
O. J. Bergmann, “The demonstration of candidal pseudohyphae in salivary smears as a method of early diagnosis of oral candidiasis in patients with acute myeloid leukemia,” Oral Microbiology and Immunology, vol. 11, no. 5, pp. 362–364, 1996.
[35]
G. Liguori, A. Lucariello, G. Colella, A. de Luca, and P. Marinelli, “Rapid identification of Candida species in oral rinse solutions by PCR,” Journal of Clinical Pathology, vol. 60, no. 9, pp. 1035–1039, 2007.
[36]
H. Tang, Z. Wu, J. Zhang, and B. Su Salivary, “lncRNA as a potential marker for oral squamous cell carcinoma diagnosis,” Molecular Medicine Reports, vol. 7, no. 3, pp. 761–766, 2013.
[37]
J. M. Yoshizawa and D. T. W. Wong, “Salivary microRNAs and oral cancer detection,” Methods in Molecular Biology, vol. 936, pp. 313–324, 2013.
[38]
L. Zhang, H. Xiao, H. Zhou et al., “Development of transcriptomic biomarker signature in human saliva to detect lung cancer,” Cellular and Molecular Life Sciences, vol. 69, no. 19, pp. 3341–3350, 2012.
[39]
Y.-H. Lee, J. H. Kim, H. Zhou, B. W. Kim, and D. T. Wong, “Salivary transcriptomic biomarkers for detection of ovarian cancer: for serous papillary adenocarcinoma,” Journal of Molecular Medicine, vol. 90, no. 4, pp. 427–434, 2012.
[40]
S. Warnakulasuriya, T. Soussi, R. Maher, N. Johnson, and M. Tavassoli, “Expression of p53 in oral squamous cell carcinoma is associated with the presence of IgG and IgA p53 autoantibodies in sera and saliva of the patients,” The Journal of Pathology, vol. 192, pp. 52–57, 2000.
[41]
F. Agha-Hosseini, I. Mirzaii-Dizgah, and A. Rahimi, “Correlation of serum and salivary CA15-3 levels in patients with breast cancer,” Medicina Oral, Patologia Oral y Cirugia Bucal, vol. 14, no. 10, pp. e521–e524, 2009.
[42]
C. Streckfus, L. Bigler, T. Dellinger, X. Dai, A. Kingman, and J. T. Thigpen, “The presence of soluble c-erbB-2 in saliva and serum among women with breast carcinoma: a preliminary study,” Clinical Cancer Research, vol. 6, no. 6, pp. 2363–2370, 2000.
[43]
J. J. Balan, R. S. Rao, B. R. Premalatha, and S. Patil, “Analysis of tumor markers CA 125 in saliva of normal and oral squamous cell carcinoma patients: a comparative study,” The Journal of Contemporary Dental Practice, vol. 13, no. 5, pp. 671–675, 2012.
[44]
Y.-Q. Huang, Y.-D. Li, G.-K. Li, Z. Jin, and J. Ma, “The evaluation of basic fibroblast growth factor and fibroblastic growth factor receptor 1 levels in saliva and serum of patients with salivary gland tumor,” DNA and Cell Biology, vol. 31, no. 4, pp. 520–523, 2012.
[45]
N. Shiiki, S. Tokuyama, C. Sato et al., “Association between saliva PSA and serum PSA in conditions with prostate adenocarcinoma,” Biomarkers, vol. 16, no. 6, pp. 498–503, 2011.
[46]
D. G. Bernabe, A. C. Tamae, G. I. Miyahara, M. L. Sundefeld, S. P. Oliveira, and E. R. Biasoli, “Increased plasma and salivary cortisol levels in patients with oral cancer and their association with clinical stage,” Journal of Clinical Pathology, vol. 65, no. 10, pp. 934–939, 2012.
[47]
S. R. Shetty, R. Chadha, S. Babu, S. Kumari, S. Bhat, and S. Achalli, “Salivary lactate dehydrogenase levels in oral leukoplakia and oral squamous cell carcinoma: a biochemical and clinicopathological study,” Journal of Cancer Research and Therapeutics, vol. 8, no. 2, pp. S123–S125, 2012.
[48]
B. Rai, J. Kaur, R. Jacobs, and S. C. Anand, “Adenosine deaminase in saliva as a diagnostic marker of squamous cell carcinoma of tongue,” Clinical Oral Investigations, vol. 15, no. 3, pp. 347–349, 2011.
[49]
D. S.-Q. Koh and G. C.-H. Koh, “The use of salivary biomarkers in occupational and environmental medicine,” Occupational and Environmental Medicine, vol. 64, no. 3, pp. 202–210, 2007.
[50]
L. Gervais, Y. Lacasse, J. Brodeur, and A. P'an, “Presence of cadmium in the saliva of adult male workers,” Toxicology Letters, vol. 8, no. 1-2, pp. 63–66, 1981.
[51]
F. Barbosa Jr., M. H. Corrêa Rodrigues, M. R. Buzalaf, F. J. Krug, R. F. Gerlach, and J. E. Tanus-Santos, “Evaluation of the use of salivary lead levels as a surrogate of blood lead or plasma lead levels in lead exposed subjects,” Archives of Toxicology, vol. 80, no. 10, pp. 633–637, 2006.
[52]
T. K. Fabian, J. Gaspar, L. Fejerdy et al., “Hsp70 is present in human saliva,” Medical Science Monitor, vol. 9, pp. BR62–BR65, 2003.
[53]
J. M. Dabbs Jr., “Salivary testosterone measurements in behavioral studies,” Annals of the New York Academy of Sciences, vol. 694, pp. 177–183, 1993.
[54]
A. L. Arregger, E. M. L. Cardoso, O. Tumilasci, and L. N. Contreras, “Diagnostic value of salivary cortisol in end stage renal disease,” Steroids, vol. 73, no. 1, pp. 77–82, 2008.
[55]
R. M. Nagler, “Saliva analysis for monitoring dialysis and renal function,” Clinical Chemistry, vol. 54, no. 9, pp. 1415–1417, 2008.
[56]
V. Savica, L. Calò, D. Santoro, P. Monardo, A. Granata, and G. Bellinghieri, “Salivary phosphate secretion in chronic kidney disease,” Journal of Renal Nutrition, vol. 18, no. 1, pp. 87–90, 2008.
