Clinical and diagnostic utility of saliva as a non-invasive diagnostic fluid:
a systematic review

This systematic review presents the latest trends in salivary research and its applications in health and disease. Among the large number of analytes present in saliva, many are affected by diverse physiological and pathological conditions. Further, the non-invasive, easy and cost-effective collection methods prompt an interest in evaluating its diagnostic or prognostic utility. Accumulating data over the past two decades indicates towards the possible utility of saliva to monitor overall health, diagnose and treat various oral or systemic disorders and drug monitoring. Advances in saliva based systems biology has also contributed towards identification of several biomarkers, development of diverse salivary diagnostic kits and other sensitive analytical techniques. However, its utilization should be carefully evaluated in relation to standardization of pre-analytical and analytical variables, such as collection and storage methods, analyte circadian variation, sample recovery, prevention of sample contamination and analytical procedures. In spite of all these challenges, there is an escalating evolution of knowledge with the use of this biological matrix.

[1]  M. Dharmalingam,et al.  Salivary glucose and antioxidant defense markers in type II diabetes mellitus. , 2015, Turkish journal of medical sciences.

[2]  S. Hegde,et al.  Salivary pH And Salivary Level of Streptococcus Mutans in Beta Thalassemia Major Patients , 2015 .

[3]  Anne L. Wyllie,et al.  Streptococcus pneumoniae in Saliva of Dutch Primary School Children , 2014, PloS one.

[4]  G. Tokajuk,et al.  The assessment of sIgA, histatin-5, and lactoperoxidase levels in saliva of adolescents with dental caries , 2014, Medical science monitor : international medical journal of experimental and clinical research.

[5]  M. Cugini,et al.  Metabolic Disease Risk in Children by Salivary Biomarker Analysis , 2014, PloS one.

[6]  D. Wong,et al.  Salivary Biomarkers for Detection of Oral Squamous Cell Carcinoma: Current State and Recent Advances , 2014, Current Oral Health Reports.

[7]  E. Reichenberger,et al.  Saliva as a source of genomic DNA for genetic studies: review of current methods and applications. , 2014, Oral health and dental management.

[8]  David E. Bruns Carl A. Burtis Tietz Fundamentals of Clinical Chemistry and Molecular Diagnostics , 2014 .

[9]  Wei Ma,et al.  Introducing rapid oral–fluid HIV testing among high risk populations in Shandong, China: feasibility and challenges , 2014, BMC Public Health.

[10]  Nirima Oza,et al.  Salivary Creatinine Estimation as an Alternative to Serum Creatinine in Chronic Kidney Disease Patients , 2014, International journal of nephrology.

[11]  S. RaviBanavar Diagnostic efficacy of saliva for dengue - a reality in near future? A piloting initiative. , 2014 .

[12]  Y. Duan,et al.  Measurement of salivary metabolite biomarkers for early monitoring of oral cancer with ultra performance liquid chromatography-mass spectrometry. , 2014, Talanta.

[13]  N. Malathi,et al.  Salivary Diagnostics: A Brief Review , 2014, ISRN dentistry.

[14]  Yousef Rezaei Chianeh,et al.  Biochemical markers in saliva of patients with oral squamous cell carcinoma , 2014 .

[15]  Y. Duan,et al.  Investigation and identification of potential biomarkers in human saliva for the early diagnosis of oral squamous cell carcinoma. , 2014, Clinica chimica acta; international journal of clinical chemistry.

[16]  Spoorthi Ravi Banavar,et al.  Diagnostic efficacy of saliva for dengue - a reality in near future? A piloting initiative. , 2014, Journal of clinical and diagnostic research : JCDR.

[17]  A. Gessain,et al.  Viral Latency in Blood and Saliva of Simian Foamy Virus-Infected Humans , 2013, PloS one.

[18]  D. V. Macedo,et al.  Saliva as a diagnostic fluid in sports medicine: potential and limitations , 2013 .

[19]  J. Ribeiro,et al.  Saliva as a potential tool for cystic fibrosis diagnosis , 2013, Diagnostic Pathology.

[20]  P. Patsalos,et al.  Therapeutic Drug Monitoring of Antiepileptic Drugs by Use of Saliva , 2013, Therapeutic drug monitoring.

[21]  M. Shirzaii,et al.  EVALUATION CHEMICAL COMPOSITION OF UNSTIMULATED SALIVA, IN PATIENTS WITH TYPE I DIABETES MELLITUS , 2013 .

[22]  K. Boaz Micronuclei and sialic acid as markers of genotoxic damage in tobacco-related oral lesions , 2013 .

[23]  W. Inder,et al.  Measurement of salivary cortisol in 2012 – laboratory techniques and clinical indications , 2012, Clinical endocrinology.

[24]  E. Franchini,et al.  Salivary Cortisol and Immunoglobulin A Responses to Simulated and Official Jiu-Jitsu Matches , 2012, Journal of strength and conditioning research.

[25]  Yixiang Duan,et al.  Saliva: a potential media for disease diagnostics and monitoring. , 2012, Oral oncology.

[26]  David Elashoff,et al.  Development of transcriptomic biomarker signature in human saliva to detect lung cancer , 2012, Cellular and Molecular Life Sciences.

[27]  António S. Barros,et al.  Salivary peptidome in type 1 diabetes mellitus. , 2012, Biomedical chromatography : BMC.

[28]  Derek G Rodeback,et al.  Salivary uric acid as a noninvasive biomarker of metabolic syndrome , 2012, Diabetology & Metabolic Syndrome.

[29]  R. Brenzikofer,et al.  Reference intervals for saliva analytes collected by a standardized method in a physically active population. , 2011, Clinical biochemistry.

[30]  C. Fanali,et al.  Potential applications of human saliva as diagnostic fluid , 2011, Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale.

[31]  Jae Hoon Kim,et al.  Salivary transcriptomic biomarkers for detection of ovarian cancer: for serous papillary adenocarcinoma , 2011, Journal of Molecular Medicine.

[32]  S. Saxena Assessment of plasma and salivary antioxidant status in patients with recurrent aphthous stomatitis , 2011 .

[33]  George P Nassis,et al.  Saliva as a tool for monitoring steroid, peptide and immune markers in sport and exercise science. , 2011, Journal of science and medicine in sport.

[34]  E. D. Geus,et al.  α-Amylase as a reliable and convenient measure of sympathetic activity: don’t start salivating just yet! , 2011, Psychoneuroendocrinology.

[35]  C. Fanali,et al.  Proteomics of saliva: personal experience. , 2010, Acta otorhinolaryngologica Italica : organo ufficiale della Societa italiana di otorinolaringologia e chirurgia cervico-facciale.

[36]  R. Shenoy,et al.  Alternative markers of glycemic status in diabetes mellitus , 2010 .

[37]  U. Nater,et al.  Salivary alpha-amylase as a non-invasive biomarker for the sympathetic nervous system: Current state of research , 2009, Psychoneuroendocrinology.

[38]  Surendra Dasari,et al.  Proteomic identification of salivary biomarkers of type-2 diabetes. , 2009, Journal of proteome research.

[39]  A. Arregger,et al.  Assessment of salivary urea as a less invasive alternative to serum determinations , 2009, Scandinavian journal of clinical and laboratory investigation.

[40]  M. Välimäki,et al.  Determination of salivary cortisol by liquid chromatography-tandem mass spectrometry , 2009, Scandinavian journal of clinical and laboratory investigation.

[41]  M. Gröschl Current status of salivary hormone analysis. , 2008, Clinical chemistry.

[42]  K. Hallikeri,et al.  Evaluation of salivary sialic acid, total protein, and total sugar in oral cancer: a preliminary report. , 2008, Indian journal of dental research : official publication of Indian Society for Dental Research.

[43]  David Elashoff,et al.  Salivary Proteomics for Oral Cancer Biomarker Discovery , 2008, Clinical Cancer Research.

[44]  R. Stauber,et al.  Reliable detection and quantitation of viral nucleic acids in oral fluid: Liquid phase‐based sample collection in conjunction with automated and standardized molecular assays , 2008, Journal of medical virology.

[45]  Timothy M. Blicharz,et al.  Use of colorimetric test strips for monitoring the effect of hemodialysis on salivary nitrite and uric acid in patients with end-stage renal disease: a proof of principle. , 2008, Clinical chemistry.

[46]  M. Rauh,et al.  Evaluation of saliva collection devices for the analysis of steroids, peptides and therapeutic drugs. , 2008, Journal of pharmaceutical and biomedical analysis.

[47]  K. Asano,et al.  A novel assay system for myeloperoxidase activity in whole saliva. , 2008, Clinical biochemistry.

[48]  John R Yates,et al.  The proteomes of human parotid and submandibular/sublingual gland salivas collected as the ductal secretions. , 2008, Journal of proteome research.

[49]  Paul D. Williams,et al.  Data mining in genomics. , 2008, Clinics in laboratory medicine.

[50]  P. Csermely,et al.  Salivary Genomics, Transcriptomics and Proteomics: The Emerging Concept of the Oral Ecosystem and their Use in the Early Diagnosis of Cancer and other Diseases , 2008, Current genomics.

[51]  Roger Persson,et al.  Sources of biological and methodological variation in salivary cortisol and their impact on measurement among healthy adults: A review , 2008, Scandinavian journal of clinical and laboratory investigation.

[52]  R. Raggam,et al.  Evaluation of a novel standardized system for collection and quantification of oral fluid , 2008, Clinical chemistry and laboratory medicine.

[53]  P. D. Dios,et al.  Relationship between lactate dehydrogenase activity in saliva and oral health status , 2007 .

[54]  T. Ebbels,et al.  Metabolic profiling, metabolomic and metabonomic procedures for NMR spectroscopy of urine, plasma, serum and tissue extracts , 2007, Nature Protocols.

[55]  Giorgia Antonelli,et al.  Saliva specimen: a new laboratory tool for diagnostic and basic investigation. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[56]  B. Rai,et al.  Salivary vitamins E and C in oral cancer , 2007, Redox report : communications in free radical research.

[57]  H. Nagata,et al.  Longitudinal study of the association between smoking as a periodontitis risk and salivary biomarkers related to periodontitis. , 2007, Journal of periodontology.

[58]  Tiedong Guo,et al.  Determination of levetiracetam in human plasma/serum/saliva by liquid chromatography-electrospray tandem mass spectrometry. , 2007, Clinica chimica acta; international journal of clinical chemistry.

[59]  P. Diz Dios,et al.  Relationship between lactate dehydrogenase activity in saliva and oral health status. , 2007, Archives of oral biology.

[60]  C. Arana,et al.  Parameters of oxidative stress in saliva from diabetic and parenteral drug addict patients. , 2006, Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology.

[61]  C. Delporte,et al.  Distribution and roles of aquaporins in salivary glands. , 2006, Biochimica et biophysica acta.

[62]  C. Llena-Puy The rôle of saliva in maintaining oral health and as an aid to diagnosis. , 2006, Medicina oral, patologia oral y cirugia bucal.

[63]  E. McPherson Genetic diagnosis and testing in clinical practice. , 2006, Clinical medicine & research.

[64]  R. L. Marca,et al.  Stress-induced changes in human salivary alpha-amylase activity—associations with adrenergic activity , 2006, Psychoneuroendocrinology.

[65]  A. Young,et al.  Assessing cortisol and dehydroepiandrosterone (DHEA) in saliva: effects of collection method , 2006, Journal of psychopharmacology.

[66]  Ting Wu,et al.  Determination of uric acid and p-aminohippuric acid in human saliva and urine using capillary electrophoresis with electrochemical detection: potential application in fast diagnosis of renal disease. , 2005, Journal of chromatography. B, Analytical technologies in the biomedical and life sciences.

[67]  M. Posner,et al.  The salivary microbiota as a diagnostic indicator of oral cancer: A descriptive, non-randomized study of cancer-free and oral squamous cell carcinoma subjects , 2005, Journal of Translational Medicine.

[68]  L. Martens,et al.  Review: The physiology of saliva and transfer of drugs into saliva. , 2005, Forensic science international.

[69]  Y Li,et al.  The Oral Fluid MEMS/NEMS Chip (OFMNC): Diagnostic & Translational Applications , 2005, Advances in dental research.

[70]  K. Carraway,et al.  Salivary Soluble CD44: A Potential Molecular Marker for Head and Neck Cancer , 2005, Cancer Epidemiology Biomarkers & Prevention.

[71]  John T McDevitt,et al.  Application of microchip assay system for the measurement of C-reactive protein in human saliva. , 2005, Lab on a chip.

[72]  Chun-Ming Huang,et al.  Comparative proteomic analysis of human whole saliva. , 2004, Archives of oral biology.

[73]  G. Mcgarry,et al.  Production of gender-specific morning salivary cortisol reference intervals using internationally accepted procedures , 2004, Clinical chemistry and laboratory medicine.

[74]  Alan Booth,et al.  The “trouble” with salivary testosterone , 2004, Psychoneuroendocrinology.

[75]  E. Veerman,et al.  Salivary Proteins: Protective and Diagnostic Value in Cariology? , 2004, Caries Research.

[76]  D. Koh,et al.  Effects of storage time on stability of salivary immunoglobulin A and lysozyme. , 2003, Clinica chimica acta; international journal of clinical chemistry.

[77]  J. M. Christensen,et al.  Evaluation of a radioimmunoassay and establishment of a reference interval for salivary cortisol in healthy subjects in Denmark , 2003, Scandinavian journal of clinical and laboratory investigation.

[78]  I. Lamster,et al.  The diagnostic applications of saliva--a review. , 2002, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[79]  R. Nagler,et al.  Characterization of the differentiated antioxidant profile of human saliva. , 2002, Free radical biology & medicine.

[80]  P. Mills,et al.  Catecholamines in human saliva. , 2001, Life sciences.

[81]  S. Humphrey,et al.  A review of saliva: normal composition, flow, and function. , 2001, The Journal of prosthetic dentistry.

[82]  E. Shirtcliff,et al.  Use of salivary biomarkers in biobehavioral research: cotton-based sample collection methods can interfere with salivary immunoassay results , 2001, Psychoneuroendocrinology.

[83]  G. Csako,et al.  Biochemical Composition and Electrolyte Balance of "Unstimulated" Whole Human Saliva , 2000, Clinical chemistry and laboratory medicine.

[84]  Margarita Pérez,et al.  Saliva Composition and Exercise , 1998, Sports medicine.

[85]  Brian Owen-Smith,et al.  Salivary urate in gout, exercise, and diurnal variation , 1998, The Lancet.

[86]  H. Mantsch,et al.  Thiocyanate levels in human saliva: quantitation by Fourier transform infrared spectroscopy. , 1996, Analytical biochemistry.

[87]  J. Parry,et al.  Detection of measles, mumps, and rubella antibodies in saliva using antibody capture radioimmunoassay , 1993, Journal of medical virology.

[88]  M. Levine,et al.  Salivary α-Amylase: Role in Dental Plaque and Caries Formation , 1993 .

[89]  M. Levine,et al.  Salivary alpha-amylase: role in dental plaque and caries formation. , 1993, Critical reviews in oral biology and medicine : an official publication of the American Association of Oral Biologists.

[90]  D. Malamud,et al.  Saliva as a diagnostic fluid. , 1992, BMJ.

[91]  M. Tennison,et al.  Intraindividual Variability of Carbamazepine, Phenobarbital, and Phenytoin Concentrations in Saliva , 1991, Therapeutic drug monitoring.

[92]  J. Parry,et al.  Diagnosis of hepatitis a and b by testing saliva , 1989, Journal of medical virology.

[93]  L. Simionescu,et al.  Serum-to-saliva transfer of the immunoreactive insulin (IRI) in children with obesity associated with insulin-resistance. , 1987, Endocrinologie.

[94]  N. Liappis,et al.  [Free amino acids in the saliva of children with phenylketonuria]. , 1986, Klinische Padiatrie.

[95]  P. Lomax,et al.  Detection of Recent Cannabis Use by Saliva Δ9-THC Radioimmunoassay , 1985 .

[96]  P. Lomax,et al.  Detection of recent cannabis use by saliva delta 9-THC radioimmunoassay. , 1985, Journal of analytical toxicology.

[97]  S. Dilli,et al.  Analysis of trace amounts of barbiturates in saliva. , 1980, Journal of chromatography.