|Year : 2018 | Volume
| Issue : 2 | Page : 115-119
A systematic review of saliva on its diagnostic utility
Neeharika Mortha1, Divya Uppala1, Nandita R Kothia2, Sumit Majumdar1, Sreekanth Kotina1, K Sravya1
1 Department of Oral and Maxillofacial Pathology, GITAM Dental College and Hospital, Visakhapatnam, Andhra Pradesh, India
2 Department of Public Health Dentistry, SIBAR Institute of Dental Sciences, Takkelapadu, Guntur, Andhra Pradesh, India
|Date of Web Publication||6-Jun-2018|
Dr. Neeharika Mortha
Department of Oral and Maxillofacial Pathology, GITAM Dental College and Hospital, Visakhapatnam - 530 045, Andhra Pradesh
Source of Support: None, Conflict of Interest: None
Introduction: A paradigm shift in recent years has led to the consideration of the oral cavity (and, thus, oral disease) not in isolation but as a component integrated with systemic physiology, important in maintaining systemic health and reflective of systemic disease. Saliva has been studied extensively as a potential diagnostic tool over the last decade due to its ease and noninvasive accessibility along with its abundance of biomarkers.
Aim and Objective: This is a systematic review of the studies published in past 15 years in electronic databases regarding the utility of saliva as a diagnostic tool. A scrutiny of abundantly studied diagnostic areas using saliva, the analytes of significance, and methodologies was performed.
Materials and Methods: Data collected from electronic databases, followed by data extraction and management.
Results and Conclusion: Eighty-five studies considered among 510 studies represent the evolution of saliva in screening neoplasms, with 34 different analytes detected in this population followed by 22 in metabolic disorders, and the least being in systemic disorders. The most abundantly applied technique is enzyme-linked immunosorbent assay, the common analyte being immunoglobulins. The application of high-throughput proteomic techniques in various studies in the past decade has led to the discovery of new biomarkers.
Keywords: Analytes, biomarkers, database, oral
|How to cite this article:|
Mortha N, Uppala D, Kothia NR, Majumdar S, Kotina S, Sravya K. A systematic review of saliva on its diagnostic utility. J NTR Univ Health Sci 2018;7:115-9
|How to cite this URL:|
Mortha N, Uppala D, Kothia NR, Majumdar S, Kotina S, Sravya K. A systematic review of saliva on its diagnostic utility. J NTR Univ Health Sci [serial online] 2018 [cited 2019 Aug 17];7:115-9. Available from: http://www.jdrntruhs.org/text.asp?2018/7/2/115/233850
| Introduction|| |
Saliva protects the teeth and the oro-esophageal mucosa through a number of mechanisms. Besides maintenance of the integrity of these tissues, saliva also has multiple functions in relation to digestion in the upper gastrointestinal tract. Lubrication of oral surfaces, tooth mineralization, buffering, and antimicrobial activity are other beneficial effects of saliva.
It is believed that changes in saliva are indicative of wellness of our health. Saliva can be considered as a good alternative over possible diagnostic biofluids, not only for the presence of targeted specific molecular constituents but also due to its ease of use as a practical method of collection.
The identification of susceptible individuals at risk from precancerous lesions, oral cancers and conditions, other oral diseases, and certain systemic illness represents a challenge to both clinicians and researchers. The term “saliva omics” was coined in 2008 to reflect the rapid development of knowledge about various “omics” constituents of saliva., This systematic review aims to collect the published data on studies using saliva as a diagnostic tool from past 15 years and determine the significant techniques involved in evaluating the various analytes detected in saliva.
| Materials and Methods|| |
- Study identification included initially electronic databases: Google Scholar and MEDLINE with keyword – “saliva as a diagnostic tool”
- The electronic databases PubMed and ScienceDirect were then searched for articles published in English since 2002 until 2017 inclusive
- Two independent reviewers extracted information regarding study design, study population, interventions, outcome measures, results, and conclusions for each article. The relevant studies were identified following a comprehensive literature search
- Assessment of the quality of the included studies was done to minimize the risk of selection bias
- The mesh terms were “saliva” AND “diagnostic tool,” “SALIVA,” “diagnostic”.
Data extraction and management
- Data were extracted from all the included studies. In a Microsoft Word document, the extracted data were entered electronically to facilitate the summary and analysis. This included (1) study details (study year, study design, study aim); (2) study and population characteristics; (3) intervention; (4) outcomes; (5) results
- Data extraction was done by two reviewers independently, to increase the accuracy, and any disagreements were resolved by consensus or by involving a third reviewer
- Collected information was entered in a spread sheet to facilitate graphical representation.
Search strategy representation was done by a flowchart [Figure 1].
- The review includes studies published between 2002 to present date on electronic databases “PubMed,” “Medline,” “ScienceDirect,” and “Biomed Central”
- Studies searched from all previous studies based on database entry date plus publication date (to ensure continuity) till date were included
- Only articles published in English were included.
- Studies that do not attempt to measure health impacts on humans
- General discussion papers not presenting data
- Any article that was obviously unsuitable was excluded in the early stages of the search (e.g., on the basis of abstracts and titles presented in electronic catalogs)
- We excluded review articles, editorials, consensus statements, and opinions.
| Results|| |
Considering the inclusion and exclusion criteria for 510 studies, 85 studies were taken for this systemic review. The studies with detailed data on sample size, methodologies, results, values of significance, sensitivity, and specificities were considered. Among 85 studies, majority were cross-sectional studies, with cohort studies and nonrandomized trials among the least. Majority of saliva-based studies are conducted in neoplasms followed by infections, metabolic disorders, periodontal, and systemic diseases [Figure 2]. Highest number of studies were conducted in the year 2015 [Figure 3]. The most commonly applied method was enzyme-linked immunosorbent assay (ELISA) followed by real-time polymerase chain reaction (PCR), quantitative PCR, and glucose oxidase peroxidase methods [Figure 4]. The studies compare and quantify the values of analytes in saliva to serum commonly, followed by plasma majorly. Abundantly studied analytes were immunoglobulins in various infections. Among the 85 studies, nearly 34 different analytes have been detected in saliva of patients with neoplasms, 22 in metabolic disorders, and the least being in systemic disorders [Figure 5]. 80% of the studies emphasize the utility of whole unstimulated saliva. The preferred method of collecting the saliva among various studies remained the passive drool method. Among the studies, saliva was compared and correlated with 10 different mediums of interest [Figure 6].
| Discussion|| |
With an expanding range of advanced technology and computational tools, today a large number of studies are being performed using saliva at a scale unrealized previously. This has served as an efficient tool for the quantification, detection, and analysis of a number of analytes and parameters, advancing toward the discovery and validation of salivary biomarkers [Table 1].,,,,
Why the timeframe?
In our present study, a time line of 15 years was considered as:
- There was consistent rise in the number of studies conducted in this span of time period with data available from standard databases
- Previous studies conducted prior to this time period had a significant literature gap
- A more standardized methodology with an enormous rise in the usage of advanced technology.
In this aspect, our systematic review showed that there were increased number of studies from 2010, the maximum being in 2015 [Figure 7].
Analytes vs methodologies
The next significant point noted was the method and the type of analyte assessed during this timeframe. ELISA was the most commonly used method in the last decade. This was partly contributed to the fact that ELISA was recently standardized for application on saliva during that period and that it being 98% sensitive and specific, it turned out to be the most sought technique after more accurate methods such as PCR and immunohistochemistry.,,,, A maximum number of studies published concentrated on ELISA, radioimmunoassay, and PCR that included chiefly detection of micro RNA, interleukin (IL)-1α, IL-6, IL-8, vascular endothelial growth factor-a, tumor necrosis factor-α, immunoglobulins, enzymes such as C-reactive proteins in saliva, and established significant results.,,,,, In 2015, 95% studies on diabetic subjects were conducted using the glucose oxidase peroxidase method with significant results [Figure 2].[17-22] This could translate into a fact that a number of studies were done on diabetes that year due to increase in the awareness and an increase in the mortality rate as reported by the International Diabetes Federation, which estimated an increase of 55% by 2035. There was 5.1 million diabetes-related deaths globally in 2013, equaling to one death every 6 s, an 11% increase over 2011.,,,,,
From 2015 onwards, a wide spectrum of analytes were assessed using saliva, and more research were done on systemic illnesses such as levels of cortisol in depression, in studying posttreatment changes in transplant patients such as renal transplant, implant placement (in periodontal diseases), and therapeutic drug monitoring., As oral cancer stands at an all-time high of standing sixth among the most mortal diseases of mankind, studies were concentrated more on detection of analytes, marking the early diagnosis of neoplasms, chiefly of head and neck.,,,,
Saliva vs blood
Though earlier studies were attempted to detect trace and major elements,,,,,,,,, their significant role in a particular diagnosis of interest was not appreciated in comparison to blood. In studies conducted in other body fluids taken as standard such as levels of urea, creatinine in urine vs saliva, it was inferred that saliva can be used as an adjunct diagnostic tool.
Moreover, in recent past, studies were published on detection of various metabolic end products such as lactic acid, pyruvic acid, sialic acid in saliva of subjects with neoplasms, including both malignant and premalignant lesions and conditions, cardiovascular diseases, etc. Significant results were established in this field with respect to the gold standard considered. Although extensive research is required to consider the most effective means of detection in saliva among all the existing methods such as gel electrophoresis, liquid chromatography, kinetic assays, and spectrophotometry, to draw further conclusions as to which analyte or biomarker is of significance in early detections, a vast number of studies are to done with respect to each analyte followed by meta-analysis.
Among the 24 studies in which subjects with neoplasms were studied, majority were oral squamous cell carcinoma followed by tongue cancer and parotid tumors the least. Of the 24 selected, 19 studies compared the levels of desirable analyte in comparison to premalignant lesions comprising oral leukoplakia, commonly followed by oral lichen planus and oral submucous fibrosis.,, A significant correlation was established with serum levels, and also, their correlation with histopathological grades of disease manifestation has been presented in maximum number of studies. It was conclusive from that group of studies that saliva can be used as a tool not just for diagnosis, but to monitor prognosis. It can be inferred that saliva can be used as an adjunct tool. A small number of studies were conducted in subjects with syndromes associated with oral lesions.
| Conclusion|| |
The emergence of saliva as a diagnostic medium evoked many research questions. The published studies have inferred the role of saliva in screening various diseases with the presence of specific analytes. Proteomics and metabolomics have steadily gathered momentum over the past decade with the emergence of high-throughput proteomic technologies such as mass spectrometry-based methods and microarrays.
Also, a good number of studies have to be done using newer methodologies with any of the chosen particular analyte, in the field of diagnostic interest. Therefore, the number of studies in relation to a specific analyte, methodologies used, and in a specific diagnostic area are limited, and there is an increased need to drive toward a more target-oriented research to derive the true potential of saliva.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Timothy MS, Nauntofte B, Svensson P. Clinical Oral Physiology. 1st
ed. Copenhagen: Quintessence, 2004. Print.
Iorgulescu G. Saliva between normal and pathological. Important factors in determining systemic and oral health. J Med Life 2009;2:303-7.
Mandel ID. The diagnostic uses of saliva. J Oral Pathol Med 1990;19:119-25.
Kaczor-Urbanowicz KE, Martin Carreras-Presas C, Aro K, Tu M, Garcia-Godoy F, Wong DT. Saliva diagnostics – current views and directions. Exp Biol Med (Maywood) 2017;242:459-72.
Wong DT. Salivaomics. J Am Dent Assoc 2012;143(10 Suppl):19S-24S.
Hansen Å, Garde A, Persson R. Sources of biological and methodological variation in salivary cortisol and their impact on measurement among healthy adults: A review. Scandinavian Journal of Clinical and Laboratory Investigation 2008;68:448-58.
Chai RC, Lim Y, Frazer IH, Wan Y, Perry C, Jones L, et al
. A pilot study to compare the detection of HPV-16 biomarkers in salivary oral rinses with tumour P16ink4a expression in head and neck squamous cell carcinoma patients. BMC Cancer 2016;16:178.
Yoon RK, Smaldone AM, Edelstein BL. Early childhood caries screening tools: A comparison of four approaches. J Am Dent Assoc 2012;143:756-63.
Papaseit E, Farré M, Graziano S, Pacifici R, Pérez-Mañá C, García-Algar O, et al
. Monitoring nicotine intake from e-cigarettes: Measurement of parent drug and metabolites in oral fluid and plasma. Clin Chem Lab Med 2017;55:415-23.
Nunes LA, Mussavira S, Bindhu OS. Clinical and diagnostic utility of saliva as a non-invasive diagnostic fluid: A systematic review. Biochem Med 2015;25:177-92.
Hansen AM, Garde AH, Persson R. Sources of biological and methodological variation in salivary cortisol and the impact on measurement among healthy adults: A review. Scand J Clin Lab Invest 2008;68:448-58.
Granger DA, Shirtcliff EA, Booth A, Kivlighan KT, Schwartz EB. The “trouble” with salivary testosterone. Psychoneuroendocrinology 2004;29:1229-40.
Shirtcliff EA, Granger DA, Curran MJ. Use of salivary bio- markers in biobehavioral research: Cotton-based sample collection methods can interfere with salivary immunoassay results. Psychoneuroendocrinology 2001;26:165-73.
Carvalho AL, Jeronimo C, Kim MM, Henrique R, Zhang Z, Hoque MO, et al
. Evaluation of promoter hypermethylation detection in body fluids as a screening/diagnosis tool for head and neck squamous cell carcinoma. Clin Cancer Res 2008;14:97-107.
Nagler R, Ben-Izhak O, Cohen-Kaplan V, Shafat I, Vlodavsky I, Akrish S, et al
. Heparanase upregulation in tongue cancer. Cancer 2007;110:2732-9.
Petraityte R, Jin L, Hunjan R, Razanskiene A, Zvirbliene A, Sasnauskas K. Use of Saccharomyces cerevisiae
-expressed recombinant nucleocapsid protein to detect hantaan virus-specific immunoglobulin G (IgG) and IgM in oral fluid. Clin Vaccine Immunol 2007;14:1603-8.
Chakravarti A, Matlani M, Jain M. Immunodiagnosis of dengue virus infection using saliva. Curr Microbiol 2007;55:461-4.
Shpitzer T, Bahar G, Feinmesser R, Nagler RM. A comprehensive salivary analysis for oral cancer diagnosis. J Cancer Res Clin Oncol 2007;133:613-7.
Giusti L, Baldini C, Bazzichi L, Ciregia F, Tonazzini I, Mascia G, et al
. Proteome analysis of whole saliva: A new tool for rheumatic diseases – the example of Sjögren's syndrome. Proteomics 2007;7:1634-43.
Znaleziona J, Petr J, Maier V, Knob R, Horakova J, Smetanova D, et al
. Capillary electrophoresis as a verification tool for immunochemical drug screening. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2007;151:31-6.
Rauh M. Steroid Measurement With LC–MS/MS In Pediatric Endocrinology. Mol Cell Endocrinol 2009;301:1-2.
Hu S, Arellano M, Boontheung P, Wang J, Zhou H, Jiang J, et al
. Salivary proteomics for oral cancer biomarker discovery. Clin Cancer Res 2008;14:6246-52.
Giovane A, Balestrieri A, Napoli C. New insights into cardiovascular and lipid metabolomics. J Cell Biochem 2008;105:648-54.
Olsen J, Bech B. Caffeine Intake During Pregnancy. Obstetric Anesthesia Digest 2009;29:137.
Rai B, Kaur J, Jacobs R, Anand SC. Adenosine deaminase in saliva as a diagnostic marker of squamous cell carcinoma of tongue. Clin Oral Investig 2010;15:347-9.
Sashikumar R, Kannan R. Salivary glucose levels and oral candidal carriage in type II diabetics. Oral Surg Oral Med Oral Pathol Oral Radiol Endodontol 2010;109:706-11.
Guariguata L. Contribute data to the 6th
edition of the IDF Diabetes Atlas. Diabetes Research and Clinical Practice 2013;100:280-1.
IDF Diabetes Atlas Group. Update of mortality attributable to diabetes for the IDF Diabetes Atlas: Estimates for the year 2011Diabetes Res. Clin Pract 2013;100:277-9.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]