Saliva as a Diagnostic Tool in Oral Diseases

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Experimed 2020; 10(3): 135-9
DERLEME
REVIEW
DOI: 10.26650/experimed.2020.0042
Saliva as a Diagnostic Tool in Oral Diseases
Ağız Hastalıklarında Tanı Aracı Olarak Tükürük
Özlem Kart1 , Ayen Yarat2
1Faculty of Dentistry, Marmara University, Istanbul, Turkey
2Basic Medical Sciences, Biochemistry, Faculty of Dentistry, Marmara University, Istanbul, Turkey
ORCID ID: Ö.K. 0000-0002-3398-6270; A.Y. 0000-0002-8258-6118
Cite this article as: Kart Ö, Yarat A. Saliva as a diagnostic tool in oral diseases. Experimed 2020; 10(3): 135-9.
ABSTRACT
Saliva is a body fluid, which is secreted from 3 major salivary
glands (parotid, submandibular and sublingual) and many minor
salivary glands. It contains organic and inorganic substances with
99% water, and has several functions such as contribution to ar-
ticulation, digestion, cleansing and protection of the oral mucosa,
and antimicrobial effects. The concentration of saliva’s substances
vary according to the responses to physiological processes in the
human body. Containing genetic materials such as DNA and RNA
also highlights saliva as a potential diagnostic tool. Saliva analysis
has advantages such as being cheaper, non-invasive, easier pa-
tient cooperation, and low technical sensitivity compared to blood
tests; it can be used in the diagnosis of many diseases or routine
risk assessments. It is also promising for its advantages in collec-
tion and storage of the samples. Advances in molecular biology,
genomics, and proteomics have revealed the importance of saliva
in the detection of many diseases, coining the term salivaomics.
The early diagnosis of the diseases in which symptoms can be seen
in late stages, may provide an easier treatment and improve the
prognosis. In this review, the biomarkers of saliva in the presence
of different diseases and the advantages of their use in diagnosis
were examined.
Keywords: Saliva, oral diseases, diagnosis
ÖZ
Tükürük; balıca üç majör tükürük bez (parotd, submandbular
ve sublngual) ve brçok mnör tükürük beznden salgılanan br
vücut sıvısıdır. İçersnde %99 suyla brlkte organk ve norgank
maddeler bulunduran tükürüğün; artkülasyon, sndrm, ağız mu-
kozasının temzlenmes ve korunması le antmkrobyal etkler gb
brçok lev vardır. Tükürüğün çersndek maddelern konsantras-
yonları vücuttak fzyolojk süreçlere verlen yanıtlara göre değk-
lk gösterr. DNA ve RNA gb genetk materyaller barındırması da
tükürüğü potansyel br tehs aracı olarak öne çıkarmaktadır. Kan
tahlllerne göre hasta kooperasyonunun daha kolay olması, daha
ucuz, non-nvazv ve teknk hassasyetn az olması gb avantajları
olan tükürük testler; brçok hastalığın tehsnde kullanılableceğ
gb rutn rsk değerlendrmelernde de kullanılablr. Örnek toplan-
ması ve saklanmasındak avantajlarından dolayı da gelecek vaad
etmektedr. Moleküler byoloj, genomk ve proteomk alanlarında-
k gelmeler sayesnde salvaomk term ortaya çıkmı ve brçok
hastalığın saptanmasında tükürüğün önem belrtlmtr. Özellkle
semptomların geç görülmeye baladığı hastalıkların tükürük test-
ler sayesnde erken tehs edlmes, tedavy büyük oranda kolay-
latırablr ve prognozu yletreblr. Bu derlemede, farklı hasta-
lıkların varlığında tükürükte bulunan byobelrteçler ve tehste
kullanımının avantajları ncelenmtr.
Anahtar Kelmeler: Tükürük, ağız hastalıkları, tehs
Corresponding Author/Sorumlu Yazar: Özlem Kart E-mail: ozlemkart08@hotmail.com
Submitted/Bavuru: 13.08.2020 Accepted/Kabul: 31.08.2020
Content of this journal is licensed under a Creative Commons
Attribution-NonCommercial 4.0 International License.
135
INTRODUCTION
Saliva is a body fluid, which is secreted from 3 major sal-
ivary glands, which are parotid, submandibular and sub-
lingual, and nearly 1000 minor salivary glands. It helps to
maintain the health and hygiene of the oral cavity and has
many functions such as contribution to articulation, swal-
lowing, and maturation of erupted teeth (1). Thanks to its
antimicrobial properties, it is beneficial for the protection
of microbial balance and the prevention of infections (2).
Saliva, secreted between 0.75 and 1.5 liters per day, is odor-
less, colorless and has a pH range of 6.5-7.5. It contains 99%
water, organic and inorganic substances, and many micro-
organisms that play roles in different diseases (3). Organic
substances are composed of urea, uric acid, glucose, fatty
acids, glycerides, creatinine, peroxidase, amylase, and hor-
mones. As for the inorganic molecules; Na+, K+, Ca2+, Cl−,
Mg2+, F−, I−, HCO3- and H2PO4- are some of the ions found in
saliva (4,5). These substances in the structure of saliva have
different functions (6). For instance, amylase and lipase

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Saliva as a Diagnostic Tool in Oral Diseases
136
catalyze the digestion of carbohydrates and fats, while thiocy-
anate ions play a bactericidal role. Calcium in saliva contributes
to the process of remineralization of tissues (7). Also, antioxi-
dant enzymes in saliva protect the oral cavity from the negative
effects of free radicals, reactive oxygen, and different forms of
nitrogen (8,9). Some of the agents in saliva pass through tran-
scellular and paracellular pathways from blood and their con-
centrations vary according to physiological processes, which
makes saliva a potentially good diagnostic tool (10). Develop-
ments in molecular biology, genomics, and proteomics led to
coining the term “salivaomics”, which reveals the importance of
salivary biomarkers in diagnosis of oral and systemic diseases
and current stages of them (10).
The most important step for the treatment is to make an accu-
rate diagnosis. When the clinical, radiological, and histological
features of the disease are known, it will be easier to eliminate
the disease factors (11). Caries, periodontal diseases, and oral
malignant lesions are some of the examples of oral diseases
that can be diagnosed with saliva tests (12). In addition to oral
diseases, saliva can be used for the diagnosis of systemic dis-
eases such as diabetes mellitus, cardiovascular diseases, and
other infections. Also, it can be used for detection of drugs, and
identification in forensics (13,14).
DENTAL CARIES
Dental caries is a common multifactorial oral disease that can
progress to the loss of teeth with symptoms of pain by demin-
eralization of mineralized tissues in enamel, dentin and cement
(6). Dental caries are not reversible especially in the later stages,
therefore it’s essential to prevent it with good oral hygiene or
to diagnose in early stages. Saliva can be easily used to detect
risk factors because it contains structures such as molecules
that cause remineralization and bacteria. There are many stud-
ies analyzing biomarkers by taking different saliva samples.
Among the most important caries markers in saliva are micro-
organisms. Lactobacilli and Streptococcus mutansare the pri-
mary bacteria that cause caries. Other bacteria such as Strep-
tococcus sobrinus, Streptococcus cricetus, Streptococcus rattus,
Streptococcus macacae, Streptococcus downei, and Prevotella ge-
nus differ between healthy individuals and patients (8,15). Pro-
teins like statherin, cystatin, histatins, and proline-rich proteins
(PRP) contribute to maintenance of enamel’s structural integri-
ty, so they are important biomarkers in caries diagnosis. It has
been shown that these proteins are found in larger amounts
in individuals without previous caries history (16). It is thought
that there is a difference in immunoglobulin (Ig) levels in the
presence of caries. Although studies on this subject are limit-
ed, it has been revealed that IgA levels are higher in individuals
with caries (17). Oxidative stress in saliva also causes the cari-
ous lesions, restricting the movement of dentin fluids, so the
inflammatory response of dentin is affected. As a result, dentin
becomes more sensitive to bacterial acids and the destruction
of hard dentin tissues is observed. A study that examines the
relation of salivary glutathione and dental health also showed
that there may be a relation between caries and antioxidants
found in saliva (18). Matrix metalloproteinases (MMP) such as
collagenase in extracellular fluids, are enzymes that show cell
death. Dentin contains collagen Type I and a small amount of
collagen Type V, so the presence of collagenase in saliva caus-
es destruction of dentin and indicates pulp or periodontal tis-
sue destruction due to severe dental caries (19). Studies have
shown that mucins may be another potential biomarker of
caries. Mucins help to enhance the agglutination of bacteria,
therefore they contribute to the protection of teeth from car-
ies. So the decrease in mucins may accelerate demineralization
(20). The amount, flow rate, and viscosity of saliva are import-
ant as well as the content for the prevention of dental caries
(21). In the patients whose salivary flow rate is insufficient, sa-
liva may not be able to clear the acids of the food consumed
and eventually, the pH balance will deteriorate thorough acidic
direction, which will increase the risk of caries (20). In a study
in which erosion was examined by taking unstimulated saliva
in children, the rate of saliva flow in children with erosion was
noticeably lower than the control group. In the same study, the
amount of chloride was higher in children with erosion (22).
PERIODONTAL DISEASES AND PERI-IMPLANTITIS
Periodontal diseases develop with inflammation of the gingi-
va, the periodontal ligament and alveolar bone around teeth
and it is one of the reasons for tooth loss (23). Peri-implantitis,
on the other hand, is a disease that develops in tissues around
the implant and includes bone loss (24). Although their etiolo-
gies are similar, resorption in peri-implantitis progresses much
faster. Many studies were carried out to provide early diagno-
sis of these diseases by detecting biomarkers in gingival fluid
and saliva. The most important biomarkers are gram (-) bacte-
ria such asAggregatibacter actinomycetemcomitans, Porphyro-
monas gingivalis, Tannerella forsythensis, Treponema denticola,
Prevotella intermedia, Campylobacter rectus, Fusobacterium
nucleatumandEikinella corrodens(4,16). Studies revealed that
an increase in the amount of salivary IgA, IgG, and IgM could
contribute to the immunological response against these bacte-
ria. The most commonly used methods for the detection of Igs
in saliva are radial immunodiffusion and nephelometer. Also,
an enzyme-linked immunosorbent assay (ELISA) can be used
in detection of many biomarkers found in saliva in addition to
Igs. Likewise, it has been observed that these glycoproteins de-
crease after treatment (25). Interleukins (IL) such as IL-1 and IL-6
are also involved in the inflammatory process in periodontitis
and they have been proved to trigger osteoclastic activity and
cause bone and tissue destruction. Interleukins may be prod-
ucts of epithelial cells, fibroblasts, osteoblasts, polymorphonu-
clear neutrophils, and endothelial cells and play a role in the ac-
tivity of MMPs and their inhibitors (26). MMP-8 and MMP-9 are
very important biomarkers in periodontal and implant-related
diseases. PerioSafe and ImplantSafe, which are developed as
applicable chair-side, are used in detecting active MMP-8,
especially in oral fluids. While active MMP-8 was positive in
patients with periodontitis or peri-implantitis, the response
turned negative after the treatments (27). Other important fac-
tors determining periodontal health are oxidative stress mark-

137
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Saliva as a Diagnostic Tool in Oral Diseases
ers. Studies that evaluated the total antioxidant capacity levels
showed a decrease in antioxidants in non-smoking individuals
with periodontal disease. The level of antioxidants rises again
after the treatment (28,29). In another study, it was observed
that the level of nitric oxide in saliva increased in patients with
gingivitis, chronic and aggressive periodontitis as compared to
healthy individuals, while adrenomedullin may be an import-
ant marker only in patients with aggressive periodontitis (8).
SJÖGREN’S SYNDROME
Sjogren’s syndrome (SS) is an autoimmune disease that affects
the secretory glands. Although the cause of this disease is not
yet fully known, it may be accompanied by some inflammato-
ry rheumatic diseases (30). Today, the diagnosis of SS is made
by evaluation of the symptoms and the biopsy of the salivary
glands. But it is possible to distinguish primary and secondary
SS from each other or other autoimmune diseases such as sys-
tematic lupus erythematosus by conducting proteomic and
transcriptomic examinations of saliva. Rheumatoid factor, An-
ti-Ro/SS-A and Anti-La/SS-B are conventional biomarkers used
in the diagnosis of SS (31). Other than that, studies showed a
relation between SS and 19 different genes, which were in-
volved in the presentation of antigens and osmosis of lym-
phocytes (32). When patients and healthy individuals are com-
pared; higher levels of IL-2, IL-4, IL-5, IL-6, clusterin, cathepsin-d,
α-enolase, and β2-microglobulin are observed (10,26). It is also
mentioned that there is oxidative stress in the presence of a
disease. Markers such as increased oxidative DNA damage can
play an important role in controlling the disease (4). A recent
study evaluating lymphocytes in patients with SS concluded
that lymphocytes are found in parotid saliva in both primary
and secondary SS while there are no findings in healthy indi-
viduals (33).
ORAL PREMALIGNANT LESIONS AND ORAL
CANCERS
Oral premalignant lesions are among the abnormalities that
dentists frequently encounter after caries and periodontal dis-
eases in their clinical applications. These lesions can turn into
cancer if they are not treated or controlled with follow-up ex-
aminations. Lichen planus (LP) especially when it shows an ero-
sive-atrophic pattern, leukoplakia, erythroplakia, precancerous
melanosis and oral submucous fibrosis are some of the prema-
lignant lesions that could be seen in the oral cavity (34).
Lichen planus: Chronic inflammation in epithelial cells can be
seen as a white lesion with reticular structure and erythem-
atous borders. Amalgam, non-steroidal anti-inflammatory
drugs, and hepatitis C virus are thought to cause antigenic
change as etiological factors (35). Currently, the most studied
biomarkers in the diagnosis of lichen planus are cortisol, Igs,
cytokines, and oxidative stress-related molecules. In a study, an
increase was observed in salivary cortisol levels due to anxiety
in patients with lichen planus when compared to healthy indi-
viduals (36). An analysis of Ig by ELISA showed an increase in
IgA and IgG levels (25).
Leukoplakia: It is one of the frequently encountered precancer-
ous lesions. There is a 10% risk of developing cancer in leuko-
plakia (37). Studies are carried out on cytokines as biomarkers.
There are studies showing the increase in IL-1β, IL-6, cystatin,
and apolipoprotein A-1 on unstimulated whole saliva in pa-
tients with leukoplakia (38,39).
Oral cancers: Carcinomas seen in the oral cavity are among the
most common cancers in the head and neck region (34). The
most common is oral squamous cell carcinoma (OSCC). It has a
high mortality rate in many countries. The initial diagnostic tool
of carcinomas today is biopsies which are mostly invasive pro-
cedures (3). So the need for non-invasive diagnostic tools is in-
creasing. More than 100 biomarkers are known for the diagno-
sis of oral cancers, primarily salivary proteins, RNA and DNA (4).
While unstimulated whole saliva is generally used in detecting
these biomarkers, there are studies showing that stimulated
saliva gives the same valuable results. MicroRNAs (miRNA) ob-
tained from saliva may have an important role in the diagnosis
of head and neck cancers (10). It has been observed that miR-
NA-9 and miRNA-191 obtained from small amounts of saliva
using the miRNA isolation kit and QIAzol methods together
can be important biomarkers while there was a decrease in
miRNA-125a and miRNA-200a levels in samples taken from
patients with OSCC (16,40). In addition to miRNA, the tumor
suppressor p53 gene and anti-p53 proteins that are produced
in the presence of multiple DNA damages, CA15-3 and CA125
can be used as biomarkers for cancers in other regions (breast,
ovarian, and lung cancers, etc.) as well as head and neck can-
cers (41). Moreover, MMPs are thought to play a role in differ-
ent stages of the progression of tumors. In the cell proliferation
phase, proteolytic MMPs may cause the activation of growth
factors or intercellular destruction (19). In angiogenesis, they
can change the activities of the endothelial and epithelial
growth factor, control the inflammatory response, and affect
invasion in the pathological process of new blood vessels. At
the stage of invasion and metastasis, tumors need MMPs to in-
teract with the membrane and extracellular matrix. Therefore,
some MMPs can be produced by tumors or growth factors,
chemokines, and cytokines. This way, tumors may grow locally
and metastasize. Studies evaluating MMPs found in higher lev-
els of MMP-1, MMP-2, MMP-9, MMP-10, and MMP-12 in patients
as compared to healthy people (12,19).
SYSTEMIC DISEASES
Cardiovascular Diseases
They are among the leading causes of death in the world, in-
clude diseases such as hypertension, atherosclerosis, and myo-
cardial infarction. In the presence of these diseases, changes in
the levels of some biomarkers can be detected in saliva (42). In
addition to the classical diagnostic methods (clinical findings
and electrocardiogram, etc.) used today, studies on saliva anal-
ysis as a supportive tool are continuing. The level of C-reactive
protein (CRP) in saliva can be determined by using a system
based on nano-biochips, that can be applied chair-side (5). In
a study of acute myocardial infarction patients who experi-

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Kart and Yarat
Saliva as a Diagnostic Tool in Oral Diseases
138
enced chest pain in the previous 48 hours, CRP, MMP-9, IL-1β,
adiponectin, gro-α, E-selectin, and IL-18 increased in saliva
more than serum (42). In addition, there are studies showing
that the amount of MMP-8 and lysozyme in saliva increases in
the presence of hypertension (42). The level of vitamin C and
antioxidants in serum and saliva can also affect the nitric oxide
level, indicating carotid endothelial damage in atherosclerosis
patients (43). In a study in individuals with ischemic heart dis-
ease and periodontitis, it was found that patients with ischemic
heart disease have lower levels of lutein, lycopene, α-tocopher-
ol and β-carotene levels in saliva (43).
Diabetes Mellitus
Today, the control of diabetes is done with blood tests, which is
an invasive method. In saliva, glucose and urea levels are found
to be in direct relation with blood levels (44). In diabetic pa-
tients, there was also an increase found in the levels of amylase,
total protein, and electrolytes such as potassium, calcium and
chloride (44,45).
Infections
It is common to use viral DNA and RNA biomarkers in saliva for
the diagnosis of infections. Saliva is used in the diagnosis of many
viruses such as Human Immunodeficiency Virus, Hepatitis A, B
and C viruses, and rubella (8). Many studies are conducted on
the use of saliva as a non-invasive tool to detect the COVID-19,
which appeared in 2019 and the number of cases is increasing
rapidly. The results of studies comparing the saliva and nasopha-
ryngeal samples are promising (46). In a study conducted with
200 patients, who have symptoms of COVID-19, with an average
age of 36, viral DNA was obtained from the samples taken and
19 patients were found to carry the virus according to the naso-
pharyngeal samples. When the saliva samples of these patients
are examined, it has been shown that saliva can be used in virus
detection by determining the compatibility of two samples with
84.2% sensitivity and 98.9% specificity (47).
Renal Diseases
Saliva can also be used in the diagnosis of renal diseases. Sal-
ivary creatinine levels show an increase in patients with renal
diseases (48). Studies also have shown that selenium in saliva
decreases in the presence of renal stones so it can be used as
a biomarker (49). In addition, dialysis patients’ salivary pH in-
creases because of high urea concentrations (48).
CONCLUSION
Saliva is an important tool that contains biomarkers that are
used in the diagnosis and treatment of many oral and systemic
diseases. Saliva analysis has advantages such as being non-in-
vasive, cheaper compared to blood tests, having good patient
cooperation and low technical sensitivity. It is also promising
for its advantages in collecting and storing samples. Saliva is
actively used for some diseases today and with the advances
in salivaomics, it can help as an alternative to serum or can be
used in addition to some conventional diagnostic methods.
However, studies need to be more comprehensive and stan-
dardized so that saliva tests will become more widespread and
gain more importance in early diagnosis by using routine con-
trols in the coming years.
Peer-review: Externally peer-reviewed.
Author Contributions: Concept - Ö.K., A.Y.; Data Collection - Ö.K., A.Y;
Data Analysis and/or Interpretation - Ö.K., A.Y.; Literature Search - Ö.K.,
A.Y.; Writing - Ö.K., A.Y.; Critical Reviews - Ö.K., A.Y.
Conflict of Interest: The authors have no conflict of interest to declare.
Financial Disclosure: The authors declared that this study has re-
ceived no financial support.
Hakem Değerlendirmesi: Dı bağımsız.
Yazar Katkıları: Çalıma Konsepti/Tasarımı - Ö.K., A.Y.; Veri Toplama -
Ö.K., A.Y.; Veri Analizi/Yorumlama - Ö.K., A.Y.; Literatür Tarama - O.K., A.Y.;
Yazım - O.K., A.Y.; İçeriğin Eletirel İncelemesi - Ö.K., A.Y.
Çıkar Çatıması: Yazarlar çıkar çatıması bildirmemilerdir.
Finansal Destek: Yazarlar bu calımada finansal destek almadıklarını
beyan etmilerdir.
REFERENCES
1. Emekli N, Yarat A. Tükürük. Nobel Tıp Kitapevleri, İstanbul, 2008.
2. Sharma S, Gaur P, Gupta S. Impact of saliva on health: An overview.
EJBPS 2018; 5(6): 202-4.
3. Martina E, Campanati A, Diotallevi F, Offidani A. Saliva and oral dis-
eases. J Clin Med 2020; 9: 466. [CrossRef]
4. Wu DT, Tao O, Trinh N, Javaid MA, Ahmed AS, Durand R, et al. Saliva
- A promising tool for diagnosing oral diseases. Curr Oral Health
Rep 2018; 5: 242-9. [CrossRef]
5. Yordanova M, Gerova D, Galunska B. Saliva application in oral and
systemic diseases. Scr Sci Med 2018; 50(2): 13-8. [CrossRef]
6. Akyüz S, Yarat A, Emekli Alturfan E, Kaya S. Flouride in saliva and its
impact on health. In: Preedy VR, editor. Fluorine: Chemistry, Analysis,
Function and Effects (Food and Nutritional Components in Focus).
London: Royal Society of Chemistry 2015.p.173-85. [CrossRef]
7. Yarat A, Emekli Alturfan E, Akyüz S. Calcium in saliva and impact
on health. In: Preedy VR, editor. Calcium: Chemistry, Analysis,
Function and Effects (Food and Nutritional Components in Focus).
London: Royal Society of Chemistry 2015.p.364-83. [CrossRef]
8. Zhang CZ, Cheng XQ, Li JY, Zhang P, Yi P, Xu X, et al. Saliva in the
diagnosis of diseases. Int. J. Oral Sci. 2016 Sep 2. [CrossRef]
9. Tóthová L, Kamodyová N, Cervenka T, Celec P. Salivary markers of
oxidative stress in oral diseases. Front Cell Infect Microbiol 2015; 5:
73. [CrossRef]
10. Tasoulas J, Patsouris E, Giaginis C, Theocharis S. Salivaomics for oral
diseases biomarkers detection. Expert Rev Mol Diagn 2015; 17.
11. Bhat M, Bhat D. Salivary diagnostics in oral diseases. In: Gokul S,
editor. Saliva and Salivary Diagnostics (book online) 2019 May (cit-
ed 2020 Mar 2): (19 pages). Available from: URL: https://www.in-
techopen.com/books/saliva-and-salivary-diagnostics/salivary-di-
agnostics-in-oral-diseases [CrossRef]
12. Buzalaf MAR, Ortiz AC, Carvalho TS, Fideles SOM, Araújo TT, Mo-
raes SM, et al. Saliva as a diagnostic tool for dental caries, peri-
odontal disease and cancer: is there a need for more biomarkers?.
Expert Rev Mol Diagn 2020; 20(3): 543-55. [CrossRef]

139
Experimed 2020; 10(3): 135-9
Kart and Yarat
Saliva as a Diagnostic Tool in Oral Diseases
13. Jessica, Auerkari EI. Saliva as a diagnostic tool in forensic odontol-
ogy. J Dentomaxillofac Sci 2019; 4(3): 124-7. [CrossRef]
14. Pillai G, Krishnan AR, Subodh A, Rajan NS. Saliva: A diagnostic tool.
World J Pharm Pharm Sci 2020; 9(5): 426-35.
15. Guo L, Shi W. Salivary biomarkers for caries risk assessment. J Calif
Dent Assoc 2013; 41(2) :107-18.
16. Zhang X, Kulasinghe A, Karim R, Punyadeera C. Saliva diagnostics
for oral diseases. In: Streckfus C, editor. Advances in Salivary Diag-
nostics. Springer, Berlin, Heidelberg 2015; 131-56. [CrossRef]
17. Silva Fidalgo TK, Freitas-Fernandes LB, Ammari M, Mattos CT, de
Souza IPR, Maia LC. The relationship between unspecific s-IgA
and dental caries: a systematic review and meta-analysis. J Dent
2014; 42(11): 1372-81. [CrossRef]
18. Öztürk LK, Furuncuoglu H, Atala MH, Uluköylü O, Akyüz S, Yarat
A. Association between dental-oral health in young adults and
salivary glutathione, lipid peroxidation and sialic acid levels and
carbonic anhydrase activity. Braz J Med Biol Res 2008; 41: 956-9.
[CrossRef]
19. Maciejczyk M, Pietrzykowska A, Zalewska A, Knaś M, Daniszewska
I. The significance of matrix metalloproteinases in oral diseases.
Adv Clin Exp Med 2016; 25: 383-90. [CrossRef]
20. Gao X, Jiang S, Koh D, Hsu CYS. Salivary biomarkers for dental car-
ies. Periodontol 2000. 2016; 70: 128-41. [CrossRef]
21. Ezhil I, Savitha G, Kumar MPS. Saliva as a diagnostic tool: A review.
Drug Invent. Today 2018; 10(11): 2188-93.
22. Zwier N, Huysmans MCDNJM, Jager DHJ, Ruben J, Bronkhorst EM,
Truin GJ. Saliva parameters and erosive wear in adolescents. Car-
ies Res 2013; 47(6): 548-52. [CrossRef]
23. Irani S, Barati I, Badiei M. Periodontitis and oral cancer - current
concepts of the etiopathogenesis. Oncol Rev 2020; 14(1): 465: 23-
34. [CrossRef]
24. Garcés MÁS, Escoda CG. Periimplantitis. Med Oral Patol Oral Cir
Bucal 2004; 9: 63-74.
25. Lorenzo-Pouso A, Pérez-Sayáns M, Bravo SB, López-Jornet P,
García-Vence M, Alonso-Sampedro M, et al. Protein-based sal-
ivary profiles as novel biomarkers for oral diseases. Dis Markers
(journal online) 2018 Nov 7 (cited 2020 Mar 2): 6141845: (22
pages). Available from: URL: https://www.hindawi.com/journals/
dm/2018/6141845/ [CrossRef]
26. Roi A, Rusu LC, Roi CI, Luca RE, Boia S, Munteanu RI. A new approach
for the diagnosis of systemic and oral diseases based on salivary
biomolecules. Dis Markers (journal online) 2019 Feb 17 (cited
2020 Mar 2): 8761860: (11 pages). Available from: URL: https://
www.hindawi.com/journals/dm/2019/8761860/ [CrossRef]
27. Alassiri S, Parnanen P, Rathnayake N, Johannsen G, Heikkinen
AM, Lazzara R et al. The ability of quantitative, specific, and sen-
sitive point-of-care/chair-side oral fluid immunotests for aMMP-
8 to detect periodontal and peri-implant diseases. Dis Mark-
ers (journal online) 2018 Aug 5 (cited 2020 Mar 2): 1306396: (5
pages). Available from: URL: https://www.hindawi.com/journals/
dm/2018/1306396/ [CrossRef]
28. Ate G, Öztürk H. Detection of total antioxidant capacity of saliva
in periodontal diseases. EÜ Dihek Fak Derg 2018; 39(3): 165-74.
[CrossRef]
29. Baer Ü, Iık HG, Ate G, Iık G. The effect of initial periodontal ther-
apy on saliva and plasma total antioxidant capacity of non-smok-
ing periodontitis patients. EÜ Dihek Fak Derg 2015; 36(1): 38-44.
[CrossRef]
30. Ramos-Casals M, Brito-Zerón P, Sisó-Almiral A, Bosch X. Primary
Sjögren Syndrome. BMJ 2012; 344: e3821. [CrossRef]
31. Akta A, Giray B, Akta G. Saliva; composition and function, impor-
tance for diagnosis. ADO Journal of Clin Sci 2009; 3(2): 361-7.
32. Khuder SA, Al-Hashimi I, Mutgi AB, Altorok N. Identification of
potential genomic biomarkers for Sjögren's Syndrome using data
pooling of gene expression microarrays. Rheumatol Int 2015;
35(5): 829-36. [CrossRef]
33. Selifanova E, Beketova T, Spagnuolo G, Leuci S, Turkina A. A novel
proposal of salivary lymphocyte detection and phenotyping in
patients affected by Sjogren's Syndrome. J Clin Med. 2020; 9(2):
521. [CrossRef]
34. Özbayrak S, Pekiner FN. Ağız Kanserleri: Erken Tanı Bakımından
Dihekimliği. İstanbul: Quintessence; 2016. p.37-55.
35. Par M, Tarle Z. Psychoneuroimmunology of oral diseases - a re-
view. Stoma Edu J 2019; 6(1): 55-65. [CrossRef]
36. Koray M, Dülger O, Ak G, Horasanli S, Üçok A, Tanyeri H, et al. The
evaluation of anxiety and salivary cortisol levels in patients with
oral lichen planus. Oral Dis 2003; 9(6): 298-301. [CrossRef]
37. Tekin M, Çam OH. Oral Mukoza Hastalıkları ve Semptomatolojisi.
Klinik Geliim 2012; 25: 93-8.
38. Brailo V, Vucicevic-Boras V, Lukac J, Biocina-Lukenda D, Zilic-Ala-
jbeg I, Milenovic A, et al. Salivary and serum interleukin 1 beta,
interleukin 6 and tumor necrosis factor alpha in patients with leu-
koplakia and oral cancer. Med Oral Patol Oral Cir Bucal 2012; 17(1):
e10-5. [CrossRef]
39. Camisasca DR, Gonçalves LR, Soares MR, Sandim V, Nogueira FCS,
Garcia CHS, et al. A proteomic approach to compare saliva from
individuals with and without oral leukoplakia. J Proteomics 2017;
151: 43-52. [CrossRef]
40. Ghizoni JS, Nichele R, Oliveira MT, Pamato S, Pereira JR. The utiliza-
tion of saliva as an early diagnostic tool for oral cancer: microRNA
as a biomarker. Clin Transl Oncol 2020; 22(6): 804-12. [CrossRef]
41. Kaczor-Urbanowicz KE, Carreras-Presas CM, Aro K, Tu M, Garcia-
Godoy F, Wong DTW. Saliva diagnostics - Current views and
directions. Exp Biol Med (Maywood) 2017; 242(5): 459-72. [CrossRef]
42. Abdul Rehman S, Khurshid Z, Hussain Niazi F, Naseem M, Al
Waddani H, Sahibzada HA, et al. Role of salivary biomarkers in
detection of cardiovascular diseases (CVD). Proteomes 2017; 5(3):
21. [CrossRef]
43. Isola G, Polizzi A, Muraglie S, Leonardi R, Lo Giudice A. Assessment
of vitamin C and antioxidant profiles in saliva and serum in pa-
tients with periodontitis and ischemic heart disease. Nutrients
2019; 11(12): 2956. [CrossRef]
44. Mrag M, Kassab A, Omezzine A, Belkacem Chebil R, Ben Fredj
Ismail F, Nabiha D, et al. Saliva diagnostic utility in patients with
type 2 diabetes: Future standard method. J Med Biochem 2019;
13. [CrossRef]
45. Abd-Elraheem SE, El Saeed AM, Mansour HH. Salivary changes in
type 2 diabetic patients. Diabetes Metab Syndr 2017; 11(2): 637-
41. [CrossRef]
46. Takeuchi Y, Furuchi M, Kamimoto A, Honda K, Matsumura H, Ko-
bayashi R. Saliva-based PCR tests for SARS-CoV-2 detection. J Oral
Sci 2020; 62(3): 350-1. [CrossRef]
47. Pasomsub E, Watcharananan SP, Boonyawat K, Janchompoo
P, Wongtabtim G, Suksuwan W, et al. Saliva sample as a non-in-
vasive specimen for the diagnosis of coronavirus disease-2019
(COVID-19): a cross-sectional study. Clin Microbiol Infect 2020; 15.
[CrossRef]
48. Deepa T, Thirrunavukkarasu N. Saliva as a potential diagnostic
tool. Indian J Med Sci 2010; 64(7): 293-306. [CrossRef]
49. Emekli Alturfan E, Yarat A, Akyüz S. Selenium in saliva and impact
on health. In: Preedy VR, editor. Selenium: Chemistry, Analysis,
Function and Effects (Food and Nutritional Components in Focus).
London: Royal Society of Chemistry; 2015.p.341-53. [CrossRef]