|Year : 2021 | Volume
| Issue : 1 | Page : 47-52
Estimation and correlation of serum and salivary C-reactive protein in oral potentially malignant disorders
Mansimranjit Kaur Uppal1, Asha R Iyengar2, BV Subash2, Seema Patil2, Manisha Lakhanpal Sharma1, Sahil Thakar3
1 Department of Oral Medicine and Radiology, I.T.S. Dental College, Hospital and Research Centre, Greater Noida, Uttar Pradesh, India
2 Department of Oral Medicine and Radiology, DAPM RV Dental College and Hospital, Bengaluru, India
3 Department of Public Health Dentistry, School of Dental Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
|Date of Submission||08-Dec-2020|
|Date of Decision||25-Dec-2020|
|Date of Acceptance||18-Jan-2021|
|Date of Web Publication||26-Mar-2021|
Dr. Sahil Thakar
Department of Public Health Dentistry, School of Dental Sciences, Sharda University, Greater Noida, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: A large proportion of oral cancers arise from oral potentially malignant disorders (OPMDs). Very few studies have assessed serum and salivary C-reactive protein (CRP) levels in OPMDs warranting further research. Furthermore, no study has evaluated the correlation of serum and salivary CRP in OPMDs to the best of our knowledge. Objectives: The study aimed to compare serum and salivary CRP levels between subjects with OPMDs and controls along with their correlation. Materials and Methods: A total of 60 subjects with 30 subjects each in the study (Group 1) and control group (Group 2) were included. Group 1 was further categorized into group 1a, 1b, and 1c comprising 10 subjects each of Leukoplakia, Oral lichen planus (OLP), and Oral submucous fibrosis (OSMF). Group 2 comprised of 30 age and gender-matched controls. Results: Higher mean serum and salivary CRP levels were found in subjects of Group 1 (5.91 ± 3.11 mg/L and 1.00 ± 0.45 mg/L, respectively) as compared to group 2 (2.18 ± 0.66 mg/L and 0.48 ± 0.33 mg/L) with a statistically significant difference (P < 0.001). There was a positive correlation between serum and salivary CRP levels values in both group 1 (P < 0.001) and group 2. Conclusion: Higher serum and salivary CRP levels in OPMD subjects in comparison with controls indicate its role as a potential biomarker in the early detection of oral cancer. A positive correlation between the two potentiates the use of saliva as a non-invasive diagnostic tool for detection of CRP.
Keywords: C-reactive protein, oral cancer, oral potentially malignant disorders, saliva, serum
|How to cite this article:|
Uppal MK, Iyengar AR, Subash B V, Patil S, Sharma ML, Thakar S. Estimation and correlation of serum and salivary C-reactive protein in oral potentially malignant disorders. J Indian Acad Oral Med Radiol 2021;33:47-52
|How to cite this URL:|
Uppal MK, Iyengar AR, Subash B V, Patil S, Sharma ML, Thakar S. Estimation and correlation of serum and salivary C-reactive protein in oral potentially malignant disorders. J Indian Acad Oral Med Radiol [serial online] 2021 [cited 2021 Apr 14];33:47-52. Available from: https://www.jiaomr.in/text.asp?2021/33/1/47/312209
| Introduction|| |
Oral potentially malignant disorders (OPMDs) are a group of several oral mucosal lesions with an increased potential for malignant transformation. The term OPMDs replaces older terminologies such as precancerous lesions and conditions. The reason behind WHO adopting the term OPMDs is because of the fact that not all precancerous lesions and conditions convert into malignancy although they do have the potential. The commonly occurring OPMDs are Leukoplakia, Oral lichen planus (OLP) and Oral submucous fibrosis (OSMF), Erythroplakia, Discoid lupus erythematosus (DLE), etc. Out of these, leukoplakia is the most common OPMD. Currently, leukoplakia is defined as “predominant white plaque of questionable risk having excluded (other) known diseases or disorders that carry no increased risk for cancer.” OLP, another common OPMD which shows mucocutaneous involvement is idiopathic in origin and is associated with chronic inflammation. Its chronicity has considerable impact on patients' quality of life. One of the complications of OLP is conversion into malignancy, although the malignant transformation potential is lesser than leukoplakia. OSMF is common in Asian countries including India and is strongly associated with the usage of betel quid.
The identification of oral cancer in its initial stage is of paramount importance as it is associated with significant morbidity and mortality. Currently, there is no definitive method of predicting the risk of malignant transformation of an oral potentially malignant disorder, however, various factors such as location of the lesion, clinical appearance (homogeneous vs. heterogeneous), and presence of dysplasia have been correlated with the risk of transformation. Recent advancements in oral cancer research have led to the development of useful diagnostic tools at the clinical and molecular level for the early detection of oral cancer. Molecular biomarkers are contemporary tools which have been gaining importance in the field of cancer diagnosis at an early stage. Blood and saliva are the frequently studied body fluids that may contain reliable biomarkers for cancer detection. In the present era of salivanomics, studies on salivary biomarkers such as interleukins, tumor necrosis factors have shown encouraging results in early detection of OPMDs.
CRP, one such biomarker, is an acute phase protein and is a member of the pentaxim protein family which was first identified by Tilet & Francis in 1930., It is normally present in trace amounts and its concentration increases with inflammation. Previous studies have demonstrated that elevated CRP levels in coronary artery disease (CAD), chronic obstructive pulmonary disease (COPD), diabetes mellitus, hypertension, etc., to be associated with poor prognosis. CRP levels have also found to be raised in several malignancies and has been associated with tumor size, depth of invasion, and metastases. However, it is still unclear whether CRP levels are elevated prior to or after the onset of cancer.
As a large proportion of oral cancers arise from oral potentially malignant conditions, the detection of serum and salivary CRP levels in OPMDs is pertinent. Very few studies have evaluated the serum and salivary CRP levels in OPMDs,, justifying the need for further research. Furthermore, no study has assessed the correlation of serum and salivary CRP levels in OPMDs to the best of our knowledge.
Hence, the present study aimed at comparing the serum and salivary CRP levels in subjects with OPMDs and controls. The correlation between serum and salivary CRP levels was also assessed.
| Materials and Methods|| |
Based on the mean values of serum CRP (reference for pilot study), percentages were calculated and sample size was estimated using the formula n = 4pq/a2. After re-confirming the sample size using open Epi software, the minimum sample size was found to be 57. A total of 60 subjects were included in the study comprising 30 subjects each in the study and control group. The study group (group 1) was further divided into group 1a, 1b, and 1c comprising 10 subjects each of leukoplakia, OLP, and OSMF. The control group (Group 2) comprised 30 age and gender-matched healthy subjects. Subjects with current or past habit of tobacco consumption in the smoked form or smokeless form were excluded. Further, subjects with underlying systemic inflammatory disorders such as diabetes mellitus, hypertension, rheumatoid arthritis etc., primary malignancies such as lung carcinoma, colorectal carcinoma, penile carcinoma, oral inflammatory conditions, viz. gingivitis and periodontitis, infections, especially bacterial in the last 1 month, which could alter the CRP levels were excluded from the study. Prior to conducting the study, ethical clearance was obtained from the institutional review board, Certificate No: 040/Vol. 1/2013 approved on 13/11/2013). On the basis of the principles of Helsinki declaration, written informed consent was taken from all subjects and the confidentiality of the data was maintained. The gingival health of the subjects was assessed using the gingival index by Loe and Silness (1963). A thorough clinical examination was carried out for all the subjects included in the study followed by a complete oral prophylaxis. For the clinical diagnosis of group Ia, diagnostic criteria given by Warnakulasuriya et al. (2007) were used and group 1b, diagnosis was based on modified WHO criteria. Group Ic subjects were diagnosed using clinical examination as proposed by Khanna and Andrade (1995). All the patients were subjected to histopathological examination following biopsy. Blood sample was obtained from the antecubital vein with minimal trauma under aseptic conditions from subjects of both group 1 and group 2. Whole unstimulated saliva was collected from both group 1 and 2 subjects for 5 min by asking the subjects to lean forward and spit into sterile precooled plastic containers (-20°C). It was allowed to stand in a test tube for 15–20 min, after which it was centrifuged at 3,000 rpm for 15–20 min. The containers with supernatant serum and saliva were kept in an ice box and transported immediately to the lab for estimation of salivary CRP levels. The method used for the measurement of the CRP in serum and saliva of the patients was CRP-Turbilatex method, a quantitative turbidimetric method.
Statistical analysis consisted of the unpaired Student's t-test, one-way ANOVA, Pearson's correlation using SPSS version 21.0. The confidence interval (CI) was kept at 95% and a statistical significance was observed when P was <0.05.
The normal established range of the serum CRP level is between 0-0.3mg/L whereas in saliva, it has been postulated to be 0.05–64.3 μg/L.
| Results|| |
Mean age and gender distribution in OPMDs and controls
The age of subjects in group 1 ranged between 18 and 72 years with a mean of 41.53 ± 17.20 years. Varied means were observed among the subjects of group 1a (40.20 ± 18.83 years), 1b (52.10 ± 17.91 years), and 1c (32.30 ± 7.54 years). In group 2, the age of subjects ranged between 19 and 83 years with a mean of 40.80 ± 17.18 years [Table 1].
|Table 1: Mean age and gender distribution in OPMDs and controls 1a Leukoplakia, 1b OLP, 1c OSMF|
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Both group 1 and group 2 comprised 25 males (83.3%) and 5 females (16.7%) each. In group 1a and group 1c, all of the 10 subjects (100%) were males. In group 1b, there was an equal number of males (5, 50%) and females (5, 50%).
Range and mean serum CRP levels in OPMDs and controls
The serum CRP levels among subjects in group 1 and group 2 ranged between 1.19 mg/L to 15.89 mg/L and 1.0 mg/L to 3.7 mg/L, respectively. It was observed that the range of CRP levels among individual subgroups of group 1 was higher as compared to group 2 and the difference was statistically significant (P < 0.001*). Asterix denotes statistically significant results [Table 2].
|Table 2: Range and mean serum CRP levels in OPMDs and controls 1a Leukoplakia, 1b OLP, 1c OSMF, *denotes statistically significant (mg/L)|
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The mean serum CRP levels of group 1 subjects (5.91 ± 3.11 mg/L) was significantly higher than that of the group 2 subjects (2.18 ± 0.66 mg/L) (P < 0.001*).
Range and mean salivary CRP levels in OPMDs and controls
The salivary CRP levels among subjects in group 1 and group 2 ranged between 0.2 mg/L to 1.82 mg/L and 0.1 mg/L to 1.60 mg/L, respectively [Table 3].
|Table 3: Range and mean salivary CRP levels in OPMDs and controls, 1a Leukoplakia, 1b OLP, 1c OSMF, 2 controls, *statistically significant (mg/L)|
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It was observed that mean salivary CRP levels of the individual subgroups of group 1 was higher as compared to controls and the difference was statistically significant (P < 0.001*).
The mean salivary CRP levels of subjects in group 1 (1.00 ± 0.45 mg/L) was significantly higher than that of the subjects in group 2 (0.48 ± 0.33 mg/L). (P < 0.001*).
Correlation between serum and salivary CRP levels in OPMDs & Controls
A positive correlation was found (r = 0.370) between the serum CRP and salivary CRP levels in group 1 subjects which was statistically significant (P = 0.04*). The serum and salivary CRP levels were found to be highest in Group 1a followed by Group 1b and Group 1c with a two-fold increase in all the groups resulting in a positive correlation between the serum and saliva. The comparison of serum CRP and salivary CRP levels in group 2 showed a weak positive correlation (r = 0.245) which was not statistically significant (P = 0.09) [Table 4].
|Table 4: Correlation between serum & salivary CRP levels in OPMDs & Controls using Pearson's Correlation statistics|
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A scatter diagram of the results was also plotted. [Figure 1]
|Figure 1: Scatterplot depicting the correlation between Serum and Salivary CRP levels (mg/L)|
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| Discussion|| |
CRP is an acute phase protein synthesized by hepatocytes in liver and the levels are known to increase in response to pro-inflammatory cytokines including Interleukins (IL-1α, IL-1β, IL-2, IL-6), tumor necrosis factor-α (TNF-α), transforming growth factor–β (TGF-β), and interferon γ (IFN-γ). IL-6 is the principal pro-inflammatory cytokine that moderates CRP synthesis. The role of IL-6 in angiogenesis and tumor progression has been established. CRP has been found to be elevated in patients with several malignancies such as pancreatic carcinoma, gastric carcinoma, prostatic carcinoma, and penile carcinoma implying a close association between inflammation and malignancy. Inflammation is a critical component of tumor progression and oral cancer can arise from sites of infection, chronic irritation, and inflammation in the oral cavity. Chronic inflammation results in excessive cell proliferation and activation of a cascade of cellular response which leads to induction of irreversible DNA damage. However, it has also been suggested that chronic inflammation induced by the tumor process could lead to CRP elevation as seen in a prospective study.
Recent studies have suggested that the serum CRP levels increase in OPMDs such as leukoplakia, OLP, and OSMF as compared to subjects with normal oral mucosa.,,, It has been put forth that the immune response triggered by the precancerous cells results in the production of the inflammatory cytokines which in turn can lead to tumor formation or tumor destruction. Hence, it may be presumed that the immune response generated by potentially malignant cells could be both pro-neoplastic and anti-neoplastic. Thus, the raised CRP levels can be ascribed to either anti-neoplastic or pro-neoplastic response. In the present study, serum CRP levels in subjects with OPMDs were significantly elevated (5.91 ± 3.11 mg/L) as compared to controls (2.18 ± 0.66 mg/L). Similar findings have been reported in studies conducted by Kumar and Bhateja, Metgud et al., and Vankadara et al. in which the role of CRP as a marker for detection of oral cancer was suggested.,,
In the present study, the mean serum CRP levels in group 1a were significantly elevated as compared to the group 2. This is in accordance with a study conducted by Gupta et al. in which there was an increase in the mean serum CRP levels in subjects with leukoplakia in comparison with controls, although the difference was not statistically significant. In the present study, serum CRP level was higher in subjects with mild to moderate dysplasia in comparison to subjects with no dysplasia. Further, dysplastic lesions are known to possess a higher degree of malignant transformation potential as compared to non-dysplastic lesions. Hence, it may be inferred that elevated CRP levels may be suggestive of a probable malignancy.
OLP is associated with an upregulation of inflammatory cytokines such as IL-2 and IFN-γ which may in turn lead to increase in CRP levels in OLP subjects. In the present study, group 1b subjects had significantly higher mean serum CRP levels of 4.51 ± 2.83 mg/L as compared to the control group (2.18 ± 0.66 mg/L) (P < 0.001*). Similar findings were reported in a few other studies done by Kumar and Bhateja, Vankadara et al.,
In OSMF, there are inflammatory changes which can be attributed to the upregulation of the inflammatory fibrogenic cytokines such as interleukin 1 and 6 and release of inflammatory mediators such as COX-2 (cyclo-oxygenase). Thus, increased CRP levels in OSMF subjects could be attributed to the above reason. In the present study, the OSMF subjects had significantly higher mean serum CRP levels (5.92 ± 2.76 mg/L) as compared to the control group (2.18 ± 0.66 mg/L).
Saliva is a biological fluid that performs various important functions in maintaining the health and homeostasis of the oral cavity. The advantages of using saliva as a diagnostic body fluid as compared to serum are manifold such as it can be collected in a simple and non-invasive manner and there is a minimal hazard of contracting infections etc., But its use can be limited by certain facts such as the reduced accuracy of processing saliva and limited volume of saliva being collected as compared to blood and increased cost of analysis.
The mean salivary CRP levels were significantly higher in subjects with OPMDs (1.00 ± 0.45 mg/L) as compared to controls (0.48 ± 0.33 mg/L) (P < 0.001*) in the present study. The significant increase in the salivary CRP levels of the study group as compared to the control group is in accordance with the data reported in a study conducted by Metgud et al. (P < 0.05*) and Krasteva et al.
The increased level of CRP in the saliva could be ascribed to the direct transudation of CRP from the blood to saliva in the diseased state. The mechanism of entry 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.
In group 1a, the mean salivary CRP levels were 1.21 ± 0.44 mg/L which were significantly elevated in comparison with controls (0.48 ± 0.33 mg/L). Similar findings have been reported in a few other studies done by Metgud et al. and Gupta et al., in which the authors emphasized on the role of salivary CRP as a potential biomarker in detection of oral cancer in OPMDs. The mean salivary CRP levels both in groups Ib and 1c were also significantly increased as compared to the control group.
Previous studies have demonstrated a moderate association between the salivary and serum CRP in health and disease., The association between salivary and serum CRP, particularly in OPMDs has not been examined in earlier studies. In the present study, a positive correlation between serum and salivary CRP levels in OPMDs was found which was statistically significant. This finding is noteworthy and highlights the probable use of saliva in place of blood in future research.
Limitations and future prospects
Certain limitations of substituting saliva over blood such as lesser concentration of CRP in saliva, collection and processing errors and diurnal variation need to be addressed in the future. Further, a larger sample size may help in establishing the role of salivary CRP in subjects with OPMDs as a diagnostic biomarker. Also, CRP levels should be correlated with the degree of dysplasia of OPMDs.
Post treatment evaluation of salivary CRP in OPMDs may indicate its role as a prognostic biomarker.
| Conclusion|| |
Higher serum and salivary CRP levels in subjects with OPMDs in comparison to controls indicate its role as a potential biomarker in the early detection of oral cancer. A positive correlation between saliva and serum CRP levels potentiates the use of saliva as a non-invasive diagnostic tool for detection of CRP levels.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Warnakulasuriya S. Clinical features and presentation of oral potentially malignant disorders. Oral Surg Oral Med Oral Pathol Oral Radiol 2018;125:582-90.
Barnes L, Eveson JW, Reichart P, Sidransky D. World Health Organization classification of tumours. Pathology and Genetics. Head and Neck Tumours. Lyon: IARC; 2005. p. 177–9.
Lodi G, Scully C, Carrozzo M, Griffiths M, Sugerman PB, Thongprasom K. Current controversies in oral lichen planus: Report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005;100:40-51.
Warnakulasuriya S, Kerr AR. Oral submucous fibrosis: A review of the current management and possible directions for novel therapies. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122:232-41.
Gillenwater A, Papadimitrakopoulou V, Kortum RR. Oral premalignancy: New methods of detection and treatment. Curr Oncol Rep 2006;8:146–54.
Shah FD, Begum R, Vajaria BN, Patel KR, Patel JB, Shukla SN, et al
. A review on salivary genomics and proteomics biomarkers in oral cancer. Indian J Clin Biochem 2011;26:326–34.
Veluchamy V, Sankaran M. The crucial role of biomarkers in oral cancer: Review. Asian J Biochem Pharm Res 2014;4:193-210.
Anand Kumar C, Bhateja S. Altered C-reactive protein levels in serum of oral precancer patients in comparison with healthy controls. Int J Oral Maxillofac Pathol. 2011;2:16-9.
Kim DK, Oh SY, Kwon HC, Lee S, Kwon KA, Kim BG, et al
. Clinical significance of preoperative serum interleukin-6 and C-reactive protein level in operable gastric cancer. BMC Cancer 2009; 9:155.
Kruse AL, Luebbers HT, Gratz KL. C-reactive protein levels: A prognostic marker for patients with head and neck cancer? Head Neck Oncol 2010;2:1-4.
Metgud R, Bajaj S. Altered serum and salivary C-reactive protein levels in patients with oral premalignant lesions and oral squamous cell carcinoma. Biotech Histochem 2016;91:96-101.
Gupta S, Tyagi N, Nadal A. Serum and Salivary C-reactive protein in patients with oral leukoplakia and squamous cell carcinoma. Int J Res Rev 2019;6:40-4
Löe H. The Gingival Index, the Plaque Index and the Retention Index Systems. J Periodontol 1967;38:610-6.
Warnakulasuriya S, Johnson NW, van der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Pathol Med 2007;36:575-80.
Rad M, Hashemipoor MA, Mojtahedi A, Zarei MR, Chamani G, Kakoei S, et al
. Correlation between clinical and histopathologic diagnoses of oral lichen planus based on modified WHO diagnostic criteria. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009;107:796-800.
Khanna JN, Andrade NN. Oral submucous fibrosis: A new concept in surgical management. Report of 100 cases. Int J Oral Maxillofac Surg 1995;24:433-9.
Kanaparthy A, Kanaparthy R, Niranjan N. Evaluation of serum C-reactive protein levels in subjects with aggressive and chronic periodontitis and comparison with healthy controls. Dent Res J (Isfahan) 2012;9:261-5.
Dillon MC, Opris DC, Kopanczyk R, Lickliter J, Cornwell HN, Bridges EG, et al
. Detection of homocysteine and C-reactive protein in the saliva of healthy adults: Comparison with blood levels. Biomarker Insights 2010;5:57-61.
Osman TA, Costea DE, Johannessen AC. The use of salivary cytokines as a screening tool for oral squamous cell carcinoma: A review of the literature. J Oral Maxillofac Pathol 2012;16:256-61. [Full text]
Szkandera J, Stotz M, Absenger G, Stojakovic T, Samonigg H, Kornprat P, et al
. Validation of C-reactive protein levels as a prognostic indicator for survival in a large cohort of pancreatic cancer patients. BJC 2014;110:183-8.
Shimura T, Kitagawa M, Yamada T, Ebi M, Mizoshita T, Tanida S, et al
. Anticancer Res 2012;32:491-6.
Graff JN, Beer TM. The role of c-reactive protein in prostate cancer. Cancer 2013;3262-4.
Steffens S, Ghazal AA, Steinestel J, Lehmann R, Wegener G, Schnoeller TJ, et al
. High CRP values predict poor survival in penile cancer patients. BMC Cancer 2013;13:223.
Wang CS, Sun CS, C-reactive Protein and Malignancy: Clinico-pathological association and therapeutic implication. Chang Gung Med J 2009;320:471-82.
Kidane D, Chae WJ, Czochor J, Eckert KA, Glazer PM, Bothwell ALM, et al
. Interplay between DNA repair and inflammation, and the link to cancer. Crit Rev Biochem Mol Biol 2014;49:116-39.
Sproston SR, Ashworth JJ. Role of c-reactive protein at sites of inflammation and infection. Front Immunol 2018;9:754.
Vankadara S, Padmaja K, Balmuri PK, Naresh G, Reddy V. Evaluation of serum CRP protein levels in oral premalignancies and malignancies: A comparative study. J Dent Teh Uni Med Sci 2018;15:358-64.
Allin KH, Nordestgaard BG. Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer. Crit Rev Clin Lab Sci 2011;48:155-70.
Gosavi SR, Torkadi AA. Serum C-reactive protein in oral submucous fibrosis and oral squamous cell carcinoma: A cross-sectional study. J Oral Maxillofac Pathol 2020;24:46–51. [Full text]
Chiappin S, Antonelli G, Gatti R, De Palo EF. Saliva specimen: A new laboratory tool for diagnostic and basic investigation. Clin Chim Acta 2007;383:30–40.
Pfaffe T, White JC, Beyerlein P, Kostner K, Punyadeera C. Diagnostic potential of saliva: Current state and future applications. Clin Chem 2011;57:675-87.
Mohamed R, Campbell JL, White JC, Dimeski G, Punyadeera C. The impact of saliva collection and processing methods on CRP, IgE, and Myoglobin Immunoassays. Clin Transl Med 2012;1:1-8.
Malathi N, Mythili S, Vasanthi HR. Salivary diagnostics: A brief review. ISRN Dent 2014;2014:158786. doi: 10.1155/2014/158786.
Yeh CK, Christodoulides NJ, Floriano PN, Miller CS, Ebersole JL, Weigum SE, et al
. Current development of saliva/oral fluid-based diagnostics. Tex Dent J 2010;127:651–61.
Krasteva A, Aleksiev E, Ivanova A, Altankova I, Bocheva T, Stanimirov P, et al
. Salivary components of treated Cancer patients and patients with precancerous lesions. J IMAB 2008;14:41-4.
Out D, Hall RJ, Granger DA, Page GG, Woods SJ. Assessing salivary C-reactive protein: Longitudinal associations with systemic inflammation and cardiovascular disease risk in women exposed to intimate partner violence. Brain Behav Immun 2012;26:543–51.
Ouellet-Morin I, Danese A, Williams B, Arseneault L. Validation of a high-sensitivity assay for C-reactive protein in human saliva. Brain Behav Immun 2011;25:640-6.
[Table 1], [Table 2], [Table 3], [Table 4]