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Noh, J.;  Jang, J.;  Yoon, H.;  Kim, K.;  Heo, M.;  Jang, H.;  Kim, Y.;  Lee, Y. Evaluation of Salivary Biomarkers of Periodontal Disease. Encyclopedia. Available online: https://encyclopedia.pub/entry/36395 (accessed on 11 December 2023).
Noh J,  Jang J,  Yoon H,  Kim K,  Heo M,  Jang H, et al. Evaluation of Salivary Biomarkers of Periodontal Disease. Encyclopedia. Available at: https://encyclopedia.pub/entry/36395. Accessed December 11, 2023.
Noh, Jin-Won, Jong-Hwa Jang, Hae-Soo Yoon, Kyoung-Beom Kim, Min-Hee Heo, Ha-Eun Jang, Young-Jin Kim, Yejin Lee. "Evaluation of Salivary Biomarkers of Periodontal Disease" Encyclopedia, https://encyclopedia.pub/entry/36395 (accessed December 11, 2023).
Noh, J.,  Jang, J.,  Yoon, H.,  Kim, K.,  Heo, M.,  Jang, H.,  Kim, Y., & Lee, Y.(2022, November 24). Evaluation of Salivary Biomarkers of Periodontal Disease. In Encyclopedia. https://encyclopedia.pub/entry/36395
Noh, Jin-Won, et al. "Evaluation of Salivary Biomarkers of Periodontal Disease." Encyclopedia. Web. 24 November, 2022.
Evaluation of Salivary Biomarkers of Periodontal Disease
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Saliva is a useful biomarker for diagnosing oral health conditions, including periodontal disease (PD). Smoking is a risk factor for PD. Smokers had increased levels of malondialdehyde, sialic acid, salivary cortisol, salivary interleukin 1β, albumin, tissue inhibitor of matrix metalloproteinase (TIMP), and the pyridinoline cross-linked carboxyterminal telopeptide of type I collagen (ICTP), as well as decreased levels of superoxide dismutase, activity of lactate dehydrogenase, activity of enzyme activity of β-glucuronidase, uric acid, matrix metalloproteinase-8 (MMP-8)/TIMP-1 ratio, and combinations of MMP-8 and ICTP. However, mixed results were observed some studies in detecting glutathione peroxidase, MMP-8, and MMP-14. The results were interpreted with caution because of limitations in the number of included studies and the study design. Some salivary biomarkers are potentially useful in combination or alone for diagnosing PD. 

biomarker diagnosis periodontal diseases

1. Introduction

Periodontal disease (PD) is one of the most common inflammatory diseases of the oral cavity, and it affects up to 90% of the global population [1]. It is caused by inflammation of the surrounding structures of teeth, such as the gingiva, periodontal ligament, and bone; if not treated properly, it can lead to tooth loss and contribute to systemic inflammation [2].
Since PD often progresses without symptoms, many patients do not receive professional dental care until the periodontal destruction that cannot be treated has progressed [3]. In addition, there is an unmet need for diagnosing PD quickly because a PD diagnosis relies on time-consuming clinical measurements [3]. Saliva is an optimal biological fluid to serve as a point-of-care (POC) diagnostic tool for PD. From this point of view, a POC diagnosis simplifies diagnosis and improves prognosis, and the feasibility of PD diagnostic testing has been reported [4].
Many promising salivary biomarkers associated with PD have been reported [3]. The pathogenesis of periodontitis is related to enzymatic alterations such as malondialdehyde (MDA), sialic acid (SA), lactate dehydrogenase (LDH), cortisol, β-glucuronidase (BetaG), interleukin 1β (IL-1β), antioxidants, oxidative stress, superoxide dismutase (SOD), 8-hydroxydeoxyguanosine, glutathione peroxidase (GPx), and 4-hydroxynonenal [5][6][7][8]. SOD is an antioxidant enzyme that is localized within human periodontal ligaments, and it provides an important defense within gingival fibroblasts against superoxide [9]. However, plasma glutathione peroxidase, a selenium-containing peroxidase, comprises a major group of enzymes that remove the hydrogen peroxide created by SOD in the cell [10]. IL-1β stimulates the expression of matrix metalloproteinases (MMPs), which contribute to bone resorption and tissue destruction [11]. To date, 24 different MMPs have been cloned, and three of them have been found in humans. Based on the substrate to be degraded, they are divided into six types: collagenase, gelatinases (type collagenase), stromelysins, matrilysins, membrane-type metalloproteinases, and others [12]. Among the MMPs, MMP-8 and MMP-9 are in the spotlight as biomarkers for periodontal disease. A kit that can test for MMP-8 in 5 min in an office has been developed [13][14].
PD progression can be influenced by various risk factors such as periodontal pathogens, host factors, anatomical factors, and iatrogenic factors [15]. Among the associated risk factors, smoking is the second-largest risk factor for PD after dental plaque [1]. Reports indicate that the prevalence of periodontitis is 3–6 times higher in smokers than in non-smokers, and the increased risk is proportional to the duration of smoking and smoking rate [16][17]. Smokers exhibit more pronounced PD clinical findings than non-smokers, such as deeper pockets, more extensive and severe loss of attachment, higher levels of bone destruction, and higher rates of tooth loss [18][19][20]. In addition, smoking negatively affects successful implant placement and non-surgical and surgical treatment [21].
Meanwhile, saliva contains a unique and complex variety of enzymes and proteins with important oral functions [5]. The use of these enzymes for diagnosing PD has unfortunately been hindered because the relevance of protein and enzymes in saliva and disease etiology remain limited. Furthermore, enzymatic alterations can be caused by various factors such as temperature, pH, enzyme substrates, and the effect of inhibitors and activators [22]. In particular, tobacco compounds the damage activities of salivary enzymes at the molecular level [23]. However, saliva samples are non-invasive, readily available, and inexpensive; therefore, saliva can be a valid alternative to blood as a biomarker [24][25]. Saliva is a favorable oral fluid to determine the health state of the oral cavity, including the presence of PD [26][27]. Therefore, an effective and reproducible salivary biomarker would be preferred over other biomarkers.

2. Evidence for Salivary Biomarkers Based on Smoking Status

As a result on salivary biomarkers for PD diagnosis by smoking status, some markers showed significant differences between smokers and non-smokers. However, certain salivary biomarkers may be potentially useful in combination and alone in the diagnosis of PD, but more systematically robust studies are needed to validate these biomarkers [28]. In a study, higher levels of MDA, SA, salivary cortisol, IL-1β, TIMP, and ICTP were found in smokers compared to non-smokers with PD. In particular, cortisol and IL-1β levels were higher in smokers than in non-smokers. These results were reported by Zhang et al. [29] and are consistent with the report that salivary cortisol levels were significantly higher in smokers with chronic periodontitis than in non-smokers with chronic periodontitis.
However, non-smokers showed high levels of SOD and UA. In addition, although not significant, they had higher levels of activity of LDH and BetaG, MMP-8/TIMP-1 ratio [30], and combined MMP-8 and ICTP. LDH and BetaG activity were significantly decreased in smokers with periodontitis [31], which is similar to the results , but the results were not statistically significant [5]. IL-1β and MMP-8 were consistent with the diagnostic value of host-derived salivary biomarkers based on the reported sensitivity and specificity in relation to the clinical parameters of the diagnosis of PD in adults [28]. In addition, research results regarding IL-1β are conflicting. Unlike the finding, another study [32] demonstrated that IL-1β gene expression was lower in smokers with chronic periodontitis than in non-smokers with chronic periodontitis (p = 0.003). Currently, there is limited evidence confirming the diagnostic power of salivary biomarkers in the clinical evaluation of PD. Nevertheless, findings from several studies, including this one, are of growing importance for salivary biomarkers and may guide larger and more well-controlled studies of diagnostic accuracy. Although not conclusive, IL-1β is reported to be a promising biomarker for future studies [29].
Saliva is an easy and non-invasive diagnostic fluid that is useful for the diagnosis of early periodontitis, and the possibility of early diagnosis of periodontitis in adolescents, especially boys, based on elevated salivary MMP-8 levels has been reported [33]. Smoking may affect the usefulness of salivary biomarker assays and should always be considered when interpreting biomarker results. Smoking is a risk factor influencing the inflammatory response leading to PD. Therefore, attention should be paid to the disturbance caused by smoking in the interpretation of potential salivary diagnostic test results [34]. While MMP-8 was mainly affected by smoking pack-years, salivary MMP-9 and TIMP-1 are reported to be mainly affected in current smokers or those who have quit smoking within the last 1 year [34]. In addition, a meta-analysis by Lin et al. [35] showed that MMP-8 is currently considered one of the most promising biomarkers for the early diagnosis of periodontitis, but conflicting results were found in several studies. Overall salivary MMP-8 levels were significantly higher in periodontitis patients compared with healthy controls. However, they reported that higher quality studies are still needed to confirm the conclusions due to the heterogeneity of studies and publication bias [36].

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