Relationship between hypothyroidism and periodontitis: A scoping review

Abstract Aim The objective of this study was to assess the existing literature to determine if a relationship exists between hypothyroidism and periodontitis. Methods We used a modified approach to the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses by searching five databases in addition to the gray literature. Keywords in the title and abstract fields, as well as subject headings for both periodontal disease and hypothyroidism, were used to search the existing literature for publications relevant to evaluation of the thyroid–periodontitis relationship. Results The authors screened 847 unique publications which, after applying inclusion and exclusion criteria, yielded 29 publications, which were further analyzed for relevance and applicability. Most of the included papers were cross‐sectional studies and retrospective chart reviews. Following critical analysis, four publications, including one abstract, were used to further assess the hypothyroid–periodontitis relationship. Conclusions There are very few high‐quality studies describing the potential association between hypothyroidism and periodontitis. In general, and among the included papers with the fewest confounding factors, a positive relationship between hypothyroidism and periodontitis was found. Further well‐controlled, prospective clinical and immunologic studies will be required to confirm that relationship.


| INTRODUCTION
Relationships between periodontal diseases and a variety of systemic conditions have been described in the literature, including cardiovascular disease, cerebrovascular disease, respiratory disease, pregnancies resulting in preterm delivery or low birth weight infants, diabetes mellitus, rheumatoid arthritis, obesity, osteoporosis, and stress (R. Genco, Offenbacher, & Beck, 2002;R. J. Genco & Borgnakke, 2013). In addition, there is evidence that the severity and prevalence of periodontitis is greater in individuals with autoimmune diseases such as rheumatoid arthritis (Wolff et al., 2014) and inflammatory bowel diseases (Brito et al., 2008;Vavricka et al., 2013). The association between those conditions and periodontal disease might be due to common immunoinflammatory pathways in disease pathogenesis (Araujo, Melo, & Lima, 2015). It has been hypothesized that inflammatory mediators such as prostaglandin E 2 , interleukin-1β, tumor necrosis factor-α, and matrix metalloproteinases released locally as a consequence of periodontal disease lead to an alteration in bone hemostasis and might represent a risk factor for other systemic diseases such as rheumatoid arthritis (Araujo et al., 2015;Habashneh, Khader, Alhumouz, Jadallah, & Ajlouni, 2012). It is well established that the endocrine system can modulate the immune system in a bidirectional manner (Klein, 2006). Indeed, the relationship between diabetes mellitus and periodontitis offers a potential explanation for how acute and chronic inflammation, such as what occurs during periodontitis, might affect thyroid hormone production (R. J. Genco & Borgnakke, 2013).
Hypothyroidism is the most common hormone abnormality in humans and represents the most common thyroid disease. Hypothyroidism presents with a wide range of severity, from asymptomatic individuals to patients with multisystem failure (Roberts & Ladenson, 2004) due to decreased production of thyroxine (T 4 ), triiodothyronine (T 3 ), and calcitonin (Little, 2006), which causes decreased bone metabolism, maturation, and turnover and negatively affects bone homeostasis (Mosekilde & Melsen, 1978).
Consequently, the primary aim of this scoping review was to evaluate the quality and quantity of the existing literature describing the potential relationship between hypothyroidism and periodontitis.
A secondary aim was to assess whether a relationship exists between hypothyroidism and periodontal disease severity.

This review used the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses reporting guideline (Moher, Liberati, Tetzlaff, & Altman, 2010) and modified them to apply to this scoping review.
An initial electronic search was created by a health sciences librarian and completed on September 4, 2018, and supplemented on April 26, 2019, in the following databases: PubMed, Embase via Embase.  (2011-present), and OpenGrey.eu. Proquest Dissertations and Theses Global allows for complex Boolean searching, which enabled the authors to use the same search that was used in the previously mentioned nongray databases. However, a search using the terms "periodontal disease" and "thyroid" or "periodontal disease" and Our initial search on September 4, 2018, yielded 1,182 articles.
When the search was updated on April 26, 2019, an additional 36 unique articles were identified. Three hundred seventy-one articles were then excluded due to duplication. Collectively, both searches resulted in 847 articles that were subsequently screened by two reviewers (H. A. amd L. Y.) and resulted in the exclusion of 746 articles due to irrelevant title and/or abstract (i.e., not related to periodontitis and hypothyroidism). Our inclusion and exclusion criteria are summarized in Table 2.
One-hundred one full-text articles were further assessed for eligibility by the same two reviewers; any conflicts were resolved by a third reviewer (R. C.). A total of 72 articles were excluded for the following reasons: no full-text available (three papers), not in English at the time of manual review (34 papers), not associated with a periodontal outcome or thyroid outcome (26 papers), related to hyperthyroidism or thyroid cancer but not hypothyroidism (two papers), incorrect/irrelevant comparator (i.e., no comparison between periodontitis and hypothyroidism; two papers), an incorrect or irrelevant intervention (i.e., an intervention not related to periodontal diagnosis; two papers), incorrect/irrelevant patient population (i.e., no comparison of periodontitis and or hypothyroidism; one paper), and if the journals of publication were cited in an open access checklist for predatory publishers (two papers). In addition, three papers were excluded due to duplication. As a result, a total of 28 full-length papers and one abstract were included for review. The selection process used in our analysis is described in more detail in Figure 1.

| Aim 1
To evaluate the quality and quantity of the existing literature describing the potential relationship between hypothyroidism and periodontitis.

| Outcome of search
After applying the inclusion, exclusion, and eligibility criteria noted above, a total of 29 publications, including one abstract, were considered for further analysis as shown in Table 3. We found that published papers describing the relationship between hypothyroid disease and periodontitis generally ranked poorly in the hierarchy of scientific evidence, and most were associated with significant methodological limitations. There were no published meta-analyses or systematic reviews available that described the thyroid-periodontal disease relationship.
Similarly, there were no randomized controlled human clinical trials and only one retrospective cohort study (that investigated dental implants). Only one intervention study and three case-control studies were available. There were 14 cross-sectional studies (five of them are retrospective chart reviews): two review papers, three case reports, and four animal studies, in addition to one abstract.

| Aim 2
To assess the relationship between periodontal disease severity and hypothyroidism.

| Relationship between hypothyroidism and periodontitis
All 29 publications noted in Table 3

| Papers excluded from analysis of hypothyroid-periodontitis relationships: Rationale and description
Two articles from Table 3 were review papers (Patil, Patil, & Gururaj, 2011;Zahid, Wang, & Cohen, 2011) that referred to primary articles also noted in that  (2015) also was excluded due to use of an adolescent patient population and a definition of pocket depths greater than 3 mm as "deep." In addition, populations, and because no association between diabetes and tooth loss was found when this association has been established. Tooth loss also might be related to nonperiodontal etiologies such as trauma or caries. Finally, the authors also acknowledged that many patients with systemic diseases such as diabetes might not have survived to old age, which is an additional study limitation.
Chatzopoulos and Tsalikis (2016) were excluded because a community periodontal index of treatment needs score of 3 was used for diagnosis of periodontitis, which would include patients having any teeth with pocket depths greater than 3 mm. No additional periodontal criteria (e.g., bone levels and histology) were considered. Moreover, patient populations with hypothyroidism, hyperthyroidism, and thyroid cancer were pooled and used for analysis. In this study, the authors also did not find a relationship between diabetes and periodontitis, which also suggests that their inclusion criteria included a considerable number of patients having gingivitis or only slight periodontitis.
The study by Molloy, Wolff, Lopez-Guzman, and Hodges (2004) found that thyroid disease was more prevalent among patients with mild bone loss, but not with tooth loss. In their analysis, the authors did not differentiate between hyperthyroidism, hypothyroidism, or thyroid cancer, which may have affected the results. In addition, it is arguable whether measurement of tooth loss is a sufficiently sensitive diagnostic indicator for periodontitis and was therefore excluded from critical analysis.
In the two publications by Chrysanthakopoulos (2013, 2016), a positive association was found between periodontal disease and hypothyroidism. They defined periodontitis by the presence of pocket depths equal or greater than 5 mm and excluded patients that had been recently treated for periodontal disease, to obtain patients with "clinically established periodontitis." However, those studies also pooled patients with thyroid disease to include hypothyroidism, hyperthyroidism, and thyroid cancer in one category. The authors further reported that as many as one third of their patient pool was reported to have hyperthyroidism. The authors also did not specifically indicate if the endocrine results had been adjusted for diabetes or smoking, and therefore, both studies were excluded.

Nesse et al. (2010) evaluated periodontitis and hypothyroidism in
control patients, periodontitis patients in dental clinics, and periodontitis patients in periodontal clinics. The results were adjusted for age, gender, and smoking. However, periodontitis was defined as having pocket depths greater than 3 mm and, although full mouth probing depths were recorded for patients with community periodontal index of treatment needs scores 3 or more, clinical periodontal data were unavailable in 28% of patients, smoking data were missing from 50% of one of the clinic sites, and smoking status was significantly different between the groups. An additional limitation of this study was that patients with periodontitis were significantly older than the control group and more likely to be female, which also might have affected the study outcome.
All of the three case reports by Patil and Giri (2012), Gupta, Goel, Solanki, and Gupta (2014), and Yussif, El-Mahdi, and Wagih (2017) were excluded because a periodontal diagnosis was not obtained in There was no control group, and no measurements of bone loss were recorded. Similarly, the rat study by Pinto (1974)

| Papers included in the analysis of hypothyroid-periodontitis relationships: Rationale and description
Of the 29 publications obtained from the results of the primary search, 25 were excluded as described above and four remained for further descriptive analysis to address Aim 2. The four remaining publications are listed in Table 4 and are described in more detail as follows: Rahangdale and Galgali (2018), in a comparative cross-sectional study involving 102 human subjects, found significantly greater mean pocket depths and more clinical attachment loss among patients with hypothyroidism, compared with patients without thyroid disease.
Groups were statistically adjusted for age, and plaque scores for both groups were similar. The authors concluded that patients taking thyroxine replacement medications were more likely to have periodontal disease than euthyroid control subjects.
Attard and Zarb (2002)  One well-designed animal study by Feitosa et al. (2009) was included in our analysis. The authors used an experimental periodontitis ligature model in a rat model system. Three groups were included in the study: control, hypothyroidism, and hyperthyroidism, and thyroid status was confirmed using laboratory blood testing for TSH.
Periodontal bone levels were measured via histomorphometric analysis. They found that an increase in periodontitis-related bone loss was associated with hypothyroidism (but not with hyperthyroidism).
One abstract by Yerke, Levine, and Cohen (2019) was included in our analysis. That study evaluated the association between hypothyroidism and severity of periodontitis among 538 patients with moderate to severe periodontitis. The extent of periodontal disease was evaluated by measuring the percentage of teeth with probing depths greater than or equal to 5 or 6 mm, and hypothyroidism was assessed through review of patient medical histories for use of prescription thyroid hormone supplementation in combination with a diagnosis of hypothyroidism. They found that patients with hypothyroidism had significantly more teeth with deeper periodontal probing depths, compared with patients without thyroid disease. In that study, all patients were examined by single examiner, but the retrospective natural of that analysis was a limitation because the dosage and duration of thyroid hormone supplementation was not determined.

| DISCUSSION
Our results indicate that there are very few high-quality studies describing the potential association between hypothyroidism and periodontitis. It appears that most of the available literature consists  (Patil et al., 2011;Zahid et al., 2011) that were identified in our scoping review for Aim 1, both of which found that, although there is evidence that a potential relationship might exist between hypothyroidism and periodontitis, existing literature lacks adequate randomized controlled clinical trials and observational studies to support this claim. Nevertheless, our review suggests that a positive relationship between hypothyroidism and periodontitis most likely exists and that this relationship might be more apparent among subjects with severe periodontitis, compared with patients with mild periodontal disease.
In the critical analysis section of our review, we identified three full-length papers and one abstract that demonstrated a positive relationship between those two conditions. All the excluded publications were compromised due to lack of defined periodontal measurements, as well as the use of relatively unreliable methods for diagnosis of hypothyroid disease. Consequently, it was not possible to perform a systematic review or meta-analysis of the periodontitis-thyroid disease relationship. Therefore, a scoping review was performed to assess the quality of the existing literature. Diseases and Conditions (Albandar, Susin, & Hughes, 2018), an established relationship between hypothyroidism and periodontitis was not described. This omission most likely was due to the lack of relevant literature supporting such an association.
One limitation of our study is that only papers written in English were included in our review, and other studies reporting results in languages other than English might be available.
With those limitations, we believe that there is evidence suggesting that a relationship between hypothyroidism and periodontitis likely exists, and we speculate that the relationship may be more apparent in individuals with more severe periodontitis. Perhaps the strongest support for that conclusion comes from the results of to advanced periodontitis, as well as by Attard and Zarb (2002), who described an association between hypothyroidism and periimplantitis.
Hypothyroid patients appear to have a decreased bone turnover rate secondary to slower resorption during bone remodeling (Mosekilde & Melsen, 1978;Mosekilde, Melsen, Bagger, Myhre-Jensen, & Schwartz Sorensen, 1977) that results in an increase in bone mass (Eriksen, Mosekilde, & Melsen, 1986). Because thyroid hormone receptors are present in human bone (Abu, Bord, Horner, Chatterjee, & Compston, 1997), it has been proposed that thyroid hormone might act directly on bone cells via specific nuclear receptors or indirectly via increasing the secretion of growth hormone and insulin-like growth factor (Abu et al., 1997). Patients with hypothyroidism tend to exhibit higher than normal bone density, whereas subjects with hyperthyroidism, characterized by lower levels of TSH, appear to experience bone loss and have a higher fracture incidence (Lakatos, 2003;Mosekilde, Eriksen, & Charles, 1990). Animal models of hypothyroidism also have demonstrated alterations in bone metabolism (Britto, Fenton, Holloway, & Nicholson, 1994;Monfoulet et al., 2011), possibly through a mechanism by which thyroid hormone has direct or indirect effects on osteoblasts and osteoclasts.
Other medications known to have thyroid effects include lithium, amiodarone, and oral estrogens (Eskes & Wiersinga, 2009;Rao et al., 2005;Schou et al., 1968;Tahboub & Arafah, 2009 From the authors' knowledge, this study is the first scoping review to evaluate the available literature regarding the association between periodontitis and hypothyroidism. Our study also identifies gaps and opportunities for future research in this area by conducting a welldesigned randomized clinical trial that include comprehensive assessment of immune status. A better understanding of the potential effect of thyroid hormone dysfunction in the outcome and severity of periodontitis might be important for the decrease in morbidity of both diseases.

| CONCLUSIONS
There are very few high-quality studies describing the potential association between periodontitis and hypothyroidism, with most of the available literature consisting of retrospective cross-sectional studies and chart reviews. In general, a positive association between periodontitis and hypothyroidism was found. Further well-controlled, prospective clinical and immunologic studies will be required to confirm that relationship, to measure the strength of any association with disease severity, to establish causality, and to establish the role of either disease in the pathogenesis of the other.

CONFLICT OF INTEREST
None of the authors have any financial or commercial associations or conflicts of interest.

SCIENTIFIC RATIONALE FOR THE STUDY
The potential association between periodontitis and a variety of immunologic and inflammatory conditions provides a foundation for a possible relationship between hypothyroidism and periodontitis.

PRINCIPAL FINDINGS
There are very few high-quality studies describing the potential association between hypothyroidism and periodontitis. Nevertheless, analysis of the most relevant clinical and experimental studies supported the existence of a positive relationship between hypothyroidism and periodontitis.

PRACTICAL IMPLICATIONS
Periodontists should consider thyroid disease, and endocrinologists should consider the presence of periodontitis, during patient evaluation because early diagnosis and intervention for both conditions is likely to mutually improve patient outcomes.