Periodontal status of hypothyroid patients on thyroxine replacement therapy: A comparative cross-sectional study.

BACKGROUND: Thyroid hormones play a significant role in bone remodeling. However, there are few studies on the effect of these hormones on periodontium. AIM: The aim of this study was to evaluate the periodontal status of hypothyroid patients on thyroxine replacement therapy.
MATERIALS AND METHODS: Clinical parameters (plaque index, bleeding index, probing pocket depth [PPD], and clinical attachment level [CAL]) and radiographic parameters (Mandibular cortical width and panoramic mandibular index) were recorded in 52 hypothyroid patients on thyroxine replacement therapy (Study group) and 50 individuals without signs and symptoms of thyroid dysfunction (Control group). The effect of dosage and duration of therapy on clinical and radiographical parameters were also assessed in the study group.
RESULTS: Statistically significant higher PPD (P = 0.008) and clinical attachment loss (P = 0.032) were observed in the study group in comparison to the control group. However, no significant differences were observed within the hypothyroid group with varying doses and duration of therapy. Furthermore, there was no correlation between the dosage and duration of therapy with periodontal status. Regression analysis showed that hypothyroidism and thyroxine replacement therapy was a significant predictor of PPD and CAL even after controlling for the effect of age in hypothyroid patients.
CONCLUSION: Hypothyroid patients on thyroxine replacement therapy may be at increased risk for periodontal destruction. However, this needs to be validated through longitudinal studies.

INTRODUCTION

Periodontal diseases are multifactorial, initiated by dental plaque and modified by local and systemic factors which influence the course and progression of these diseases. Their extent of the association has been described and established through various studies.[1]

Thyroid dysfunctions are common, and biochemical evidence of thyroid dysfunction either hypothyroidism or hyperthyroidism has been found in 2% of the global adult population. Patients, who have primary hypothyroidism, have elevated thyroid-stimulating hormone (TSH) and decreased levels of thyroid hormones (T3 and T4). Both TSH and thyroid hormones seem to have effect on bone through their receptors. TSH has a wide functional role as receptors for TSH have been identified in many tissues. Thyroid hormone receptors TR α-2 and TR β-1 are identified in chondrocytes, osteoblasts, and bone marrow cultures. Thyroid hormone preparations in varying doses are used to correct hypothyroidism of any etiology. Slightly supraphysiological doses of thyroxine administered to suppress thyrotropin secretion can have adverse effects on bone such as reduced density and bone mass.[2] Detrimental effects of thyroxine replacement therapy have been reported in hip, spine, femur, and radius with an accelerated rate of remodeling of cortical and cancellous bone resulting in reduced bone mass and increased risk of osteoporosis.[345]

Bones of the skeleton vary in their response to thyroxine replacement therapy. A significant decrease in bone density of mandible was reported in a study in rats with increasing doses of thyroxine.[6] Another study on rats with hypothyroidism reported improved healing around implants after administration of thyroxine.[7]

Furthermore, it was reported that thyroid hormone-deficient state (hypothyroidism) in rats may potentiate the bone loss resulting from ligature-induced periodontitis whereas no significant impact of thyroid hormone changes was observed in the noninflamed state.[8]

Although periodontitis is an inflammatory disease that develops in response to the biofilm in the subgingival area, it is modified by a number of risk factors. While osteoporosis is considered as a risk factor for periodontitis, others have suggested that periodontitis may be an early manifestation of generalized osteopenia and osteoporosis. It has been suggested that a local reduction in bone mineral density in jaws could set the stage for rapid periodontal destruction after injury from periodontal bacteria.[9] Long-term treatment with levothyroxine in dentate patients may result in more periodontal destruction because of the persistent subclinical infection at the gingival crevice.

This study, therefore, is a preliminary investigation of the possible effects of hypothyroidism and thyroxine replacement therapy on the periodontal status.

MATERIALS AND METHODS

This comparative cross-sectional study with purposive sampling was conducted in accordance with the applicable ethical principles, independently reviewed and approved by the Ethical Committee of the Institution. The patients, attending the Department of Periodontics and the General Medicine Department of the Institution, were screened for suitability for the study and written informed consent was obtained from those who agreed to participate voluntarily in this study.

Study design

Fifty-two participants with primary hypothyroidism on thyroxine replacement therapy and 50 systemically healthy controls not having any signs and symptoms suggestive of thyroid dysfunction and who had not undergone any periodontal therapy in the past 6 months were selected as the study and control groups, respectively. This study was conducted over a period of 12 months. The age of the participants ranged from 18 to 57 years. The duration of therapy in hypothyroid participants ranged from 1 month to 20 years, and the dosage varied from 25 to 150 mcg. The threshold for TSH values was set as 0.35–5 μIU/mL which was used as a diagnostic measure.

Hypothyroid patients, with any other systemic or endocrine disorders, patients with a history of antibiotic therapy 3 months before the study, pregnant and lactating women, patients on corticosteroid supplement, smokers, patients on long-term medication such as Vitamin D and calcium supplements, and nonsteroidal anti-inflammatory drugs, were excluded from the study.

The participants completed a questionnaire on demographic factors, medical and dental history, and thyroxine use (dosage and duration).

Six patients in the study group were found to have less than normal TSH value including one patient having very low TSH value, i.e., <0.1 μIU/ml. TSH values of the participants belonging to the control group were within the normal range.

The following clinical and radiographical parameters were evaluated:

Clinical parameters

Plaque index (PI) (Silness and Loe 1964), gingival bleeding index (BI) (Ainamo and Bay 1975), probing pocket depth (PPD), and clinical attachment level (CAL).[1]

PPD and CAL were recorded at six sites per tooth using a University of North Carolina 15 probe. The mean PI, PPD, and CAL were calculated for each patient. Percentage of sites with bleeding on probing was calculated for each patient. All measurements were made by an examiner who was blinded about the groups to prevent bias.

Radiographic measurements

Panoramic radiography was carried out using a Planmeca Proline, etc., (Helsinki Finland) operating at 70–78 KVp and 190 mAs with a magnification factor of 1.2. Images were recorded on Kodak 15–30 cm-films in a standard cassette and processed manually. Tracing paper was used to record important anatomical landmarks such as superior and inferior borders of mandibular cortex, condyles, and mental foramina on orthopantomograms (OPG). However, the OPGs in which the mental foramen was not clear or difficult to locate were excluded from the study. Mandibular cortical width (MCW) and panoramic mandibular index (PMI) as surrogate markers of decreased bone density were assessed by an independent examiner who was unaware of the patients’ status.

Mandibular cortical thickness

The thickness of the mandibular cortex was measured on the right and left sides of the mandible along the lower border. A line passing through the middle of the mental foramen and perpendicular to the tangent to the inferior border of the mandibular cortex was drawn on the radiograph. Superior border of the mandibular cortex was also marked, and measurements of the cortical thickness were made along these lines, using a Vernier caliper and magnifying lens. Measurements were estimated to the nearest 0.1 mm.[10]

Panoramic mandibular index

The PMI is described as a measure of the mandibular osteoporosis. The PMI is the ratio of the thickness of the mandibular cortex to the distance between the mental foramen and the inferior mandibular cortex. Using the same line as described above for measuring cortical thickness, measurements between the lower border of the mandible and both the superior and inferior margins of the mental foramen were recorded, and the average of these two values was calculated. Using this cortical thickness measurement, the PMI for both the superior and inferior margins of the mental foramen was measured bilaterally, and the mean PMI was calculated for each participant.[10]

Hormone assays

Blood samples were drawn (i.v.) after an overnight fast. Serum samples for the determination of TSH were frozen at −90°C until analysis. Serum TSH was measured using electrochemiluminescence immunoassay technique according to the manufacturer's instructions (Roche Diagnostics GmbH, Mannheim). The lowest detection limit for this assay was 0.005 μIU/mL, and the functional sensitivity was 0.014 μIU/mL.

Data obtained were subjected to the statistical analysis.

Statistical analysis

The descriptive statistical analysis was carried out in this study using the SPSS (SPSS v.20.0, IBM, Chicago, IL) statistical software. Measurements on the continuous scale are represented as the mean and standard deviation (SD). Categorical measurements are represented as the percentage. Significance was assessed at 5%.

Unpaired t-test was used to assess the significance of clinical and radiographical parameters when data followed normal distribution. Mann–Whitney test, a nonparametric test, was used if the data did not follow normal distribution. Pearson correlation was used to assess the relation between the duration of therapy and PPD and CAL. Multiple regression model (STEP method) was used to assess the influence of hypothyroid status on periodontal parameters.

RESULTS

A total of 102 participants were enrolled in this cross-sectional study. Both the groups were gender matched. The mean PI was almost similar in both the groups [Table 1], and the difference in the mean bleeding scores between the two groups was not statistically significant (55.47 ± 25.62 SD vs. 49.88 ± 23.75 SD; P = 0.257) [Table 2 and Figures 1, 2]. There was a statistically significant difference in the age between the study and control groups (P = 0.024) [Table 2]. Higher mean PPD was observed in the study group compared to the control group, and this difference was statistically significant (1.97 ± 0.83 SD vs. 1.61 ± 0.43 SD; P = 0.008) [Table 2 and Figure 3]. A slightly higher mean loss of clinical attachment was observed in the study group, i.e., 0.70 ± 1.09 SD than the control group, i.e., 0.33 ± 0.53 SD with statistically significant difference (P = 0.032) [Table 2 and Figure 4]. Radiographical parameters, i.e., mean cortical width and mean PMI scores, did not differ significantly between the study and control groups [Table 2 and Figures 5, 6]. No significant differences were observed within the hypothyroid group with varying doses and duration of therapy. No significant correlation was observed between the dosage of the drug and duration of therapy and periodontal status. Regression analysis showed that hypothyroidism was a significant predictor for increased pocket depth and attachment loss after adjusting for age [Tables 3 and 4]. There was no significant correlation between the periodontal parameters and dosage and duration of therapy. Further, the PPD and CAL of participants who were undergoing treatment for Less than or more than 5 years were not statistically significant [Table 5].

Table 1

Comparison of plaque scores between study and control groups

Table 2

Comparison of clinical variables and radiographic measurements between two groups

Figure 1

Comparison of plaque index between controls and cases. Similar plaque index score was observed in the study group (1.39 ± 0.45 standard deviation) and control group (1.37 ± 0.47 standard deviation)

Figure 2

Comparison of bleeding index between controls and cases. The mean bleeding index score in the study group (55.47 ± 25.62 standard deviation) was slightly higher than that in the control group (49.88 ± 23.75 standard deviation). The difference between the two groups was not statistically significant (P = 0.257)

Figure 3

Comparison of probing pocket depth between controls and cases. Higher mean probing pocket depth was observed in the study group (1.97 ± 0.83 standard deviation) compared to the control group (1.61 ± 0.43 standard deviation), and this difference was statistically significant (P = 0.008)

Figure 4

Comparison of clinical attachment loss between controls and cases. Higher mean loss of clinical attachment was observed in the study group (0.70 ± 1.09 standard deviation) than the control group (0.33 ± 0.52 standard deviation) with statistically significant difference (P = 0.032)

Figure 5

Comparison of mandibular cortical width between controls and cases. The mean mandibular cortical width in the study and control groups was 4.43 ± 1.02 standard deviation and 4.59 ± 0.69 standard deviation, respectively, with no statistically significant difference between the two (P = 0.372)

Figure 6

Comparison of the panoramic mandibular index between controls and cases. The mean panoramic index score was 0.32 ± 0.09 and 0.33 ± 0.06 standard deviation, respectively. This difference between the study and control groups, however, was not statistically significant (P = 0.752)

Table 3

Multiple linear regression model with age and hypothyroidism as independent variables and probing pocket depth as the dependent variable

Table 4

Multiple linear regression model with age and hypothyroidism as independent variables and clinical attachment level as the dependent variable (step method)

Table 5

Correlation between drug dosage and duration for hypothyroidism, probing pocket depth, and clinical attachment loss

DISCUSSION

TSH and thyroid hormones whether endogenous or exogenous affect bone metabolism and homeostasis. The bones of the skeleton are known to respond differently to these hormones.[11] Interleukin-6 and tumor necrosis factor-α are the two major proinflammatory cytokines that are locally produced in different tissues in different pathological situations including thyroid dysfunction.[1213] These cytokines can stimulate the resident cells of the periodontium to produce metalloproteinases, molecules that mediate connective tissue destruction and induce the differentiation, and activation of osteoclasts leading to alveolar bone destruction.[14] The endotoxins produced by the bacteria in dental plaque combine with these cytokines further aggravate the inflammatory cascade by the production of more cytokines responsible for matrix metalloproteinases activation and periodontal breakdown.[15]

However, there is a paucity of information on the effects of hypothyroidism and thyroxine replacement therapy on periodontal status. Changes in the periodontium cannot be predicted only on the basis of studies on other parts of the skeleton because periodontium is subject to the combined effect of persistent subclinical infection at the gingival crevice and factors influencing bone remodeling.

The present study, therefore, aimed to investigate the impact of thyroid hormones on the periodontal status of hypothyroid patients on thyroxine replacement therapy.

Comparison between hypothyroid and control groups showed no statistically significant differences in the plaque scores. Plaque levels being similar in both the groups reduced the effect of this variable on the disease status.

Bleeding on probing is a reliable indicator of supragingival plaque control. Increased periodontal vascularity and widened periodontal ligament space following the administration of very large doses of thyroxine have been reported in the previous animal studies.[16] Vascular modifications in intrinsically disordered proteins, such as increase in capillary density and reduction in capillary diameter, have been suggested as a possible cause of periodontal changes in patients with Hashimoto's thyroiditis.[17] However, no statistically significant differences in bleeding scores between the study and control groups were observed in our study probably because both groups were similar with respect to the plaque scores.

Studies have shown that radiographic bone loss highly correlates with the attachment loss measured with periodontal probe. Furthermore, for cross-sectional studies, either CAL or radiographic measurements can be used as an independent measure of periodontal destruction.[18] Agreement between the measurement of attachment levels and radiographic measurements has been reported both at the site and the subject level.[19] There were statistically significant differences in mean PPD and CALs between the study and control groups. A history of hypothyroidism and replacement therapy probably had an effect on PPD and CAL – a reliable measure of periodontitis. Earlier investigators reported clinical observations of severe alveolar bone loss in patients with myxoedema. However, other than some case reports, where periodontal destruction was found to be associated and influenced by hypothyroidism,[202122] contemporary studies evaluating the effect of thyroid hormones are lacking.[202122]

A statistically significant difference was observed in the age between the study and control groups. Age is considered a nonmodifiable risk factor for periodontitis. Numerous cross-sectional studies indicate that the prevalence and severity of the periodontitis increase with age.[23] Adjustments were made for this parameter through regression analysis. It was observed that thyroxine therapy for hypothyroidism was a significant predictor of PPD and CAL even after adjusting for the influence of age.

A significant decrease in bone density with increasing doses of thyroxine hormone has been reported in the mandible compared to hard palate, skull, and alveolar bone in rats.[6] Dual-energy X-ray absorptiometry (DXA) is considered to be the reference-standard examination for bone marrow density (BMD) assessment. However, it is expensive and cannot be used as a screening tool. OPG, routinely done in dental clinics is inexpensive and can be used for screening and selecting high-risk osteoporosis patients for bone densitometry. OPG provides broad anatomic coverage of maxilla and mandible making it a useful tool in the detection of osteoporotic changes in maxilla and mandible.[24] PMI and MCW were used as indirect measures of bone mineral density based on the observations of earlier studies reporting a good correlation between these indices and BMD measurements in osteoporotic individuals.[1025] However, there were no differences found in mean PMI and MCW scores of study and the control groups.

This study had certain limitations. It was a comparative cross-sectional study. Cross-sectional investigations lack the power to show true negative results and biases can occur if cases and controls are not appropriately matched. This study is characterized by the inclusion of small number of patients, thus decreasing the chance of finding significant differences and increasing the risk of missing the real difference. Furthermore, the inclusion of both men and women both premenopausal and postmenopausal, in the same study, may also be a source of confusion. Overreplacement with thyroxine replacement therapy is best assessed with a serum-free T4 level which was not assessed in this study. Although OPG is a reliable tool to identify the individuals at risk for osteoporosis, it has to be validated against a gold standard method, such as bone histomorphometry or DXA, which was not carried out in this study.

This was a preliminary investigation to evaluate the effects of hypothyroidism and thyroxine replacement therapy on the periodontal status. However, more studies with larger sample size should be considered to specifically address the effect of thyroxine replacement therapy on periodontal status.

CONCLUSION

Within the limitations of this study, it can be concluded that hypothyroid patients on thyroxine therapy are at increased risk for periodontal destruction as indicated by increased probing depth and attachment loss even after adjusting for other risk factors. Thus, thyroxine replacement therapy in hypothyroid patients may have an impact on the periodontal status.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.