Temporomandibular disorder (TMD) is characterized by pain and dysfunction in the temporomandibular join (TMJ) and the masticatory apparatus. Associations with autoimmune diseases, inflammatory conditions, and nutrition deficiencies have been reported in previous studies of TMD patients. To evaluate essential proteins, hormones, electrolytes, and vitamins in serum from TMD patients, a standard blood sample analysis was performed in 60 TMD patients and 60 healthy controls matched for age and gender, retrieving 19 different analyses. We found that TMD patients had significantly higher values of hemoglobin (
Temporomandibular disorder (TMD) is characterized by pain and dysfunction in the masticatory apparatus and the temporomandibular joint (TMJ). A significant higher prevalence of comorbidities, such as degenerative arthritis, gastrointestinal symptoms, fibromyalgia, depression, and fatigue, has been revealed in this group of patients [
In TMD patients, few studies analyzing health status in serum have been published previously. Significantly, higher levels of parathyroid hormone (PTH) have been observed in TMD patients compared to a control group [
Levels of the current hormones, electrolytes, and vitamins can easily be detected by blood sampling. Standardized serum tests can be used in diagnostics and evaluation of patient’s health to detect diseases [
To our knowledge, the present study is the first to reveal as many as 19 different determinants in serum from TMD patients at the same time. The primary aim of the present study was to evaluate essential proteins, hormones, electrolytes, and vitamins in serum from TMD patients. Our hypothesis is that TMD patients have significantly different values of essential proteins, hormones, electrolytes, and vitamins in serum, compared to a healthy control group, and this may influence TMD symptoms.
The present study was a controlled cross-sectional study, as part of a multidisciplinary investigation of TMD patients at Haukeland University Hospital (HUS) in Bergen, Norway [
Ethical approval was granted by the Regional Ethical Review Board South East (2015/930), in accordance with the Helsinki Declaration (1964). All subjects submitted written informed consent as a prerequisite for participating in the study.
The study population consisted of 60 TMD patients with severe symptoms and long-term pain and 60 healthy controls matched for age and gender. A previous study regarding stress and HPA axis regulation, involving the majority of the present study group, has been published [
The control group consisted of employees and students from the Department of Clinical Dentistry at the University of Bergen and was not a part of the study research group; additionally, there were a few subjects from the general population in Bergen. The inclusion criterion was age- and gender-matched with the patient group. The exclusion criteria were TMD symptoms, musculoskeletal pain, and symptoms in the head and neck area.
A standard blood sample analysis was conducted at Haukeland University Hospital and analyzed at the Laboratory for Clinical Biochemistry. The serum analyses retrieved 19 different analyses consisting of essential proteins, hormones, electrolytes, and vitamins. Those were hemoglobin (Hb), erythrocyte volume fraction (EVF), mean corpuscular volume (MCV), homocysteine, transferrin receptor (TfR), thyroid stimulating hormone (TSH), free thyroxine (FT4), parathyroid hormone (PTH), cobalamin, folate, C-reactive protein (CRP), creatinine, estimated glomerular filtration rate (GFR), sodium, potassium, calcium, gamma-glutamyl transferase (GT), albumin, and 25 (OH) vitamin D3 (vitamin D). CRP levels lower than 1 mg/L were registered as 1 mg/L due to limitations in the laboratory.
Statistical analyses were performed in STATA. Mean, range, and standard deviation (SD) were calculated for all variables in both groups. Since our study matched age and gender between the groups, paired
The group of 60 TMD patients consisted of 51 women and 9 men, all affected with severe TMD symptoms. Mean pain duration in the patient group was 11 years (ranged 1–40 years). Mean age of the patient group was 45 years (ranged 20–69 years). Registered diagnoses on our clinical examination of the TMD group were fibromyalgia (
Flow chart of the study population: TMD patients and healthy controls.
Results revealed that TMD patients had significantly higher values of hemoglobin (
Serum analyses resulted in nineteen different determinants common in diagnostics. Second column shows normal values for women and men at all ages. Most TMD patients and controls had values within normal biologic range. TMD patients had significantly higher values of hemoglobin (
Serum analyses | Reference values | TMD | Control |
| ||||
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Mean | ±SD | Range | Mean | ±SD | Range | ( |
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Hemoglobin |
|
14.1 | 1.28 | 8.1, 16.2 | 13.8 | 0.83 | 11.5, 16 | 0.036 |
EVF |
|
0.41 | 0.04 | 0.28, 0.48 | 0.41 | 0.02 | 0.35, 0.48 | 0.325 |
MCV | 82–98 | 91.2 | 4.66 | 76, 102 | 90.1 | 3.62 | 83, 100 | 0.299 |
Homocysteine | <15 umol/L | 11.1 | 3.79 | 5.8, 28.0 | 11.3 | 3.03 | 5.7, 24.2 | 0.459 |
Transferrin R |
|
3.27 | 1.78 | 1.7, 14.6 | 2.98 | 0.80 | 1.7, 5.9 | 0.103 |
TSH | 0.4–4.5 mlE/L | 1.63 | 0.83 | 0.01, 4.31 | 1.80 | 0.98 | 0.14, 4.72 | 0.191 |
FT4 | 9.5–22.0 pmol/L | 16.0 | 3.13 | 7.8, 29 | 15.7 | 2.26 | 11.5, 27.0 | 0.266 |
Cobalamin | 175–700 pmol/L | 422 | 194.8 | 167, 1322 | 363 | 124.9 | 129, 702 | 0.023 |
Folate | >8 nmol/L | 20.7 | 10.41 | 7.7, 45.3 | 20.2 | 7.38 | 7.5, 45.3 | 0.450 |
CRP |
<5 mg/L | 2.43 | 3.09 | 1.0, 14.0 | 2.10 | 2.84 | 1.0, 20.0 | 0.268 |
Creatinine |
|
65.6 | 10.47 | 45, 93 | 69.7 | 12.14 | 49, 108 | 0.006 |
Estimated GFR | >90 mL/min/l | >60 | — | — | >60 | — | — | — |
Sodium | 137–145 mmol/L | 140.1 | 1.48 | 137, 144 | 140.0 | 1.39 | 136, 144 | 0.227 |
Potassium | 3.5–5.0 mmol/L | 4.0 | 0.25 | 3.2, 4.6 | 4.1 | 0.31 | 3.4, 5.3 | 0.011 |
Calcium | 2.20–2.55 mmol/L | 2.40 | 0.09 | 2.21, 2.63 | 2.40 | 0.08 | 2.15, 2.59 | 0.456 |
GT |
|
22.2 | 19.63 | 8.0, 145.0 | 17.9 | 12.20 | 6.0, 72.0 | 0.078 |
Albumin | <39y: 39–50, 40–69y: 39–48, >70y: 36–48 g/L | 46.3 | 2.94 | 40.0, 53.0 | 45.1 | 1.96 | 40.0, 49.0 | 0.005 |
PTH | 1.3–6.8 pmol/L | 3.4 | 1.53 | 0.9, 8.2 | 2.9 | 1.09 | 1.0, 6.0 | 0.038 |
Vitamin D | 50–113 nmol/L | 72.4 | 26.93 | 19.0, 187.0 | 61.1 | 18.68 | 22.0, 127.0 | 0.005 |
Gender-matched serum analyses: Results from serum analyses showed mean levels statistically differed between TMD patients and controls, divided into subgroups of women and men. The second column shows normal values for women and men at all ages. Significantly higher levels of hemoglobin (
Gender-matched serum analyses | Reference values | TMD ( |
Control ( |
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Mean | ±SD | Range | Mean | ±SD | Range | ( |
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Women ( |
11.7–15.3 g/dL | 13.9 | 1.22 | 8.1, 15.7 | 13.6 | 0.70 | 11.5, 14.7 | 0.045 |
Men ( |
13.4–17.0 g/dL | 15.2 | 1.13 | 13.4, 16.2 | 14.9 | 0.62 | 14.0, 16.0 | 0.288 |
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Women ( |
0.4–4.5 mlE/L | 1.52 | 0.82 | 0.01, 4.31 | 1.80 | 1.04 | 0.14, 4.72 | 0.111 |
Men ( |
0.4–4.5 mlE/L | 2.24 | 0.59 | 1.25, 3.34 | 1.84 | 0.52 | 1.17, 2.49 | 0.040 |
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Women ( |
175–700 pmol/L | 425 | 210.0 | 167, 1322 | 355 | 128.4 | 129, 702 | 0.020 |
Men ( |
175–700 pmol/L | 401 | 60.67 | 310, 455 | 403 | 100.3 | 291, 568 | 0.483 |
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Women ( |
45–90 umol/L | 62.8 | 8.01 | 45, 81 | 66.2 | 8.77 | 49, 84 | 0.018 |
Men ( |
60–105 umol/L | 81.3 | 8.93 | 68, 93 | 88.9 | 9.97 | 74, 108 | 0.098 |
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Women ( |
3.5–5.0 mmol/L | 4.0 | 0.25 | 3.2, 4.6 | 4.1 | 0.30 | 3.4, 5.3 | 0.002 |
Men ( |
3.5–5.0 mmol/L | 4.1 | 0.21 | 3.9, 4.5 | 4.0 | 0.33 | 3.5, 4.5 | 0.267 |
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Women ( |
Age dependent <39y: 39–50, 40–69y: 39–48, | 45.9 | 2.98 | 40.0, 53.0 | 44.9 | 1.91 | 40.0, 49.0 | 0.017 |
Men ( |
>70y: 36–48 g/L | 48.0 | 2.08 | 45.0, 51.0 | 46.6 | 1.59 | 44.0, 48.0 | 0.026 |
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Women ( |
1.3–6.8 pmol/L | 3.5 | 1.58 | 0.9, 8.2 | 2.9 | 1.03 | 1.0, 5.2 | 0.040 |
Men ( |
1.3–6.8 pmol/L | 2.7 | 1.10 | 1.1, 4.2 | 2.58 | 1.39 | 1.4, 6.0 | 0.385 |
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Women ( |
50–113 nmol/L | 75.3 | 26.23 | 19.0, 187.0 | 61.8 | 19.78 | 22.0, 127.0 | 0.002 |
Men ( |
50–113 nmol/L | 55.8 | 26.21 | 21.0, 111.0 | 57.6 | 11.02 | 42.0, 72.0 | 0.426 |
Elevated and lowered values: observed number and percent of patients and controls with elevated and lowered values of the different determinants from the serum analyses. Mild to moderate vitamin D level deficiency was seen in 11 TMD patients compared to 18 controls. Furthermore, we observed marginally elevated levels of CRP (
Elevated and lowered values | TMD | Control | ||||||
---|---|---|---|---|---|---|---|---|
Elevated | Lowered | Elevated | Lowered | |||||
|
% |
|
% |
|
% |
|
% | |
Hemoglobin | 1 | 1.7 | 2 | 3.3 | 0 | 0.0 | 1 | 1.7 |
EVF | 1 | 1.7 | 5 | 8.3 | 0 | 0.0 | 0 | 0.0 |
MCV | 1 | 1.7 | 3 | 5.0 | 4 | 6.7 | 0 | 0.0 |
Homocysteine | 6 | 10.0 | 0 | 0.0 | 3 | 5.0 | 0 | 0.0 |
Transferrin R | 7 | 11.7 | 3 | 5.0 | 3 | 5.0 | 2 | 3.3 |
TSH | 0 | 0.0 | 2 | 3.3 | 1 | 1.7 | 1 | 1.7 |
FT4 | 3 | 5.0 | 1 | 1.7 | 1 | 1.7 | 0 | 0.0 |
Cobalamin | 5 | 8.3 | 1 | 1.7 | 1 | 1.7 | 1 | 1.7 |
Folate | 0 | 0.0 | 2 | 3.3 | 0 | 0.0 | 1 | 1.7 |
CRP | 7 | 11.7 | 0 | 0.0 | 4 | 6.7 | 0 | 0.0 |
Creatinine | 0 | 0.0 | 0 | 0.0 | 1 | 1.7 | 0 | 0.0 |
Estimated GFR | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
Sodium | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 | 1 | 1.7 |
Potassium | 0 | 0.0 | 1 | 1.7 | 1 | 1.7 | 1 | 1.7 |
Calcium | 1 | 1.7 | 0 | 0.0 | 3 | 5.0 | 1 | 1.7 |
GT | 2 | 3.3 | 5 | 8.3 | 0 | 0.0 | 7 | 11.7 |
Albumin | 9 | 15.0 | 0 | 0.0 | 0 | 0.0 | 0 | 0.0 |
PTH | 2 | 3.3 | 4 | 6.7 | 0 | 0.0 | 1 | 1.7 |
Vitamin D | 3 | 5.0 | 11 | 18.3 | 1 | 1.7 | 18 | 30.0 |
Linear correlation between parathyroid hormone and vitamin D in the TMD group (black) and the control group (grey). Low levels of vitamin D were significantly correlated (
Regular medications used by the patients were paracetamol (
Based on the results of the present study, we were unable to associate any severe systemic disease, malnutrition, or systemic inflammation with TMD. We performed nineteen different, common diagnostic serum analyses determining essential proteins, hormones, ions, and vitamins, and most of the TMD patients and controls showed values within normal biologic range. Medications used by the patients were not found to have any major impact on serum analyses. Findings from our study support results from the OPPERA project, suggesting that TMD is a complex disorder influenced by psychosocial factors and pain sensation rather than being a state of disease indicated by analyses of serum compounds [
An unexpected result revealed that the control group had significantly lower values of vitamin D compared to the TMD group. In both groups, deficiency in D vitamins was commonly observed. A high prevalence of vitamin D deficiencies in both TMD patients and healthy controls [
Parathyroid hormone (PTH) was significantly higher in the TMD group of the present study. However, both elevated and lowered levels of PTH were observed in the TMD patient group on the individual level. A high level of PTH reflects hyperparathyroidism, while low levels reflect hypoparathyroidism. Elevated levels of PTH in TMD patients compared to healthy controls have previously been reported [
Elevated PTH is often seen in association with low vitamin D, leading to elevated calcium absorption from bone [
There were no significant differences in CRP levels between the TMD group and the control group. Mean CRP levels have previously been observed within the normal range in patients with TMJD and were not affected by pain [
Another indicator of high doses of nutritional supplementation in our group of TMD patients was significantly higher levels of cobalamin, possibly due to vitamin B12 supplementation. On the other hand, 10% of the TMD patients had elevated levels of homocysteine, even though there were no statistical differences in mean levels of homocysteine compared to the control group. High homocysteine levels reflect low levels of vitamin B12, vitamin B6, and folate, and the observed elevated levels in some patients may potentially be explained by the possibility of reduced intake of diet sources in the patient group because of jaw impairment and pain from chewing. However, there was no statistical difference in serum folate levels between the TMD patients and controls. A previous study of serum analyses in TMD patients reported a high prevalence of low vitamin B levels, including folate and vitamin B complex [
In the TMD group, we observed some patients with elevated levels of transferrin receptor (TfR) and low erythrocyte volume fraction (EVF), which potentially could indicate iron deficiency or an increase in erythropoiesis [
The levels of creatinine were significantly lower in the TMD patient group. Creatinine is a degradation product of creatine phosphate, which has an important role in muscle function and fast energy production [
Potassium was significantly lower in the TMD group. Potassium homeostasis is regulated by renal and extrarenal mechanisms, affected by acid-base balance and hormonal regulation by epinephrine, insulin, and aldosterone [
The prevalence and severity of TMD is higher in women compared to men [
Because of the higher prevalence of TMD in women, we found it interesting to reveal gender differences in the serum analyses in both groups. The gender-matched serum analyses showed significantly higher levels of hemoglobin, cobalamin, PTH, and vitamin D, as well as significantly lower levels of creatine and potassium only in women in the TMD group, compared to the control group. Albumin levels were significantly higher in both men and women in the TMD group, and TSH was significantly higher only in men in the TMD patient group, compared to the control group. The results showed that most of the observed differences in serum analyses, for both groups, were in the subgroup of women. However, the observed gender differences may be affected by the fact that men were a very small population sample comprising only 9 subjects in each group. More research must be carried out to fully examine the possibility of an association between gender and serum levels in TMD.
The present study is one of the few studies on serum analyses in TMD patients comparing levels in healthy individuals. To our knowledge, this is the first study to use as many as 19 different variables at the same time. Despite a relatively small study sample, the results of our study may contribute toward assessing and mapping risk factors and characteristics of TMD. One limitation of the study was the fact that the serum samples were taken at all seasons of the year, while levels of some determinants, e.g., vitamin D and PTH, may have some seasonal variability in the Scandinavian countries. The fact that there was some geographical difference between the TMD patient group and the control group may also have had an effect on the results. The possibility of cultural, diet-related, and socioeconomic factors affecting serum levels of the presented determinants in our study, as well as other similar reports, should also be kept in mind. Another limitation is that ultrasound was not used for diagnostics of TMD, which has been tried but had too many obstacles to pass and therefore was not used. The gold standard for diagnostics of TMJ disease is magnetic resonance imaging (MRI) together with a clinical investigation for function and pain. However, ultrasound for diagnostics has recently been shown to be effective in the limb muscle and shoulders [
In the present study, no clear indication of systemic disease or malnutrition in the TMD patient group was seen. The results from the serum analyses were mostly within normal reference values, which resulted in rejection of our hypothesis. All observed deficiencies in both groups were weak. One of the most surprising results was that vitamin D levels were lower in the control group compared to the TMD group. Despite minor observed differences in TMD patients, as compared with healthy subjects, we conclude that serum analyses should be not be used as a biomarker of TMD nor as a diagnostic tool for an individual subject with TMD. As an outcome from our clinical investigation, we observed a small group within the TMD group which likely took high doses of vitamin supplements, which contributed to elevated serum levels in some variables. Due to a relatively low number in the study population, more research is warranted to clarify the relationship between different serum determinants and the etiology and maintenance of TMD.
Data used to support the findings of this study are available from the corresponding author upon request.
The authors declare no conflicts of interest with respect to the authorship and/or publication of this article.
The authors thank the Norwegian Ministry of Health for funding this study. The present study was presented as a conference abstract/poster at World Congress on Pain and International Association for the Study of Pain (IASP), Boston, USA, in September 2018.