Adhesive capsulitis of the shoulder is a condition characterized by intense shoulder pain, gradual fibrosis of the glenohumeral joint that causes a limited range of motion, and contracture of the glenohumeral joint capsule1. The prevalence of adhesive capsulitis is between 2% and 5%, and it primarily occurs in women. The incidence of adhesive capsulitis is between 2 to 3 percent in the general population, and it primarily occurs in women2. Disability because of adhesive capsulitis symptoms can influence work performance and increase public-health medical expenditures3. Pathogenesis mechanisms have been proposed, such as endocrine, immunological, and inflammatory processes4. In addition, thyroid diseases, diabetes mellitus, Dupuytren contractures, breast cancer treatment, and autoimmune diseases have been associated with adhesive capsulitis in previous studies5,6,7,8,9. Furthermore, patients diagnosed with myocardial infarctions and cerebral vascular diseases are reportedly at risk of adhesive capsulitis10,11.
A previous cross-sectional study reported that thyroid disorders are frequently accompanied by musculoskeletal disorders, such as adhesive capsulitis, Dupuytren contractures, trigger finger syndrome, and carpal tunnel syndrome. Overall, 137 patients with thyroid disorders were enrolled; of these, 15 had been diagnosed with adhesive capsulitis12. One case report described a subclinical hyperthyroid patient who was diagnosed with comorbid bilateral adhesive capsulitis7. The researchers stated that autonomic nervous system dysfunctions could play a key role in pathogenesis. The activation of the sympathetic nervous system in hyperthyroid patients may underlie the association of adhesive capsulitis and shoulder-hand syndrome7. However, the definitive pathogenesis factor of adhesive capsulitis in hyperthyroid patients remains undetermined.
Only one cross-sectional prevalence study on adhesive capsulitis in thyroid disorder patients has been conducted12. The influence of thyroid disorder status on developing adhesive capsulitis was not determined in this study, and longitudinal and large-scale studies are lacking. Limited information is available regarding the risk of adhesive capsulitis in hyperthyroid patients. Therefore, we conducted a longitudinal population-based study, controlling risk factors such as diabetes and dyslipidemia, to investigate the risk of hyperthyroid patients developing adhesive capsulitis.
We identified 4472 hyperthyroid patients in the age- and sex-matched control cohorts. Compared with the control cohort (Table 1), hyperthyroid patients are more likely to have comorbid autoimmune diseases (P < .001), diabetes mellitus (P < .001), hypertension (P < .001), hyperlipidemia (P < .001), coronary heart disease (P < .001), and chronic liver disease (P < .001). Figure 1 presents the hazard curves of hyperthyroid patients diagnosed with adhesive capsulitis and the control cohort during the 7-year follow-up period, after adjusting for patient age, sex, diabetes mellitus, coronary heart disease, hypertension, hyperlipidemia, autoimmune diseases, chronic liver disease, cancer, and urbanization level (log-rank test, P < .001).
Table 2 shows the incidence and hazard ratios (HRs) of adhesives capsulitis in hyperthyroid patients and the control cohort. Of the 4472 hyperthyroid patients, 162 patients (671/100 000 person-years) exhibited adhesive capsulitis during the 24 122 person-year follow-up period. The crude HR of stroke was 1.26 (95% confidence interval [CI], 1.06 to 1.49), which was larger than that obtained for the control group.
Table 3 presents the adjusted HRs of adhesive capsulitis in both the hyperthyroid patients and control cohort. The adjusted HR obtained for hyperthyroid patients was 1.22 (95% CI, 1.03 to 1.45), which was statistically significant. In addition, other confounding factors of adhesive capsulitis were analyzed. The results showed that age (adjusted HR: 1.05, 95% CI, 1.04 to 1.05), the male sex (adjusted HR: 069, 95% CI, 0.58 to 0.82), hyperlipidemia (adjusted HR: 1.49, 95% CI, 1.25 to 1.77), and chronic liver disease (adjusted HR: 1.37, 95% CI, 1.14 to 1.66) were all statistically significant regarding the development of frozen shoulder during the 7-year follow-up period.
This study showed that hyperthyroid patients have 1.22 times the risk of developing adhesive capsulitis compared to the general population. Until now, no relevant large-scale longitudinal population-based study has been conducted on the risk of adhesive capsulitis in hyperthyroid patients. All previously conducted studies regarding the risk of adhesive capsulitis in thyroid-disorder patients have been small-sample cross-sectional studies12. Limited information has been obtained regarding the temporal relationship between hyperthyroidism and adhesive capsulitis in previous studies. We adjusted for factors, such as diabetes and dyslipidemia, and identified hyperthyroid patients who were subsequently diagnosed with adhesive capsulitis. The results show that hyperthyroidism patients have a high comorbidity risk of adhesive capsulitis.
The definite pathogenesis of adhesive capsulitis remains under investigation. Shoulder pain onset that indicates adhesive capsulitis is considered to be mediated through nerve stimulation. Adhesive-capsulitis shoulder pain can be caused by alpha-adrenoreceptor hyperresponsiveness, in which both nociceptive and proprioceptive fibers are stimulated, resulting in pain13. The inflammatory process is considered another pathogenesis of adhesive capsulitis. Rodeo et al found elevated levels of pro-inflammatory cytokines in adhesive capsulitis patients14. They proposed that the stimulation of inflammation caused by cytokines can engender shoulder synovitis, and this can result in a fibrotic cascade that is associated with growth factors such as TGF-beta14. The chronic fibrosis process of capsulitis is confirmed by observing the histologic presentation of fibroblast cell proliferation. Matrix metalloproteinase and fibrogenic growth factors are also increased in adhesive capsulitis patients15.
Similar to the inflammatory and fibrosis process pathogenesis of adhesive capsulitis patients, hyperthyroid patients also present an inflammatory cytokine release and fibrosis phenomenon. Regarding thyroid disorder-associated ophthalmopathy patients, cell-mediated (Th1) and humoral-mediated immune responses infiltrate the orbital area. High levels of IL-2, IFN-γ, and TNF-α cytokines are secreted by Th1 cells in the retro-orbital area of patients who are diagnosed with Graves disease16,17. However, another study found Th2 cell-secreted cytokines, such as IFN-γ, IL-4, and IL-10, in patients18. Moreover, a previous study described the cytokine profiles of patients diagnosed with Graves disease and thyroid disorder-associated ophthalmopathy17. Cytokines have been proven as capable of inducing several proteins in orbital fibroblasts, and these cytokines have the ability to stimulate orbital fibroblast proliferation19. We propose that cytokine and fibroblast proliferation contributes to not only the process of thyroid ophthalmopathy but also to adhesive capsulitis. This can explain why hyperthyroid patients are vulnerable to adhesive capsulitis.
SLE and RA patients were analyzed in this study, but were not found to have a high risk of adhesive capsulitis. Regarding SLE patients, cytokines have been proposed to have a pathogenic role in autoantibody production and immune complex deposition. These cytokines are interleukin-6, interleukin-17, interleukin-18, type I interferons, and TNF-alpha20. Cytokines have also been found in the pathogenesis of rheumatoid arthritis. One review article provided a comprehensive list of related cytokines, such as TNF-alpha, IL 1, 6, 15, 17, and 18, GM-CSF, VEGF, and TGF-beta21. However, this article stated that how these cytokines are organized within a hierarchical regulatory network remains unclear. In addition, the article stated that TNF-alpha plays a key role because TNF-alpha-blockage agents can are involved in successfully treating RA21. We propose that the pro-inflammatory cytokine and fibrosis process modulation is different in these autoimmune diseases and adhesive capsulitis.
We controlled other possible hazard factors for developing adhesive capsulitis. In addition to hyperthyroidism, the results showed that hyperlipidemia patients have a high risk of adhesive capsulitis. These results support those of a previous case-controlled study that analyzed the lipid profiles of patients diagnosed with frozen shoulders and found that fasting serum triglyceride and cholesterol levels were increased in these patients compared with the levels of participants without frozen shoulders22. However, the pathogenesis of adhesive capsulitis in hyperlipidemia patients remains unclear.
In contrast to a previous population-based longitudinal study, our results showed that diabetes mellitus patients do not have an increased risk of adhesive capsulitis23. This could be because the controlled group selection was different from that of the previous study either because of differing circumstances or participant matching to the hyperthyroid group. Our patients were predominantly women and were younger than those in the previous study on diabetes mellitus and frozen shoulders. A different control group selection can result in the influence of confounding factors. Long longitudinal follow-up data collection is the strength of our study. In addition, we attempted to control confounding factors, such as diabetes, hyperlipidemia, and autoimmune diseases such as SLE and RA. The long follow-up period and large number of potential confounding factors that were considered in this study enabled producing reliable results.
The LHID2005 data released by the Taiwan NHI Institutes were used in this study. However, this study has several possible limitations. First, the diagnosis of adhesive capsulitis and hyperthyroidism was determined using the ICD codes listed in the NHI claim database; however, the diagnostic accuracy of the results obtained from the database were not confirmed. To increase the accuracy of diagnoses, the NHI Bureau has formed various audit committees that randomly sample claim data regularly to verify diagnostic validity and care quality. In addition, we used only consecutively coded cases to avoid inaccurate codes in the database records. These methods might improve the accuracy of registering rheumatic diseases. Second, the NHIRD records do not contain the laboratory data of hyperthyroid patients, and information regarding disease stratification severity is also limited. Third, the influences of thyroid medications, I131 radioiodine therapy, and thyroid surgery were not analyzed. Finally, our results were based on a retrospective cohort study. Information regarding lifestyles, obesity, cigarette smoking, and alcohol consumption cannot be obtained from the administrative database.