- Email: [email protected]
Incidence of thyroid disease in patients with forefoot deformity
G Model FAS 1315 No. of Pages 4
Foot and Ankle Surgery xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Foot and Ankle Surgery journal homepage: www.elsevier.com/locate/fas
Incidence of thyroid disease in patients with forefoot deformity Sterling K. Tran2 , James B. Carr2 , Matthew J. Hall1,2 , Joseph S. Park2 , Minton T. Cooper* University of Virginia School of Medicine, Charlottesville, VA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 24 January 2019 Received in revised form 16 May 2019 Accepted 21 May 2019 Available online xxx
Background: Hallux valgus and lesser toe deformities are common foot disorders with substantial functional consequences. While the exact etiologies are multi-factorial, it is unknown if certain endocrine abnormalities, such as thyroid dysfunction, may be associated with these pathologies. The current study sought to investigate the prevalence of thyroid disease in patients with hallux valgus or lesser toe deformities. Methods: Every new patient who presented to our institution’s foot and ankle clinic during a three-month time period was given a survey to determine the presence of a known thyroid disorder. The diagnosis for each visit was then recorded. Additionally, a national, publicly available database was queried for patients diagnosed with thyroid disease and concomitant hallux valgus or specific forefoot pathology. Odds ratios for the presence of thyroid dysfunction were then calculated for each patient group. Results: Three-hundred and fifty initial visit patient surveys were collected, and 74 (21.1%) patients had a known diagnosis of thyroid disease. The most common diagnoses were primary hypothyroidism (n = 61, 17.4%), secondary hypothyroidism (n = 6, 1.7%), thyroiditis (n = 4, 1.1%), and hyperthyroidism (n = 3, 0.9%). Thyroid disease was present in 16 of 26 patients (61.5%) with a diagnosis of hallux valgus (OR 7.3, CI[3.16– 16.99], p < 0.0001). Lesser toe deformities, including hammertoes, mallet toes, bunionettes and crossover toes, were also significantly associated with thyroid disease (OR 5.45, CI[1.83–16.26], p < 0.002). The national database revealed 905,924 patients with a diagnosis of a specific forefoot deformity, and 321,656 of these patients (35.5%) had a concomitant diagnosis of a thyroid condition (OR 2.11, CI[2.10–2.12], p < 0.0001). Conclusions: The current study suggests a significant association between forefoot pathology and thyroid dysfunction, especially hallux valgus and lesser toe deformities. Increased understanding of these correlations may offer an important opportunity in population health management, both in diagnosis and treatment. While further studies with long-term outcomes are necessary, the early diagnosis of thyroid disease may provide an opportunity to predict and potentially alter the course of forefoot pathology. © 2019 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Thyroid disease Hypothyroidism Hyperthyroidism Forefoot pathology Lesser toe deformity Hallux valgus
1. Introduction Forefoot disorders, such as hallux valgus and lesser toe deformities (i.e. mallet toe, hammer toe, claw toe, curly toe and crossover toe) are common pathologies with functional consequences. Hallux valgus has been reported to affect up to 23% of adults between the ages of 18–65 years and 35.7% of adults older than 65 years with a higher prevalence in females compared to males [1]. While the epidemiology of lesser toe deformities is less well-characterized, the incidence has been estimated to range between 2–20%, reaching a prevalence as high as 60% in one
* Corresponding author at: 545 Ray C. Hunt Dr., Charlottesville, VA 22908, USA. E-mail address: [email protected] (M.T. Cooper). 1 Present address: Harvard Medical School, Boston, MA, USA. 2 These authors are contributing authors to this manuscript.
community survey [2,3]. Of all patients with hallux valgus deformity, 5–22% undergo operative correction with an average bundled cost of $18,332 per procedure [2,4]. Operative management of lesser toe deformities accounts for 28–46% of all forefoot surgeries performed in the United States [2,5]. The exact etiologies of forefoot deformities are not completely understood and are likely multifactorial. Many foot and ankle deformities, such as hallux valgus, lesser toe deformities and pes planus tend to be coincident and progressive [6,7]. Forefoot disorders are commonly associated with inflammatory arthritides, improper shoe wear, genetics, trauma, and neuromuscular conditions such as cerebral palsy, stroke, or Charcot–Marie–Tooth disease [8,9]. To our knowledge, thyroid disease has never been correlated with an increased incidence of forefoot pathology. Autoimmune thyroiditis is the most common form of thyroid disease [10,11]. The prevalence of autoimmune thyroiditis has been estimated at 5% in adults with higher rates in females and
https://doi.org/10.1016/j.fas.2019.05.014 1268-7731/© 2019 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: S.K. Tran, et al., Incidence of thyroid disease in patients with forefoot deformity, Foot Ankle Surg (2019), https://doi.org/10.1016/j.fas.2019.05.014
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increasing incidence with age [10,11]. Histologically, it is characterized by lymphocytic infiltration of the thyroid parenchyma [10]. Clinically, patients may be euthyroid and asymptomatic, hypothyroid, or hyperthyroid with multiple effects on various organ systems [10]. While definitive risk factors for autoimmune thyroiditis are largely unknown, both genetic and environmental factors are implicated in its development [10]. Furthermore, autoimmune thyroid disease has been associated with several other systemic autoimmune and rheumatologic diseases, including Sjogren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus [12,13]. To our knowledge, an association between thyroid dysfunction and foot disorders has never been investigated despite the high prevalence of both conditions. We sought to characterize the relationship between thyroid dysfunction and forefoot pathology. We hypothesized that there would be a greater incidence of thyroid dysfunction in patients with forefoot disorders compared to other disorders of the foot and ankle. 2. Methods All initial visit patients who presented to our institution’s orthopaedic foot and ankle clinic over a three-month period were prospectively surveyed. The survey consisted of three questions: Have you ever been diagnosed with a thyroid condition? Is your thyroid overactive or underactive? Do you take medicine for your thyroid condition? The survey also contained a space for the physician to note the visit diagnoses. Demographic data for these patients was collected through retrospective chart review. Additionally, a publicly available, for-fee database of patients, PearlDiver Patient Record Database (PearlDiver Inc, Fort Wayne, Indiana), was queried for the incidence of thyroid disease in patients with a diagnosis of forefoot disorders. The database contains demographic data and procedure volumes for patients with ICD-9 diagnoses and procedures recorded by Current Procedural Terminology (CPT) codes. Data for the present study was derived from a Medicare portion of the database, which contains over 100 million patient records from 2005 to 2012. Access was granted by PearlDiver Technologies for the purpose of academic research, and the database was stored on a passwordprotected server maintained by PearlDiver. The Medicare database was chosen due to its size and prevalence of patients with a diagnosis of forefoot pathology. The database was queried for patients with the diagnosis of thyroid disease and forefoot pathology using the associated ICD-9 codes. Forefoot pathology was searched for using the ICD-9 codes 735.0 (Hallux valgus, acquired), 735.4 (hammertoe), 735.8 (other acquired deformities of the toe), and 735.9 (other acquired toe deformity). The ICD-9 codes 244.8 (other acquired hypothyroidism) and 244.9 (unspecified hypothyroidism) were then used to identify all patients with a diagnosis of thyroid dysfunction. Data acquisition was performed to include all patients with a forefoot disorder or thyroid disorder in isolation and in combination. Demographic information, including sex, age group (<65, 65–69, 70–74, 75–79, 80–84, and >85) and medical co-morbidity profiles (need to include which co-morbidity profiles) were also obtained. Statistical analysis was performed using the chi-square (χ2) test and Fisher’s Exact test when appropriate. For all statistical comparisons, a p-value <0.05 was considered significant. This project was reviewed by our Institutional Review Board.
Table 1 Demographic data of initial visit clinic patients. Total Age Sex Male Female Thyroid condition Primary hypothyroidism Secondary hypothyroidism Hyperthyroidism Thyroiditis Thyroid medication Forefoot condition Hallux valgus Lesser toe deformity Metatarsalgia
n = 350 49.1 (range, 31.5–66.7) n = 104 (29.8%) n = 246 (70.2%) n = 74 (21.1%) n = 61 (17.4%) n = 6 (1.7%) n = 3 (0.9%) n = 4 (1.1%) n = 65 (18.6%) n = 26 (7.4%) n = 14 (4%) n = 21 (6%)
female (Table 1). A diagnosis of thyroid disease was present in 74 (21.1%) of patients. Primary hypothyroidism was the most common diagnosis (n = 61, 17.4%), followed by secondary hypothyroidism (n = 6, 1.7%), thyroiditis (n = 4, 1.1%), and hyperthyroidism (n = 3, 0.9%). Of initial visit patients, 65 patients (18.6%) took a medication for a thyroid condition. Thyroid disease was present in 16 of 26 patients (61.5%) with a diagnosis of hallux valgus (OR 7.3, CI[3.16–16.99], p < 0.0001) (Table 2). Lesser toe deformities, including hammertoes, mallet toes, bunionettes and crossover toes, were also significantly associated with thyroid disease (OR 5.45, CI[1.83–16.26], p < 0.002). Associations between thyroid disease and metatarsalgia (OR 1.53, CI[0.57–4.10], p = 0.41), midfoot arthritis (OR 1.17, CI [0.50–2.69], p = 0.71), and pes planovlagus (OR 1.64, CI[0.69–3.91], p = 0.26) did not reach clinical significance (Table 2). The national data from the Pearldiver database revealed 905,924 patients with a diagnosis of a forefoot disorder, and 321,656 of these patients (35.5%) had a concomitant diagnosis of a thyroid condition (OR 2.11, CI[2.10–2.12], p < 0.0001) (Table 3). 4. Discussion This study identifies a relationship between thyroid disease and forefoot deformities amongst patients presenting to a single institution’s orthopaedic foot and ankle clinic. Thyroid disease was present in 21.1% of the studied patient population, and it was Table 2 Odds ratios for thyroid disease in foot pathology in foot and ankle clinic visits. Foot pathology
Thyroid No disease thyroid disease
Odds ratio (95% confidence interval), p-values
Hallux valgus Lesser toe deformity Metatarsalgia Midfoot arthritis Pes planovalgus
16 8 6 8 8
7.3 (3.16–16.99), p < 0.0001 5.45 (1.83–16.26) p < 0.002 1.53 (0.57–4.10), p = 0.41 1.17 (0.50–2.69), p = 0.71 1.64 (0.69–3.91), p = 0.26
10 8 15 26 19
Table 3 Association of thyroid disease and forefoot disorders in a large national Medicare population. Thyroid condition
No thyroid condition
Total
3. Results Three-hundred and fifty initial visit patient surveys were collected over the three-month period. The mean patient age was 49.1 (range, 31.5–66.7) years, and 246 (70.2%) of patients were
Total 10,290,018 population Forefoot 321,656 disorder
Odds ratio (95% confidence interval), p value
38,730,233 49,020,251 584,268
905,924
(2.10–2.12), p < 0.0001
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significantly associated with both hallux valgus and lesser toe deformities, which were also the most common forefoot pathologies diagnosed. The associations between thyroid disease and forefoot disorders were independent of any comorbidities. Additionally, the national data confirms a high incidence of thyroid disease in patients with a forefoot disorder, but a low incidence of forefoot disorders in the general population of patients with thyroid disease. Thyroid hormones triiodothyronine (T3) and thyroxine (T4) play an essential role in metabolic homeostasis for many adult tissues and organ systems. The relationship between autoimmune thyroiditis and rheumatic manifestations has been previously described [12,13]. These manifestations are most commonly characterized by non-erosive arthritis and polyarthralgia [12]. While these manifestations occur at higher rates in the hypothyroid population, they have also been shown to occur in euthyroid patients with autoimmune thyroiditis [12]. Current hypotheses about the pathophysiology of this association include attack on synovial tissue from anti-thyroid autoantibodies, overlap between chronic autoimmune thyroiditis and other subclinical rheumatic disorders, and a systemic progression of an autoimmune process [12,14,15]. While thyroid dysfunction has been linked with rheumatologic disorders, few studies have investigated a possible role of thyroid dysfunction in other musculoskeletal disorders of connective tissues, such as ligaments and tendons. Most of the available studies have investigated the effects of thyroid hormone on collagen metabolism [16,17]. One of the first studies to investigate this relationship was by Kivirikko in 1967 [16]. He investigated changes in collagen synthesis rates in rats who were either in a hyperthyroid or hypothyroid state and discovered that collagen synthesis is decreased in both hyperthyroidism and hypothyroidism. Specifically, hyperthyroidism led to an increased catabolic rate of collagen while hypothyroidism led to a decreased rate of both anabolic and catabolic activity in collagen homeostasis. This has led to a variety of studies that have analyzed the effects of thyroid hormones on tendons, especially the rotator cuff [16– 18]. Recently, Oliva et al. discovered that thyroid hormone receptors are ubiquitous in both healthy and pathologic rotator cuff tendons, suggesting a possible role for thyroid hormone in the proliferation and apoptosis of human tenocytes [18]. Furthermore, they discovered that thyroid hormones increase growth while decreasing apoptosis in healthy tenocytes. These rates were both dose and time dependent, suggesting that hypothyroidism may be implicated in a variety of tendonopathies and tendon tears [18,19]. Furthermore, Grunfeld et al. has reported a threefold increase in frequency of wound dehiscence in the postoperative period for hypothyroid patients compared to control patients following foot and ankle surgery [20]. Given the diverse factors that may contribute to forefoot disorders, several potential etiologies may explain the relationship between thyroid disease and forefoot deformities. Primary hypothyroidism has been associated with neurologic abnormalities, such as carpal tunnel syndrome [13,21]. It is possible that neurologic involvement in the foot may play a role in disrupting the balance of the intrinsic and extrinsic muscles stabilizing the MTP joint. As previously discussed, thyroid disease has been implicated in idiopathic tendinopathies due to the role of thyroxine in collagen synthesis and matrix metabolism and the presence of thyroid hormone receptors on tenocytes [17,22]. While this has mostly been considered the setting of shoulder pain and carpal tunnel syndrome, it warrants exploration as an etiology for forefoot disorders [23,24]. Finally, MTP joint instability may be an important contributor to forefoot deformity. Specifically, it may contribute to the development of hallux
3
valgus and lesser toe deformities or present clinically as metatarsalgia [8,25,26]. The high coincidence of these conditions in our study may suggest a central role for MTP synovitis as a potential link between thyroid disease and forefoot disorders. This link could also be suggested by a study performed by Dorwart and Shumacher, who found mild inflammation in synovial tissue surrounding thickened finger flexor tendons in the setting of hypothyroidism [27]. Future studies should focus on characterizing the cellular mechanisms that underlie this clinical association between thyroid disease and forefoot deformities. To our knowledge, our study is the first description of a relationship between thyroid disease and forefoot deformities [12]. The importance of this association lies in its potential role in population health management. The data of the current study suggests that screening for thyroid disease in patients with forefoot pathology could be a reasonable application given the high incidence of thyroid disease in patients with a forefoot disorder. A better understanding of the pathophysiology underlying this association may enable practitioners to screen for and prevent forefoot deformity progression in patients with thyroid disease. There are several limitations to this study. First, this is a relatively small number of patients with hallux valgus deformity and lesser toe deformities, 26 and 14 respectively. With a larger sample size, our conclusions might be more convincing. Second, false positive and false negative data cannot be ruled out since the diagnosis of thyroid disease was based on medical history obtained from the patients. Third, data from our clinical survey only accounted for the primary visit diagnoses. It is possible that some patients could have had forefoot deformities that were not accounted for in the analysis of data. However, this type of error would lead to an underestimation of the association between thyroid disease and forefoot disorders. Lastly, the national data is subject to the limitations of any national database, including unknown reliability of coding and potential lack of representation from various demographic regions. 5. Conclusions The current study suggests that there is a significant association between forefoot disorders and thyroid dysfunction, especially hallux valgus and lesser toe deformities. Given the prevalence of forefoot disorders, their significant functional consequences, and the rates and cost of operative correction, preventing these disorders offers an important opportunity in population health management. While further studies with long-term outcomes are necessary, the early diagnosis of thyroid disease may provide an opportunity to predict and alter the course of forefoot pathology. Additionally, with such a high rate of thyroid dysfunction associated with certain foot pathologies, it may be prudent to screen certain groups of patients for thyroid disease based on foot pathology. This study serves as a pilot study, with plans to further investigate this relationship with prospective studies, including histologic examination of synovial tissue. Further studies are needed to better understand the relationship between thyroid disease and foot and ankle pathology. Declarations of interest None. Acknowlegements This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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References [1] Nix S, Smith M, Vicenzino B. Prevalence of hallux valgus in the general population: a systematic review and meta-analysis. J Foot Ankle Res 2010;3:, doi:http://dx.doi.org/10.1186/1757-1146-3-21 21-1146-3-21. [2] Saro C, Bengtsson AS, Lindgren U, Adami J, Blomqvist P, Fellander-Tsai L. Surgical treatment of hallux valgus and forefoot deformities in Sweden: a population-based study. Foot Ankle Int 2008;29(3):298–304, doi:http://dx. doi.org/10.3113/FAI.2008.0298. [3] Dunn JE, Link CL, Felson DT, Crincoli MG, Keysor JJ, McKinlay JB. Prevalence of foot and ankle conditions in a multiethnic community sample of older adults. Am J Epidemiol 2004;159(5):491–8. [4] Willey JC, Reuter LS, Belatti DA, Phisitkul P, Amendola N. Availability of consumer prices for bunion surgery. Foot Ankle Int 2014;35(12):1309–15, doi: http://dx.doi.org/10.1177/1071100714549045. [5] Menz HB, Gilheany MF, Landorf KB. Foot and ankle surgery in Australia: a descriptive analysis of the medicare benefits schedule database, 1997-2006. J Foot Ankle Res 2008;1(1)10-1146-1-10, doi:http://dx.doi.org/10.1186/17571146-1-10. [6] Louwerens JW, Schrier JC. Rheumatoid forefoot deformity: pathophysiology, evaluation and operative treatment options. Int Orthop 2013;37(9):1719–29, doi:http://dx.doi.org/10.1007/s00264-013-2014-2. [7] Coughlin MJ, Jones CP. Hallux valgus: demographics, etiology, and radiographic assessment. Foot Ankle Int 2007;28(7):759–77, doi:http://dx.doi.org/ 10.3113/FAI.2007.0759. [8] Shirzad K, Kiesau CD, DeOrio JK, Parekh SG. Lesser toe deformities. J Am Acad Orthop Surg 2011;19(8):505–14. [9] Hecht PJ, Lin TJ. Hallux valgus. Med Clin North Am 2014;98(2):227–32, doi: http://dx.doi.org/10.1016/j.mcna.2013.10.007. [10] Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev 2015;14(2):174–80, doi: http://dx.doi.org/10.1016/j.autrev.2014.10.016. [11] Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull 2011;99:39–51, doi:http://dx.doi.org/10.1093/bmb/ldr030. [12] Punzi L, Betterle C. Chronic autoimmune thyroiditis and rheumatic manifestations. Joint Bone Spine 2004;71(4):275–83, doi:http://dx.doi.org/10.1016/j. jbspin.2003.06.005. [13] Bourji K, Gatto M, Cozzi F, Doria A, Punzi L. Rheumatic and autoimmune thyroid disorders: a causal or casual relationship? Autoimmun Rev 2015;14(1) 57–63 https://doi.org/10.1016/j.autrev.2014.10.007.
[14] Blake DR, McGregor AM, Stansfield E, Smith BR. Antithyroid-antibody activity in the snyovial fluid of patients with various arthritides. Lancet 1979;2(8136) 224–6 https://doi.org/S0140-6736(79)90238-1. [15] Punzi L, Schiavon F, Ramonda R, Cavasin F, Ruffatti A, Todesco S. Anti-thyroid microsomal antibody in synovial fluid as a revealing feature of seronegative autoimmune thyroiditis. Clin Rheumatol 1991;10(2):181–3. [16] Kivirikko KI, Laitinen O, Aer J, Halme J. Metabolism of collagen in experimental hyperthyroidism and hypothyroidism in the rat. Endocrinology 1967;80 (6):1051–61, doi:http://dx.doi.org/10.1210/endo-80-6-1051. [17] Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev 2001;81(3):1097–142. [18] Oliva F, Berardi AC, Misiti S, Verga Falzacappa C, Iacone A, Maffulli N. Thyroid hormones enhance growth and counteract apoptosis in human tenocytes isolated from rotator cuff tendons. Cell Death Dis 2013;4:e705, doi:http://dx. doi.org/10.1038/cddis.2013.229. [19] Pantazis K, Roupas ND, Panagopoulos A, Theodoraki S, Tsintoni A, Kyriazopoulou V. Spontaneous rupture of the long head of the biceps tendon in a woman with hypothyroidism: a case report. J Med Case Rep 2016;10(1)2-0150794-2, doi:http://dx.doi.org/10.1186/s13256-015-0794-2. [20] Grunfeld R, Kunselman A, Bustillo J, Juliano PJ. Wound complications in thyroxine-supplemented patients following foot and ankle surgery. Foot Ankle Int 2011;32(1):38–46. [21] Palumbo CF, Szabo RM, Olmsted SL. The effects of hypothyroidism and thyroid replacement on the development of carpal tunnel syndrome. J Hand Surg Am 2000;25(4):734–9, doi:http://dx.doi.org/10.1053/jhsu.2000.8642. [22] Oliva F, Berardi AC, Misiti S, Maffulli N. Thyroid hormones and tendon: current views and future perspectives. Concise review. Muscles Ligaments Tendons J 2013;3(3):201–3. [23] Purnell DC, Daly DD, Lipscomb PR. Carpal-tunnel syndrome associated with myxedema. Arch Intern Med 1961;108:751–6. [24] Anwar S, Gibofsky A. Musculoskeletal manifestations of thyroid disease. Rheum Dis Clin North Am 2010;36(4):637–46, doi:http://dx.doi.org/10.1016/j. rdc.2010.09.001. [25] DiPreta JA. Metatarsalgia, lesser toe deformities, and associated disorders of the forefoot. Med Clin North Am 2014;98(2):233–51, doi:http://dx.doi.org/ 10.1016/j.mcna.2013.10.003. [26] Smith BW, Coughlin MJ. Disorders of the lesser toes. Sports Med Arthrosc 2009;17(3):167–74, doi:http://dx.doi.org/10.1097/JSA.0b013e3181a5cd26. [27] Dorwart BB, Schumacher HR. Joint effusions, chondrocalcinosis and other rheumatic manifestations in hypothyroidism. A clinicopathologic study. Am J Med 1975;59(6):780–90.
Please cite this article in press as: S.K. Tran, et al., Incidence of thyroid disease in patients with forefoot deformity, Foot Ankle Surg (2019), https://doi.org/10.1016/j.fas.2019.05.014
Foot and Ankle Surgery xxx (2019) xxx–xxx
Contents lists available at ScienceDirect
Foot and Ankle Surgery journal homepage: www.elsevier.com/locate/fas
Incidence of thyroid disease in patients with forefoot deformity Sterling K. Tran2 , James B. Carr2 , Matthew J. Hall1,2 , Joseph S. Park2 , Minton T. Cooper* University of Virginia School of Medicine, Charlottesville, VA, USA
A R T I C L E I N F O
A B S T R A C T
Article history: Received 24 January 2019 Received in revised form 16 May 2019 Accepted 21 May 2019 Available online xxx
Background: Hallux valgus and lesser toe deformities are common foot disorders with substantial functional consequences. While the exact etiologies are multi-factorial, it is unknown if certain endocrine abnormalities, such as thyroid dysfunction, may be associated with these pathologies. The current study sought to investigate the prevalence of thyroid disease in patients with hallux valgus or lesser toe deformities. Methods: Every new patient who presented to our institution’s foot and ankle clinic during a three-month time period was given a survey to determine the presence of a known thyroid disorder. The diagnosis for each visit was then recorded. Additionally, a national, publicly available database was queried for patients diagnosed with thyroid disease and concomitant hallux valgus or specific forefoot pathology. Odds ratios for the presence of thyroid dysfunction were then calculated for each patient group. Results: Three-hundred and fifty initial visit patient surveys were collected, and 74 (21.1%) patients had a known diagnosis of thyroid disease. The most common diagnoses were primary hypothyroidism (n = 61, 17.4%), secondary hypothyroidism (n = 6, 1.7%), thyroiditis (n = 4, 1.1%), and hyperthyroidism (n = 3, 0.9%). Thyroid disease was present in 16 of 26 patients (61.5%) with a diagnosis of hallux valgus (OR 7.3, CI[3.16– 16.99], p < 0.0001). Lesser toe deformities, including hammertoes, mallet toes, bunionettes and crossover toes, were also significantly associated with thyroid disease (OR 5.45, CI[1.83–16.26], p < 0.002). The national database revealed 905,924 patients with a diagnosis of a specific forefoot deformity, and 321,656 of these patients (35.5%) had a concomitant diagnosis of a thyroid condition (OR 2.11, CI[2.10–2.12], p < 0.0001). Conclusions: The current study suggests a significant association between forefoot pathology and thyroid dysfunction, especially hallux valgus and lesser toe deformities. Increased understanding of these correlations may offer an important opportunity in population health management, both in diagnosis and treatment. While further studies with long-term outcomes are necessary, the early diagnosis of thyroid disease may provide an opportunity to predict and potentially alter the course of forefoot pathology. © 2019 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Keywords: Thyroid disease Hypothyroidism Hyperthyroidism Forefoot pathology Lesser toe deformity Hallux valgus
1. Introduction Forefoot disorders, such as hallux valgus and lesser toe deformities (i.e. mallet toe, hammer toe, claw toe, curly toe and crossover toe) are common pathologies with functional consequences. Hallux valgus has been reported to affect up to 23% of adults between the ages of 18–65 years and 35.7% of adults older than 65 years with a higher prevalence in females compared to males [1]. While the epidemiology of lesser toe deformities is less well-characterized, the incidence has been estimated to range between 2–20%, reaching a prevalence as high as 60% in one
* Corresponding author at: 545 Ray C. Hunt Dr., Charlottesville, VA 22908, USA. E-mail address: [email protected] (M.T. Cooper). 1 Present address: Harvard Medical School, Boston, MA, USA. 2 These authors are contributing authors to this manuscript.
community survey [2,3]. Of all patients with hallux valgus deformity, 5–22% undergo operative correction with an average bundled cost of $18,332 per procedure [2,4]. Operative management of lesser toe deformities accounts for 28–46% of all forefoot surgeries performed in the United States [2,5]. The exact etiologies of forefoot deformities are not completely understood and are likely multifactorial. Many foot and ankle deformities, such as hallux valgus, lesser toe deformities and pes planus tend to be coincident and progressive [6,7]. Forefoot disorders are commonly associated with inflammatory arthritides, improper shoe wear, genetics, trauma, and neuromuscular conditions such as cerebral palsy, stroke, or Charcot–Marie–Tooth disease [8,9]. To our knowledge, thyroid disease has never been correlated with an increased incidence of forefoot pathology. Autoimmune thyroiditis is the most common form of thyroid disease [10,11]. The prevalence of autoimmune thyroiditis has been estimated at 5% in adults with higher rates in females and
https://doi.org/10.1016/j.fas.2019.05.014 1268-7731/© 2019 European Foot and Ankle Society. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: S.K. Tran, et al., Incidence of thyroid disease in patients with forefoot deformity, Foot Ankle Surg (2019), https://doi.org/10.1016/j.fas.2019.05.014
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increasing incidence with age [10,11]. Histologically, it is characterized by lymphocytic infiltration of the thyroid parenchyma [10]. Clinically, patients may be euthyroid and asymptomatic, hypothyroid, or hyperthyroid with multiple effects on various organ systems [10]. While definitive risk factors for autoimmune thyroiditis are largely unknown, both genetic and environmental factors are implicated in its development [10]. Furthermore, autoimmune thyroid disease has been associated with several other systemic autoimmune and rheumatologic diseases, including Sjogren’s syndrome, rheumatoid arthritis, systemic lupus erythematosus, and type 1 diabetes mellitus [12,13]. To our knowledge, an association between thyroid dysfunction and foot disorders has never been investigated despite the high prevalence of both conditions. We sought to characterize the relationship between thyroid dysfunction and forefoot pathology. We hypothesized that there would be a greater incidence of thyroid dysfunction in patients with forefoot disorders compared to other disorders of the foot and ankle. 2. Methods All initial visit patients who presented to our institution’s orthopaedic foot and ankle clinic over a three-month period were prospectively surveyed. The survey consisted of three questions: Have you ever been diagnosed with a thyroid condition? Is your thyroid overactive or underactive? Do you take medicine for your thyroid condition? The survey also contained a space for the physician to note the visit diagnoses. Demographic data for these patients was collected through retrospective chart review. Additionally, a publicly available, for-fee database of patients, PearlDiver Patient Record Database (PearlDiver Inc, Fort Wayne, Indiana), was queried for the incidence of thyroid disease in patients with a diagnosis of forefoot disorders. The database contains demographic data and procedure volumes for patients with ICD-9 diagnoses and procedures recorded by Current Procedural Terminology (CPT) codes. Data for the present study was derived from a Medicare portion of the database, which contains over 100 million patient records from 2005 to 2012. Access was granted by PearlDiver Technologies for the purpose of academic research, and the database was stored on a passwordprotected server maintained by PearlDiver. The Medicare database was chosen due to its size and prevalence of patients with a diagnosis of forefoot pathology. The database was queried for patients with the diagnosis of thyroid disease and forefoot pathology using the associated ICD-9 codes. Forefoot pathology was searched for using the ICD-9 codes 735.0 (Hallux valgus, acquired), 735.4 (hammertoe), 735.8 (other acquired deformities of the toe), and 735.9 (other acquired toe deformity). The ICD-9 codes 244.8 (other acquired hypothyroidism) and 244.9 (unspecified hypothyroidism) were then used to identify all patients with a diagnosis of thyroid dysfunction. Data acquisition was performed to include all patients with a forefoot disorder or thyroid disorder in isolation and in combination. Demographic information, including sex, age group (<65, 65–69, 70–74, 75–79, 80–84, and >85) and medical co-morbidity profiles (need to include which co-morbidity profiles) were also obtained. Statistical analysis was performed using the chi-square (χ2) test and Fisher’s Exact test when appropriate. For all statistical comparisons, a p-value <0.05 was considered significant. This project was reviewed by our Institutional Review Board.
Table 1 Demographic data of initial visit clinic patients. Total Age Sex Male Female Thyroid condition Primary hypothyroidism Secondary hypothyroidism Hyperthyroidism Thyroiditis Thyroid medication Forefoot condition Hallux valgus Lesser toe deformity Metatarsalgia
n = 350 49.1 (range, 31.5–66.7) n = 104 (29.8%) n = 246 (70.2%) n = 74 (21.1%) n = 61 (17.4%) n = 6 (1.7%) n = 3 (0.9%) n = 4 (1.1%) n = 65 (18.6%) n = 26 (7.4%) n = 14 (4%) n = 21 (6%)
female (Table 1). A diagnosis of thyroid disease was present in 74 (21.1%) of patients. Primary hypothyroidism was the most common diagnosis (n = 61, 17.4%), followed by secondary hypothyroidism (n = 6, 1.7%), thyroiditis (n = 4, 1.1%), and hyperthyroidism (n = 3, 0.9%). Of initial visit patients, 65 patients (18.6%) took a medication for a thyroid condition. Thyroid disease was present in 16 of 26 patients (61.5%) with a diagnosis of hallux valgus (OR 7.3, CI[3.16–16.99], p < 0.0001) (Table 2). Lesser toe deformities, including hammertoes, mallet toes, bunionettes and crossover toes, were also significantly associated with thyroid disease (OR 5.45, CI[1.83–16.26], p < 0.002). Associations between thyroid disease and metatarsalgia (OR 1.53, CI[0.57–4.10], p = 0.41), midfoot arthritis (OR 1.17, CI [0.50–2.69], p = 0.71), and pes planovlagus (OR 1.64, CI[0.69–3.91], p = 0.26) did not reach clinical significance (Table 2). The national data from the Pearldiver database revealed 905,924 patients with a diagnosis of a forefoot disorder, and 321,656 of these patients (35.5%) had a concomitant diagnosis of a thyroid condition (OR 2.11, CI[2.10–2.12], p < 0.0001) (Table 3). 4. Discussion This study identifies a relationship between thyroid disease and forefoot deformities amongst patients presenting to a single institution’s orthopaedic foot and ankle clinic. Thyroid disease was present in 21.1% of the studied patient population, and it was Table 2 Odds ratios for thyroid disease in foot pathology in foot and ankle clinic visits. Foot pathology
Thyroid No disease thyroid disease
Odds ratio (95% confidence interval), p-values
Hallux valgus Lesser toe deformity Metatarsalgia Midfoot arthritis Pes planovalgus
16 8 6 8 8
7.3 (3.16–16.99), p < 0.0001 5.45 (1.83–16.26) p < 0.002 1.53 (0.57–4.10), p = 0.41 1.17 (0.50–2.69), p = 0.71 1.64 (0.69–3.91), p = 0.26
10 8 15 26 19
Table 3 Association of thyroid disease and forefoot disorders in a large national Medicare population. Thyroid condition
No thyroid condition
Total
3. Results Three-hundred and fifty initial visit patient surveys were collected over the three-month period. The mean patient age was 49.1 (range, 31.5–66.7) years, and 246 (70.2%) of patients were
Total 10,290,018 population Forefoot 321,656 disorder
Odds ratio (95% confidence interval), p value
38,730,233 49,020,251 584,268
905,924
(2.10–2.12), p < 0.0001
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significantly associated with both hallux valgus and lesser toe deformities, which were also the most common forefoot pathologies diagnosed. The associations between thyroid disease and forefoot disorders were independent of any comorbidities. Additionally, the national data confirms a high incidence of thyroid disease in patients with a forefoot disorder, but a low incidence of forefoot disorders in the general population of patients with thyroid disease. Thyroid hormones triiodothyronine (T3) and thyroxine (T4) play an essential role in metabolic homeostasis for many adult tissues and organ systems. The relationship between autoimmune thyroiditis and rheumatic manifestations has been previously described [12,13]. These manifestations are most commonly characterized by non-erosive arthritis and polyarthralgia [12]. While these manifestations occur at higher rates in the hypothyroid population, they have also been shown to occur in euthyroid patients with autoimmune thyroiditis [12]. Current hypotheses about the pathophysiology of this association include attack on synovial tissue from anti-thyroid autoantibodies, overlap between chronic autoimmune thyroiditis and other subclinical rheumatic disorders, and a systemic progression of an autoimmune process [12,14,15]. While thyroid dysfunction has been linked with rheumatologic disorders, few studies have investigated a possible role of thyroid dysfunction in other musculoskeletal disorders of connective tissues, such as ligaments and tendons. Most of the available studies have investigated the effects of thyroid hormone on collagen metabolism [16,17]. One of the first studies to investigate this relationship was by Kivirikko in 1967 [16]. He investigated changes in collagen synthesis rates in rats who were either in a hyperthyroid or hypothyroid state and discovered that collagen synthesis is decreased in both hyperthyroidism and hypothyroidism. Specifically, hyperthyroidism led to an increased catabolic rate of collagen while hypothyroidism led to a decreased rate of both anabolic and catabolic activity in collagen homeostasis. This has led to a variety of studies that have analyzed the effects of thyroid hormones on tendons, especially the rotator cuff [16– 18]. Recently, Oliva et al. discovered that thyroid hormone receptors are ubiquitous in both healthy and pathologic rotator cuff tendons, suggesting a possible role for thyroid hormone in the proliferation and apoptosis of human tenocytes [18]. Furthermore, they discovered that thyroid hormones increase growth while decreasing apoptosis in healthy tenocytes. These rates were both dose and time dependent, suggesting that hypothyroidism may be implicated in a variety of tendonopathies and tendon tears [18,19]. Furthermore, Grunfeld et al. has reported a threefold increase in frequency of wound dehiscence in the postoperative period for hypothyroid patients compared to control patients following foot and ankle surgery [20]. Given the diverse factors that may contribute to forefoot disorders, several potential etiologies may explain the relationship between thyroid disease and forefoot deformities. Primary hypothyroidism has been associated with neurologic abnormalities, such as carpal tunnel syndrome [13,21]. It is possible that neurologic involvement in the foot may play a role in disrupting the balance of the intrinsic and extrinsic muscles stabilizing the MTP joint. As previously discussed, thyroid disease has been implicated in idiopathic tendinopathies due to the role of thyroxine in collagen synthesis and matrix metabolism and the presence of thyroid hormone receptors on tenocytes [17,22]. While this has mostly been considered the setting of shoulder pain and carpal tunnel syndrome, it warrants exploration as an etiology for forefoot disorders [23,24]. Finally, MTP joint instability may be an important contributor to forefoot deformity. Specifically, it may contribute to the development of hallux
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valgus and lesser toe deformities or present clinically as metatarsalgia [8,25,26]. The high coincidence of these conditions in our study may suggest a central role for MTP synovitis as a potential link between thyroid disease and forefoot disorders. This link could also be suggested by a study performed by Dorwart and Shumacher, who found mild inflammation in synovial tissue surrounding thickened finger flexor tendons in the setting of hypothyroidism [27]. Future studies should focus on characterizing the cellular mechanisms that underlie this clinical association between thyroid disease and forefoot deformities. To our knowledge, our study is the first description of a relationship between thyroid disease and forefoot deformities [12]. The importance of this association lies in its potential role in population health management. The data of the current study suggests that screening for thyroid disease in patients with forefoot pathology could be a reasonable application given the high incidence of thyroid disease in patients with a forefoot disorder. A better understanding of the pathophysiology underlying this association may enable practitioners to screen for and prevent forefoot deformity progression in patients with thyroid disease. There are several limitations to this study. First, this is a relatively small number of patients with hallux valgus deformity and lesser toe deformities, 26 and 14 respectively. With a larger sample size, our conclusions might be more convincing. Second, false positive and false negative data cannot be ruled out since the diagnosis of thyroid disease was based on medical history obtained from the patients. Third, data from our clinical survey only accounted for the primary visit diagnoses. It is possible that some patients could have had forefoot deformities that were not accounted for in the analysis of data. However, this type of error would lead to an underestimation of the association between thyroid disease and forefoot disorders. Lastly, the national data is subject to the limitations of any national database, including unknown reliability of coding and potential lack of representation from various demographic regions. 5. Conclusions The current study suggests that there is a significant association between forefoot disorders and thyroid dysfunction, especially hallux valgus and lesser toe deformities. Given the prevalence of forefoot disorders, their significant functional consequences, and the rates and cost of operative correction, preventing these disorders offers an important opportunity in population health management. While further studies with long-term outcomes are necessary, the early diagnosis of thyroid disease may provide an opportunity to predict and alter the course of forefoot pathology. Additionally, with such a high rate of thyroid dysfunction associated with certain foot pathologies, it may be prudent to screen certain groups of patients for thyroid disease based on foot pathology. This study serves as a pilot study, with plans to further investigate this relationship with prospective studies, including histologic examination of synovial tissue. Further studies are needed to better understand the relationship between thyroid disease and foot and ankle pathology. Declarations of interest None. Acknowlegements This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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References [1] Nix S, Smith M, Vicenzino B. Prevalence of hallux valgus in the general population: a systematic review and meta-analysis. J Foot Ankle Res 2010;3:, doi:http://dx.doi.org/10.1186/1757-1146-3-21 21-1146-3-21. [2] Saro C, Bengtsson AS, Lindgren U, Adami J, Blomqvist P, Fellander-Tsai L. Surgical treatment of hallux valgus and forefoot deformities in Sweden: a population-based study. Foot Ankle Int 2008;29(3):298–304, doi:http://dx. doi.org/10.3113/FAI.2008.0298. [3] Dunn JE, Link CL, Felson DT, Crincoli MG, Keysor JJ, McKinlay JB. Prevalence of foot and ankle conditions in a multiethnic community sample of older adults. Am J Epidemiol 2004;159(5):491–8. [4] Willey JC, Reuter LS, Belatti DA, Phisitkul P, Amendola N. Availability of consumer prices for bunion surgery. Foot Ankle Int 2014;35(12):1309–15, doi: http://dx.doi.org/10.1177/1071100714549045. [5] Menz HB, Gilheany MF, Landorf KB. Foot and ankle surgery in Australia: a descriptive analysis of the medicare benefits schedule database, 1997-2006. J Foot Ankle Res 2008;1(1)10-1146-1-10, doi:http://dx.doi.org/10.1186/17571146-1-10. [6] Louwerens JW, Schrier JC. Rheumatoid forefoot deformity: pathophysiology, evaluation and operative treatment options. Int Orthop 2013;37(9):1719–29, doi:http://dx.doi.org/10.1007/s00264-013-2014-2. [7] Coughlin MJ, Jones CP. Hallux valgus: demographics, etiology, and radiographic assessment. Foot Ankle Int 2007;28(7):759–77, doi:http://dx.doi.org/ 10.3113/FAI.2007.0759. [8] Shirzad K, Kiesau CD, DeOrio JK, Parekh SG. Lesser toe deformities. J Am Acad Orthop Surg 2011;19(8):505–14. [9] Hecht PJ, Lin TJ. Hallux valgus. Med Clin North Am 2014;98(2):227–32, doi: http://dx.doi.org/10.1016/j.mcna.2013.10.007. [10] Antonelli A, Ferrari SM, Corrado A, Di Domenicantonio A, Fallahi P. Autoimmune thyroid disorders. Autoimmun Rev 2015;14(2):174–80, doi: http://dx.doi.org/10.1016/j.autrev.2014.10.016. [11] Vanderpump MP. The epidemiology of thyroid disease. Br Med Bull 2011;99:39–51, doi:http://dx.doi.org/10.1093/bmb/ldr030. [12] Punzi L, Betterle C. Chronic autoimmune thyroiditis and rheumatic manifestations. Joint Bone Spine 2004;71(4):275–83, doi:http://dx.doi.org/10.1016/j. jbspin.2003.06.005. [13] Bourji K, Gatto M, Cozzi F, Doria A, Punzi L. Rheumatic and autoimmune thyroid disorders: a causal or casual relationship? Autoimmun Rev 2015;14(1) 57–63 https://doi.org/10.1016/j.autrev.2014.10.007.
[14] Blake DR, McGregor AM, Stansfield E, Smith BR. Antithyroid-antibody activity in the snyovial fluid of patients with various arthritides. Lancet 1979;2(8136) 224–6 https://doi.org/S0140-6736(79)90238-1. [15] Punzi L, Schiavon F, Ramonda R, Cavasin F, Ruffatti A, Todesco S. Anti-thyroid microsomal antibody in synovial fluid as a revealing feature of seronegative autoimmune thyroiditis. Clin Rheumatol 1991;10(2):181–3. [16] Kivirikko KI, Laitinen O, Aer J, Halme J. Metabolism of collagen in experimental hyperthyroidism and hypothyroidism in the rat. Endocrinology 1967;80 (6):1051–61, doi:http://dx.doi.org/10.1210/endo-80-6-1051. [17] Yen PM. Physiological and molecular basis of thyroid hormone action. Physiol Rev 2001;81(3):1097–142. [18] Oliva F, Berardi AC, Misiti S, Verga Falzacappa C, Iacone A, Maffulli N. Thyroid hormones enhance growth and counteract apoptosis in human tenocytes isolated from rotator cuff tendons. Cell Death Dis 2013;4:e705, doi:http://dx. doi.org/10.1038/cddis.2013.229. [19] Pantazis K, Roupas ND, Panagopoulos A, Theodoraki S, Tsintoni A, Kyriazopoulou V. Spontaneous rupture of the long head of the biceps tendon in a woman with hypothyroidism: a case report. J Med Case Rep 2016;10(1)2-0150794-2, doi:http://dx.doi.org/10.1186/s13256-015-0794-2. [20] Grunfeld R, Kunselman A, Bustillo J, Juliano PJ. Wound complications in thyroxine-supplemented patients following foot and ankle surgery. Foot Ankle Int 2011;32(1):38–46. [21] Palumbo CF, Szabo RM, Olmsted SL. The effects of hypothyroidism and thyroid replacement on the development of carpal tunnel syndrome. J Hand Surg Am 2000;25(4):734–9, doi:http://dx.doi.org/10.1053/jhsu.2000.8642. [22] Oliva F, Berardi AC, Misiti S, Maffulli N. Thyroid hormones and tendon: current views and future perspectives. Concise review. Muscles Ligaments Tendons J 2013;3(3):201–3. [23] Purnell DC, Daly DD, Lipscomb PR. Carpal-tunnel syndrome associated with myxedema. Arch Intern Med 1961;108:751–6. [24] Anwar S, Gibofsky A. Musculoskeletal manifestations of thyroid disease. Rheum Dis Clin North Am 2010;36(4):637–46, doi:http://dx.doi.org/10.1016/j. rdc.2010.09.001. [25] DiPreta JA. Metatarsalgia, lesser toe deformities, and associated disorders of the forefoot. Med Clin North Am 2014;98(2):233–51, doi:http://dx.doi.org/ 10.1016/j.mcna.2013.10.003. [26] Smith BW, Coughlin MJ. Disorders of the lesser toes. Sports Med Arthrosc 2009;17(3):167–74, doi:http://dx.doi.org/10.1097/JSA.0b013e3181a5cd26. [27] Dorwart BB, Schumacher HR. Joint effusions, chondrocalcinosis and other rheumatic manifestations in hypothyroidism. A clinicopathologic study. Am J Med 1975;59(6):780–90.
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