- Email: [email protected]
Risk of obstructive sleep apnea among patients with Cushing's syndrome: a nationwide longitudinal study
Accepted Manuscript Risk of obstructive sleep apnea among patients with Cushing’s syndrome: A nationwide longitudinal study Ling-Uei Wang, M.D., Tsung-Yang Wang, M.D., Ya-Mei Bai, M.D., PH.D., Ju-Wei Hsu, M.D., Kai-Lin Huang, M.D., Tung-Ping Su, M.D., Cheng-Ta Li, M.D., Ph.D., WeiChen Lin, M.D., Tzeng-Ji Chen, M.D., PH.D., Mu-Hong Chen PII:
S1389-9457(17)30210-1
DOI:
10.1016/j.sleep.2017.04.016
Reference:
SLEEP 3394
To appear in:
Sleep Medicine
Received Date: 28 March 2017 Revised Date:
24 April 2017
Accepted Date: 27 April 2017
Please cite this article as: Wang L-U, Wang T-Y, Bai Y-M, Hsu J-W, Huang K-L, Su T-P, Li C-T, Lin WC, Chen T-J, Chen M-H, Risk of obstructive sleep apnea among patients with Cushing’s syndrome: A nationwide longitudinal study, Sleep Medicine (2017), doi: 10.1016/j.sleep.2017.04.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Risk of obstructive sleep apnea among patients with Cushing’s syndrome: a nationwide longitudinal ACCEPTED MANUSCRIPT study
Ling-Uei Wang 6,*, M.D., Tsung-Yang Wang 1,2,5,*, M.D., Ya-Mei Bai 1,2, M.D., PH.D., Ju-Wei Hsu 1,2, M.D., Kai-Lin Huang 1,2,#, M.D., Tung-Ping Su 1,2, M.D., Cheng-Ta Li 1, 2, M.D., Ph.D., Wei-Chen Lin 1, 2, M.D.,
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Tzeng-Ji Chen 3,4, M.D., PH.D., Mu-Hong Chen 1,2,#
1. Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; 2. Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan
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3. Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 4. Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan 5. Department of Forensic and Neurodevelopmental Sciences, London, United Kingdom 6. Division of medicine, National Yang-Ming University, Taipei, Taiwan *: equally contributed. # Corresponding authors:
Dr Mu-Hong Chen (E-mail: [email protected])
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Address: Department of Psychiatry, Taipei Veterans General Hospital, Taipei, TAIWAN, 112 TEL: 886-2-28757027; FAX: 886-2-28757592
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Kai-Lin Huang, M.D. E-mail: [email protected] Department of Psychiatry, No. 201, Shih-Pai Road, Sec. 2, 11217, Taipei, Taiwan.
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Tel：886 -2- 28344012. Fax：886 -2- 28344012.
Words: 1828
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Abstract
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OBJECTIVE: Previous studies have demonstrated the association between Cushing’s syndrome (CS), obstructive sleep apnea (OSA), and the risk factors for OSA, but rarely provided the evidence within a large population. Using the Taiwan National Health Insurance Research Database, we attempted to investigate the association between CS and OSA, and to provide persuading evidences.
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METHODS: In our study, 1612 patients with CS and 1612 age-, sex-, and comorbidities-matched controls were included, and followed up to the end of 2011. Cases of OSA were identified during the follow-up. RESULTS: Among patients with CS, 53 developed OSA (incidence: 4.11 per thousand person-year)
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compared with 22 in the control group (incidence: 1.70 per thousand person-year) during the follow-up (p<.001). CS patients had a 2.82-fold higher risk of developing OSA (HR = 2.82; 95% CI: 1.67–4.77) in
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later life.
DISCUSSION: Our study was the first longitudinal study to support the temporal association between CS and risk of OSA. Patients with CS were associated with an increased likelihood of OSA. Further studies would be required to investigate the exact underlying mechanisms between CS and OSA, and elucidate
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whether the prompt intervention for CS may reduce the risk of subsequent OSA.
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Keywords: Cushing’s syndrome; obstructive sleep apnea; temporal association.
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Introduction
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Cushing’s syndrome (CS), defined as exogenous or endogenous pathological hypercortisolism, manifests various clinical presentations, covering almost every subspecialty. These include gynecological (oligomenorrhea, hirsutism, and infertility), dermatological (red facial skin, poor wound healing, striae, and acne), orthopedic and rheumatological (fracture and osteoporosis), metabolic (type 2 diabetes mellitus and
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dyslipidemia), cardiovascular (hypertension, stroke, and myocardial infarction), neurological (headaches and decreased memory and cognition), psychiatric (depression and anxiety), and nonspecific (fatigue, backache, and weight gain) symptoms.1 The annual incidence of CS is 0.7–2.4 cases per million population2,3.
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Previous studies suggested that patients with CS may have more sleep disturbance, especially insomnia 4,5. Starkman et al reported that up to 70% of CS patients suffered from insomnia, including difficulty in falling
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asleep or waking during the night or in the early morning, and nearly all patients complained of daytime fatigue 5. However, the etiology of insomnia among patients with CS was rarely further clarified. In recent decades, increasing evidence has shown a significant relationship between CS and risk factors for obstuctive sleep apnea (OSA), such as obesity, hypertension, diabetes, and dyslipidemia. 6 Feelders et al revealed
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that 58-85% of patients had hypertension, 32-41% were obese, 20-47% had diabetes mellitus, and 38-71% had dyslipidemia 6. However, the association of CS with OSA itself has rarely been investigated. This potential association was first described in 1992, when seven of 22 patients with CS presented OSA-
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hypopnea syndrome7. Gokosmanog et al evaluated the OSA condition among 30 female patients with CS and age-, sex- and body mass index (BMI)-matched controls, and found that patients with CS had a
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significantly higher prevalence of OSA (50% vs 23%, P = 0.003); the higher apnea-hypopnea index (AHI) (P = 0.028) scores compared with the control subjects.8 The mechanisms underlying this association were then hypothesized in some studies—for instance, centripetal accumulation of adipose tissue9 and weakness of proximal muscles.10 However, these studies employed an insufficient sample size. Moreover, only a few studies have reported results relevant to the Taiwan population. By using a large sample size from the Taiwan National Health Insurance Research Database along with a longitudinal study design in our current study, we investigated the temporal association between CS and OSA. We hypothesized that patients with CS have an elevated risk of developing OSA later in life compared 3
to those without CS.
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Methods Data source. The Taiwan National Health Insurance (NHI) program was implemented in 1995 and offers comprehensive medical coverage for all residents of Taiwan. The National Health Research Institute (NHRI)
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is in charge of the entire insurance claims database, namely, the NHIRD, which consists of healthcare data from > 99% of the entire Taiwan population. The NHRI audits and releases the NHIRD for use in health service studies. Subjects included in the NHIRD are anonymous to maintain individual privacy.
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Comprehensive information on insured subjects is included in the database, including demographic data, dates of clinical visits, disease diagnoses, and medical procedures. The diagnostic codes used were based on
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the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan.11-13
Inclusion criteria for subjects with CS and the control group. Subjects were identified with CS diagnosed (ICD-9-CM code: 255.0) by endocrinologists, pedestrians, and internal medicine physicians
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between January 1, 1998 and December 31, 2009, and who had no history of any sleep apnea (ICD-9-CM codes: 327.2x, 780.51, 780.53, 780.57) before enrollment, were included as the CS cohort. The controls were randomly selected from the same database after eliminating the CS cohort, those who had been given a
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diagnosis of CS at any time, and those with any sleep apnea before enrollment. Each individual in the CS cohort was matched on the basis of age, sex, time of enrollment, residence, income, and medical
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comorbidities (obesity, hypertension, diabetes mellitus, and dyslipidemia) with an individual without CS in a comparison cohort. Diagnosis of OSA (ICD-9-CM codes: 327.23, 780.51, 780.53, 780.57) given by pulmonologists, psychiatrists, neurologists, and otolaryngologists after the evaluation of polysomnography were identified during the follow-up (to December 31 2011 or to the date of death). Level of urbanization (level 1 to level 5; level 1: most urbanized region; level 5: least urbanized region) was also assessed.14 Taipei Veterans General Hospital Institutional Review Board permitted this study. Statistical analysis. For between-group comparisons, the independent t test was used for continuous variables and Pearson's X2 test for nominal variables, where appropriate. The Cox regression model was 4
used to investigate the HR with 95% CI of developing OSA after adjusting for demographic data and
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medical comorbidities. Subanalysis stratified by sex was performed to calculate the risk of OSA. Sensitivity analyses were performed to investigate the above associations after excluding the first year or first threeyears of observation. All data processing and statistical analyses were performed with Statistical Package for Social Sciences (SPSS) version 17 software (SPSS Inc.) and Statistical Analysis Software (SAS) version 9.1
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(SAS Institute, Cary, NC).
Results
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Table 1 presented the distributions of demographic characteristics and selected medical comorbidities between the CS cohort and matched controls. In total, 53 of CS patients (incidence 4.11 per 1000 person-
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years) and 22 of comparison patients (incidence 1.70 per 1000 person-years) developed OSA during the follow-up (p<0.001).
The Kaplan-Meier survival curve with log-rank test (p<0.001) for the development of OSA in both cohorts was shown in Figure 1. When examining the association of CS with OSA risk, patients with CS had
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a 2.82-fold higher risk of developing OSA than the controls did (HR = 2.82; 95% CI: 1.67–4.77) (Table 2). Both men (HR: 3.10, 95% CI: 1.22~7.89) and women (HR: 2.74, 95% CI: 1.45~5.18) with CS were prone to developing OSA in later life compared with the control group (Table 2). Sensitivity tests after excluding the
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first years (HR: 2.90, 95% CI: 1.61~5.22) and first 3-years (HR: 2.75, 95% CI: 1.37~5.50) of observation
Discussion
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revealed the consistent findings (Table 2).
Our results support the hypothesis that patients with CS, regardless of their sex, had an increased risk of developing OSA in later life compared with those without CS; OSA risk was approximately three times higher in the presence of CS. Few studies have suggested the potential association between CS and OSA. Berger et al. investigated the association between three-month steroid intervention mimicking CS and the risk of sleep apnea, and they demonstrated that the mean AHI of patients undergoing steroid intervention increased by 56%, from 5
9.8 ± 11.8 to 15.4 ± 15.8 (p = 0.004); this increment in AHI was significantly higher compared with that of
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untreated mild OSA patients.15 Shipley et al. polysomnographically evaluated sleep in 22 patients with CS and demonstrated that 32% of these patients at least had ≥9.4 events/h (mild sleep apnea) and 18% had ≥17.5 events/h7. Evaluating the risk of OSA between 30 patients with CS and age-/sex-/BMI-matched controls by overnight polysomnography, Gokosmanog et al indicated that CS patients were prone to having
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OSA and higher AHI compared with the controls, and further revealed that serum cortisol level was an independent predictor for AHI after controlling for BMI and homeostasis model assessment (HOMA) scores (an index of insulin resistance).8 Nevertheless, our study is the first longitudinal follow-up study with a large
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sample size supporting the temporal association between CS and OSA. Compatible with previous findings, we also suggested that CS was an independent risk factor for developing OSA after adjusting for OSA-
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related physical comorbidities, such as obesity and diabetes mellitus.
The definite mechanism underlying the relationship between CS and OSA risk remains unclear. CSrelated weight gain and centripetal adipose tissue were assumedly to contributing to the development of OSA.9,16,17 Davies et al. conducted a prospective study analyzing 85 patients referred to a sleep clinic and
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reported that neck circumference is a more useful predictor of OSA than is general obesity.9 By contrast, among patients with long-term steroid intervention, Berger et al. noted that OSA was not correlated with the corresponding body weight gain and increased neck girth.15 In our study, we also found that CS was an
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independent risk factor of subsequent OSA regardless of the presence of obesity. In addition to consequent physical changes, myopathies are common among patients with hypercortisolism and previous study found a
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significant relationship between serum cortisol level and AHI among patents with CS8; the weakness of geniohyoid and genioglossus muscles may regulate the relationship of CS with OSA; however, additional detailed studies are required to confirm this hypothesis.18 Furthermore, we discussed the international impact of our work in the current and future investigation of CS and OSA. Growing evidence reported a progressive increase in the incidence of CS in recent decades, from 2.3 cases per million between 1985 and 1995 in a Danish study to nearly 49 cases per million in 2009 in a US study.3,19 CS-related medical comorbidities (such as obesity and diabetes mellitus), have been regarded as the risk factors of OSA. Under the influence of the western diet and lifestyle, increasing 6
prevalence rates of obesity and diabetes mellitus were reported worldwide, and the occult CS hidden behind
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obesity and diabetes mellitus gained clinical and scientific attention, and concern.20,21 However, only several studies with a cross-sectional study design and a small sample size investigated the relationship between CS and the risk of OSA. Our study was the first longitudinal study with a large sample size supported this association, suggesting a potential role of cortisol in the pathophysiology of OSA. Dysregulated cortisol
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levels and altered hypothalamic–pituitary–adrenal (HPA) axis were one of the core clinical phenomena in CS, and were also observed in other metabolic disorders, such as diabetes mellitus.22,23 However, the potential role of cortisol in the pathophysiology and risk of OSA was rarely investigated worldwide. Kritiko
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et al examined the cortisol levels at baseline and after two-month continuous positive airway pressure (CPAP) treatment among 35 patients with OSA and 37 controls, and found that OSA was associated with
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significantly higher 24-hour cortisol levels at baseline compared with the controls, whereas CPAP lowered cortisol levels significantly, close to those of controls.24 Taken the aforementioned evidences together, our result of a positive association between CS and OSA reminded the clinicians to survey the risk of OSA among CS patients when they had sleep disturbances, and suggested the researchers to further
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clarify the role of cortisol and HPA axis in the pathophysiology of OSA.
Our study has some limitations. First, the incidence of OSA may have been underestimated because only patients seeking medical help were enrolled; nevertheless, we enrolled patients who were diagnosed by
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board-certified physicians, thus yielding reliable validity. Second, we combined Cushing’s disease and CS into a single category of CS, because the diagnostic code of Cushing’s diseases is unavailable in ICD-9-CM;
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thus, further studies are necessary to investigate the risk of OSA in Cushing’s diseases and CS separately. Third, some information, such as CS severity, BMI, personal lifestyle, and family history, is unavailable in the Taiwan National Health Insurance Research Database; therefore, we could not investigate the effects of these parameters on the relationship between CS and OSA. In conclusion, our study is the first longitudinal study supporting the temporal association between CS and risk of OSA. Patients with CS showed
an increased OSA risk. Further research is required for
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investigating the precise mechanism underlying the relationship between CS and OSA and elucidating ACCEPTED MANUSCRIPT
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whether a prompt intervention for CS reduces subsequent OSA risk.
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Acknowledgements
We thank Dr MHC, Dr KLH, Dr TYW, and Dr LUW, who designed the study, wrote the protocol and manuscripts, Dr YMB, Dr JWH, Dr TPS, Dr CTL, Dr WCL, Dr MHC, Dr TYW, and Dr LUW, who assisted with the preparation and proof-reading of the manuscript, and Dr MHC and Dr TJC, who provided the advices on statistical analysis.
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We thank Mr I-Fan Hu for his friendship and support.
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Conflict of Interest: All authors certify that they have No conflict of interest. ACCEPTED MANUSCRIPT Funding Source: The study was supported by grant from Taipei Veterans General Hospital (V103E10-001, V104E10-002, V105E10-001-MY2-1, V105A-049). The sponsor had no role in the design or conduct of this research.
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Financial Disclosure: All authors have no financial relationships relevant to this article to disclose.
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References ACCEPTED MANUSCRIPT 1. Nieman LK. Cushing's syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol 2015;173:M33-8. 2. Etxabe J, Vazquez JA. Morbidity and mortality in Cushing's disease: an epidemiological approach. Clin Endocrinol (Oxf) 1994;40:479-84. 3. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. The Journal of clinical endocrinology and metabolism 2001;86:117-23. 4. Starkman MN, Schteingart DE. Neuropsychiatric manifestations of patients with Cushing's syndrome.
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Relationship to cortisol and adrenocorticotropic hormone levels. Archives of internal medicine 1981;141:215-9. 5. Starkman MN, Schteingart DE, Schork MA. Depressed mood and other psychiatric manifestations of Cushing's syndrome: relationship to hormone levels. Psychosomatic medicine 1981;43:3-18.
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6. Feelders RA, Pulgar SJ, Kempel A, Pereira AM. The burden of Cushing's disease: clinical and healthrelated quality of life aspects. European journal of endocrinology 2012;167:311-26. 7. Shipley JE, Schteingart DE, Tandon R, Starkman MN. Sleep architecture and sleep apnea in patients with Cushing's disease. Sleep 1992;15:514-8. 8. Gokosmanog Lu F, Guzel A, Kan EK, Atmaca H. Increased prevalence of obstructive sleep apnea in patients with Cushing's syndrome compared with weight- and age-matched controls. European journal of endocrinology 2017;176:267-72.
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9. Davies RJ, Ali NJ, Stradling JR. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome. Thorax 1992;47:101-5. 10. Pecori Giraldi F, Moro M, Cavagnini F, Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of E. Gender-related differences in the presentation and course of Cushing's disease. J Clin
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Endocrinol Metab 2003;88:1554-8. 11. Chen MH, Su TP, Chen YS, et al. Attention deficit hyperactivity disorder, tic disorder, and allergy: is there a link? A nationwide population-based study. Journal of child psychology and psychiatry, and allied disciplines 2013;54:545-51.
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12. Chen MH, Li CT, Tsai CF, et al. Risk of dementia among patients with asthma: a nationwide longitudinal study. Journal of the American Medical Directors Association 2014;15:763-7. 13. Shen CC, Tsai SJ, Perng CL, Kuo BI, Yang AC. Risk of Parkinson disease after depression: a nationwide population-based study. Neurology 2013;81:1538-44. 14. Liu CY, Hung, Y. T., Chuang, Y. L., Chen, Y. J., Weng, W. S., Liu, J. S. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Management (Chin) 2006;4:1-22. 15. Berger G, Hardak E, Shaham B, Avitan E, Yigla M. Preliminary prospective explanatory observation on the impact of 3-month steroid therapy on the objective measures of sleep-disordered breathing. Sleep Breath 2012;16:549-53. 16. Rosenow F, McCarthy V, Caruso AC. Sleep apnoea in endocrine diseases. J Sleep Res 1998;7:3-11. 17. Grunstein R, Wilcox I, Yang TS, Gould Y, Hedner J. Snoring and sleep apnoea in men: association with central obesity and hypertension. Int J Obes Relat Metab Disord 1993;17:533-40. 11
18. Yanovski JA, Cutler GB, Jr. Glucocorticoid action and the clinical features of Cushing's syndrome. ACCEPTED MANUSCRIPT Endocrinol Metab Clin North Am 1994;23:487-509. 19. Broder MS, Neary MP, Chang E, Cherepanov D, Ludlam WH. Incidence of Cushing's syndrome and Cushing's disease in commercially-insured patients <65 years old in the United States. Pituitary 2015;18:283-9. 20. Sharma ST, Nieman LK, Feelders RA. Cushing's syndrome: epidemiology and developments in disease management. Clinical epidemiology 2015;7:281-93. 21. Tabarin A, Perez P. Pros and cons of screening for occult Cushing syndrome. Nature reviews
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Endocrinology 2011;7:445-55. 22. Joseph JJ, Golden SH. Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus. Annals of the New York Academy of Sciences 2017;1391:20-34. 23. Raff H, Carroll T. Cushing's syndrome: from physiological principles to diagnosis and clinical care.
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The Journal of physiology 2015;593:493-506. 24. Kritikou I, Basta M, Vgontzas AN, et al. Sleep apnoea and the hypothalamic-pituitary-adrenal axis in men and women: effects of continuous positive airway pressure. The European respiratory journal 2016;47:531-40.
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Table 1. Demographic data and incidence of obstructive sleep apnea among patients with Cushing’s syndrome and controls.
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Patients with Cushing
Control group
syndrome
Sex (Female, %) Obstructive sleep apnea (n, 1000 person-years) Age at diagnosis (years, SD) Duration between enrollment and diagnosis (years, SD)
(n=1612)
(n=1612)
47.59 (19.52)
47.57 (19.52)
1142 (70.8)
1142 (70.8)
53 (4.11)
22 (1.70)
<0.001
47.18 (14.98)
53.47 (15.24)
0.104
4.07 (2.95)
3.09 (3.69)
0.230
742 (46.0)
0.697
408 (25.3)
0.903
429 (26.6)
0.937
29 (1.8)
0.323
Medical comorbidities (n, %) Hypertension
730 (45.3)
Dyslipidemia
404 (25.1)
Diabetes mellitus
432 (26.8) 38 (2.4)
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Obesity Level of urbanization (n, %)
442 (27.4)
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1 (most urbanized) 2 3 4 5 (most rural) Income-related insured amount
≥ 25,001NTD/month
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SD: standard deviation.
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≤ 15,840 NTD/month 15,841~25,000NTD/month
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Age at enrollment (years, SD)
p-value
1
0.976
0.304
479 (29.7)
486 (30.1)
486 (30.1)
251 (15.6)
249 (15.4)
236 (14.6)
198 (12.3)
197 (12.2)
200 (12.4) 0.955
665 (41.3)
665 (41.3)
605 (37.5)
603 (37.4)
342 (21.2)
344 (21.3)
Table 2. Cox regression models and sensitivity tests of developing obstructive apnea among patients with Cushing’s syndrome and
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controls. Sex
Sensitivity tests
Males
Females
> 1 years
> 3 years
Total
HR (95% CI)
HR (95% CI)
HR (95% CI)
HR (95% CI)
HR (95% CI)
Absence
1
1
1
1
1
Presence
3.10 (1.22~7.89)
2.74 (1.45~5.18)
2.90 (1.61~5.22)
2.75 (1.37~5.50)
2.82 (1.67~4.77)
Cushing’s syndrome
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HR: hazard ratio; CI: confidence interval.
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Bold type indicates the statistical significance.
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Figure 1. Survival curve of developing obstructive apnea among patients with Cushing’s syndrome and controls.
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ACCEPTED MANUSCRIPT Highlights 1. Patients with Cushing’s syndrome (CS) had an increased risk of developing OSA in later life.
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2. Both men and women with CS were prone to developing OSA. 3. CS was an independent risk factor of OSA regardless of obesity and diabetes mellitus.
S1389-9457(17)30210-1
DOI:
10.1016/j.sleep.2017.04.016
Reference:
SLEEP 3394
To appear in:
Sleep Medicine
Received Date: 28 March 2017 Revised Date:
24 April 2017
Accepted Date: 27 April 2017
Please cite this article as: Wang L-U, Wang T-Y, Bai Y-M, Hsu J-W, Huang K-L, Su T-P, Li C-T, Lin WC, Chen T-J, Chen M-H, Risk of obstructive sleep apnea among patients with Cushing’s syndrome: A nationwide longitudinal study, Sleep Medicine (2017), doi: 10.1016/j.sleep.2017.04.016. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Risk of obstructive sleep apnea among patients with Cushing’s syndrome: a nationwide longitudinal ACCEPTED MANUSCRIPT study
Ling-Uei Wang 6,*, M.D., Tsung-Yang Wang 1,2,5,*, M.D., Ya-Mei Bai 1,2, M.D., PH.D., Ju-Wei Hsu 1,2, M.D., Kai-Lin Huang 1,2,#, M.D., Tung-Ping Su 1,2, M.D., Cheng-Ta Li 1, 2, M.D., Ph.D., Wei-Chen Lin 1, 2, M.D.,
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Tzeng-Ji Chen 3,4, M.D., PH.D., Mu-Hong Chen 1,2,#
1. Department of Psychiatry, Taipei Veterans General Hospital, Taipei, Taiwan; 2. Department of Psychiatry, College of Medicine, National Yang-Ming University, Taipei, Taiwan
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3. Department of Family Medicine, Taipei Veterans General Hospital, Taipei, Taiwan 4. Institute of Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan 5. Department of Forensic and Neurodevelopmental Sciences, London, United Kingdom 6. Division of medicine, National Yang-Ming University, Taipei, Taiwan *: equally contributed. # Corresponding authors:
Dr Mu-Hong Chen (E-mail: [email protected])
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Address: Department of Psychiatry, Taipei Veterans General Hospital, Taipei, TAIWAN, 112 TEL: 886-2-28757027; FAX: 886-2-28757592
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Kai-Lin Huang, M.D. E-mail: [email protected] Department of Psychiatry, No. 201, Shih-Pai Road, Sec. 2, 11217, Taipei, Taiwan.
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Tel：886 -2- 28344012. Fax：886 -2- 28344012.
Words: 1828
1
Abstract
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OBJECTIVE: Previous studies have demonstrated the association between Cushing’s syndrome (CS), obstructive sleep apnea (OSA), and the risk factors for OSA, but rarely provided the evidence within a large population. Using the Taiwan National Health Insurance Research Database, we attempted to investigate the association between CS and OSA, and to provide persuading evidences.
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METHODS: In our study, 1612 patients with CS and 1612 age-, sex-, and comorbidities-matched controls were included, and followed up to the end of 2011. Cases of OSA were identified during the follow-up. RESULTS: Among patients with CS, 53 developed OSA (incidence: 4.11 per thousand person-year)
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compared with 22 in the control group (incidence: 1.70 per thousand person-year) during the follow-up (p<.001). CS patients had a 2.82-fold higher risk of developing OSA (HR = 2.82; 95% CI: 1.67–4.77) in
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later life.
DISCUSSION: Our study was the first longitudinal study to support the temporal association between CS and risk of OSA. Patients with CS were associated with an increased likelihood of OSA. Further studies would be required to investigate the exact underlying mechanisms between CS and OSA, and elucidate
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whether the prompt intervention for CS may reduce the risk of subsequent OSA.
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Keywords: Cushing’s syndrome; obstructive sleep apnea; temporal association.
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Introduction
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Cushing’s syndrome (CS), defined as exogenous or endogenous pathological hypercortisolism, manifests various clinical presentations, covering almost every subspecialty. These include gynecological (oligomenorrhea, hirsutism, and infertility), dermatological (red facial skin, poor wound healing, striae, and acne), orthopedic and rheumatological (fracture and osteoporosis), metabolic (type 2 diabetes mellitus and
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dyslipidemia), cardiovascular (hypertension, stroke, and myocardial infarction), neurological (headaches and decreased memory and cognition), psychiatric (depression and anxiety), and nonspecific (fatigue, backache, and weight gain) symptoms.1 The annual incidence of CS is 0.7–2.4 cases per million population2,3.
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Previous studies suggested that patients with CS may have more sleep disturbance, especially insomnia 4,5. Starkman et al reported that up to 70% of CS patients suffered from insomnia, including difficulty in falling
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asleep or waking during the night or in the early morning, and nearly all patients complained of daytime fatigue 5. However, the etiology of insomnia among patients with CS was rarely further clarified. In recent decades, increasing evidence has shown a significant relationship between CS and risk factors for obstuctive sleep apnea (OSA), such as obesity, hypertension, diabetes, and dyslipidemia. 6 Feelders et al revealed
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that 58-85% of patients had hypertension, 32-41% were obese, 20-47% had diabetes mellitus, and 38-71% had dyslipidemia 6. However, the association of CS with OSA itself has rarely been investigated. This potential association was first described in 1992, when seven of 22 patients with CS presented OSA-
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hypopnea syndrome7. Gokosmanog et al evaluated the OSA condition among 30 female patients with CS and age-, sex- and body mass index (BMI)-matched controls, and found that patients with CS had a
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significantly higher prevalence of OSA (50% vs 23%, P = 0.003); the higher apnea-hypopnea index (AHI) (P = 0.028) scores compared with the control subjects.8 The mechanisms underlying this association were then hypothesized in some studies—for instance, centripetal accumulation of adipose tissue9 and weakness of proximal muscles.10 However, these studies employed an insufficient sample size. Moreover, only a few studies have reported results relevant to the Taiwan population. By using a large sample size from the Taiwan National Health Insurance Research Database along with a longitudinal study design in our current study, we investigated the temporal association between CS and OSA. We hypothesized that patients with CS have an elevated risk of developing OSA later in life compared 3
to those without CS.
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Methods Data source. The Taiwan National Health Insurance (NHI) program was implemented in 1995 and offers comprehensive medical coverage for all residents of Taiwan. The National Health Research Institute (NHRI)
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is in charge of the entire insurance claims database, namely, the NHIRD, which consists of healthcare data from > 99% of the entire Taiwan population. The NHRI audits and releases the NHIRD for use in health service studies. Subjects included in the NHIRD are anonymous to maintain individual privacy.
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Comprehensive information on insured subjects is included in the database, including demographic data, dates of clinical visits, disease diagnoses, and medical procedures. The diagnostic codes used were based on
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the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). The NHIRD has been used extensively in many epidemiologic studies in Taiwan.11-13
Inclusion criteria for subjects with CS and the control group. Subjects were identified with CS diagnosed (ICD-9-CM code: 255.0) by endocrinologists, pedestrians, and internal medicine physicians
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between January 1, 1998 and December 31, 2009, and who had no history of any sleep apnea (ICD-9-CM codes: 327.2x, 780.51, 780.53, 780.57) before enrollment, were included as the CS cohort. The controls were randomly selected from the same database after eliminating the CS cohort, those who had been given a
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diagnosis of CS at any time, and those with any sleep apnea before enrollment. Each individual in the CS cohort was matched on the basis of age, sex, time of enrollment, residence, income, and medical
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comorbidities (obesity, hypertension, diabetes mellitus, and dyslipidemia) with an individual without CS in a comparison cohort. Diagnosis of OSA (ICD-9-CM codes: 327.23, 780.51, 780.53, 780.57) given by pulmonologists, psychiatrists, neurologists, and otolaryngologists after the evaluation of polysomnography were identified during the follow-up (to December 31 2011 or to the date of death). Level of urbanization (level 1 to level 5; level 1: most urbanized region; level 5: least urbanized region) was also assessed.14 Taipei Veterans General Hospital Institutional Review Board permitted this study. Statistical analysis. For between-group comparisons, the independent t test was used for continuous variables and Pearson's X2 test for nominal variables, where appropriate. The Cox regression model was 4
used to investigate the HR with 95% CI of developing OSA after adjusting for demographic data and
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medical comorbidities. Subanalysis stratified by sex was performed to calculate the risk of OSA. Sensitivity analyses were performed to investigate the above associations after excluding the first year or first threeyears of observation. All data processing and statistical analyses were performed with Statistical Package for Social Sciences (SPSS) version 17 software (SPSS Inc.) and Statistical Analysis Software (SAS) version 9.1
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(SAS Institute, Cary, NC).
Results
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Table 1 presented the distributions of demographic characteristics and selected medical comorbidities between the CS cohort and matched controls. In total, 53 of CS patients (incidence 4.11 per 1000 person-
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years) and 22 of comparison patients (incidence 1.70 per 1000 person-years) developed OSA during the follow-up (p<0.001).
The Kaplan-Meier survival curve with log-rank test (p<0.001) for the development of OSA in both cohorts was shown in Figure 1. When examining the association of CS with OSA risk, patients with CS had
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a 2.82-fold higher risk of developing OSA than the controls did (HR = 2.82; 95% CI: 1.67–4.77) (Table 2). Both men (HR: 3.10, 95% CI: 1.22~7.89) and women (HR: 2.74, 95% CI: 1.45~5.18) with CS were prone to developing OSA in later life compared with the control group (Table 2). Sensitivity tests after excluding the
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first years (HR: 2.90, 95% CI: 1.61~5.22) and first 3-years (HR: 2.75, 95% CI: 1.37~5.50) of observation
Discussion
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revealed the consistent findings (Table 2).
Our results support the hypothesis that patients with CS, regardless of their sex, had an increased risk of developing OSA in later life compared with those without CS; OSA risk was approximately three times higher in the presence of CS. Few studies have suggested the potential association between CS and OSA. Berger et al. investigated the association between three-month steroid intervention mimicking CS and the risk of sleep apnea, and they demonstrated that the mean AHI of patients undergoing steroid intervention increased by 56%, from 5
9.8 ± 11.8 to 15.4 ± 15.8 (p = 0.004); this increment in AHI was significantly higher compared with that of
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untreated mild OSA patients.15 Shipley et al. polysomnographically evaluated sleep in 22 patients with CS and demonstrated that 32% of these patients at least had ≥9.4 events/h (mild sleep apnea) and 18% had ≥17.5 events/h7. Evaluating the risk of OSA between 30 patients with CS and age-/sex-/BMI-matched controls by overnight polysomnography, Gokosmanog et al indicated that CS patients were prone to having
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OSA and higher AHI compared with the controls, and further revealed that serum cortisol level was an independent predictor for AHI after controlling for BMI and homeostasis model assessment (HOMA) scores (an index of insulin resistance).8 Nevertheless, our study is the first longitudinal follow-up study with a large
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sample size supporting the temporal association between CS and OSA. Compatible with previous findings, we also suggested that CS was an independent risk factor for developing OSA after adjusting for OSA-
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related physical comorbidities, such as obesity and diabetes mellitus.
The definite mechanism underlying the relationship between CS and OSA risk remains unclear. CSrelated weight gain and centripetal adipose tissue were assumedly to contributing to the development of OSA.9,16,17 Davies et al. conducted a prospective study analyzing 85 patients referred to a sleep clinic and
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reported that neck circumference is a more useful predictor of OSA than is general obesity.9 By contrast, among patients with long-term steroid intervention, Berger et al. noted that OSA was not correlated with the corresponding body weight gain and increased neck girth.15 In our study, we also found that CS was an
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independent risk factor of subsequent OSA regardless of the presence of obesity. In addition to consequent physical changes, myopathies are common among patients with hypercortisolism and previous study found a
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significant relationship between serum cortisol level and AHI among patents with CS8; the weakness of geniohyoid and genioglossus muscles may regulate the relationship of CS with OSA; however, additional detailed studies are required to confirm this hypothesis.18 Furthermore, we discussed the international impact of our work in the current and future investigation of CS and OSA. Growing evidence reported a progressive increase in the incidence of CS in recent decades, from 2.3 cases per million between 1985 and 1995 in a Danish study to nearly 49 cases per million in 2009 in a US study.3,19 CS-related medical comorbidities (such as obesity and diabetes mellitus), have been regarded as the risk factors of OSA. Under the influence of the western diet and lifestyle, increasing 6
prevalence rates of obesity and diabetes mellitus were reported worldwide, and the occult CS hidden behind
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obesity and diabetes mellitus gained clinical and scientific attention, and concern.20,21 However, only several studies with a cross-sectional study design and a small sample size investigated the relationship between CS and the risk of OSA. Our study was the first longitudinal study with a large sample size supported this association, suggesting a potential role of cortisol in the pathophysiology of OSA. Dysregulated cortisol
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levels and altered hypothalamic–pituitary–adrenal (HPA) axis were one of the core clinical phenomena in CS, and were also observed in other metabolic disorders, such as diabetes mellitus.22,23 However, the potential role of cortisol in the pathophysiology and risk of OSA was rarely investigated worldwide. Kritiko
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et al examined the cortisol levels at baseline and after two-month continuous positive airway pressure (CPAP) treatment among 35 patients with OSA and 37 controls, and found that OSA was associated with
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significantly higher 24-hour cortisol levels at baseline compared with the controls, whereas CPAP lowered cortisol levels significantly, close to those of controls.24 Taken the aforementioned evidences together, our result of a positive association between CS and OSA reminded the clinicians to survey the risk of OSA among CS patients when they had sleep disturbances, and suggested the researchers to further
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clarify the role of cortisol and HPA axis in the pathophysiology of OSA.
Our study has some limitations. First, the incidence of OSA may have been underestimated because only patients seeking medical help were enrolled; nevertheless, we enrolled patients who were diagnosed by
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board-certified physicians, thus yielding reliable validity. Second, we combined Cushing’s disease and CS into a single category of CS, because the diagnostic code of Cushing’s diseases is unavailable in ICD-9-CM;
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thus, further studies are necessary to investigate the risk of OSA in Cushing’s diseases and CS separately. Third, some information, such as CS severity, BMI, personal lifestyle, and family history, is unavailable in the Taiwan National Health Insurance Research Database; therefore, we could not investigate the effects of these parameters on the relationship between CS and OSA. In conclusion, our study is the first longitudinal study supporting the temporal association between CS and risk of OSA. Patients with CS showed
an increased OSA risk. Further research is required for
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investigating the precise mechanism underlying the relationship between CS and OSA and elucidating ACCEPTED MANUSCRIPT
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whether a prompt intervention for CS reduces subsequent OSA risk.
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Acknowledgements
We thank Dr MHC, Dr KLH, Dr TYW, and Dr LUW, who designed the study, wrote the protocol and manuscripts, Dr YMB, Dr JWH, Dr TPS, Dr CTL, Dr WCL, Dr MHC, Dr TYW, and Dr LUW, who assisted with the preparation and proof-reading of the manuscript, and Dr MHC and Dr TJC, who provided the advices on statistical analysis.
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We thank Mr I-Fan Hu for his friendship and support.
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Conflict of Interest: All authors certify that they have No conflict of interest. ACCEPTED MANUSCRIPT Funding Source: The study was supported by grant from Taipei Veterans General Hospital (V103E10-001, V104E10-002, V105E10-001-MY2-1, V105A-049). The sponsor had no role in the design or conduct of this research.
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Financial Disclosure: All authors have no financial relationships relevant to this article to disclose.
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References ACCEPTED MANUSCRIPT 1. Nieman LK. Cushing's syndrome: update on signs, symptoms and biochemical screening. Eur J Endocrinol 2015;173:M33-8. 2. Etxabe J, Vazquez JA. Morbidity and mortality in Cushing's disease: an epidemiological approach. Clin Endocrinol (Oxf) 1994;40:479-84. 3. Lindholm J, Juul S, Jorgensen JO, et al. Incidence and late prognosis of cushing's syndrome: a population-based study. The Journal of clinical endocrinology and metabolism 2001;86:117-23. 4. Starkman MN, Schteingart DE. Neuropsychiatric manifestations of patients with Cushing's syndrome.
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Relationship to cortisol and adrenocorticotropic hormone levels. Archives of internal medicine 1981;141:215-9. 5. Starkman MN, Schteingart DE, Schork MA. Depressed mood and other psychiatric manifestations of Cushing's syndrome: relationship to hormone levels. Psychosomatic medicine 1981;43:3-18.
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6. Feelders RA, Pulgar SJ, Kempel A, Pereira AM. The burden of Cushing's disease: clinical and healthrelated quality of life aspects. European journal of endocrinology 2012;167:311-26. 7. Shipley JE, Schteingart DE, Tandon R, Starkman MN. Sleep architecture and sleep apnea in patients with Cushing's disease. Sleep 1992;15:514-8. 8. Gokosmanog Lu F, Guzel A, Kan EK, Atmaca H. Increased prevalence of obstructive sleep apnea in patients with Cushing's syndrome compared with weight- and age-matched controls. European journal of endocrinology 2017;176:267-72.
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9. Davies RJ, Ali NJ, Stradling JR. Neck circumference and other clinical features in the diagnosis of the obstructive sleep apnoea syndrome. Thorax 1992;47:101-5. 10. Pecori Giraldi F, Moro M, Cavagnini F, Study Group on the Hypothalamo-Pituitary-Adrenal Axis of the Italian Society of E. Gender-related differences in the presentation and course of Cushing's disease. J Clin
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Endocrinol Metab 2003;88:1554-8. 11. Chen MH, Su TP, Chen YS, et al. Attention deficit hyperactivity disorder, tic disorder, and allergy: is there a link? A nationwide population-based study. Journal of child psychology and psychiatry, and allied disciplines 2013;54:545-51.
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12. Chen MH, Li CT, Tsai CF, et al. Risk of dementia among patients with asthma: a nationwide longitudinal study. Journal of the American Medical Directors Association 2014;15:763-7. 13. Shen CC, Tsai SJ, Perng CL, Kuo BI, Yang AC. Risk of Parkinson disease after depression: a nationwide population-based study. Neurology 2013;81:1538-44. 14. Liu CY, Hung, Y. T., Chuang, Y. L., Chen, Y. J., Weng, W. S., Liu, J. S. Incorporating development stratification of Taiwan townships into sampling design of large scale health interview survey. J Health Management (Chin) 2006;4:1-22. 15. Berger G, Hardak E, Shaham B, Avitan E, Yigla M. Preliminary prospective explanatory observation on the impact of 3-month steroid therapy on the objective measures of sleep-disordered breathing. Sleep Breath 2012;16:549-53. 16. Rosenow F, McCarthy V, Caruso AC. Sleep apnoea in endocrine diseases. J Sleep Res 1998;7:3-11. 17. Grunstein R, Wilcox I, Yang TS, Gould Y, Hedner J. Snoring and sleep apnoea in men: association with central obesity and hypertension. Int J Obes Relat Metab Disord 1993;17:533-40. 11
18. Yanovski JA, Cutler GB, Jr. Glucocorticoid action and the clinical features of Cushing's syndrome. ACCEPTED MANUSCRIPT Endocrinol Metab Clin North Am 1994;23:487-509. 19. Broder MS, Neary MP, Chang E, Cherepanov D, Ludlam WH. Incidence of Cushing's syndrome and Cushing's disease in commercially-insured patients <65 years old in the United States. Pituitary 2015;18:283-9. 20. Sharma ST, Nieman LK, Feelders RA. Cushing's syndrome: epidemiology and developments in disease management. Clinical epidemiology 2015;7:281-93. 21. Tabarin A, Perez P. Pros and cons of screening for occult Cushing syndrome. Nature reviews
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Endocrinology 2011;7:445-55. 22. Joseph JJ, Golden SH. Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus. Annals of the New York Academy of Sciences 2017;1391:20-34. 23. Raff H, Carroll T. Cushing's syndrome: from physiological principles to diagnosis and clinical care.
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The Journal of physiology 2015;593:493-506. 24. Kritikou I, Basta M, Vgontzas AN, et al. Sleep apnoea and the hypothalamic-pituitary-adrenal axis in men and women: effects of continuous positive airway pressure. The European respiratory journal 2016;47:531-40.
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Table 1. Demographic data and incidence of obstructive sleep apnea among patients with Cushing’s syndrome and controls.
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Patients with Cushing
Control group
syndrome
Sex (Female, %) Obstructive sleep apnea (n, 1000 person-years) Age at diagnosis (years, SD) Duration between enrollment and diagnosis (years, SD)
(n=1612)
(n=1612)
47.59 (19.52)
47.57 (19.52)
1142 (70.8)
1142 (70.8)
53 (4.11)
22 (1.70)
<0.001
47.18 (14.98)
53.47 (15.24)
0.104
4.07 (2.95)
3.09 (3.69)
0.230
742 (46.0)
0.697
408 (25.3)
0.903
429 (26.6)
0.937
29 (1.8)
0.323
Medical comorbidities (n, %) Hypertension
730 (45.3)
Dyslipidemia
404 (25.1)
Diabetes mellitus
432 (26.8) 38 (2.4)
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Obesity Level of urbanization (n, %)
442 (27.4)
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1 (most urbanized) 2 3 4 5 (most rural) Income-related insured amount
≥ 25,001NTD/month
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SD: standard deviation.
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≤ 15,840 NTD/month 15,841~25,000NTD/month
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Age at enrollment (years, SD)
p-value
1
0.976
0.304
479 (29.7)
486 (30.1)
486 (30.1)
251 (15.6)
249 (15.4)
236 (14.6)
198 (12.3)
197 (12.2)
200 (12.4) 0.955
665 (41.3)
665 (41.3)
605 (37.5)
603 (37.4)
342 (21.2)
344 (21.3)
Table 2. Cox regression models and sensitivity tests of developing obstructive apnea among patients with Cushing’s syndrome and
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controls. Sex
Sensitivity tests
Males
Females
> 1 years
> 3 years
Total
HR (95% CI)
HR (95% CI)
HR (95% CI)
HR (95% CI)
HR (95% CI)
Absence
1
1
1
1
1
Presence
3.10 (1.22~7.89)
2.74 (1.45~5.18)
2.90 (1.61~5.22)
2.75 (1.37~5.50)
2.82 (1.67~4.77)
Cushing’s syndrome
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HR: hazard ratio; CI: confidence interval.
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Bold type indicates the statistical significance.
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Figure 1. Survival curve of developing obstructive apnea among patients with Cushing’s syndrome and controls.
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ACCEPTED MANUSCRIPT Highlights 1. Patients with Cushing’s syndrome (CS) had an increased risk of developing OSA in later life.
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2. Both men and women with CS were prone to developing OSA. 3. CS was an independent risk factor of OSA regardless of obesity and diabetes mellitus.