The Relationship between Sleep Apnea Syndrome and Hypothyroidism*

Transcription

1 The Relationship between Sleep Apnea Syndrome and Hypothyroidism* Ching-Chi Lin, M.D., F.C.C.P.; Kun-Wu Tsan, M.D.; and Pei-]an Chen, M.D., F.C.C.P. To evaluate the prevalence of obstructive sleep apnea syndrome (OSAS) in patients with hypothyroidism, the prevalence of hypothyroidism in patients with OSAS, the possible factors predisposing to sleep-related breathing disorder in hypothyroid patients, and the effect of thyroid hormone in treating hypothyroidism associated with OSAS, we studied 65 patients with proven OSAS (apnea index [AI] >5) and 20 hypothyroid patients. All patients were monitored for one overnight sleep study using polysomnography (Grass 78). We found only two (3.1 percent) of 65 OSAS patients had thyroid hypofunction. Of 20 patients with hypothyroidism, two showed moderate to severe OSAS and three had mild OSAS. Patients with both hypothyroidism and OSAS had impaired respiratory drive, but this was corrected by thyroid hormone therapy. Patients with hypothyroidism without OSAS were younger and had a lower percentage of ideal body weight than those with both hypothyroidism and OSAS. All hypothyroid patients were snorers. Thyroid hormone replacement was effective in correcting snoring only after one year of therapy. We conclude the following: (I) an overnight sleep study is not necessary in every case of hypothyroidism; (2) thyroid function studies need not be done routinely for every OSAS patient; (3) thyroid hormone therapy is effective for OSAS but it takes longer to correct the snore than respiratory drive; and (4) age and body weight are related to the development of OSAS. (Chest 1992; 102: ) AI=apnea index; DEF=desaturation event frequency; Fll= free thyroid index; MI =movement index; MMH =Mackay Memorial Hospital; OSAS =obstructive sleep apnea syndrome; SE =sleep efficiency; TSH =thyroid stimulating hormone sleep-related breathing disorders are not rare.' They are composed of a well-characterized group of complex syndromes and are closely related to many clinical disorders. 2 In recent years, much progress has been made in understanding the pathophysiology of these syndromes and in developing a variety of new treatment methods. 3 6 Hypothyroidism has been shown to be frequently related to the development of obstructive sleep apnea syndrome (OSAS). Thyroxine replacement therapy in these patients often improves sleep-related breathing disorders. 7 Narrowing of the upper airway due to mucoprotein deposition in the tongue and nasopharynx or abnormalities of ventilatory control are two possible mechanisms for OSAS in these patients The aims of this study are as follows: (1) to evaluate the prevalence ofosas in patients with hypothyroidism; (2) to evaluate the prevalence of hypothyroidism in patients with sleep-related breathing disorders; (3) to discuss the possible factors predisposing to sleep-related breathing disorders in hypothyroid patients; (4) to evaluate the effect of thyroid hormone in treating hypothyroidism-induced OSAS; and (5) to compare the respiratory drive before and after thyroid hormone therapy. *From the Chest Division (Drs. Lin and Chen) and Endocrine Division {Dr. Tsan), Department of Internal Medicine, Mackay Memorial Hospital, Taipei, Taiwan, Republic of China. This study was supported by a grant from the National Science Council of the Republic of China (NSC ). Manuscript received January 27; revision acce_pted May 15 Reprint requests: Dr. Lin, Mackay Meroorial Hospital, 92 Sec 2, Chung San North Road, Taipei, Taiwan, Republic of China Subject Selection MATERIAL AND METHOD Group 1 included 65 newly diagnosed OSAS patients (23 patients with mild OSAS [group 1a], 42 patients with moderate to severe OSAS patients [group 1b]). These patients were identified at the Sleep and Breathing Disorder Center of Mackay Memorial Hospital {MMH) during the period from June 1, 1987 to July 31, Group 2 included 20 cases of newly diagnosed hypothyroidism, identified by the Endocrine Department of MMH over the same period. OSAS was diagnosed by an apnea index (AI) equal to or greater than 5 on overnight polysomnography study." Mild OSAS was defined as an AI equal to or greater than 5, but less than 20; moderate OSAS was defined as an AI equal to or greater than 20, but less than 50 and the lowest SaO, greater than 50 percent; and severe OSAS was defined as an AI greater than 50 and the lowest Sa0 2 less than 50 percent. Primary hypothyroidism was defined by a free thyroid index (FTI) ofless than 1.0 and a thyroid stimulating hormone {TSH) greater than 25 miu/l." Panhypopituitarism was defined by low FTI, TSH, and other pituitary hormones (eg, growth hormone). Apnea episodes were defined by the absence of nasal and oral air flow for at least 10 s. Central apnea refers to cessation of nasal and oral airflow with cessation of respiratory effort; obstructive apnea is defined as absence of nasal and oral airflow despite continuing respiratory effort. Mixed apnea has both central and obstructive components, the obstructive part usually following the central. Hypopnea was defined as a drop in tidal volume below 50 percent of the resting value for at least 10 s, without a major change in respiratory frequency. The diagnosis of sleep apnea syndrome was based on the presence of at least five apneas per hour of sleep. OSAS was diagnosed when obstructive and mixed apneas represented more than 80 percent of all the apneas. Apnea index is defined as the mean number of apneas per hour of sleep. Oxygen desaturation is defined as reduction of oxygen saturation of 4 percent or more from the baseline. Desaturation event frequency (DEF) is defined as the mean number of oxygen desaturation episodes per hour of sleep. Arousal was defined as an increase in CHEST I 102 I 6 I DECEMBER

2 Table 1-Prevalence of OSAS* in lbtient& with Hypothyroidism Severity of OSAS Case No. Percentage Non Mild 3 15 Moderate 0 0 Severe 2 10 Total *OSAS =obstructive sleep apnea syndrome. EMG tone for greater than 1.5 s, associated with a or 9 EEG activity. Arousal index is defined as the mean number of arousals per hour of sleep. Movement index (MI) is defined as the mean number of leg movements per hour of sleep. To measure and calibrate the severity of snoring, a sound meter (Real-Time Sound Level Analyzer, model NA-23, Rion Co, LTD, Tokyo, Japan) attached to a microphone and was placed in the cricothyroid notch during each study. The sound channel was calibrated in the range from 50 to 100 db using a 1-kHz audiosignal. Only snores higher than 60 db were counted; the total number of snores per hour of sleep was defined as the snore index. The severity of snoring was also evaluated by the same experienced technician's observation from 0 (no snoring), + (mild), + + (moderate), (severe), to (very severe). Sleep was staged by the method of Rechtschaffen and Kales 14 on the basis of 30-s epochs. Progressive hyperoxic hypercapnic ventilatory response was measured by the Read" rebreathing method. Progressive isocapnic hypoxic ventilatory response was measured by the Rebuck and Campbell method. Minute ventilation (obtained by integration of pneumotachograph How) and P (the mouth occlusion pressure over the first 100 ms of inspiration against an occluded airway'') were regressed linearly against the end-tidal Pco 1 values or l1 Sa0 2 (fall in Sa0 1 from baseline). No patient had evidence of acute infection for at least one month prior to the study. None of the patients took alcohol or sedatives for at least one week before the overnight sleep study. All OSAS patients underwent blood tests for FTI and TSH (measured by radioimmunoassay). All hypothyroid patients were given overnight sleep studies before starting their thyroid hormone replacement therapy. Replacement therapy was started with small doses of levothyroxine, one fourth tablet every day, and increased by one fourth tablet every week until reaching a full dose (one or two tablets every day). The second overnight sleep study was done again four months later after the beginning of thyroid hormone replacement therapy. Overnight sleep studies were done by complete polysomnography recording. The recordings include EEG, EOG, submental EMG, and both tibial EMG and ECG from surface electrodes. Arterial oxygenation saturation and heart rate were continuously recorded from pulse oximeter (Omheda). Respiratory movement was monitored by inductance plethysmography, with transducers placed around the chest and abdomen. Nasal How and oral How were monitored by thermocouple. Data Analysis We used the paired, unpaired Student's t test or ANOVA test for statistical analysis when appropriate. If the ANOVA test was statistically significant, the Schelfe test was used. All values were expressed as the mean± standard deviation, with significance accepted when p was less than RESULTS In group 1, of 65 proven OSAS patients, only two (3.1 percent) showed thyroid hypofunction. One was a case of hypothyroidism (low FTI and high TSH), and the other was a case of panhypopituitarism (low FTI, TSH, and other pituitary hormones). In group 2, 20 hypothyroid patients underwent an overnight sleep study. Fifteen patients (75 percent) (group 2b) showed no OSAS. Group 2a consisted of three patients with (15 percent) of mild OSAS and two cases (10 percent) of severe OSAS (Table I). All 20 hypothyroid patients snored. The clinical and sleep examination data of groups 1a, 1b, 2a, and 2b are shown in Table 2. There was no significant change in percentage of ideal body weight before treatment (134.6 ± 23.2 percent), four months after therapy (129.8 ± 21.8), and one year after therapy (132.6±22.6 percent) in group 2a (ANOVA test was used). The data for AI, sleep efficiency (SE), RDI, lowest Sa0 2, DEF, MI, and arousal index for the five hypothyroid patients associated with OSAS before and after thyroid hormone therapy are shown in Table 3. Oxygen saturation, AI, DEF, MI, and arousal index Table 2-Clmical and Sleep Emmination Demographic Dota* la 1b 2a 2b Patient No Age, y 48.7± ± ± ±4.2 Sex, male/female 19/ l/4 l/14 %IBW,% 114.8± ± ± ±6.3 Sleep efficiency, % 80.4± ± ± ±3.7 Stage 1,% 26.9± ± ± ±3.7 Stage 2,% 47.7± ± ± ±2.1 Stage3+4,% 7.9± ± ± ±2.0 REM,% 17.5± ± ± ±3.8 AI, timeslhr 12.4± ± ± ±3.4 DEF, timeslhr 11.4± ± ± ± 1.5 Lowest sao % 81.3± ± ± ±2.35 Arousal index, timeslhr 7.9± ± ± ± 1.3 Ml, timeslhr 8.2± ± ± ±3.8 Sl, timeslhr 164.2± ± ± ± 10.8 *AI= apnea index; DEF = desaturation event frequency; MI =movement index; Sl =snore index Sleep Apnea Syndrome and Hypolhyroidlsm (Un, Tsan, Chen)

3 Table 3-Effect of Thyroid Hormone Replacement TheraPfl on Total Overnight Sleep Efficiency, Heapiratory Disturbance Index (BDI), Movement Index (MI), Arouaallndex, and Apnea Index (Al) Before Thyroid Hormone After 4 mo Thyroid Hormone After 1 yr Thyroid Hormone Replacement Therapy Replacement Therapy Replacement Therapy Sleep AI, U>west DEF, Arousal Sleep AI, Lowest DEF, Arousal Sleep AI, Lowest DEF, Arousal Patient Elliciency, Ttmesl SaO,, Tunes/ Index, Efficiency, Ttmesl SaO,, Tunes/ Index, Efficiency, TIDies/ SaO,, TIDies/ Index, No. % hr % hr TIDiest1rr % hr % br TIDiest1rr % hr % hr Ttmeslhr fr fr Mean * * 91.0* 1.2* * 1.3* 3.5 ±SO *ANOVA test was used; p<0.05. Table 4-E.ffectt of before, after 4 Montha, and after One Year of Thyroid Hormone Heplacement TheraPfl Before Thyroid Hormone After 4 mo Thyroid Hormone After 1 yr Thyroid Hormone Replacement Therapy Replacement Therapy Replacement Therapy SI, Snore SI, Snore SI, Snore Ttmeslhr Severity Ttmeslhr Severity Ttmeslhr Severity * + 117* *ANOVA test was used; p<0.05; snore severity was evaluated by technician's observation. all improved significantly (p<0.05) after four months of thyroid hormone replacement. Snoring actually worsened after four months of therapy but improved at one year. The percentage of supine position to total sleep time is no different among baseline (68 ± 12 percent), four months (78± 14 percent), and one year (71 ± 15 percent) after thyroid hormone replacement therapy (by ANOVA test) (Table 4). We found that before thyroid hormone therapy, hypothyroid patients with OSAS spent more time in stage 1 sleep and less time in stage sleep (Table 5, cases 2 to 5). One patient with secondary hypothyroidism and OSAS had severe hypoventilation, resulting in C0 2 narcosis (Table 5, case 1). She was already asleep at the start and throughout the sleep study, but returned to a normal sleep pattern after thyroid hormone replacement treatment. The results of progressive hyperoxic hypercapnic and isocapnic hypoxic ventilatory response were examined in four patients of group 2a before and four months after thyroid hormone replacement therapy. Ventilatory response and P0.1 after either hypercapnic or hypoxic stimulation test improved significantly four months after thyroid hormone therapy (Table 6). Table 5-The Effect of Thyroid Hormone Beplacement TheraPfl on 1btal Overnight Sleep Architecture Before Thyroid Hormone Replacement Therapy After Thyroid Hormone Replacement Therapy Sleep Stage Sleep Stage Patient No REM REM Mean ±SO CHEST I 102 I 6 I DECEMBER,

4 Table 6-Hypercapnic and Hypoxic Reaponae before and Four Months afrer Thyroid Hormone Replacement Therapy in Patients with Hypothyroidiam* Patient 2 Patient3 Patient4 Patient 5 Mean±SD Before During Before During Before During Before During Before During Hypercapnic response ~ V E I 2 ~, PUcmoi Hg n / m m ±0.40t 2.15±0.24t ~ P O. l 2 i ~ P 20/mm c o Hg O.ll±0.04t 0.53±0.22t H rpoxic response ~ V E I ~ Uminl% S a o sao ±0.05t -0.70±0.17t ~ P O. l 2 i, ~ %, S a 0 em H 20/% SaO, ±0.03t -0.18±0.03t *VE =Change of minute ventilation before and after hypercapnic or hypoxic stimulation. tp<0.05. There was a biostatistically significant difference between group 2a and 2b with group 2a (hypothyroid with OSAS) being older and having a higher body weight compared with group 2b (hypothyroid without OSAS) (p<0.05). All group 2b patients were premenopausal women. There was no statistical difference in the TSH level between these two groups (Table 7). DISCUSSION There are many clinically apparent similarities between patients with OSAS and those with hypothyroidism,2-s but the prevalence of thyroid deficiency states in patients with OSAS is not known. Likewise, there is a high prevalence of OSAS in patients with hypothyroidism Improvement of OSAS in hypothyroid patients treated using thyroid hormone replacement therapy has been reported. 1 H 1 However, this raises an important question: should thyroid function studies be done routinely in all patients with OSAS, and vice versa, and should all hypothyroid patients undergo a sleep study? In this study, all65 patients with OSAS had complete thyroid function studies, including FTI and TSH, but only two female patients (3 percent) showed thyroid hypofunction, one with primary hypothyroidism and one with secondary hypothyroidism due to Sheehan's syndrome with myxedema. OSAS per se is more common in male patients 12 in contrast to OSAS with hypothyroidism, which is more common in female patients. Both of our patients were female and one patient had myxedema. Table 7 -Compariaon Age, Percent of Ideal Body Weight (IBW), and Thyrotropin (TSH) L.eoel between Group!a and 2b Patients* Patient Age, %ofibw, TSH, No. yr % miuil Group 2a ± ± ±77.2 Group2b ± ± ±34.8 Pvalue *Group 2a=patients of hypothyroidism associated with OSAS; group 2b =patients of hypothyroidism without OSAS With regard to the second question, whether sleep studies should be done in every patient with hypothyroidism, we found only five cases of demonstrable OSAS out of the 20 hypothyroid patients studied. These five patients all had clinical manifestations of OSAS (not only snoring but also daytime somnolence, irritable sleep, etc). Therefore, we suggest that only hypothyroid patients with clinical manifestations of OSAS should have an overnight sleep study. Grunstein and Sullivan 13 reported a high incidence of OSAS in patients with untreated hypothyroidism in contrast with our population showing only a 25 percent incidence. This discrepancy may be explained by the following differences: (1) all of the patients of Grunstein and Sullivan were referred cases, (2) they were older (the youngest was 47 years old) than our patients, and (3) all their patients were heavy snorers with hypersomnolence. In contrast, our patients were randomly sampled and younger (mean age, 36.1 ± 5.4 years). Comparing our patients with hypothyroidism and OSAS (group 2a) and those with only hypothyroidism (group 2b), we found group 2a to be significantly older and to have a higher percentage of ideal body weight. These are risk factors associated with OSAS. All group 2b patients are premenopausal. TSH levels did not differ significantly between the two groups. We were unable to evaluate whether the severity and duration of hypothyroidism is a risk factor. Interestingly, all our hypothyroid patients (with or without OSAS) were snorers. Snoring is highly correlated with OSAS and the severity of snoring parallels the severity of OSAS. Thus, the high prevalence of snoring in hypothyroid patients may be the initial manifestation of OSAS and it suggests the possibility that if the hypothyroidism is untreated, OSAS may be likely to develop. Although Bahemuka and Hodkinson 18 recommended TSH as the best screening test for early detection of thyroid function impairment, 18 an elevated value only diagnoses primary, not secondary hypothyroidism Therefore, we propose that both FTI and TSH tests be used when evaluating the Sleep Apnea Syndrome and Hypothyroidism (Un, Tsan, Chen)

5 possibility of thyroid hypofunction. Two postulated mechanisms concerning OSAS in hypothyroidism have received major attention: (1) upper airway obstruction with or without obesity, and (2) a reduction in ventilatory drive. Orr et al 3 stated that deposition of mucopolysaccharides and extravasation of protein into the tissues of the tongue and pharyngeal structures, as well as an increase in skeletal muscle volume, especially in the genioglossus, are factors predisposing to OSAS. Willson and Bedell 21 found that both depression of the respiratory center and altered bellows action of the thorax were present in hypothyroid patients. Zwillich et al 22 demonstrated that a decreased hypoxic ventilatory drive can be corrected by thyroid hormone replacement therapy. All of our patients with hypothyroidism with OSAS had significant improvement in RDI, oxygen desaturation, and respiratory drive after four months of thyroid hormone replacement therapy. Even though snoring became worse after four months of treatment, it improved after one year of hormone replacement therapy. It may be that thyroid hormone quickly results in an improved respiratory drive causing stronger respiratory efforts against a persistently narrowed upper airway, thus producing a paradoxic increase in snoring. Improvement in airway dimensions apparently requires a longer period of therapy, after which snoring will decrease. We conclude that overnight sleep studies are not required in every case of hypothyroidism, nor is thyroid function evaluation routinely required for every OSAS patient. Thyroid hormone therapy is effective in improving OSAS within four months but a longer period is required before snoring improves. Finally, age and body weight are related to the development of OSAS in hypothyroid patients. REFERENCES 1 Guilleminault C, Tulkian A, Dement WC. The sleep apnea syndromes. Ann Rev Med 1976; 27: Bolek AJ. Sleep apnea and related disorders. DM 1985; 31: Orr WC, Imes NK, Marlin RJ. Progesterone therapy in obese patients with sleep apnea. Arch Intern Med 1979; 139: Iss FG, Sullivan CE. Reversal of central sleep apnea using nasal CPAP. Chest 1986; 90: Guilleminault C, Simmons FB, Motta ]. Obstructive sleep apnea and tracheostomy long term follow by experience. Arch Intern Med 1981; 141: Sullivan CE, Issa FG, Berthon-Jones M. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1981; 1: Domm BM, Vassallo CL. Myxedema coma with respiratory failure. Am Rev Respir Dis 1973; 107: Yamamoto T, Hirose N, Miyoshi K. Polygraphic study of periodic breathing and hypersomnolence in patient with severe hypothyroidism. Eur Neurol1977; 15: Rajagapal KR, Derderian SS, Jabbari B. Obstructive sleep apnea in hypothyroidism. Am Rev Respir Dis 1981; 123(suppl}:l88 10 Skatrud J, Iber C, Ewart R. Disordered breathing during sleep in hypothyroidism. Am Rev Respir Dis 1983; 127:504-o7 11 Rajagopal KR, Abbrecht PH, Derderian SS. Obstructive sleep apnea in hypothyroidism. Ann Intern Med 1984; 101: Guilleminault C, Van Den Hoed J, Mitler M. Clinical overview of the sleep apnea syndromes. In: Guilleminault C, Dement WC, eds. Sleep apnea syndromes. New York: Alan R Liss Inc, 1978:9: Grunstein RR, Sullivan CE. Sleep apnea and hypothyroidism: mechanisms and management. Am J Med 1988; 85: Rechtschaffea A, Kales A, eds. A manual of standard terminology techniques and scoring systems for sleep stages of human subjects. Bethesda, Md: National Institutes of Health, Read DJC. A clinical method for assessing the ventilatory response to carbon dioxide. Australas Ann Med 1967; 16: Rebuck AS, Campbell EJM. A clinical method for assessing the ventilatory response to hypoxia. Am Rev Respir Dis 1974; 109: Burld NK, Mitchell LK, Chaudhary BA. Measurement of mouth occlusion pressure as an index of respiratory centre output in man. Clin Sci Mol Med 1977; 53: Bahemuka M, Hodkinson HM. Screening for hypothyroidism in elderly in patients. BMJ 1975; 2:601-o3 19 Vagenalcis AG, Rapoport B, Azizi F. Hyperresponse to thyrotropin-releasing hormone accompanying small decrease in serum thyroid hormone concentrations.] Clin Invest 1974; 54: Saberi M, Utiger RD. Augmentation of thyrotropin response to thyrotropin-releasing hormone following small decrease in serum thyroid hormone concentrations. J Clin Endocrinol Metab 1975; 40: Willson WR, Bedell GN. The pulmonary abnormalities in myxedema. J Clin Invest 1960; 39: Zwillich CW, Pierson DJ, Hofeldt FD. Ventilatory control in myxedema and hypothyroidism. N Eng) ] Med 1975; 292: CHEST 1102 I 6 I DECEMBER,