Thyroid testing and thyroid hormone replacement in patients with sleep disordered breathing.

Abstract

The current literature recommends that patients who have symptoms of sleep disordered breathing should be evaluated for hypothyroidism. Thyroid hormone replacement therapy has been reported by some authors to be effective in treating obstructive sleep apnea in hypothyroid patients. The present study prospectively evaluated the prevalence of hypothyroidism in 1,000 consecutively presenting patients who came to the office for evaluation of snoring or obstructive sleep apnea syndrome. The authors also examined the efficacy of treatment for hypothyroidism on sleep apnea in patients with both disorders.

Of the 1,000 patients, routine thyroid testing was performed on 834; only 10 of these patients (1.2%) were discovered to have previously undiagnosed clinical hypothyroidism. Four of the 10 patients with newly diagnosed clinical hypothyroidism had obstructive sleep apnea syndrome, and they received thyroid hormone replacement therapy. Once these four patients achieved a euthyroid state, repeat polysomnography showed that there was no significant difference between their pre-and posttreatment respiratory disturbance index.

Based on the results of our study, we conclude the following: 1) The prevalence of hypothyroidism in patients who are evaluated for sleep disordered breathing is no greater than that of the general population. 2) Thyroid replacement therapy results in little or no improvement in sleep apnea in patients with clinical hypothyroidism. 3) Routine thyroid function screening is not indicated for patients who are being evaluated for sleep disordered breathing.

Introduction

Some researchers have found that thyroid hormone replacement therapy ameliorates symptoms of obstructive sleep apnea in patients with clinical hypothyroidism. [1-3] Other investigators have reported little benefit from thyroid replacement in these patients. [4] Although patients who have myxedema or symptomatic hypothyroidism have a high incidence of sleep apnea, [1,2,5] patients with sleep apnea syndrome appear to have the same prevalence of hypothyroidism as the general population. [2]

Nonetheless, routine screening for hypothyroidism has been recommended for patients with obstructive sleep apnea syndrome (OSAS). [6,7] The present study examines the prevalence of hypothyroidism in patients evaluated for sleep disordered breathing and assesses the efficacy of treatment of the hypothyroid state in a large case series.

Materials and methods

Thyroid function testing (measurement of thyroid-stimulating hormone [TSH]) was recommended for essentially all patients seen for evaluation of snoring or sleep apnea syndrome by the senior author. Patients who had a diagnosis of primary snoring without apnea and without any symptoms of hypothyroidism were not tested. Patients who had elevated levels of TSH were further evaluated for hypothyroidism by measurements of serum free thyroxin ([T.sub.4]) levels and other appropriate tests. Medical records of patients whose thyroid test results were abnormal were reviewed retrospectively. Patients were classified either as being euthyroid or as having subclinical hypothyroidism (mildly elevated TSH with normal [T.sub.4]), known hypothyroidism (which was being treated with thyroid hormone replacement therapy at the time of the evaluation), clinical hypothyroidism (TSH [greater than]10 mU/L and low [T.sub.4]), or subclinical hyperthyroidism (low TSH and normal [T.sub.4]).

OSAS was defined as the presence of sleep apnea symptoms and a respiratory disturbance index (RDI) of 10 or more on polysomnography (PSG), as evaluated by standard criteria [8]; RDI is calculated by averaging the number of apneic and hypopneic events per hour of sleep.

Primary snoring was defined as the presence of significant snoring and an RDI of less than 10 on PSG or the presence of significant regular snoring on audiotape recording without any symptoms of sleep apnea.

The four patients with both clinical hypothyroidism and OSAS were treated with thyroid hormone replacement by an endocrinologist. After these patients became euthyroid, PSG was repeated 4 to 12 months later. Pre-and posttreatment PSG results were compared, and a statistical analysis was performed with the student's t test (statistical significance: p[less than]]0.05).

Results

Between January 1993 and March 1996, an evaluation of sleep disordered breathing was performed on 1,000 consecutively presenting patients (mean age: 47; 80% men; mean body mass index: 32 kg/[m.sup.2]). Of these patients, 834 were tested for hypothyroidism. The remaining 166 patients either had refused thyroid screening, had symptoms of primary snoring only (therefore, thyroid screening was not recommended), or underwent testing elsewhere and were lost to followup.

OSAS was identified in 542 of the 834 patients (65%). Primary snoring was found in 270 patients (32%), while 22 patients (2.6%) were either normal or had other primary sleep disorders.

A euthyroid state was found in 790 patients (95%). Five patients (0.5%) had subclinical hypothyroidism and did not require thyroid hormone replacement (three with OSAS and two with nonapneic snoring). Twelve patients (1.4%) had known hypothyroidism. Of these 12, nine with OSAS were euthyroid, two with nonapneic snoring were euthyroid, and one with OSAS had a markedly elevated TSH level; this last patient was treated with a higher dose of thyroid hormone, but he did not return for a repeat PSG. Seventeen patients (2.0%) with subclinical hyperthyroidism had a low TSH but were asymptomatic and had a normal [T.sub.4] level.

Ten patients (1.2%) were newly diagnosed with clinical hypothyroidism. Of these, five were primary snorers (two by history and three by PSG), one had symptoms of OSAS but refused PSG, and four had OSAS confirmed on PSG. These four OSAS patients were placed on thyroid replacement hormone by an endocrinologist, and their sleep study was repeated at least 4 months after they became euthyroid (range: 4-12 mo). The five patients with primary snoring were also treated with thyroid replacement hormone by an endocrinologist. After 6 to 12 months of treatment, only one of these five patients reported any significant reduction in snoring. The patient who refused a sleep study was lost to followup.

The four newly diagnosed hypothyroid patients with OSAS had a mean pretreatment RDI of 64.4 ([plus or minus]19.4) and a lowest oxygen saturation level of 80.3% ([plus or minus]8.7%). After treatment, their mean RDI was 55.6 ([plus or minus]36.3) and their lowest oxygen saturation was 75.8% ([plus or minus]13.3%) (table). The difference between the pre- and posttreatment results was not statistically significant (one patient did lower his RDI from 44 to 18). There were also no statistically significant differences between pre- and posttreatment apnea index, body mass index, sleep efficiency, and sleep architecture.

The OSAS patients were compared with nonapneic snorers. Of the 270 patients with nonapneic snoring, 261 (96.7%) had normal TSH levels, two patients (0.7%) had subclinical hypothyroidism, two patients had known hypothyroidism, and five patients (1.9%) were newly diagnosed with clinical hypothyroidism. Of the 542 patients with OSAS, 524 patients (96.7%) had normal TSH levels, three patients (0.6%) had subclinical hypothyroidism, ten patients (1.8%) had known hypothyroidism, and five patients (0.9%) had newly diagnosed clinical hypothyroidism. There was no significant difference between the two groups in the percentage of patients who had clinical or subclinical hypothyroidism.

Discussion

The earliest biochemical evidence of hypothyroidism is a mild elevation of the serum TSH level. When levels of circulating thyroid hormone ([T.sub.3] and [T.sub.4]) are normal in these patients, their condition has been termed subclinical hypothyroidism or compensated hypothyroidism. However, as the disease progresses, the levels of serum [T.sub.4], and later [T.sub.3], begin to decrease. As these circulating thyroid hormone levels fall, many patients exhibit signs and symptoms of hypothyroidism. The term myxedema is generally used to describe overt manifestations of hypothyroidism.

Whether or not subclinical hypothyroidism should be treated is still open to debate. As part of this study, we consulted four endocrinologists regarding how to manage our patients with newly diagnosed subclinical hypothyroidism. All four recommended no active treatment. Their prevailing belief was that mild thyroid dysfunction has nothing to do with sleep disordered breathing.

While several studies have examined the prevalence of OSAS in patients with myxedema or clinical hypothyroidism, [1,2,5] only three studies have evaluated the prevalence of hypothyroidism in patients with OSAS. Lin et al found that only two of 65 OSAS patients (3.1%) were hypothyroid. [2] Meslier et al found that only one of 101 OSAS patients (0.99%) had hypothyroidism. [9] While studying patients who underwent PSG to evaluate possible sleep apnea, Winkelman et al detected hypothyroidism in three of 103 patients with documented OSAS (2.9%) and in one of 135 patients without OSAS (0.7%). [10] Of these four hypothyroid patients, two were already on thyroid replacement hormone therapy. In our study, 10 of 842 patients (1.2%) who were referred for evaluation of sleep disordered breathing were diagnosed with clinical hypothyroidism (1.9% of the primary snorers and 0.9% of those with sleep apnea).

Many authors have studied the prevalence of hypothyroidism in the general population. In a study of the Framingham population, hypothyroidism (TSH[greater than]10 mU/L) was found in 5.9% of women and 2.4% of men. [11] Two Swedish studies found that the prevalence of newly diagnosed hypothyroidism in women was 1.5% and 2%. [12,13] In a study of 2,000 patients in a primary care unit in Denmark, 16 new cases of hypothyroidism (0.8%) were discovered. [14] In a Norwegian study, 1.8% of 114 women and 1.2% of 86 men were identified with a new diagnosis of hypothyroidism. [15] It appears that the prevalence of hypothyroidism in patients who are being evaluated for OSAS, in patients with confirmed OSAS, and in patients with nonapneic snoring falls within the range of the prevalence of hypothyroidism in the general population--that is, within the range of 0.8 to 5.9%.

Routine screening for hypothyroidism has been recommended as part of the workup of obstructive sleep apnea in the sleep medicine literature. [6,7] As the basis for this recommendation, reference has been made to a study by Rajagopal et al, who reported a marked improvement in sleep apnea in nine hypothyroid patients during thyroid hormone replacement therapy. [1] Their mean apnea frequency fell from 71.8 episodes per hour prior to treatment to 12.7 episodes per hour 3 to 12 months after the initiation of treatment. Thus, Rajagopal et al concluded that thyroid replacement therapy ameliorates obstructive sleep apnea in patients with newly diagnosed hypothyroidism.

Several other investigators reported on the efficacy of thyroid replacement hormone in patients with hypothyroidism and sleep apnea. Orr et al reported that three patients with profound myxedema experienced a nearly complete resolution of the obstructive apnea after administration of levothyroxine. [16] Skatrud et al reported an elimination of mild obstructive apnea (apnea index: 10 during rapid eye movement [REM] sleep and 4 during non-REM sleep) in a man after 2 months of levothyroxine treatment. [3] Millman et al reported a resolution of central apnea in a male patient once a euthyroid state was achieved. [17] VanDyck et al reported one case of severe sleep apnea in a grossly myxedematous patient who improved dramatically after thyroid replacement therapy. [18] In a study of two patients who presented with depression, McNaMara et al found subclinical hypothyroidism in association with sleep apnea. [19] Thyroid hormone replacement led to a resolution of both apnea and depression.

In a more detailed report, Lin et al described the effects of thyroid replacement therapy on five patients with hypothyroidism and sleep apnea. [2] After 4 months of therapy, their apnea index decreased from 35.8 ([plus or minus]39.4; range: 7.9-97.2) to 3.4 ([plus or minus]3.4; range: 0.8-9.1). The benefit of hormone replacement in these patients was still evident during testing performed at 12 months. Although their frequency of snoring had increased significantly at 4 months, it had decreased at 12 months.

In contrast with these positive results, Grunstein and Sullivan studied eight patients after treatment with levothyroxine. [4] Even after the eight patients became euthyroid, six of them (75%) still had persistent sleep apnea. Their mean pretreatment apnea index, which was 51 ([plus or minus]6), fell only a few points to 45 ([plus or minus]8) after treatment. Grunstein and Sullivan concluded that the apnea index does not decrease significantly in all patients who have both hypothyroidism and sleep apnea after they have been treated for the hypothyroidism. In a case study of a hypothyroid patient with OSAS, Meslier reported that 6 months of hormone replacement up to the euthyroid state did not improve the patient's apnea. [9]

Our study confirms the impressions of Grunstein and Sullivan inasmuch as treatment of hypothyroidism improved the RDI in only one of four patients (25%). [4] Even though the one improved patient had a reduction in RDI of more than 50%, he still continued to experience significant apnea. When reviewing our results and other reports in the literature, it is clear that thyroid hormone replacement might not ameliorate obstructive sleep apnea.

Our study does not address the issue of the prevalence of sleep apnea in patients with newly diagnosed hypothyroidism. Lin et al found that 5 of 20 (25%) hypothyroid patients had sleep apnea. [2] On the other hand, Rajagopal found 9 of 11 (82%) patients to be so affected. [1] Pelttari et al [5] compared hypothyroid patients and controls who underwent sleep studies and found that nocturnal breathing abnormalities were common in both groups (50 and 29%, respectively). They found that 7.7% of hypothyroid patients and 1.5% of controls had severe obstructive apneas; however, statistical analysis revealed that the variance between the groups was primarily dependent on obesity and male gender. It is likely that hypothyroidism can contribute to the development of OSAS, but it is unclear whether its effect is independent or is related to other factors such as obesity.

In 1996, the average charge for a thyroid function test (TSH) at our clinical laboratory was $60. The cost of testing our entire study group was more than $50,000. Although the cost of an individual TSH test is less than the cost of a sleep study, a CPAP machine, or surgery, it is nonetheless a significant amount of money, an amount that proved to be spent to little avail. Our routine screening of 1,000 patients resulted in only a modest benefit for only two patients. Eliminating routine thyroid screening in patients who present for an evaluation of sleep disordered breathing could save a large number of healthcare dollars.

The results of our study lead us to three conclusions: 1) The prevalence of clinical hypothyroidism in patients seen for an evaluation of sleep disordered breathing is no greater than that seen in the general population. 2) Thyroid replacement therapy in hypothyroid patients with obstructive sleep apnea results in little or no improvement in apnea symptoms. Therefore, 3) routine screening of thyroid function is not indicated for these patients.

From the Atlanta Ear, Nose, and Throat Associates (Dr. Mickelson), the Washington University School of Medicine, St. Louis (Dr. Lian), and the Sleep Disorders and Sleep Research Center, Henry Ford Hospital, Detroit (Dr. Rosenthal).

Reprint requests: Samuel A. Mickelson, MD, Atlanta Ear, Nose, and Throat Associates P.C., 5555 Peachtree Dunwoody Rd., Suite 201, Atlanta, GA 30342. Phone: [phone]; fax: [phone].

References

(1.) Rajagopal KR, Abbrecht PH, Derderian 55, et al. Obstructive sleep apnea in hypothyroidism. Ann Intern Med 1984;101:491-4.

(2.) Lin CC, Tsan KW, Chen PJ. The relationship between sleep apnea syndrome and hypothyroidism. Chest 1992;102:1663-7.

(3.) Skatrud 3, Iber C, Ewart R, et al. Disordered breathing during sleep in hypothyroidism. Am Rev Respir Dis 1981;124:325-9.

(4.) Grunstein RR, Sullivan CE. Sleep apnea and hypothyroidism: Mechanisms and management. Am J Med 1988;85:775-9.

(5.) Pelttari L, Rauhala E, Polo O, et al. Upper airway obstruction in hypothyroidism. J Intern Med 1994:236:177-81.

(6.) Kryger MH, Roth T, Dement WC, eds. Principles and Practice of Sleep Medicine. 2nd ed. Philadelphia: W.B. Saunders, 1994:683.

(7.) Fairbanks DN, Fujita S, eds. Snoring and Obstructive Sleep Apnea. 2nd ed. New York: Raven Press, 1994:61.

(8.) Rechtschaffen 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, 1968.

(9.) Meslier N, Giraud P, Person C, et al. Prevalence of hypothyroidism in sleep apnoea syndrome. Eur J Med 1992;1:437-8.

(10.) Winkelman JW, Goldman H, Piscatelli N, et al. Are thyroid function tests necessary in patients with suspected sleep apnea? Sleep 1996;19:790-3.

(11.) Sawin CT, Castelli WP, Hershman JM, et al. The aging thyroid: Thyroid deficiency in the Framingham Study. Arch Intern Med 1985;145:1386-8.

(12.) Falkenberg M, Kagedal B, Norr A. Screening of an elderly female population for hypo- and hyperthyroidism by use of a thyroid hormone panel. Acta Med Scand 1983;214:361-5.

(13.) Nystrom E, Bengtsson C, Lindquist O, et al. Thyroid disease and high concentration of serum thyrotrophin in a population sample of women: A 4-year follow-up. Acta Med Scand 1981;210:39-46.

(14.) Eggertsen R, Petersen K, Lundberg PA, et al. Screening for thyroid disease in a primary care unit with a thyroid stimulating hormone assay with a low detection limit. BMJ 1988;297:1586-92.

(15.) Brochmann H, Bjoro T, Gaarder PI, et al. Prevalence of thyroid dysfunction in elderly subjects: A randomized study in a Norwegian rural community (Naeroy). Acta Endocrinol (Copenh) 1988;117:7-12.

(16.) Orr WC, Males JL, Imes NK. Myxedema and obstructive sleep apnea. Am J Med 1981;70:1061-6.

(17.) Millman RP, Bevilacqua J, Peterson DD, Pack AI. Central sleep apnea in hypothyroidism. Am Rev Respir Dis 1983;127:504-7.

(18.) VanDyck P, Chadband R, Chaudhary B, Stachura ME. Sleep apnea, sleep disorders, and hypothyroidism. Am J Med Sci 1989;298:119-22.

(19.) MeNamara ME, Southwick SM, Fogel BS. Sleep apnea and hypothyroidism presenting as depression in two patients. J Clin Psychiatry 1987;48:164-5.

               Polysomnographic data before and after thyroid
          hormone replacement in four patients with hypothyrodism
                    and obstructive sleep apnea syndrome
        Pretreatment           Posttreatment
Patient     RDI [*]   LSAT [+]      RDI      LSAT
   1         58         83          32        80
   2         44         79          18        82
   3         66         90          95        85
   4         90         69          77        56
 Mean       64.4       80.3        55.6      75.8
SD [++]     19.4       8.7         36.3      13.3
(*.)Respiratory disturbance index.
(+.)Lowest oxygen saturation (%).
(++.)Standard deviation.