Original article

Thyroxine replacement therapy reverses sleep-disordered breathing

in patients with primary hypothyroidism

Ashish Jhaa, Surendra K. Sharmaa,*, Nikhil Tandonb, Ramakrishnan Lakshmyc,

Tamilarasu Kadhiravana, K.K. Handad, Rajiva Guptaa, Ravindra M. Pandeye,

Pradeep K. Chaturvedif

aDivision of Pulmonary and Critical Care Medicine, Department of Medicine, All India Institute of Medical Sciences, New Delhi 110029, IndiabDepartment of Endocrinology, All India Institute of Medical Sciences, New Delhi, India

cDepartment of Cardiac Biochemistry, All India Institute of Medical Sciences, New Delhi, IndiadDepartment of Otorhinolaryngology, All India Institute of Medical Sciences, New Delhi, India

eDepartment of Biostatistics, All India Institute of Medical Sciences, New Delhi, IndiafDepartment of Reproductive Biology, All India Institute of Medical Sciences, New Delhi, India

Received 1 March 2005; received in revised form 25 April 2005; accepted 1 May 2005

Available online 28 September 2005

Abstract

Background and purpose: Anecdotal reports suggest that sleep-disordered breathing (SDB) is common among patients with primary

hypothyroidism. This study was undertaken to determine the prevalence of SDB and to evaluate the effect of thyroxine replacement therapy

on SDB in patients with primary hypothyroidism.

Patients and methods: Fifty consecutive newly diagnosed, untreated symptomatic patients with primary hypothyroidism (age: 34G11 years;

males: 21 [42%]) were prospectively studied. Physical examination, anthropometry, fasting blood glucose and serum lipids were performed

in all patients at baseline. Polysomnography was done at baseline in all patients and was repeated after adequate thyroxine replacement in

those who had SDB.

Results: SDB defined as apnea–hypopnea index (AHI) R5 was present in 15 patients (30%) at baseline and was reversible in 10 of the 12

patients evaluated following thyroxine replacement therapy (PZ0.006). Thyroxine replacement therapy was associated with improvement in

findings that reflect a compromised upper airway, such as macroglossia (4 [33%] vs. 1 [8%]; PZ0.083), myoedema (5 [42%] vs. 1 [8%]; PZ0.046) and facial puffiness (10 [83%] vs. 1 [8%]; PZ0.003).

Conclusions: Reversible SDB is common among patients with primary hypothyroidism. Changes in upper airway anatomy resulting from

hypothyroidism probably contribute to the development of SDB in these patients.

q 2005 Elsevier B.V. All rights reserved.

Keywords: Hypothyroidism; Sleep-disordered breathing; Treatment

1. Introduction

Obstructive sleep apnea (OSA) and hypothyroidism are

common problems in clinical practice and either of them

have been found to be prevalent in at least 2% of general

population [1,2]. Hypothyroidism and OSA have

1389-9457/$ - see front matter q 2005 Elsevier B.V. All rights reserved.

doi:10.1016/j.sleep.2005.05.003

* Corresponding author. Tel.: C91 11 2659 4415; fax: C91 11 2658

9898.

E-mail address: sksharma@aiims.ac.in (S.K. Sharma).

overlapping clinical presentations. Excessive daytime

somnolence, apathy and lethargy are known to occur in

patients with hypothyroidism. These symptoms have been

attributed to hypothyroid metabolic state and are often

alleviated by thyroxine replacement therapy [3]. Patients

with OSA also complain of similar symptoms, which

suggests that OSA could be associated with hypothyroidism

[4]. However, hypothyroidism has been found to be

uncommon among patients with OSA [5,6]. In patients

presenting to sleep clinics, OSA and hypothyroidism coexist

in 1.6–11% of patients [5–8]. Notwithstanding, patients

with hypothyroidism are at increased risk for secondary

sleep-disordered breathing (SDB). They can have

Sleep Medicine 7 (2006) 55–61

www.elsevier.com/locate/sleep

A. Jha et al. / Sleep Medicine 7 (2006) 55–6156

obstructive, central and mixed sleep apneas [9–13]. SDB

secondary to hypothyroidism may result in a misdiagnosis

of OSA in patients with undiagnosed hypothyroidism.

Prevalence of SDB among patients with hypothyroidism

has been found to be high, but the range of frequencies

observed in different studies is quite wide, varying from 25

to 100% [10–14]. Moreover, the effect of thyroxine

replacement therapy on SDB in patients with hypothyroid-

ism is not well studied. A few earlier studies have found

significant improvement [10,12], whereas other studies have

found a lesser degree of improvement or no improvement

[11,13]. In this context, the present study was undertaken to

determine the prevalence of SDB in patients with untreated

primary hypothyroidism and to evaluate the effect of

thyroxine replacement therapy in those who had SDB.

2. Patients and methods

2.1. Study population

This study was conducted at the All India Institute of

Medical Sciences (AIIMS) Hospital, New Delhi, India. This

is a tertiary level referral center located in north India. The

study protocol was reviewed and approved by the

departmental research review committee at the AIIMS

hospital. Informed written consent was obtained from all

patients. All newly diagnosed, untreated patients with

clinical and laboratory features suggestive of primary

hypothyroidism (serum thyroxine stimulating hormone

[TSH]O5 mIU/mL), attending medicine and endocrinology

outpatient departments, from January 2003 to September

2004 were eligible for inclusion in the study. Patients were

evaluated by one of the study physicians who was unaware

of polysomnography (PSG) findings, using a pre-designed

instrument regarding presenting symptoms, including

features of SDB, demographic characteristics, any drug

intake and drinking habits. Patients presenting primarily for

sleep-related problems were excluded. Patients with goiter,

history of alcohol abuse, chronic anxiolytic/sedative drug

use, associated respiratory, renal, hepatic or cardiovascular

disease or upper respiratory tract infection within the past

one week, as well as those who were pregnant or critically

ill, were excluded.

All patients underwent a standardized physical examin-

ation, and evaluation was repeated by the same physician at

every visit. An otorhinolaryngology specialist blinded to

PSG findings carried out examination of upper airway in all

patients included in the study, for features such as

macroglossia, pharyngeal crowding, bulky uvula, retro-

gnathia, tonsillar enlargement and deviated nasal septum.

Presence of hypertension, dyslipidemia and metabolic

syndrome was defined by cut-offs as per the seventh report

of the Joint National Committee on prevention, detection,

evaluation, and treatment of high blood pressure (JNC 7)

and the National Cholesterol Education Program (NCEP)

expert panel on detection, evaluation, and treatment of high

blood cholesterol in adults (Adult Treatment Panel III)

guidelines [15,16].

2.2. Anthropometric measurements

Body weight was recorded (to nearest 0.5 kg) in all

patients, in erect position without shoes and wearing only

light indoor clothes, with an electronic scale (Tanita body

composition analyzer-TBF 300 G.S., Japan). Total body fat,

excess body fat and total body water were estimated by

bipedal bioelectric impedance technique. Height was

measured to the nearest 1 cm and body mass index (BMI)

was calculated as body weight/height2 (kg/m2). Neck

circumference (NC) was measured at the level of

cricothyroid membrane using a non-elastic measuring

tape. Neck length (NL) was measured from occipital

tubercle to the vertebra prominens. A height-corrected

measure for NC, percentage predicted neck circumference

(PPNC), was computed using the formula: PPNCZ(1000!NC)/(0.55HC310) [17]. Waist circumference was

measured midway between the lower rib cage margin and

the anterior superior iliac spine. Hip circumference was

measured at the maximum circumference of the buttocks,

the subject standing with feet placed together, and waist-hip

ratio (WHR) was calculated. Skinfold thickness was

measured using Lange skinfold calipers (Beta Technology,

Inc., Santa Cruz, CA, USA) to the nearest 1 mm. Triceps

and biceps skinfold thicknesses were measured midway

between the acromion process of the scapula and the

olecranon process of the right arm. Subscapular skinfold

thickness was measured at the inferior angle of the scapula

in the mid-axillary line and suprailiac skinfold thickness

was measured just above the highest point of iliac crest. All

measurements were done in triplicate, and the mean was

recorded.

2.3. Biochemical investigations

All patients underwent fasting blood glucose and serum

lipids estimation at baseline. Thyroid function tests were

done at a central facility. Fluorescence polarization

immunoassay was used for estimating serum tetra-iodothyr-

onine (T4) and thyroxine-stimulating hormone (TSH)

levels. Normal range for T4 was 4.5–12.0 mg/dL and for

TSH was 0.49–4.67 mIU/mL. Estimation of T4 and TSH

was done at baseline and repeated at 6-week intervals

following initiation of thyroxine replacement until the time

of normalization.

2.4. Pulmonary function tests

Lung volumes and their subdivisions were measured

using a constant volume variable pressure body plethysmo-

graph (P.K. Morgan Chatham, Kent, UK) as described

previously [18].

A. Jha et al. / Sleep Medicine 7 (2006) 55–61 57

2.5. Sleep study questionnaire

A sleep study questionnaire based on the Wisconsin sleep

cohort questionnaire (Courtesy: Terry Young, Wisconsin,

USA) was administered by the principal investigator to

patients in the presence of their bed partners. A four-point

frequency scale was used for quantifying snoring, choking

and alcohol intake. Patients were stratified into high-risk and

low-risk categories based on presence or absence of habitual

snoring or choking (frequencyR3–4 nights/week) [1].

Excessive daytime sleepiness (EDS) was assessed based

upon patients’ response to questions regarding probability of

dozing in eight specific situations [19]. Patients were asked to

answer using a scale of 0–3 (0: would never doze, 1: slight

chance of dozing, 2: moderate chance of dozing, 3: high

chance of dozing) for each question. The Epworth sleepiness

score (ESS) was calculated by adding the scores in response

to all eight questions. EDS was defined as ESSO10 [25].

2.6. Polysomnography (PSG)

All patients underwent PSG at baseline, before initiation

of thyroxine replacement therapy. PSG was performed as

described previously [20]. Briefly, patients reported to the

sleep laboratory at 8:00 p.m. on the day of appointment.

Patients were hooked up to an Alice-3 PSG machine

(Healthdyne Technologies, USA) by standard gold cups

after cleansing the area of attachment with alcohol followed

by Omniprepw and requested to sleep at around 9:00 p.m.

Recording was started after ensuring that the impedance of

recording electrodes was set to zero. Parameters monitored

include electroencephalogram (EEG), electrooculogram

(EOG), electrocardiogram (ECG), chin and leg electro-

myograms (EMG), nasal airflow (using a pressure transdu-

cer), tracheal breath sounds, thoracic and abdominal wall

movements, transcutaneous oxygen saturation and body

position. Recorded sleep data were manually scored for

sleep stages, apnea, and hypopnea by an experienced

technician blinded to clinical data. Apnea was defined as

cessation of oronasal airflow for R10 s. Obstructive apnea

was scored when airflow was absent but respiratory efforts

were present. Hypopnea was defined as a discernible

reduction in respiratory airflow (R50%) lasting for

R10 s, accompanied by a decrease of R4% in oxygen

saturation. Apnea–hypopnea index (AHI) was calculated as

AHIZ(total number of obstructive apneasCtotal number of

hypopneas)/total sleep time (hours). Patients with AHIR5

were defined as having SDB [21].

2.7. Post-thyroxine replacement polysomnography

All patients were started on thyroxine replacement

therapy with oral levothyroxine (Eltroxinw, Glaxo Limited,

Mumbai, India) at a dosage of 50 mg/day. Subsequent

titration of dose was done every 6 weeks in increments of

50 mg so as to achieve normalization of serum TSH levels

(!5 mIU/mL). After achieving euthyroid status, PSG was

repeated in those patients found to have SDB (AHIR5) at

baseline.

2.8. Statistical analysis

Mean prevalence of SDB in patients with hypothyroid-

ism as observed in earlier studies was 40%. Allowing for a

permissible error of 15%, the minimum sample size

required for the study was calculated to be 43 patients.

Data were recorded on an Excel spreadsheet. After assessing

for approximate normal distribution, continuous variables

are presented as meanGSD if normally distributed, or as

median (IQR) if the distribution was skewed. Categorical

variables are presented as proportions, n(%). Comparison of

pre-treatment and post-treatment observations was done

using paired samples t-test for continuous variables and

McNemar test for categorical variables. Statistical analysis

was performed using a statistical software package STATA

version 8.0 (intercooled version, Stata Corporation, Hous-

ton, TX, USA). All tests were two-sided and P!0.05 was

considered statistically significant.

3. Results

Over a period of 21 months, 54 patients with newly

diagnosed, untreated primary hypothyroidism were seen, of

which 52 patients were found eligible (two patients were

excluded: pregnancy [one patient], critically ill [one

patient]). Of those found eligible, 50 patients were included

in the study (two patients declined consent). Twenty-nine

patients were females (58%). Mean age of patients in the

study group was 34G11 years (range: 12–58 years). The

majority of the patients (36 [72%]) were in the age group of

21–40 years. Baseline characteristics of the patients are

shown in Table 1. Overall, 18 patients (36%) were

overweight (BMI 25–29.9 kg/m2) and eight (16%) were

obese (BMIR30 kg/m2). Seventeen patients (34%) had

hypertension. Abnormalities of upper airway were found in

11 patients, which included macroglossia in seven (14%),

pharyngeal crowding in two (4%) and bulky uvula in two

(4%). Myoedema was present in 10 patients (20%).

No significant abnormality was found in pulmonary

functions. Fasting blood glucose was impaired

(R100 mg/dL and !126 mg/dL) in 10 patients (20%) and

was in diabetic range (R126 mg/dL) in four patients (8%).

Forty-four patients had dyslipidemia (88%). Elevated total

cholesterol (R200 mg/dL) was observed in 33 patients

(66%), elevated LDL cholesterol (R160 mg/dL) in 23

patients (46%) and raised serum triglyceride levels

(R150 mg/dL) in 27 patients (54%). Metabolic syndrome

was present in 21 patients (42%).

Findings of polysomnographic study at baseline are

shown in Table 2. Fractions of slow wave sleep (SWS) and

rapid eye movement (REM) sleep were decreased in

Table 1

Baseline characteristics of 50 patients with primary hypothyroidism

Characteristic All patients (nZ50)a AHI! 5 (nZ35)a AHIR5 (nZ15)a

Age (years) 34G11 33G13 36G8

Male genderb 21 (42) 11 (31) 10 (66)c

BMI (kg/m2) 25.3G5.1 23.9G4.5 28.6G4.8c

Total body fat (%) 28.9G7.8 28.6G10.5 29.9G10

Total body water (%) 51.7G8.4 51.7G8.9 51.4G7.3

Neck circumference (cm) 35.6G3.8 34.3G3.0 38.8G3.6c

PPNC 90G9.1 86.4G7.1 97.2G8.4c

WHR 0.94G0.08 0.94G0.01 0.95G0.02

Triceps SFT (mm)d 18.5 (10.0–22.3) 18.0 (8–23) 19 (13–22)

Subscapular SFT (mm)d 21.5 (12.8–27.0) 17 (9–25) 27 (23–30)c

Mean SFT (mm)d 18.3 (13.9–23.3) 17 (10–21) 22 (17–24)c

Myoedemab 9 (18) 2 (5.7) 7 (46.7)c

FBG (mg/dL) 96.1G19.1 90.9G16.4 105.2G18.1c

Total cholesterol (mg/dL) 233.7G74.7 220G62.3 265G92.7

LDL-C (mg/dL) 156.9G61.5 148G56 177G71

TG (mg/dL)d 154 (117–222) 146 (108–206) 207 (141–236)

T4 (mg/dL)d 1.2 (0.6–3.1) 1.4 (0.6–2.4) 1.2 (0.1–1.9)

TSH (mIU/mL)d 100 (47.8–107) 100 (36–110) 100 (77–106)

Habitual snoring (O3–4 nights/week)b 22 (44) 11 (31) 11 (73)c

Excessive daytime sleepiness (ESS O10)b 27 (54) 19 (54) 10 (67)

AHI: apnea–hypopnea index, BMI: body-mass index, PPNC: percentage predicted neck circumference, WHR: waist–hip ratio, SFT: skinfold thickness, FBG:

fasting blood glucose, LDL-C: low density lipoprotein cholesterol, TG: triglyceride, T4: serum tetra-iodothyronine, TSH: serum thyroxine stimulating

hormone, ESS: Epworth sleepiness score.a Data presented as meanGSD.b Data presented as n (%).c Difference between patients with AHI!5 and AHIR5 was significant (P!0.05).d Values expressed as median (IQR).

A. Jha et al. / Sleep Medicine 7 (2006) 55–6158

the study group in comparison to the general population.

Obstructive apnea and hypopnea were much more frequent

than central and mixed apneas. SDB, defined as AHIR5,

was present in 15 patients (30%). SDB was mild

Table 2

Polysomnographic parameters at baseline in 50 patients with primary hypothyroi

Variable All patients (nZ50)a

TST (min) 418.8 (344–459)

REM (%) 9.7 (0–15.1)

SWS (%) 18.7 (12.2–26.2)

CA (events/study) b

OA (events/study) 0.5 (0–13.5)

MA (events/study) b

HA (events/study) 2 (0–19.25)

AHI (events/study) 1.2 (0–7.4)

TpO2 sat!90% 1.5 (0.1–7.5)

Minimum SpO2% 86 (76.5–88)

Arousal index (per h) 14.5 (7.2–19.6)

TSE (episodes/study) 107.3 (14–341)

MSD (s) 8.9 (6.2–16.3)

TSTS (% of TST) 21 (0.8–27.4)

AHI: apnea–hypopnea index, TST: total sleep time, REM%: % sleep time with ra

central apnea, OA: obstructive apnea, MA: mixed apnea, HA: hypopnea, TpO2

saturation by pulse oximetry, TSE: total snoring episode, MSD: mean snoring dua Values represented as median (IQR).b Only three patients had central apnea and mixed apnea.c Not tested for significance.d P!0.05.

(AHIZ5–14.9) in eight patients, moderate (AHIZ15–

29.9) in one and severe (AHIR30) in six patients.

Habitual snoring was present in 22 patients (44%),

and habitual choking was present in six patients (12%).

dism

AHI!5 (nZ35)a AHI R5 (nZ15)a

423 (355–467) 388.5 (311.9–437)

9.7 (0–19.8) 9.1 (0–12.3)

19.3 (14.4–27) 18.4 (7.2–25.2)b b

0 (0–1) 21 (13–166)c

b 1 (0–8)c

0 (0–3) 22 (19–34)c

0 (0–1.3) 14.5 (9.7–33.9) c

0.2 (0–3) 18.1 (3–31)d

88 (83.5–92) 78 (72–82)d

14.7 (6.6–18.1) 12.3 (10.1–20.4)

35 (3–192) 360 (248–982)d

8 (5.2–16.5) 12.9 (9.4–17.3)d

1.5 (0.4–16.7) 35 (16.2–49.1)d

pid eye movement sleep, SWS%: % sleep time with slow wave sleep, CA:

sat!90%: % time of sleep with oxygen saturation! 90%, SpO2: oxygen

ration, TSTS (%): % of total sleep time with snoring.

Table 3

Effect of thyroxine replacement therapy in 12 patients with primary

hypothyroidism and SDB

Variable Pre-treatmenta Post-treatmenta

BMI (kg/m2) 28G3.7 26.4G2.9b

Neck circumference (cm) 38.6G3.8 36.6G3.5

PPNC 96.5G8.2 92G8.3

WHR 0.94 0.96

Mean SFT (mm)c 22 (17.4–24.8) 17 (13–22)b

Myoedemad 5 (42) 1 (8.3)b

FBG (mg/dL) 105G17.9 93.5G8b

Total cholesterol (mg/dL) 264.2G101.8 183.1G25.2b

LDL-C (mg/dL) 179.6G88 108G17.6b

T4 (mg/dL)c 0.9 (0.03–1.9) 11.4 (8.5–14)b

TSH (mIU/mL)c 100 (78.9–104.5) 1.1 (0.37–2.18)b

TST (min)c 397 (316–432) 383 (333–452)

REM%c 8.7 (0–18.9) 6.9 (0–13.3)

SWS%c 18.4 (7.2–25.2) 28.2 (15–33.4)b

CA (events/study)c 0 (0–15) 0 (0–0)

OA (events/study)c 7 (2.08–29.5) 0 (0–21)b

MA (events/study)c 0.5 (0–18.5) 0 (0–0)

HA (events/study)c 22 (17.5–34) 8 (2.25–23)b

AHI (per h)c 14.3 (7.4–33.6) 2.1 (0.8–4.6)b

TpO2 sat!90%c 14 (2.2–19.9) 0.2 (0–1.7)b

MinSpO2c 78 (72–82) 88 (84.5–91.2)b

BMI: body-mass index, PPNC: percentage predicted neck circumference,

WHR: waist–hip ratio, SFT: skinfold thickness, FBG: fasting blood

glucose, LDL-C: low density lipoprotein cholesterol, T4: serum tetra-

iodothyronine, TSH: serum thyroxine stimulating hormone, TST: total

sleep time, REM%: % sleep time with rapid eye movement sleep, SWS%:

% sleep time with slow wave sleep, CA: central apnea, OA: obstructive

apnea, MA: mixed apnea, HA: hypopnea, AHI: apnea–hypopnea index,

TpO2 sat!90%: % time of sleep with oxygen saturation!90%, MinSpO2:

minimum oxygen saturation.a Values represented as meanGSD.b P!0.05.c Expressed as median (IQR).d Presented as n (%).

A. Jha et al. / Sleep Medicine 7 (2006) 55–61 59

Twenty-seven patients (54%) had EDS. Based upon

habitual snoring or choking, 22 patients (44%) were

stratified as high-risk for SDB, and 12 (54%) of them had

SDB. EDS was present in 10 of 15 patients with SDB. The

questionnaire had 80% sensitivity and 71% specificity, 54%

positive predictive value and 89% negative predictive

value for SDB in the study group. SDB was significantly

more common in patients classified as high-risk based on

the questionnaire (unadjusted odds ratioZ6.0; 95%CIZ1.6–23.1).

Patients with SDB had significantly higher BMI, neck

circumference, subscapular and mean skinfold thickness

than those without SDB (Table 1). There was significant

positive correlation between AHI and neck circumference

(rZ0.65, PZ0.001) as well as BMI (rZ0.301, PZ0.03).

Habitual snoring and myoedema were significantly more

frequent in patients with SDB (Table 1). No significant

difference was seen in SWS and REM sleep between the

patients with SDB and those without it. Mean fasting blood

glucose was significantly higher in those patients who had

SDB. However, no significant difference was observed

between the two groups in mean TSH level and serum lipids

(Table 1) and no significant correlation was observed

between AHI and serum TSH levels (rZ0.183, PZ0.202).

Polysomnography was repeated after normalization of

thyroid functions in 12 of 15 patients with SDB at baseline

(median [IQR] duration of follow-up was 9 [7–11] months);

three patients (two females) were lost to follow-up.

Significant improvement was observed in the symptoms of

snoring and EDS following thyroxine replacement therapy

(data not shown). Statistically significant decrease in BMI,

hip circumference and subscapular, suprailiac and mean

skinfold thicknesses were observed after normalization of

thyroid functions (Table 3). Significant improvement was

observed in serum lipids, fasting blood sugar and thyroid

functions, following adequate treatment of hypothyroidism

(Table 3).

A statistically significant decline was found in total

number of episodes of obstructive apnea, hypopnea and AHI

following thyroxine replacement in patients who had SDB

at baseline (Table 3). Percentage of sleep time with oxygen

desaturation as well as minimum oxygen saturation during

sleep also showed a significant improvement on post-

treatment PSG study. No significant change was observed in

the frequency of central apnea, mixed apnea, arousal index

and percentage of REM sleep, following thyroxine

replacement therapy. A significant increase in SWS was

observed on PSG following normalization of the thyroid

functions (Table 3). Of the 12 patients with SDB in whom

PSG was repeated following normalization of thyroid

functions, AHI decreased to !5 in 10 patients and remained

R5 in two patients (Fig. 1). In one of these two patients,

AHI decreased from 30 to 16.5 on follow-up; in the other,

AHI increased from 41 to 50 despite normalization of

thyroid functions. These two patients had no weight loss

and no improvement in snoring, choking or EDS with

thyroxine replacement therapy.

4. Discussion

The association between SDB and hypothyroidism is a

widely accepted belief in clinical practice; however, there

are only a few studies in the literature to substantiate it. Data

regarding the prevalence of SDB in hypothyroidism are

sparse. Most of the published literature consists of case

reports [14,22] or small case series [10–13] and the findings

of these studies have been highly variable. Prevalence of

SDB in hypothyroidism varied from 25–100% in these

studies.

Hypothyroidism is more common among females than

males in the general population [2]. In earlier studies on

prevalence of SDB in patients with hypothyroidism, the

number of male patients was more than female patients

[12,14]. This selection bias could have led to an over-

estimation of SDB in these studies, as the latter is more

0

10

20

30

40

50

60

70

Baseline Post-thyroxinereplacement

Apn

ea-h

ypop

nea

inde

xP = 0.006

Fig. 1. Scatter diagram depicting apnea–hypopnea indices of 12 patients

with concomitant primary hypothyroidism and SDB and the effect of

thyroxine replacement therapy on the latter.

A. Jha et al. / Sleep Medicine 7 (2006) 55–6160

common among males. In the present study, female patients

outnumbered the male patients. Moreover, an adequate

number of patients was included. All earlier studies

involved smaller number of patients (%20 patients in all

studies) [10–14,22]. Care was taken not to introduce any

selection bias into the study population by including

consecutive patients irrespective of their T4/TSH levels,

symptoms of SDB and obesity. Moreover, all patients were

naive to treatment. Earlier studies had the drawbacks of

either selection bias (only patients presenting with SDB-

related symptoms and concomitant hypothyroidism were

included) [11,12,14] or potential confounding by prior

thyroxine replacement [11].

Thus the estimate of the prevalence of SDB among patients

with hypothyroidism as found in the present study is more

reliable. However, it should be mentioned that more than half

of the patients in the present study had marked hypothyroid-

ism, as evidenced by the fact that serum TSH levels were O100 mIU/mL in 28 patients (56%), and all patients had

symptomatic hypothyroidism and sought healthcare for the

same. It is possible that patients with lesser degree of

hypothyroidism might have lower prevalence of SDB.

However, this is unavoidable due to the inherent nature of

the study design itself (hospital-based study).

As reported in the literature, obesity, hypertension,

macroglossia and facial puffiness were found to be frequent

in patients with hypothyroidism [2]. Further, within the

study group, these abnormalities were comparatively more

common among patients who had SDB than those who did

not. Laboratory investigations revealed a high frequency of

dyslipidemia, hyperglycemia and metabolic syndrome in

these patients. In addition to the role of hypothyroidism per

se in the pathogenesis of these co-morbidities, SDB might

have played a contributory role [23,24].

SDB was documented in 30% of patients with

hypothyroidism in the present study. Significantly, in almost

all of the hypothyroid patients who had SDB, the latter was

found to be completely reversible with thyroxine replace-

ment alone, obviating the need for continuous positive

airway pressure (CPAP) therapy. Thyroxine replacement

was accompanied not only by improvement in measures of

thyroid functions but also by improvement in BMI, skinfold

thickness, blood glucose, serum lipids and AHI on

polysomnography. Apart from these, physical findings

such as macroglossia, facial puffiness and myoedema also

showed significant improvement in these patients following

thyroxine replacement.

Interestingly, SDB persisted in two of 12 patients in the

present study, despite adequate thyroxine replacement

therapy (post-replacement TSHZ3.2 and 2.1 mIU/mL).

Compliance with therapy was good in both cases. One of

these patients showed an incomplete improvement in AHI

following treatment; however, the patient was lost to further

follow-up and additional PSG could not be performed. It

was probably a case of delayed response in this particular

patient. In the other instance, AHI increased from 41 to 50;

an additional PSG performed five months later revealed

persistent SDB with an AHI of 56. Noteworthy is the fact

that this patient was overweight (BMIZ27.2 kg/m2) and

there was no reduction in body weight with thyroxine

replacement therapy. This suggests that in this particular

patient obesity or some factor other than hypothyroidism

was responsible for SDB.

The proposed factors predisposing to the development of

SDB in patients with hypothyroidism include mucoprotein

deposition in upper airways leading to airway narrowing

and decreased neuronal output to upper airway musculature.

Additionally, obesity, abnormalities in ventilatory control

and myopathy involving genioglossus and other pharyngeal

dilators leading to increased collapsibility of upper airways

may also contribute. The proximate cause of improvement

in SDB is difficult to dissect from the observations of the

current study. The improvement could have been due to

direct action of thyroxine or else due to changes in the upper

airway brought about by thyroxine replacement, albeit

indirectly. Since the nature of sleep apnea in these patients,

as observed in the present study, was predominantly

obstructive rather than central, it seems likely that the

latter, i.e. changes in upper airway, were responsible. More

importantly, improvement in SDB temporally correlated

with improvement in measures that reflect a compromised

upper airway in these patients, such as macroglossia,

myoedema and facial puffiness. This is supportive of the

view that changes in upper airway occurring secondary to

A. Jha et al. / Sleep Medicine 7 (2006) 55–61 61

hypothyroidism contribute to the development of SDB.

Analogous to our findings, it has been shown that in patients

with acromegaly, the improvement in SDB following

octreotide treatment, correlated with a decrease in tongue

volume [25].

To conclude, the present study has given a more reliable

estimate of the prevalence of SDB in patients with untreated

primary hypothyroidism and has shown that SDB is

reversible following thyroxine replacement therapy in a

majority of them. Moreover, findings of the present study

suggest a possible role for upper airway changes in the

pathogenesis of SDB in these patients. Future studies should

focus more specifically on anatomical and functional

changes occurring in upper airway and the causative role

played by these changes in the pathogenesis of SDB in these

patients.

Acknowledgement

The authors thank the patients who volunteered to

participate in the study. Authors also thank Mr. Jitender

Sharma and Mr. Jitender Kumar for their technical help in

carrying out the PSG studies.

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