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Table of Contents
REVIEW ARTICLE
Year : 2019  |  Volume : 8  |  Issue : 2  |  Page : 89-94

Respiratory dysfunction in hypothyroidism


1 Department of Endocrinology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
2 Department of Medicine, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India

Date of Web Publication11-Nov-2019

Correspondence Address:
V Suresh
Professor, Department of Endocrinology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JCSR.JCSR_54_19

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  Abstract 


Hypothyroidism is one of the most common endocrine disorders in adults. While it affects almost all systems of the body, little attention has been paid to the involvement of the respiratory system and its function in hypothyroidism. The present review summarises the available literature on respiratory function in patients with hypothyroidism. Hypothyroidism has myriad effects on respiratory function. It is known to cause upper airway obstruction during sleep causing sleep disordered breathing (obstructive sleep apnoea). It affects the respiratory drive causing reduced responsiveness to hypoxia or hypercapnia, potentially causing life-threatening hypoventilation on rare occasions. Pleural effusions solely attributable to hypothyroidism are a relatively uncommon occurrence. Deficiency of thyroid hormones reduces the strength of the respiratory muscles. A reduction in diffusion lung capacity for carbon monoxide points to lung parenchymal involvement as well. These two changes lead to a predominantly restrictive pulmonary physiology on spirometry. Studies show that the restrictive pattern improves after thyroxin replacement. Since pulmonary involvement is a relatively underevaluated aspect of hypothyroidism, more studies in this area are the need of the hour, to fill the current lacunae in our knowledge and understanding.

Keywords: Hypothyroidism, obstructive sleep apnoea, respiratory muscle weakness, restrictive lung disease


How to cite this article:
Krishna Chaitanya PS, Suresh V, Mohan A, Sachan A. Respiratory dysfunction in hypothyroidism. J Clin Sci Res 2019;8:89-94

How to cite this URL:
Krishna Chaitanya PS, Suresh V, Mohan A, Sachan A. Respiratory dysfunction in hypothyroidism. J Clin Sci Res [serial online] 2019 [cited 2019 Dec 9];8:89-94. Available from: http://www.jcsr.co.in/text.asp?2019/8/2/89/270752




  Introduction Top


Hypothyroidism is widely prevalent all over the world including India. Decreased production of thyroid hormone is a key feature of the clinical state known as hypothyroidism. Decreased thyroid function despite adequate stimulation from the pituitary gland is known as primary hypothyroidism.[1],[2] It may be either subclinical or overt. Subclinical hypothyroidism is characterised by a serum thyroid-stimulating hormyone (TSH) above the upper reference limit in combination with a normal free thyroxin (fT4). An elevated TSH, in combination with a subnormal fT4 characterises overt primary hypothyroidism.[1] On the other hand, central or secondary hypothyroidism is caused by insufficient stimulation of normal thyroid gland and is the result of hypothalamic or pituitary disease or defects in the TSH molecule. Primary hypothyroidism is the aetiology in approximately in 99% of cases of hypothyroidism.

The incidence of overt hypothyroidism has been estimated to be 4.1/1000 women/year and 0.6/1000 men/year.[3] The prevalence of subclinical hypothyroidism in the developed world is about 4.3%–8.5%, while that of overt hypothyroidism ranges from 0.3% to 0.4%[4],[5] in unselected populations. However, in the elderly (i.e., >60 years of age), TSH levels >10 mIU/L consistent with significant hypothyroidism was present in 4.4% of the population.[6]

In India, studies[7],[8] have found hypothyroidism to be a common form of thyroid dysfunction. Prevalence of hypothyroidism in adults in India has been reported to be between 3.9%[7] and 10.95%.[8] The prevalence of previously undetected hypothyroidism was 3.47%.[8]


  Pulmonary Function In Hypothyroidism Top


Pulmonary manifestations are rarely a major problem in hypothyroid patients though several abnormalities in respiratory reserve function may be found. Pulmonary manifestations may range from mild dyspnoea to life-threatening respiratory failure.[9] There is also a high incidence of obstructive sleep apnoea (OSA) in untreated hypothyroidism.[10] Impaired ventilatory response to hypoxia and hypercapnia are noted in primary hypothyroidism.[11] Mild-to-severe diaphragmatic muscle dysfunction has also been reported in these patients,[12] Many patients with hypothyroidism complain of fatigue and dyspnoea on exertion.

There are also defects in spirometric indices in hypothyroidism in relation to that in controls.[13],[14],[15],[16] These are suggestive of a restrictive rather than an obstructive pathology and may result from interstitial oedema as a manifestation of myxoedema itself, as well as from the aforementioned respiratory muscle weakness.


  Obstructive Sleep Apnoea In Hypothyroidism Top


A study[10] involving 11 newly diagnosed patients with primary hypothyroidism demonstrated an increased incidence and frequency of OSA in hypothyroidism. Among the 11 patients, nine had a mean 71.8 (range 17–176) episodes of apnoea. Obesity was noted in six of the nine patients with sleep apnoea. On an average, obese patients had 99.5 episodes/hour compared with 16.3 episodes/hour in the 3 non-obese patients (P< 0.02). After levothyroxine replacement for 3–12 months, the authors noted a decrease in the mean apnoea frequency from 71.8 ± 18.0 (standard error of mean) to 12.7 ± 6; one episode/hour, without any change in the body weight.

On the other hand, in another study,[17] it was observed that sleep apnoea persisted in six out of eight patients who were followed-up despite restoration of euthyroid status (Apnoea Index before thyroxine, 51 ± 6 and Apnoea Index after thyroxine, 45 ± 8). They concluded that though Apnoea Index decreases following achievement of euthyroid state, the change was not clinically significant.

In a systematic review[18] on respiratory manifestations of hypothyroidism, that included 22 articles, it was observed that OSA was seen in 30% of newly diagnosed hypothyroidism and showed reversibility after adequate treatment.

A meta-analysis of 12 studies and 5 case reports[19] involving 192 patients with OSA and hypothyroidism and 1423 euthyroid patients with OSA showed that Apnoea–Hypopnoea Index, scores on Epworth Sleepiness Scale and the duration of sleep spent under conditions of oxygen desaturation were more in hypothyroid patients with OSA as compared to euthyroid patients with OSA. Overall, 8.12% ± 7.13% of OSA patients had overt hypothyroidism, while 11.07% ± 8.49% had subclinical hypothyroidism.


  Respiratory Drive in Hypothyroidism Top


Ventilatory responses to hypoxia and hypercapnia in 38 hypothyroid patients before treatment and after short-term (7 days) and long-term (12–24 weeks) thyroxin replacement therapy were studied.[11] At baseline, ventilatory responses to hypercapnia were blunted in 10 of 29 patients (34%) and ventilatory responses to hypoxia were abnormal in 8 of 30 patients (i.e., 27%). Hypothyroid women and those with markedly elevated TSH (>90 mIU/L) were more likely to have impaired ventilatory responses. There was a significant increase in ventilatory responses, both to hypoxia and to hypercapnia after just 7 days of thyroxin replacement. In 7 of 9 patients with abnormal hypercapnic ventilatory responses and 6 of 8 patients with abnormal hypoxic responses, normal ventilatory responsiveness was restored after 1 week of therapy. The authors concluded that a subset of hypothyroid patients have blunted ventilatory responses to hypoxia and hypercapnia and thyroid hormone therapy even for just 1 week reverses the impaired ventilatory responses to hypothyroidism.

A study[20] evaluated the abnormalities in ventilator control system in patients with severe hypothyroidism. The authors concluded that patients with severe hypothyroidism have alterations in the ventilator control system at the neural level as evidenced by reduced chemosensitivity to carbon dioxide and thyroxine replacement restores the response to hypercapnic stimulation.


  Respiratory Muscle Strength In Hypothyroidism Top


A study from Egypt[21] assessed the respiratory muscle function in patients with hypothyroidism and an equal number of euthyroid controls (n = 30). The author measured maximum inspiratory and expiratory pressures to assess the strength of inspiratory and expiratory muscles, respectively. There was a statistically significant reduction in both pressures in patients with hypothyroidism compared to euthyroid controls suggestive of respiratory muscle weakness in hypothyroidism.

To evaluate the effect of treatment of hypothyroidism on respiratory muscle strength, a before-after interventional study[22] was conducted. This study included a total of 43 patients with overt hypothyroidism, of which 15 were of idiopathic cause and 28 cases were iatrogenic. Iatrogenic cases had a history of thyroidectomy for papillary thyroid cancer at least 1 year before entry into the study. In these iatrogenic cases, thyroxine was stopped a minimum of 4 weeks prior to testing. To assess the respiratory muscle strength maximum inspiratory (PImax) and maximum expiratory pressures (PEmax) were measured at baseline and 3 months after thyroxine replacement. Mean PImax increased from 83 ± 25 cmH2O before treatment to 117 ± 98 cmH2O after 3 months of thyroxine replacement (P< 0.0001). Similarly, PEmax also rose from 79 ± 31 cmH2O before treatment to 115 ± 32 cm after treatment suggesting an increase in respiratory muscle strength.

A group of researchers[23] studied the control of breathing in patients who had previously undergone complete thyroidectomy for thyroid cancer and were subsequently exposed to a short period of primary hypothyroidism caused by withdrawal of suppressive thyroxin therapy for the purpose of a whole body radio-iodine scan as part of their follow-up evaluation for recurrence of thyroid carcinoma. The authors showed that short term primary hypothyroidism does not seem to be associated with blunted neural inspiratory output. Respiratory control system seems to be affected mostly at peripheral (muscular) level and thyroid hormone replacement increases both the force and velocity of inspiratory muscle contraction.

Respiratory muscle function was studied in male albino rats who were rendered hypothyroid by thyroidectomy.[24] There was a decrease in diaphragmatic muscle enzymes required to generate adenosine triphosphate, such as, fatty acid oxidation, glycolysis and tricarboxylic acid cycle pathway enzymes concomitant with an increase in alkali labile muscle fibres (slow twitch Type 1 muscle fibres). An increase in Type 1 muscle fibre in hypothyroidism was also reported by another group of investigators.[25] Another study[26] looked at the effect of hypothyroidism on rat diaphragmatic muscle fibres. Hypothyroidism decreased maximum specific force across all myosin heavy chain isoforms in the diaphragm muscle fibres, with the greatest decrease being noted in fibres expressing fast myosin heavy chain isoforms They noticed myosin heavy chain content per half-sarcomere was reduced in fibres expressing myosin heavy chain ×2 and/or myosin heavy chain 2B. Electron microscopy revealed a reduction in myofibrillar volume density and thick filament density.


  Hypothyroidism And Pleural Effusion Top


Hypothyroidism is known to be associated with pleural effusion. However, most of the effusions in hypothyroidism were due to other causes.[27] Hypothyroidism as a sole cause of pleural effusion was noted only in a few patients. Occurrence of pleural effusion may however be one of the causes for impaired lung function in hypothyroidism.


  Impact Of Thyroid Hormones On Alveolar Fluid Clearance And Surfactant Production Top


Tri-iodothyronine was seen to enhance alveolar fluid clearance in normal rat lungs and rat lungs with hypoxic lung injury.[28] It also enhance the production of phosphatidylcholine (pulmonary surfactant) in fetal rabbit lung.[29] It improves the morphogenesis of lung histological structures with development of basal lamina, Type 2 pneumocytes and alveolar-like lumen in foetal rat lung.[30] Both the clinical and embryological significance of these effects of thyroxin on alveoli are not currently known.


  Hypothyroidism And Interstitial Lung Disease Top


Turkish investigators[31] studied the association of interstitial lung disease (ILD) with autoimmune thyroid disease. A total of 24 cases with the diagnosis of ILD were included. They performed thyroid function tests, thyroid auto-antibodies and thyroid ultrasonography in all cases. Autoimmune thyroiditis was noted in 15 patients (62.5%). This study showed that autoimmune thyroiditis was prevalent widely in patients with ILD.

Researchers[32] studied the association between hypothyroidism and idiopathic pulmonary fibrosis (IPF). This study included 196 cases with IPF and 196 controls with chronic obstructive pulmonary disease. The prevalence of hypothyroidism was found to be 16.8% in cases compared to 7.1% in controls (P = 0.004). They also observed that patients with IPF and hypothyroidism were found to have a significantly lower mean diffusion capacity of the lung for carbon monoxide (DLCO; % predicted) compared to those with IPF alone. Hypothyroidism was also independently predictive of mortality in this study.


  Spirometry In Hypothyroidism Top


Researchers in Turkey[13] studied spirometric parameters in patients with clinical and subclinical hypothyroidism. The study included 87 patients with clinical hypothyroidism, 120 (114 women) patients with subclinical hypothyroidism and 60 (51 women) healthy subjects. The comparison between clinical hypothyroidism and control group demonstrated that all of spirometric parameters were higher in control group but only the differences in forced vital capacity (FVC), observed FVC as a percentage of predicted FVC (FVC%), forced expiratory volume in the first second (FEV1) and the maximum mid-expiratory flow rate forced expiratory flow (FEF25%–75%) reached statistical significance (P< 0.05). When subclinical hypothyroidism was compared with the control group, spirometric parameters were higher in the control group, and there was a statistically significant difference regarding FVC, FVC%, FEV1 and FEF25%–75%(P< 0.05) between the two groups. FEV1/FVC ratio was comparable across all the three groups (i.e., clinical hypothyroidism, subclinical hypothyroidism and healthy controls). These findings are consistent with a restrictive pulmonary defect.

A study from Kolkata[14] evaluated pulmonary function by spirometry in Indian patients with primary hypothyroidism in comparison with healthy controls. It was a cross-sectional single centre study in a tertiary care centre comprising 55 hypothyroid and 55 age- and sex-matched controls. They observed a highly significant decrease in FVC (1.71 ± 0.45 L) and FEV1(1.55 ± 0.40 L) in hypothyroids when compared with FVC (3.11 ± 0.35 L) and FEV1(2.45 ± 0.31 L) in controls, while the FEV1/FVC ratio was actually higher in patients than controls. Again this is also suggestive of a restrictive pathology. They also found a significant positive correlation between fT4 with each of the following: FVC, FEV1 and FEV1/FVC ratio.

A group of investigators[15] compared spirometry between 21 hypothyroid patients with TSH >10 mIU/L with 21 healthy controls. Only the FVC was lower in patients with hypothyroidism, while all other spirometric parameters were similar across the two groups. T4 in hypothyroid patients was positively correlated to each of FVC, FEV1 and the FEV1/FVC ratio, while the TSH was negatively correlated to each of these three parameters. Another group[16] reported that FVC, FVC%, FEV1 and FEV1% were lower in 20 patients with clinical hypothyroidism in comparison to 20 healthy controls. The FEV1/FVC ratio was similar between the two groups.

A cross-sectional study[33] was conducted to know the effect of hypothyroidism on spirometric parameters in patients with hypothyroidism. The study included three groups, Group A comprising 31 patients with clinical hypothyroidism, Group B comprising 30 patients with subclinical hypothyroidism and Group C comprising 27 healthy controls. Spirometry was performed in all the three groups. They found that the mean percentage predicted values of the spirometric variables FVC and FEV1 were significantly lower in hypothyroid patients (clinical and subclinical) when compared to healthy controls. They also noted that FVC and FEV1 were significantly lower in group A compared with Groups B and C.

In a case-control study,[34] to determine the effects of hypothyroidism on pulmonary function, 42 patients with overt hypothyroidism and 12 age- and gender-matched controls were included. In all the patients and controls, arterial blood gases, resting spirometry, DLCO, gas exchange values and exercise parameters were measured. The authors noticed a significant reduction in FVC and DLCO in hypothyroid patients compared to controls. Comparison of exercise parameters between hypothyroid patients and controls revealed a significant reduction in oxygen consumption (VO2), carbon dioxide output (VCO2), minute ventilation, tidal volume and oxygen pulse in hypothyroid patients.

A cross-sectional study[21] was conducted in Egypt to assess the functional abnormalities of the respiratory system in thyroid disorders. The study included 30 patients with hypothyroidism and an equal number of euthyroid healthy controls. All the patients underwent spirometry to measure FVC, FEV1, FEV1/FVC, FEF25%–75% and peak expiratory flow rate (PEFR). DLCO was measured in all the patients. Respiratory symptoms were more frequent among hypothyroid patients compared to euthyroid patients. They also noted a decrease in FVC, FEV1, FEV25%–75% and PEFR in patients with hypothyroidism compared with normal euthyroid controls. DLCO was also lower in hypothyroidism group compared with euthyroid controls.

A cross-sectional study[35] from Kerala attempted to assess the effects of hypothyroidism on pulmonary function tests. Their study included 60 patients with overt hypothyroidism in whom spirometry was performed and the observed values of spirometric parameters were compared with predicted values of same spirometric parameters. This showed a lower than predicted value for FVC, FEV1, FEV25%–75% and PEFR.

[Table 1] summarises the findings in the above studies. As can be seen, most studies showed low FVC in patients as compared to controls, while the FEV1/FVC ratio was similar between patients and controls. These findings are consistent with a restrictive pathology on spirometry.
Table 1: Comparison of spirometric parameters in patients with overt hypothyroidism and healthy controls in various studies

Click here to view



  Effect Of Treatment Of Hypothyroidism On Spirometry Top


Investigators[36] studied the effects of thyroid hormone replacement on respiratory function test in hypothyroid women. This was a cross-sectional study and included three groups of patients. Group 1 consisted of 26 recently diagnosed hypothyroid women, Group 2 included 22 women with hypothyroidism on thyroxine replacement for the last 6–8 months while Group 3 consisted of 25 apparently euthyroid patients. Spirometric variables including FVC, FEV1, FEV1/FVC and PEFR were measured in all the three groups. All the spirometric parameters except FEV1/FVC showed a significant decrease in untreated hypothyroid compared to treated hypothyroid patients and euthyroid controls.

Pulmonary function tests, including FVC, FEV1 and FEV1/FVC, were performed at baseline and 3 months after thyroxine replacement[22] in an intervention study. In this study, the mean lung volumes FVC and FEV1 increased significantly following thyroxin replacement, whereas FEV1/FVC ratio did not show any change.

In another interventional study,[37] the effects of levothyroxine on pulmonary function tests in patients with hypothyroidism before and after treatment were investigated. Thirty patients (24 females) were included in the study. At baseline, 16 patients had mild and 10 patients had moderate restrictive pulmonary abnormalities while 4 patients had a normal spirometry. After 3 months of euthyroid state, the results of spirometry were normal in 12 patients, with mild restrictive abnormalities in 14 and moderate restrictive abnormality in 4 patients. They noticed a significant increase in FEV1, FVC and FEF25%–75%, after treatment with levothyroxine (P< 0.05). There were no changes in FEV1/FVC ratio post-treatment. The above results are summarised in [Table 2].
Table 2: Comparison of spirometric parameters in patients with overt hypothyroidism before and after restoration of euthyroid status in prospective studies

Click here to view


The above two studies show that while lung volumes and flow rates may improve with thyroxin treatment in hypothyroid patients, there is no change in the ratio of FEV1 to the FVC, thereby suggesting again that the predominant effect of hypothyroidism is restrictive rather than obstructive and also that this restrictive defect can be ameliorated by treatment.

Hypothyroidism is associated with a predominantly restrictive pulmonary physiology on spirometry possibly due to the collection of glycosaminoglycans in the interstitium of the alveoli as a part of myxoedema or due to respiratory muscle weakness. However, this restrictive pathology shows improvement with thyroxin replacement.[35] An impaired ventilator drive and OSA are other features of hypothyroidism. In a systematic review,[18] it was suggested that as most studies had small number of patients and many were uncontrolled, and there were issues with randomisation and blinding, it is difficult to draw firm conclusions from the rather limited data. The impact of thyroid hormones on pulmonary function and respiratory drive continue to be important areas for future research.

Financial support and sponsorship

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Conflicts of interest

There are no conflicts of interest.



 
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[PUBMED]  [Full text]  
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Introduction
Pulmonary Functi...
Obstructive Slee...
Respiratory Driv...
Respiratory Musc...
Hypothyroidism A...
Impact Of Thyroi...
Hypothyroidism A...
Spirometry In Hy...
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