The association of lymphocyte with hypothyroidism in obstructive sleep apnea

Obstructive sleep apnea is a condition in which the periodic collapse of the upper airway during sleep causes complete or partial airway obstruction, resulting in apnea and hypoventilation [1]. Studies have shown that the prevalence of OSA in the adult population is approximately 9%-38%, fluctuates between 13%-33% in men, and is approximately 6%-19% in the female population [2]. Nocturnal intermittent hypoxia can lead to exacerbation of neurologic, cardiovascular, endocrine-metabolic, and other systemic disorders, increasing the risk of death. [3] All-cause mortality in untreated patients with severe OSA (AHI > 30) was 3.8 times higher than in those without sleep apnea [4]. Studies have shown that common comorbidities of OSA are hypertension, arrhythmia, coronary artery disease, and diabetes [5]. This shows that OSA can cause a significant health hazard and disease burden.

Hypothyroidism is a common disorder of the endocrine system. In iodine-sufficient countries, the prevalence of clinical hypothyroidism is approximately 1% to 2% [6]. The prevalence of subclinical hypothyroidism has been reported to be 4%-20% in the adult population [7]. Hypothyroidism is most often caused by autoimmunity. In addition, thyroid surgery, radioactive iodine treatment, and related medications are essential causes of hypothyroidism [7, 8]. Chronic lymphocytic thyroiditis is an autoimmune disease of the thyroid gland and is the most common cause of hypothyroidism [8]. Hashimoto's thyroiditis (HT) is a familiar type of autoimmune thyroiditis characterized by T lymphocyte infiltration of target tissues. It mediates the process of target cell destruction and apoptosis, resulting in hypofunction of the target gland [9]. Th1 and Th17 lymphocytes have been shown to infiltrate thyroid tissue and mediate thyroid cell death in autoimmune thyroiditis [10].

Many previous studies have confirmed the close association between lymphocytes and hypothyroidism [9, 11]. Lymphocytes are involved in the process of hypothyroidism, especially in autoimmune diseases of the thyroid, such as Hashimoto's thyroiditis. However, the relationship between lymphocytes and hypothyroidism in patients with OSA is unclear. This study aimed to assess the association of lymphocytes with hypothyroidism in patients with OSA, which has not been studied previously.

Patients with OSA and hypothyroidism share common clinical manifestations, such as excessive daytime sleepiness, apathy, decreased cognitive function, obesity, and decreased libido [15]. Numerous studies have shown a strong correlation between OSA and hypothyroidism. For example, Jha A et al. reported a 30% prevalence of OSA in newly diagnosed hypothyroidism [16]. Sorensen et al. claimed the prevalence of OSA to be 25%-50% in patients with overt hypothyroidism [17]. In a meta-analysis, Zhang M et al. concluded that the prevalence of clinical hypothyroidism in OSA patients was 8.12 ± 7.13%, and the prevalence of subclinical hypothyroidism was 11.07 ± 8.49% [18]. This shows that there is a close association between OSA and hypothyroidism.

Studies have suggested that hypothyroidism can lead to OSA through the following mechanisms: 1) infiltration of soft tissues by mucopolysaccharides aggravates airway narrowing [19]; 2) muscle dysfunction leads to hypotonia of the respiratory muscles [20, 21]; and 3) a low metabolic rate leads to obesity, and further fat accumulation in the neck and abdomen causes obesity hypoventilation [22]. We similarly observed a higher BMI in the hypothyroid group than controls in the total OSA population (34.78 ± 8.99 vs 32.38 ± 7.79, p = 0.055), although there was no significant difference.

Studies have shown that intermittent hypoxia also appears to have a negative effect on thyroid function. Elevated plasma IL-6 levels and decreased IL-10 levels support the prevalent activation of Th1-type cytokine patterns in OSA patients, suggesting the presence of Th1 cell activation in OSA patients [23]. Cytokines secreted by Th1 cells are also common in patients with Hashimoto's thyroiditis [24], and peripheral Th1 cells are more abundant in patients with severe Hashimoto's thyroiditis [25]. In Hashimoto's thyroiditis, Th1 cells can mediate an autoimmune response in the thyroid, with intense inflammatory infiltration and further thyroid destruction [26].

In addition to Th1 cells, several studies have shown that Th17 is closely associated with OSA and hypothyroidism. The findings showed that the proportion of peripheral blood Th17 cells and the relative expression of RORγt mRNA (RORγt is a crucial nuclear transfer factor for Th17 cell differentiation and secretion of IL-17A, which induces differentiation and maturation of Th0 cells into Th17 cells.) were higher in OSA patients than in controls and correlated with the severity of OSA [27]. Similarly, Ye et al. found higher levels of Th17 cells in the peripheral blood of patients with severe OSA compared to the mild group and controls. This result suggests that increased Th17 cell differentiation correlates with OSA severity [28]. Serum IL-17A levels were elevated in OSA patients and positively correlated with AHI [29]. Furthermore, cytology experiments revealed that a hypoxic environment promotes Th17 cell differentiation [30]. Related studies suggest that intermittent hypoxia in OSA may promote increased differentiation of Th17 cells through the hypoxia-inducible factor 1 (HIF-1) and NF-κB pathways [27]. Similarly, in patients with HT, the number of Th17 lymphocytes and Th17 cytokines in the peripheral blood and thyroid were increased [31]. Horie et al. found increased Th17 cells in the thyroid gland in a mouse model of Hashimoto's thyroiditis, confirming the importance of Th17 cells in autoimmune thyroiditis [32].

Therefore, we speculated that lymphocytes might be involved in the process of hypothyroidism in patients with OSA. These findings suggest that intermittent hypoxia may induce lymphocyte activation and thus promote thyroid immune responses, which may contribute to hypothyroidism. Thus, intermittent hypoxia may be an important initiating factor in the development of hypothyroidism, but its intrinsic connection still needs to be further explored. The above findings imply that there may be a bidirectional effect between OSA and hypothyroidism, rather than just hypothyroidism, as we know it is able to cause OSA.

In the present study, we observed a prevalence of hypothyroidism of 4.46% in the OSA population. The prevalence in the male and female patient groups was 3.4% and 6.6%, respectively. Because subclinical hypothyroidism and overt clinical hypothyroidism are different stages of the same disease, the process from subclinical hypothyroidism to clinical hypothyroidism is a continuous progression of the disease [33]. It has been reported that approximately 2%-5% of patients with subclinical hypothyroidism may progress to overt hypothyroidism each year [33]. Therefore, in this study, we categorized subclinical hypothyroidism and hypothyroidism in the same group. We further found that lymphocyte levels were apparently higher in the hypothyroid group than in the euthyroid group, although the difference was insignificant in female OSA patients. Except for lymphocytes, ESS scores were significantly higher in patients with hypothyroidism than in the euthyroid group in the OSA population. Lymphocyte level and ESS score can be used as independent predictors of hypothyroidism in patients with OSA. In the subgroup analysis performed, it was found that the number of lymphocytes was distinctly higher in the hypothyroid group than in the control group in the OSA population younger than 60 years old and patients with mild to moderate OSA, and the difference was statistically significant. Based on the above subgroups, the optimal threshold for lymphocyte count for the diagnosis of hypothyroidism fluctuated between 2.5–2.6 (× 10*9/L) in the OSA population. These results indicate that lymphocyte count can be a valuable biomarker for identifying the presence of hypothyroidism in OSA patients. The prevalence of hypothyroidism in patients with OSA increases as the number of lymphocytes increases. Therefore, lymphocyte levels can be used to estimate a patient's risk of developing hypothyroidism in the future. However, further research is needed to validate these findings and explore the underlying mechanisms of this association.

It is well known that hypothyroidism is one of the risk factors for OSA. Several studies have shown that LT4 therapy can reduce or even eliminate nocturnal apnea for patients with sleep apnea in combination with hypothyroidism [17]. Levothyroxine replacement therapy in patients with OSA combined with subclinical hypothyroidism may reduce the tendency to sleep [34]. These results support the perspective that thyroid function should be investigated in all OSA patients, at least in those with a high risk of hypothyroidism.

There are several limitations to our study. First, some OSA patients were excluded from the study due to incomplete data, resulting in a reduced sample size. Second, because this study was a cross-sectional design, long-term follow-up of the subjects was unrealistic, so their stable thyroid function status could not be known. Third, we did not evaluate the effect of CPAP or hormone supplementation therapy on lymphocyte levels in patients, which requires a prospective interventional study. Fourth, Serum concentrations of serum thyroid peroxidase (TPO) and thyroglobulin antibodies were not further determined to assess the prevalence of autoimmune thyroid disease. Last but not least, this study failed to further analyze the role played by lymphocyte subtypes and cytokines in hypothyroidism in patients with OSA.

In brief, the present study aimed to assess the correlation between lymphocyte count and hypothyroidism in patients with OSA. Based on our findings, lymphocyte levels tend to be higher in patients with OSA who also have hypothyroidism, and this association is particularly significant in the overall OSA population and male patients. Furthermore, we discovered that lymphocyte count independently predicts the development of hypothyroidism in patients with OSA, which has not been previously reported. Therefore, a simple blood test for lymphocyte count could indicate the occurrence of hypothyroidism in OSA patients, proving valuable in clinical practice.