COVID-19 and thyroid function: What do we know so far?

Abstract

Coronavirus disease 2019 (COVID-19) was characterized as a pandemic in March, 2020 by the World Health Organization. COVID-19 is a respiratory syndrome that can progress to acute respiratory distress syndrome, multiorgan dysfunction, and eventually death. Despite being considered a respiratory disease, it is known that other organs and systems can be affected in COVID-19, including the thyroid gland. Thyroid gland, as well as hypothalamus and pituitary, which regulate the functioning of most endocrine glands, express angiotensin-converting enzyme 2 (ACE2), the main protein that functions as a receptor to which SARS-CoV-2 binds to enter host cells. In addition, thyroid gland is extremely sensitive to changes in body homeostasis and metabolism. Immune system cells are targets for thyroid hormones and T3 and T4 modulate specific immune responses, including cell-mediated immunity, natural killer cell activity, the antiviral action of interferon (IFN) and proliferation of T- and B-lymphocytes. However, studies show that patients with controlled hypothyroidism and hyperthyroidism do not have a higher prevalence of COVID-19, nor do they have a worse prognosis when infected with the virus. On the other hand, retrospective observational studies, prospective studies, and case reports published in the last two years reported abnormal thyroid function related to acute SARS-CoV-2 infection or even several weeks after its resolution. Indeed, a variety of thyroid disorders have been documented in COVID-19 patients, including non-thyroidal illness syndrome (NTIS), subacute thyroiditis and thyrotoxicosis. In addition, thyroid disease has already been reported as a consequence of the administration of vaccines against SARS-CoV-2. Overall, the data revealed that abnormal thyroid function may occur during and in the convalescence post-COVID condition phase. Although the cellular and molecular mechanisms are not completely understood, the evidence suggests that the "cytokine storm" is an important mediator in this context. Thus, future studies are needed to better investigate the pathophysiology of thyroid dysfunction induced by COVID-19 at both molecular and clinical levels.

Keywords: COVID-19; NTIS; SARS-CoV-2; hyperthyroidism; hypothyroidism; non-thyroidal illness syndrome; subacute thyroiditis.

Figure 1

SARS-Cov-2 infection affects and damages a wide-ranging of human organs and systems. The manifestation of endocrine disorders, including thyroid-related pathologies, have been diagnosed in COVID-19 patients, suggesting a possible causal relationship between these conditions.

Figure 2

Mechanistic insights into COVID-19-induced Non-thyroidal illness syndrome (NTIS). Multiple mechanisms might be involved in the pathogenesis of NTIS. During severe illness, the hypothalamus-pituitary-thyroid (HPT) axis is profoundly affected, which is primarily mediated by pro-inflammatory cytokines. In the hypothalamus, illness promotes TRH downregulation due to abnormal T3-induced negative feedback. Potential mechanisms involved include increased local T3 production by D2 and increased expression in TH transporters (MCT10 and OATP1C1). At the pituitary level, illness impairs TSH response to low levels of circulating T₃ and T_4, which can be secondary to reduced TRH levels or the direct effect of pro-inflammatory cytokines. Modulation of deiodinase activity might be additionally involved. Cytokines also inhibit multiple steps of TH biosynthesis and D1 activity in the thyroid gland, decreasing hormonal synthesis and secretion. In other peripheral tissues, suppressed D1 and increased D3 expression/activity could contribute to low T₃ and high rT₃ levels observed in sick individuals.

Figure 3

The course of Subacute Thyroiditis (SAT). Subacute Thyroiditis is a self-limited inflammatory disorder of the thyroid gland that often follows a viral infection. The damage and rupture of follicular cells, caused by the inflammatory process, results in the release of T₃ and T₄ in circulation, inducing thyrotoxicosis symptoms in the first weeks of disease. When extensive follicular destruction occurs, subacute thyroiditis can progress to hypothyroidism before returning to the euthyroid state.