key: cord-0710735-yqifs706
authors: Sadoughi, Fatemeh; Dana, Parisa Maleki; Hallajzadeh, Jamal; Asemi, Zatollah; Mansournia, Mohammad Ali; Yousefi, Bahman
title: Severe acute respiratory syndrome and thyroid: A molecular point of view
date: 2022-02-24
journal: Clin Nutr ESPEN
DOI: 10.1016/j.clnesp.2022.02.116
sha: 90d11baaad0489515afe7ba13a6d4b245a729d9b
doc_id: 710735
cord_uid: yqifs706

SARS-CoV-2 and some other members of Coronaviridae family have recently forced a great deal of health, social, and economic issues globally. To that end, investigations have been oriented towards finding ways for reducing the burden of COVID-19. One of the occurrences which stands in the way of making the treatment of this disease less complicated is the way coronaviruses involve a variety of cells, tissues, organs, and even systems. This action is possible as a result of viral attachment to the angiotensin-converting enzyme 2 or ACE2. Thus, any kind of cell expressing ACE2 is prone to be affected by both SARS-COV and SARS-COV-2. Endocrine system is one of these at-risk systems. In this review, we have considered the relation between coronaviruses and one of the most essential organs of endocrine system: thyroid gland. This relation can be probed from two aspects: how underlying thyroid dysfunction can increase the risk of being infected by these viruses and how these viruses can alter the function of thyroid gland.

COVID-19 is a severe disease clinically manifested by respiratory symptoms which is able to cause the death of 15.2% of total infected individuals after 2-8 weeks of the disease initiation (1) .

Recently, expanding the research domains on the effects of SARS-CoV-2 or 2019-nCoV on other tissues, organs, and systems then respiratory system has led to some significant results (2-4). The importance of these subsidiary-affected tissues, organs, and systems is in complicating the treatment process, decreasing the survival rate, and increasing the global economic burden.

Endocrine system is one of the pivotal players of regulating the homeostasis by providing chemical signals between a diversity of cells (5) . Thyroid gland as an essential component of this system is able to regulate the rate of metabolism by secreting a class of hormones including thyroxine (5) .

Currently, thyroid dysfunction has attracted a great deal of interest because of two reasons: first, its role in increasing the risk of being infected by SARS-CoV-2 as an underlying disease and second, occurring in individuals as a complication secondary to SARS-CoV-2 infection. In this paper, on the one hand, we reviewed a number of evidences manifesting the characteristics of COVID-19 patients in order to find the association between thyroid dysfunction, as a metabolic disease, and the risk of SARS-CoV-2 infection. On the other hand, we have looked into thyroidrelated diseases as a side effect of COVID-19. This review might give a new insight on prognostic testing and managing COVID-19 patients for a more qualified after-survival life and a lower chance of mortality.

Coronavirus, ACE2, and endocrine system According to our recent knowledge of coronaviruses, ACE2 takes a critical part in COVID-19 pathogenesis (6) . ACE2 or angiotensin-converting enzyme 2 is capable of binding to the spike protein of this member of Coronaviridae family (7) . In addition to the disease severity, this connection has also another disadvantage for the human body during SARS-CoV-2 infection:

decreased amounts of ACE2 on the cellular surface (7, 8) . The importance of this action can be understood after discussing the functions of ACE2 in a normal state. ACE2 is a homolog of ACE which has the ability to collate its actions by forming angiotensin (Ang) 1-7 from Ang II (9) .

This suggests that ACE2 is actually functioning as a regulator of the renin-angiotensin system or RAS (10) . Being involved in RAS is enabling this enzyme to have both local and systemic impacts, in addition to altering the performance of a diversity of our systems (11, 12) . we can classify the roles of ACE2 by the organs which are expressing this protein on their cells (organs including brain, heart, lung, testis, and kidneys (12)):

1. Heart and vasculture: decreasing blood pressure, making some changes in cardiac structure, preventing heart failure, and enhancing cardiac remodeling (13-19).

Interestingly, recent investigations have revealed a relation between ACE2 and another ingredient of the endocrine system: thyroid gland (27) . As reported by Li et al. ACE2 is expressed highly in some organs including thyroid gland. Furthermore, they revealed that there is a positive correlation between ACE2 expression and CD8+ T cell enrichment and interferon response in men (28) . Recently, Rotondi et al. has also detected that the mRNA of the ACE2 gene can be found in follicular cells of thyroid sample tissues (29) . Furthermore, a recent pilot study revealed that not only thyroid cells express ACE2 gene but this expression can also be modulated by IFN-γ and TNF-α (30) . On the other hand, thyroid hormones are also capable of activating RAS by influencing the levels of other proteins such as renin and angiotensinogen (31) . Overall, infection with SARS-CoV-2 might be related to metabolic diseases because of ACE2 endocytosis after the viral attachment.

Investigations manifesting the characteristics of COVID-19 patients identified some underlying conditions frequently repeated in these patients. Metabolic diseases seem to be a constant ingredient of these conditions (4, 32, 33) . However, still the booster impact of thyroid dysfunctions, as important metabolic diseases, on the risk of being infected by SARS-CoV-2 or its mortality rate needs deeper explorations. According to a report by Garg Furthermore, they also suggest that reduced TSH might be the consequence of two different effects of SARS-CoV-2: increasing the proinflammatory cytokines such as interleukin-6 and/or cortisol (41) . They were able to suggest the second mechanism by excluding the patients who were receiving exogenous steroids (41) . In contrast, a retrospective study represented "a high prevalence of overt and subclinical thyrotoxicosis in patients with COVID-19" which is probably correlated with the cytokine storm and IL-6 secretion in COVID-19 patients (42) .

Notwithstanding the limitations of this study, they suggested that destructive thyroiditis might be the reason why TSH and FT4 reduced due to SARS-CoV-2 infection (42) . This study disagreed with another previous study relating the low levels of TSH and TT3 to the non-thyroidal illness (NTI) (43) . On the other hand, there is an association between the time of viral nucleic acid cleaning and thyroid dysfunction which might strengthen the idea of direct viral infection (43) .

The non-thyroidal illness (NTI) hypothesis indicates that during a systemic illness, a total reduction can be observed in T3, T4, and TSH which is preserving energy in the body (44) . NTI is mediated through a variety of factors including circulating cytokines including IL-6 and TNFα. Considering the SARS-related cytokine storm, Croce and colleagues suggested that NTI is an J o u r n a l P r e -p r o o f explanation for thyroid dysfunction in COVID-19 patients (44) . Additionally, Chen and colleagues examined 50 patients and detected that "the degree of the decreases in TSH and TT3 levels was positively correlated with the severity of the disease" (45) . Recently, a review of reviews also declared that the most frequent thyroid dysfunction found in COVID-19 patients is non-thyroidal illness syndrome (36) .

What we have observed while considering SARS-associated studies is that there is no reliable can cause NTI, and fourth, reducing the number of ACE2 on the surface of thyroid cells might be disadvantageous. Still, these hypotheses need more investigations to be confirmed. Furthermore, the effects of immunotherapy and anti-coagulant drugs used for COVID-19 patients, increased cortisol secretion, and sick euthyroid syndrome (2) should be taken into consideration.

Finally, "The thyroid dysfunction seems to dynamically change within the course of disease and recover gradually and spontaneously" and therefore, therapeutic measurements in early stages might not be needed. In advanced patients, on the other hand, thyroid dysfunction is transient and after COVID-19 treatment, TSH levels get back to normal, thus it seems that treatment might be necessary only in patients with specific indicators of a serious thyroid disease.

J o u r n a l P r e -p r o o f

Real estimates of mortality following COVID-19 infection. The Lancet infectious diseases. 2020. 2. Pal R, Banerjee M. COVID-19 and the endocrine system: Exploring the unexplored

COVID-19 and cardiovascular disease

Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? The Lancet Respiratory Medicine

The physiology of the endocrine system

Receptor recognition and cross-species infections of SARS coronavirus

Coronaviruses post-SARS: update on replication and pathogenesis

ACE2 -from the renin-angiotensin system to gut microbiota and malnutrition. Microbes and infection

A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1-9

Angiotensin-converting enzyme 2, angiotensin-(1-7) and Mas: new players of the renin-angiotensin system

ACE2 and vasoactive peptides: novel players in cardiovascular/renal remodeling and hypertension. Therapeutic advances in cardiovascular disease

Angiotensin-converting enzyme 2 is an essential regulator of heart function

Circulating ACE2 in Cardiovascular and Kidney Diseases

Expression of an angiotensin-(1-7)-producing fusion protein produces cardioprotective effects in rats

Deletion of angiotensin-converting enzyme 2 accelerates pressure overload-induced cardiac dysfunction by increasing local angiotensin II

Heart block, ventricular tachycardia, and sudden death in ACE2 transgenic mice with downregulated connexins

Onset of experimental severe cardiac fibrosis is mediated by overexpression of Angiotensin-converting enzyme 2

Loss of angiotensin-converting enzyme-2 leads to the late development of angiotensin II-dependent glomerulosclerosis. The American journal of pathology

Evidence for angiotensin-converting enzyme 2 as a therapeutic target for the prevention of pulmonary hypertension. American journal of respiratory and critical care medicine

Angiotensin converting enzyme-2 is protective but downregulated in human and experimental lung fibrosis. 23. Ferrario CM

Vasopeptidase inhibition and Ang-(1-7) in the spontaneously hypertensive rat

Myocardial infarction increases ACE2 expression in rat and humans

Increased ACE 2 and decreased ACE protein in renal tubules from diabetic mice: a renoprotective combination?

Renal ACE2 expression in human kidney disease

Angiotensin converting enzymes ACE and ACE2 in thyroid cancer progression

Expression of the SARS-CoV-2 cell receptor gene ACE2 in a wide variety of human tissues. Infectious diseases of poverty

Detection of SARS-COV-2 receptor ACE-2 mRNA in thyroid cells: a clue for COVID-19-related subacute thyroiditis

Modulation of ACE-2 mRNA by inflammatory cytokines in human thyroid cells: a pilot study

Renin-angiotensin-aldosterone (RAAS): The ubiquitous system for homeostasis and pathologies

Hospitalization rates and characteristics of patients hospitalized with laboratoryconfirmed coronavirus disease 2019-COVID-NET, 14 States

COVID-19, diabetes mellitus and ACE2: the conundrum. diabetes research and clinical practice

Preliminary estimates of the prevalence of selected underlying health conditions among patients with coronavirus disease 2019-United States

Thyroid disease in the time of COVID-19

Thyroid sequelae of COVID-19: a systematic review of reviews

Pathology of the thyroid in severe acute respiratory syndrome

Hypocortisolism in survivors of severe acute respiratory syndrome (SARS)

Organ distribution of severe acute respiratory syndrome (SARS) associated coronavirus (SARS-CoV) in SARS patients: implications for pathogenesis and virus transmission pathways

A pathological report of three

cases by minimally invasive autopsies. Zhonghua bing li xue za zhi= Chinese journal of pathology

Thyroid function before, during, and after COVID-19

Thyrotoxicosis in patients with COVID-19: the THYRCOV study

Resveratrol inhibits the tumor migration and invasion by upregulating TET1 and reducing TIMP2/3 methylation in prostate carcinoma cells. The Prostate

The cytokine storm and thyroid hormone changes in COVID-19

Thyroid function analysis in 50 patients with COVID-19: a retrospective study

Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus

The authors declare no conflict of interest.J o u r n a l P r e -p r o o f