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

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.

The prognostic utility of serum thyrotropin in hospitalized Covid-19 patients: statistical and machine learning approaches.

PURPOSE: To assess the prognostic value of serum TSH in Greek patients with COVID-19 and compare it with that of commonly used prognostic biomarkers. METHODS: Retrospective study of 128 COVID-19 in patients with no history of thyroid disease. Serum TSH, albumin, CRP, ferritin, and D-dimers were measured at admission. Outcomes were classified as "favorable" (discharge from hospital) and "adverse" (intubation or in-hospital death of any cause). The prognostic performance of TSH and other indices was assessed using binary logistic regression, machine learning classifiers, and ROC curve analysis. RESULTS: Patients with adverse outcomes had significantly lower TSH compared to those with favorable outcomes (0.61 versus 1.09 mIU/L, p < 0.001). Binary logistic regression with sex, age, TSH, albumin, CRP, ferritin, and D-dimers as covariates showed that only albumin (p < 0.001) and TSH (p = 0.006) were significantly predictive of the outcome. Serum TSH below the optimal cut-off value of 0.5 mIU/L was associated with an odds ratio of 4.13 (95% C.I.: 1.41-12.05) for adverse outcome. Artificial neural network analysis showed that the prognostic importance of TSH was second only to that of albumin. However, the prognostic accuracy of low TSH was limited, with an AUC of 69.5%, compared to albumin's 86.9%. A Naïve Bayes classifier based on the combination of serum albumin and TSH levels achieved high prognostic accuracy (AUC 99.2%). CONCLUSION: Low serum TSH is independently associated with adverse outcome in hospitalized Greek patients with COVID-19 but its prognostic utility is limited. The integration of serum TSH into machine learning classifiers in combination with other biomarkers enables outcome prediction with high accuracy.

Thyrotropin Levels in Patients with Coronavirus Disease 2019: Assessment during Hospitalization and in the Medium Term after Discharge.

BACKGROUND: The objectives of this study were (1) to compare TSH levels between inpatients with critical versus non-critical coronavirus disease 19 (COVID-19), and (2) to describe the status of TSH levels three months after hospitalization. METHODS: We collected data on adult patients hospitalized with COVID-19 at Amiens University Hospital. We compared TSH levels between inpatients with critical (intensive care unit admission and/or death) versus non-critical COVID-19. Thereafter, survivors were invited to return for a three-month post-discharge visit where thyroid function tests were performed, regardless of the availability of TSH measurement during hospitalization. RESULTS: Among 448 inpatients with COVID-19, TSH assay data during hospitalization were available for 139 patients without prior thyroid disease. Patients with critical and non-critical forms of COVID-19 did not differ significantly with regard to the median (interquartile range) TSH level (0.96 (0.68-1.71) vs. 1.27 mIU/L (0.75-1.79), p = 0.40). Abnormal TSH level was encountered in 17 patients (12.2%); most of them had subclinical thyroid disease. TSH assay data at the three-month post-discharge visit were available for 151 patients without prior thyroid disease. Only seven of them (4.6%) had abnormal TSH levels. Median TSH level at the post-discharge visit was significantly higher than median TSH level during hospitalization. CONCLUSIONS: Our findings suggest that COVID-19 is associated with a transient suppression of TSH in a minority of patients regardless of the clinical form. The higher TSH levels three months after COVID-19 might suggest recovery from non-thyroidal illness syndrome.

SARS-COV-2 INFECTION AND THYROID DISEASES

The severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) virus, was identified as the cause of a pandemic of respiratory illness in Wuhan, China one year ago. The Coronavirus disease 2019 (COVID-19), may cause mild disease with nonspecific signs and symptoms such as fever, cough, myalgia, and fatigue, or severe pneumonia with respiratory failure and sepsis. However, endocrinological manifestations are yet to be established, in patients with COVID-19. The effect of COVID-19 on thyroid function is unknown at this time. Evidence support that patients with COVID-19 who are followed up in intensive care units may develop thyroid dysfunction as a non-thyroidal illness syndrome. Until now, twenty-two cases with subacute thyroiditis and five cases with Graves’ Diseases potentially associated with SARS-CoV-2 infection have been reported in literature. Physicians should be aware of possible relationships between thyroid dysfunction and COVID-19. This study aimed to review thyroid dysfunction in patients with COVID-19, and to overview thyroid diseases that are probably related to COVID-19. © 2021 Universidad Compultense Madrid. All right reserved.

Suppression of the hypothalamic-pituitary-thyroid axis is associated with the severity of prognosis in hospitalized patients with COVID-19.

BACKGROUND: The outbreak of severe acute respiratory syndrome novel coronavirus 2 (SARS-CoV-2) has spread rapidly worldwide. SARS-CoV-2 has been found to cause multiple organ damage; however, little attention has been paid to the damage to the endocrine system caused by this virus, and the subsequent impact on prognosis. This may be the first research on the hypothalamic-pituitary-thyroid (HPT) axis and prognosis in coronavirus disease 2019 (COVID-19). METHODS: In this retrospective observational study, 235 patients were admitted to the hospital with laboratory-confirmed SARS-CoV-2 infection from 22 January to 17 March 2020. Clinical characteristics, laboratory findings, and treatments were obtained from electronic medical records with standard data collection forms and compared among patients with different thyroid function status. RESULTS: Among 235 patients, 17 (7.23%) had subclinical hypothyroidism, 11 (4.68%) severe non-thyroidal illness syndrome (NTIS), and 23 (9.79%) mild to moderate NTIS. Composite endpoint events of each group, including mortality, admission to the ICU, and using IMV were observed. Compared with normal thyroid function, the hazard ratios (HRs) of composite endpoint events for mild to moderate NTIS, severe NTIS, subclinical hypothyroidism were 27.3 (95% confidence interval [CI] 7.07-105.7), 23.1 (95% CI 5.75-92.8), and 4.04 (95% CI 0.69-23.8) respectively. The multivariate-adjusted HRs for acute cardiac injury among patients with NTF, subclinical hypothyroidism, severe NTIS, and mild to moderate NTIS were 1.00, 1.68 (95% CI 0.56-5.05), 4.68 (95% CI 1.76-12.4), and 2.63 (95% CI 1.09-6.36) respectively. CONCLUSIONS: Our study shows that the suppression of the HPT axis could be a common complication in COVID-19 patients and an indicator of the severity of prognosis. Among the three different types of thyroid dysfunction with COVID-19, mild to moderate NTIS and severe NTIS have a higher risk of severe outcomes compared with subclinical hypothyroidism.

Non-thyroidal illness syndrome and SARS-CoV-2-associated multisystem inflammatory syndrome in children.

PURPOSE: COVID-19 disease may result in a severe multisystem inflammatory syndrome in children (MIS-C), which in turn may alter thyroid function (TF). We assessed TF in MIS-C, evaluating its impact on disease severity. METHODS: We retrospectively considered children admitted with MIS-C to a single pediatric hospital in Milan (November 2019-January 2021). Non-thyroidal illness syndrome (NTIS) was defined as any abnormality in TF tests (FT3, FT4, TSH) in the presence of critical illness and absence of a pre-existing hormonal abnormality. We devised a disease severity score by combining severity scores for each organ involved. Glucose and lipid profiles were also considered. A principal component analysis (PCA) was performed, to characterize the mutual association patterns between TF and disease severity. RESULTS: Of 26 (19 M/7F) patients, median age 10.7 (IQR 5.8-13.3) years, 23 (88.4%) presented with NTIS. A low FT3 level was noted in 15/23 (65.3%), while the other subjects had varying combinations of hormone abnormalities (8/23, 34.7%). Mutually correlated variables related to organ damage and inflammation were represented in the first dimension (PC1) of the PCA. FT3, FT4 and total cholesterol were positively correlated and characterized the second axis (PC2). The third axis (PC3) was characterized by the association of triglycerides, TyG index and HDL cholesterol. TF appeared to be related to lipemic and peripheral insulin resistance profiles. A possible association between catabolic components and severity score was also noted. CONCLUSIONS: A low FT3 level is common among MIS-C. TF may be useful to define the impact of MIS-C on children's health and help delineate long term follow-up management and prognosis.

Thyroid dysfunction in COVID-19 patients.

PURPOSE: "Non thyroidal illness syndrome" (NTIS) or "euthyroid sick syndrome" (ESS) is a possible biochemical finding in euthyroid patients with severe diseases. It is characterized by a reduction of serum T3 (fT3), sometimes followed by reduction of serum T4 (fT4). The relationship between thyroid hormones levels and mortality is well known and different studies showed a direct association between NTIS and mortality. The sudden spread of the 2019 novel coronavirus (SARS-CoV 2) infection (COVID-19) and its high mortality become a world healthcare problem. Our aim in this paper was to investigate if patients affected by COVID-19 presented NTIS and the relationship between thyroid function and severity of this infection. METHODS: We evaluated the thyroid function in two different groups of consecutive patients affected by COVID-19 with respect to a control group of euthyroid patients. Group A included patients hospitalized for COVID-19 pneumonia while patients requiring intensive care unit (ICU) for acute respiratory syndrome formed the group B. Group C identified the control group of euthyroid patients. RESULTS: Patients from group A and group B showed a statistically significant reduction in fT3 and TSH compared to group C. In group B, compared to group A, a further statistically significant reduction of fT3 and TSH was found. CONCLUSIONS: COVID-19 in-patients can present NTIS. FT3 and TSH serum levels are lower in patients with more severe symptoms.

Prognostic significance of low TSH concentration in patients with COVID-19 presenting with non-thyroidal illness syndrome.

BACKGROUND: Low free triiodothyronine (FT3) levels are related to a poor prognosis deterioration in patients with COVID-19 presenting with non-thyroidal illness syndrome (NTI). This study was designed to explore whether free thyroxin (FT4) or thyroid stimulating hormone (TSH) levels affected the mortality of patients with COVID-19 presenting with NTI. METHODS: Patients with COVID-19 complicated with NTI who were treated at our hospital were included in this retrospective study. Patients were divided into low TSH and normal TSH groups, as well as low and normal-high FT4 group, according to the reference range of TSH or FT4 levels. The 90-day mortality and critical illness rates were compared among patients with low and normal TSH levels, as well as among patients with low FT4 levels and normal-high FT4 levels; in addition, differences in demographic and laboratory data were compared. A Kaplan-Meier analysis and Cox proportional hazards models were used to assess the associations of TSH and FT4 levels with mortality. RESULTS: One hundred fifty patients with low FT3 levels and without a history of thyroid disease were included, 68% of whom had normal FT4 and TSH levels. Critical illness rates (74.07% VS 37.40%, P = 0.001) and mortality rates (51.85% VS 22.76%, P = 0.002) were significantly higher in the low TSH group than in the normal TSH group. Although no significant difference in the critical illness rate was found (P = 0.296), the mortality rate was significantly higher in the low FT4 group (P = 0.038). Low TSH levels were independently related to 90-day mortality (hazard ratio = 2.78, 95% CI:1.42-5.552, P = 0.003). CONCLUSIONS: Low FT4 and TSH concentrations were associated with mortality in patients with COVID-19 presenting with NTI; moreover, low TSH levels were an independent risk factor for mortality in these patients.

Physiological Role and Use of Thyroid Hormone Metabolites - Potential Utility in COVID-19 Patients.

Thyroxine and triiodothyronine (T3) are classical thyroid hormones and with relatively well-understood actions. In contrast, the physiological role of thyroid hormone metabolites, also circulating in the blood, is less well characterized. These molecules, namely, reverse triiodothyronine, 3,5-diiodothyronine, 3-iodothyronamine, tetraiodoacetic acid and triiodoacetic acid, mediate both agonistic (thyromimetic) and antagonistic actions additional to the effects of the classical thyroid hormones. Here, we provide an overview of the main factors influencing thyroid hormone action, and then go on to describe the main effects of the metabolites and their potential use in medicine. One section addresses thyroid hormone levels in corona virus disease 19 (COVID-19). It appears that i) the more potently-acting molecules T3 and triiodoacetic acid have shorter half-lives than the less potent antagonists 3-iodothyronamine and tetraiodoacetic acid; ii) reverse T3 and 3,5-diiodothyronine may serve as indicators for metabolic dysregulation and disease, and iii) Nanotetrac may be a promising candidate for treating cancer, and resmetirom and VK2809 for steatohepatitis. Further, the use of L-T3 in the treatment of severely ill COVID-19 patients is critically discussed.