Thyroid dysfunction in the wake of Omicron: understanding its role in COVID-19 severity and mortality.

Purpose: SARS-CoV-2 can invade the thyroid gland. This study was to delineate the risk of thyroid dysfunction amidst the prevalence of the Omicron variant, and to investigate the correlation between thyroid function and Coronavirus disease 2019 (COVID-19) outcomes. The study also aimed to ascertain whether thyroid dysfunction persisted during COVID-19 recovery phase. Methods: This was a retrospective cohort study. COVID-19 patients from the Renmin Hospital of Wuhan University, China during the epidemic of Omicron variants were included, and their thyroid function were analyzed in groups. Results: A history of thyroid disease was not associated with COVID-19 outcomes. COVID-19 can lead to a bimodal distribution of thyroid dysfunction. The severity of COVID-19 was inversely proportional to the levels of thyroid- stimulating hormone (TSH), free triiodothyronine (FT3) and free thyroxine (FT4), leading to a higher prevalence of thyroid dysfunction. Severe COVID-19 was a risk factor for euthyroid sick syndrome (ESS) (OR=22.5, 95% CI, 12.1 - 45.6). Neutrophil to lymphocyte ratio mediated the association between severe COVID-19 and ESS (mediation effect ratio = 41.3%, p < 0.001). ESS and decreased indicators of thyroid function were associated with COVID-19 mortality, while high levels of FT3 and FT4 exhibited a protective effect against death. This effect was more significant in women (p < 0.05). During the recovery period, hyperthyroidism was quite uncommon, while a small percentage of individuals (7.7%) continued to exhibit hypothyroidism. Conclusion: COVID-19 severity was linked to thyroid dysfunction. Severe COVID-19 increased the risk of ESS, which was associated with COVID-19 mortality. Post-recovery, hyperthyroidism was rare, but some individuals continued to have hypothyroidism.

Assessment of thyroid function of newly diagnosed SARS-CoV-2 infected patients in Nigeria.

INTRODUCTION: the outbreak and rapid spread of the novel SARS-CoV-2, the causative agent of the coronavirus disease 2019 (COVID-19), has evolved into an unprecedented global pandemic. The infection impairs several human organs and systems, however, it is not clear how it affects thyroid function. The study therefore aimed at measuring plasma levels of thyroid hormones and Hs-CRP in COVID-19 patients and apparently healthy uninfected controls to assess the possible effect of SAR-CoV-2 infection on thyroid function. METHODS: in this cross-sectional study carried out between May-August 2020, 90 consenting participants comprising 45 COVID-19 patients and 45 apparently healthy uninfected controls were recruited. Plasma FT3, FT4, TSH and Hs-CRP were measured using Enzyme Linked Immunosorbent Assay (ELISA) method. Data was analysed using SPSS version 20 and statistical significance set at p < 0.05. RESULTS: the mean plasma FT3 and TSH concentrations were significantly higher in COVID-19 patients compared to controls (p < 0.001, p < 0.001 respectively). Euthyroidism was observed in all uninfected controls, whereas 35 (77.8%) COVID-19 patients were euthyroid. Sick euthyroid and subclinical hypothyroidism was observed in 7 (15.6%) and 3 (6.7%) COVID-19 patients, respectively. CONCLUSION: though there was a preponderance of euthyroidism among COVID-19 patients, significantly higher mean plasma levels of TSH and FT3, sick euthyroid syndrome and subclinical hypothyroidism observed among some COVID-19 patients may be indicative of disease-related thyroid function changes. Hence, there is need to pay attention to thyroid function during and after treatment of COVID-19.

Coronavirus Disease 2019 and the Thyroid - Progress and Perspectives.

SARS-CoV-2 infection (COVID-19) is currently a tremendous global health problem. COVID-19 causes considerable damage to a wide range of vital organs most prominently the respiratory system. Recently, clinical evidence for thyroidal insults during and after COVID-19 has been accumulated. As of today, almost all non-neoplastic thyroid diseases, i.e., Graves' disease, Hashimoto's thyroiditis, subacute, painless and postpartum thyroiditis, have been reported as a complication of COVID-19, and causality by the virus has been strongly implicated in all of them. Similar thyroid problems have been reported in the past with the SARS-CoV outbreak in 2002. In this review, we briefly look back at the reported evidence of alteration in thyroid functionality and thyroid diseases associated with SARS-CoV and then proceed to examine the issue with COVID-19 in detail, which is then followed by an in-depth discussion regarding a pathogenetic link between Coronavirus infection and thyroid disease.

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.

SARS-COV-2-related immune-inflammatory thyroid disorders: facts and perspectives.

Introduction: During the COVID-19 pandemic thyroid gland alteration/dysfunction has been emerged as a possible endocrine complication. The present review is focused on inflammatory and autoimmune thyroid complications triggered by SARS-CoV-2 infection by searching through databases like MEDLINE and Scopus up to April 2021.Areas covered: Beside the occurrence of 'non-thyroidal illness' in severe clinical conditions, alterations of thyroid function and structure may occur during COVID-19 as a consequence of either direct or indirect effects of SARS-CoV-2 infection on the gland. On the one hand, SARS-CoV-2 uses ACE2 as a receptor to infect the host cells and ACE2 is highly expressed by follicular thyroid cells. On the other hand, COVID-19 is associated with a systemic inflammatory and immune response, involving Th1/Th17/Th2 lymphocytes and proinflammatory cytokines, which resembles the immune activation that occurs in immune-mediated thyroid diseases. COVID-19-related thyroid disorders include destructive thyroiditis and onset or relapse of autoimmune thyroid disorders, leading to a broad spectrum of thyroid dysfunction ranging from thyrotoxicosis to hypothyroidism, that may worsen COVID-19 clinical course and affect prognosis.Expert opinion: Physicians should be aware of the possible occurrence of thyroid dysfunction during and after SARS-CoV-2 infection. Further longitudinal studies are warranted to evaluate potential long-term sequelae.

Cell and Molecular Biology of Thyroid Disorders 2.0.

This issue is the second volume of the previous Special Issue, "Cell and Molecular Biology of Thyroid Disorders" [...].

The Independent Association of TSH and Free Triiodothyronine Levels With Lymphocyte Counts Among COVID-19 Patients.

Background: Both lymphopenia and thyroid dysfunction are commonly observed among COVID-19 patients. Whether thyroid function independently correlates with lymphocyte counts (LYM) remains to be elucidated. Methods: We included consecutive adults without known thyroid disorder admitted to Queen Mary Hospital for COVID-19 from July 2020 to April 2021 who had thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3) and LYM measured on admission. Results: A total of 541 patients were included. Median LYM was 1.22 x 109/L, with 36.0% of the cohort lymphopenic. 83 patients (15.4%) had abnormal thyroid function tests (TFTs), mostly non-thyroidal illness syndrome (NTIS). Patients with lymphopenia had lower TSH, fT4 and fT3 levels than those without. Multivariable stepwise linear regression analysis revealed that both TSH (standardized beta 0.160, p<0.001) and fT3 (standardized beta 0.094, p=0.023), but not fT4, remained independently correlated with LYM, in addition to age, SARS-CoV-2 viral load, C-reactive protein levels, coagulation profile, sodium levels and more severe clinical presentations. Among the 40 patients who had reassessment of TFTs and LYM after discharge, at a median of 9 days from admission, there were significant increases in TSH (p=0.031), fT3 (p<0.001) and LYM (p<0.001). Furthermore, patients who had both lymphopenia and NTIS were more likely to deteriorate compared to those who only had either one alone, and those without lymphopenia or NTIS (p for trend <0.001). Conclusion: TSH and fT3 levels showed independent positive correlations with LYM among COVID-19 patients, supporting the interaction between the hypothalamic-pituitary-thyroid axis and immune system in COVID-19.

Epstein-Barr Virus-Associated Langerhans Cell Histiocytosis of the Thyroid Gland.

Thyroid gland involvement of Langerhans cell histiocytosis (LCH) is extremely rare in both systemic and isolated disease. The role of viral infection in LCH development is not yet fully understood. Although several viruses are proposed as etiologic factors, such as Epstein-Barr virus (EBV) and human herpesvirus 6 (HHV-6), they seem to play a bystander role in LCH. A 29-year old female patient with a prior history of multisystemic LCH (pituitary gland and skull bone), presented with a thyroid nodule. The patient underwent a total thyroidectomy and the histological examination revealed nodular lesions composed of sheets and clusters of histiocytes in the inflammatory background. The histiocytes stained positive for S-100 and CD1a and were negative for HHV-8, cytomegalovirus, and VE1 (anti-BRAFV600E) on immunohistochemistry. The EBER in situ hybridization for EBV showed frequent positive-stained cells. The conventional PCR analysis for EBV was positive and qPCR analysis confirmed a significant DNA copy number difference (p = 0.02) between the tumor and adjacent non-neoplastic thyroid tissue. PCR analysis for HHV-6, HPV, HSV was negative in both tumor and benign samples. In conclusion, the presented case showed a rare thyroid involvement by LCH associated with EBV infection, which has not been reported before. Further studies are required to investigate a possible etiologic link between EBV infection and LCH.

COVID-19 and Thyroid: Progress and Prospects.

The outbreak of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly spread worldwide. A number of serious effects on various organs and systems have been reported in humans, and recently emerging evidence on the potential association between the infection and thyroid dysfunction are attracting attention from the scientific community. This editorial critically summarizes the main findings on this topic published so far and defines research lines according to the translational approach from the bench to the bed to epidemiological studies and back again, aimed at patient care and effective public health measures.

Endocrine Significance of SARS-CoV-2's Reliance on ACE2.

The current COVID-19 pandemic is the most disruptive event in the past 50 years, with a global impact on health care and world economies. It is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), a coronavirus that uses angiotensin-converting enzyme 2 (ACE2) as an entry point to the cells. ACE2 is a transmembrane carboxypeptidase and member of the renin-angiotensin system. This mini-review summarizes the main findings regarding ACE2 expression and function in endocrine tissues. We discuss rapidly evolving knowledge on the potential role of ACE2 and SARS coronaviruses in endocrinology and the development of diabetes mellitus, hypogonadism, and pituitary and thyroid diseases.

Thyroid disease in the time of COVID-19.

The novel coronavirus disease COVID-19 is produced by SARS-CoV-2. WHO has declared COVID-19 as a public health emergency, with the most susceptible populations (requiring ventilation) being the elderly, pregnant women and people with associated co-morbidities including heart failure, uncontrolled diabetes, chronic obstructive pulmonary disease, asthma and cancer. However, such general guidance does not provide information regarding COVID-19 risks in patients with suffering from pre-existing thyroid problems, and furthermore, we do not know whether patients with COVID-19 (symptomatic or without symptoms), who have not previously had thyroid issues develop endocrine thyroid dysfunction after infection. The European Society for Endocrinology recently published a statement on COVID-19 and endocrine diseases (Endocrine, 2020); however, thyroid diseases were not mentioned specifically. We have therefore reviewed the current literature on thyroid diseases (excluding cancer) and COVID-19, including data from the previous coronavirus pandemic caused by the SARS-associated coronavirus (SARS-CoV), a member of the same family Coronaviridae leading to severe acute respiratory syndrome (SARS). At the moment there are no data suggesting that thyroid patients are at higher risk of COVID-19, but this requites further research and data analysis.

Presence of B19V in Patients with Thyroid Gland Disorders.

Background and Objectives: Viral infections are frequently cited as a major environmental factor implicated in thyroid gland diseases. This work aimed to estimate the presence of B19V infection in patients with thyroid gland disorders. Materials and Methods: Thyroid gland tissue and blood samples of 50 patients with autoimmune thyroid gland diseases (AITDs), 76 patients with non-autoimmune thyroid gland diseases (non-AITDs), and 35 deceased subjects whose histories did not show any autoimmune or thyroid diseases (control group) were enrolled in the study. Virus-specific IgM and IgG were detected using ELISA, and the presence and viral load of B19V in the tissue and blood were detected using PCRs. Results: B19V IgG antibodies were detected in 35/50 AITDs patients and in 51/76 non-AITDs patients, and B19V IgM antibodies were detected in 1/50 patients with AITDs and in none of the 76 patients with non-AITDs. The B19V NS sequence was found in the tissue DNA of 10/50 patients with AITDs, in 30/76 with non-AITDs, and in 1/35 control group individuals. The median B19V load in the tissue of patients with AITDs and non-AITDs was 423.00 copies/µg DNA (IQR: 22.50-756.8) and 43.00 copies/µg DNA (IQR: 11.50-826.5), respectively. The viral load in one of the 35 nPCR B19V-positive thyroid tissue samples from the deceased subjects was 13.82 copies/µg DNA. The viral load in the tissue of patients with AITDs was higher than in whole blood, which possibly indicates B19V persistency in thyrocytes (p = 0.0076). Conclusion: The fact that the genoprevalence of B19V NS was significantly higher in patients with non-AITDs compared to the control group and in the thyroid gland tissue of patients with AITDs, and that the non-AITDs viral load was higher than in tissue derived from the control group individuals, suggest the possibility that B19V infection could be involved in the development of thyroid gland diseases.

Human Immunodeficiency Virus Infection and the Endocrine System.

In the current era of effective antiretroviral therapies (ARTs), human immunodeficiency virus (HIV) infection became a chronic disorder that requires long term follow-up. Among other medical issues, these patients may develop endocrine problems, specific to HIV infection and its treatment. The purpose of this review is to give an overview of common endocrine complications associated with HIV infection, and to propose diagnostic and therapeutic strategies. HIV can affect the endocrine system at several levels. Adrenal and gonadal dysfunction, osteoporosis with increased fracture risk, dyslipidemia with increased cardiovascular risk, are some of the endocrine disorders prevalent in HIV-infected patients that may negatively influence quality of life, and increase morbidity and mortality. While ARTs have dramatically increased life expectancy in the HIV-infected population, they are not devoid of adverse effects, including endocrine dysfunction. Physicians caring for HIV-infected patients should be knowledgeable and exercise a high index of suspicion for the diagnosis of endocrine abnormalities, and in particular be aware of those that can be life threatening. Endocrine evaluation should follow the same strategies as in the general population, including prevention, early detection, and treatment.

Changes in Lipid Indices in HIV+ Cases on HAART.

We assess long-term changes in lipid levels in human immunodeficiency disease- (HIV-) infected patients undergoing highly active antiretroviral treatment (HAART) and their association with diabetes mellitus (DM) and thyroid dysfunction. We observed changes in the levels of total cholesterol (TC) and total triglyceride (TG) of 63 HIV-infected patients in the 6 years from starting HAART and analyzed correlations between relevant parameters. TC levels of patients with normal baseline TC levels as well as those diagnosed with DM or impaired fasting glucose (IFG) increased significantly (P < 0.05) as did the TG levels of patients with normal baseline TG levels (P < 0.05). TC levels of patients with hypercholesterolemia in the year HAART was initiated were significantly higher than those of patients with normal baseline TC levels (P < 0.05) for all 6 years. TC levels of patients diagnosed with DM were significantly higher than those with euglycemia (P < 0.05) 2 and 4 years after HAART commencement. Levels of TC, high-density lipoprotein-cholesterol (HDL-C), and low-density lipoprotein-cholesterol (LDL-C) were correlated negatively with viral load, whereas levels of TC and very-low-density lipoprotein-cholesterol (VLDL-C) were correlated positively with CD4+ cell counts before HAART commencement. Linear mixed-effect model demonstrated disturbance of glucose metabolism and HAART containing nevirapine and CD4+ cell count were positively correlated with TC levels after HAART commencement. These findings suggest that there are changes in the lipid levels of patients undergoing HAART, with the potential risk of dyslipidemia.

Prevalence of thyroid stimulating hormone dysfunction among sofosbuvir-treated HCV-infected patients: A real-world clinical experience.

Thyroid dysfunctions occur frequently among hepatitis C virus (HCV)-infected patients. Accumulating evidence has shown the higher incidence of thyroid dysfunctions in interferon-treated patients that was previously the standard of care therapy. However, the prevalence of thyroid disorders has not been studied in the recently developed interferon-free regimens or direct-acting antiviral (DAA) drugs-treated patients. We recruited 37 patients who had just completed 6 months long sofosbuvir-based treatment, and 26 interferon-treated patients were also included in the study. Serum thyrotropin level of all participants was measured using VIDAS. We observed thyroid dysfunctions in both pegylated interferon-experienced and DAA drug-experienced patients but the prevalence of hyperthyroidism was found significantly higher in patients treated with interferon-based regimen as compared with interferon-free regimens. This high prevalence of hypothyroidism in patients with HCV posttreatment highlights the need for regular periodic screening of patients during the treatment.

The role of human parvovirus B19 and hepatitis C virus in the development of thyroid disorders.

The presence of viruses in the thyroid has been shown, but whether they are implicated in thyroid diseases or are only spectators is under investigation. The most important candidate viruses for autoimmune thyroid disorders (AITD) are hepatitis C virus (HCV) and human parvovirus B19 (or Erythrovirus B19 or EVB19). Retrospective and prospective case-control studies conducted on pathology slides showed (by PCR, in situ hybridization or immunohistochemistry) EVB19 was present in thyroid tissues of patients with autoimmune thyroiditis (AT), Graves' disease and thyroid cancer. Though AITD can be associated with acute EVB19 infection, it is not clear whether EVB19 could have a pathogenetic role in autoimmune thyroid diseases pathophysiology. Many studies have shown that frequently, patients with HCV chronic infection (CHC) show elevated serum anti-thyroperoxidase (TPOAb) and/or anti-thyroglobulin autoantibodies levels, ultrasonographic signs of chronic AT, and subclinical hypothyroidism. In patients with HCV-associated mixed cryoglobulinemia (MC + HCV), AITD were more prevalent with respect to controls, and also vs HCV patients without cryoglobulinemia. Papillary thyroid cancer was more prevalent in MC + HCV or CHC patients than in controls, especially in patients with AT. Recently it has been shown an elevated incidence of new cases of AT and thyroid dysfunction in MC patients. These results suggest an attentive monitoring of thyroid function and nodules in HCV patients with risk factors (female gender, a borderline high initial thyrotropin, TPOAb positivity, a hypoechoic and small thyroid) for the development of thyroid disorders.

Immunohistochemical- and PCR-based assay for the reproducible, routine detection of erythrovirus B19 in thyroid tissues.

It is generally accepted that thyroid follicle cells are at least semi-permissive for erythrovirus B19 (EVB19). Thus, various laboratory techniques have been successfully used to detect EVB19 in the thyroid gland, including polymerase chain reaction (PCR), immunohistochemistry, and in situ hybridization. However, the detection of EVB19 within the thyroid gland is problematic, and none of the detection protocols in the literature have been unequivocally validated. This multidisciplinary study in which 32 thyroidectomy subjects undergoing thyroidectomy in a French University hospital were prospectively recruited was performed over a period of 3 years. Prior to surgery, all the subjects were assayed for blood levels of anti-EVB19 antibodies and (using a quantitative PCR [qPCR] assay) EVB19 itself. A qPCR assay for EVB19 and an immunohistochemical assay (based on polyclonal anti-VP2 antibodies) were performed on the thyroidectomy samples. None of the subjects had an acute EVB19 infection. A viral load was detected in two serum samples and six thyroid biopsies. Three subjects had both a positive immunohistochemical assay and a positive qPCR assay for the thyroid tissue. It is noteworthy that the thyroid immunohistochemical and qPCR assays were negative in the two patients with detectable serum loads of EVB19. In conclusion, EVB19 can be detected in thyroid follicle cells by using immunohistochemical and qPCR assays. Ideally, patients should be tested with both PCR and immunohistochemical assays, in order to unequivocally confirm or rule out the presence of EVB19 in the thyroid gland. The present protocol must now be validated in larger series--notably with respect to its reliability and in order to determine qPCR positivity thresholds for application in future large-scale studies.

Erythrovirus B19 and autoimmune thyroid diseases. Review of the literature and pathophysiological hypotheses.

Erythrovirus B19 (EVB19) has been incriminated, over recent years, in the onset and/or pathogenesis of many diseases, especially autoimmune thyroid diseases. This review of the literature (published over the last 40 years using Pubmed and Science Direct search engines) was designed to define the role of EVB19, particularly in autoimmune thyroid diseases.Two cases of subacute thyroiditis, one case of Graves' disease (associated with type 1 diabetes and rheumatoid arthritis), and one case of Hashimoto's thyroiditis following acute EVB19 infection were reported. A retrospective case-control study in a pediatric population demonstrated the role of EVB19 in Hashimoto's thyroiditis. Four retrospective studies of pathology slides (including PCR, immunohistochemistry or in situ hybridization) and a prospective case-control study on pathology slides demonstrated the presence of EVB19 in thyroid tissue of patients with benign multinodular goiter, Graves' disease, autoimmune thyroiditis (including Hashimoto's thyroiditis), and thyroid cancer. EVB19 can be demonstrated in the thyroid gland in a wide range of diseases. Although acute EVB19 infection could theoretically trigger autoimmune thyroid disease, there is currently no evidence that EVB19 plays a specific role in the pathophysiology of autoimmune thyroid diseases.