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.

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" [...].

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.

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.

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.

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.

Endocrine manifestations of hepatitis C virus infection.

Chronic infection with hepatitis C virus (HCV) can result in both hepatic and extrahepatic disease and endocrine dysfunction represents an important class of HCV-related extrahepatic disease. The most frequently occurring--and clinically important--of these endocrine disorders are thyroid disease and type 2 diabetes mellitus. In this Review, we evaluate the evidence in support of a link between HCV infection and endocrine-system dysfunction, and discuss potential pathophysiological mechanisms. A meta-analysis of the literature has revealed significant associations between chronic HCV infection, thyroid autoimmunity and hypothyroidism. Furthermore, a high prevalence of thyroid cancer has been reported in HCV-positive patients. Several clinicoepidemiological studies have demonstrated that chronic HCV infection could lead to the development of type 2 diabetes mellitus, possibly as a result of HCV-induced metabolic disturbances. Some researchers have postulated that a type 1 T-helper -cell mediated immune response underpins the association of chronic HCV infection with endocrine disease. Indeed, the available data suggest that a common immunological, type 1 T-helper cell pattern of cytokine expression and activation (via interferon-gamma) could provide the pathophysiological basis for this association. Nonetheless, additional studies will be necessary to elucidate fully all the mechanisms involved in HCV-related endocrine dysfunction.

Detection of human parvovirus B19 in papillary thyroid carcinoma.

To evaluate whether parvovirus B19, a common human pathogen, was also involved in papillary thyroid carcinoma (PTC), 112 paraffin-embedded thyroid specimens of benign nodules, papillary, medullary and follicular carcinomas, and normal controls were examined for B19 DNA and capsid protein by nested PCR, in situ hybridisation (ISH) and immunohistochemistry (IHC). The expression of the nuclear factor-kappaB (NF-kappaB) was investigated by IHC. The results showed B19 DNA commonly exists in human thyroid tissues; however, there were significant differences between PTC group and normal controls, and between PTC and nonneoplastic adjacent tissues (P<0.001). The presence of viral DNA in PTC neoplastic epithelium was confirmed by laser-capture microdissection and sequencing of nested PCR products. B19 capsid protein in PTC group was significantly higher than that of all the control groups and nonneoplastic adjacent tissues (P

Thyroid disorders in chronic hepatitis C virus infection.

The prevalence of thyroid disorders has been evaluated in patients with hepatitis C virus (HCV) infection by many studies. From a review of the published controlled studies, it is possible to observe that: (1) most investigated patients with chronic HCV hepatitis, while a minority evaluated hepatitis C virus antibody (HCVAb)- seropositive patients (the two conditions are not comparable with regards to thyroidal repercussions, in fact, HCVAb-seropositive patients do not necessarily display changes of the immune system present in chronically infected HCV patients); and (2) some authors selected as internal control hepatitis B virus (HBV)-infected patients, while others selected apparently healthy controls or HCVAb-negative subjects. Pooling all data about HCV-positive patients (with chronic hepatitis or HCVAb positivity) and using as control the sum of healthy controls, HBV-infected patients and sera negative for HCVAb, a significant increase of the prevalence has been observed both for thyroid autoimmune disorders (odds ratio [OR] = 1.6; 95% confidence interval = [C]) 1.4-1.9) as well as for hypothyroidism (OR = 2.9; 95% CI = 2.0-4.1). The results of the epidemiologic studies showing an association between HCV infection and thyroid cancer need to be confirmed. The abovementioned evidences seem sufficient to suggest careful thyroid monitoring during the follow-up of patients with HCV infection.

Thyroid involvement in patients with overt HCV-related mixed cryoglobulinaemia.

BACKGROUND: Mixed cryoglobulinaemia (MC), a systemic vasculitis associated with hepatitis C virus (HCV) infection in >90% of cases, is frequently complicated by multiple organ involvement. The prevalence of thyroid disorders in MC has not yet been studied. AIM: To investigate the prevalence and clinical features of thyroid involvement in patients with HCV-associated MC (HCV + MC). DESIGN: Case-control study. METHODS: HCV + MC patients (n = 93, 17 men and 76 women, mean +/- SD age 63 +/- 10 years, mean disease duration 14 +/- 7 years) consecutively referred to the Rheumatology Unit were matched by sex and age (+/- 2 years) to (i) 93 patients with chronic C hepatitis (CH) without MC and (ii) 93 healthy (HCV-negative) controls from the local population. Measurements included prevalence of hypo- or hyperthyroidism, thyroid autoantibodies, thyroid nodules and thyroid cancer. RESULTS: By McNemar's chi(2) test, the following thyroid abnormalities were significantly more frequent in HCV + MC patients than in HCV-negative controls: serum anti-thyroperoxidase autoantibody (AbTPO) (28% vs. 9%, p = 0.001); serum AbTPO and/or anti-thyroglobulin autoantibody (31% vs. 12%, p = 0.004); subclinical hypothyroidism (11% vs. 2%, p = 0.038); thyroid autoimmunity (35% vs. 16%, p = 0.006). Serum AbTPO were also significantly more frequent in HCV + MC patients than in CH controls (28% vs. 14%, p = 0.035). DISCUSSION: The prevalence of thyroid disorders is increased in patients with HCV-related mixed cryoglobulinaemia. We suggest careful monitoring of thyroid function in these patients.

Human immunodeficiency virus infection and the thyroid.

Abnormalities of thyroid function are associated with a number of systemic conditions, including patients infected with human immunodeficiency virus (HIV). Most patients with early HIV infection and a stable body weight have normal thyroid function. Subtle abnormalities of a number of thyroid function tests have been reported during the early asymptomatic phase of HIV disease. These include an inappropriately normal triiodothyronine (T(3)) and reduced reverse triiodothyronine (rT(3)), and increased thyroxine-binding globulin (TBG) levels. Opportunistic infections involving the thyroid gland, neoplasms such as lymphoma and Kaposi's sarcoma, and medications can alter the thyroid function in individuals with more advanced HIV infection. If thyroid dysfunction is diagnosed in an HIV-infected patient, it should be treated in the usual manner. However, high index of suspicion and caution in the interpretation of thyroid function tests in patients with HIV disease are needed for optimal diagnosis and treatment.

HTLV-I-associated myelopathy: analysis of 213 patients based on clinical features and laboratory findings.

We studied the clinical features and laboratory findings in 213 patients with HTLV-I-associated myelopathy/tropical spastic paraparesis as diagnosed in Kagoshima University Hospital. Some aspects of clinical features in HTLV-I-associated myelopathy/tropical spastic paraparesis were characterized by mode of HTLV-I transmission and age of onset. The patients with onset after 15 years old and no history of blood transfusion before the onset of the disease (151 patients, group I) showed a shorter interval between the time of disease onset and that of inability to walk. The patients with onset before 15 years old and without history of blood transfusion (21 patients, group II) had short stature and slow progression of the disease. The interval time and the progression of the disease in patients with history of blood transfusion before onset of disease (41 patients, group III) were in between those of the above two groups. Patients whose ages of onset were older than 61 years old showed a faster progression than those with younger onset regardless of the mode of HTLV-I transmission. HTLV-I-associated myelopathy/tropical spastic paraparesis patients often also showed other organ disorders such as leukoencephalopathy (69%), abnormal findings on chest X-ray (50%), Sjögren syndrome (25%) and arthropathy (17%). The patients with low anti-HTLV-I antibody titers in the cerebrospinal fluid (2X-8X by PA method) had an older age of onset on average, milder clinical symptoms and lesser increase of neopterin in the cerebrospinal fluid than those in the high titer subgroup whose titers were higher than 1024X in cerebrospinal fluid regardless of the mode of HTLV-I transmission. We speculate that the clinical course of HTLV-I-associated myelopathy/tropical spastic paraparesis mainly shows a slow progression which consists of an initial progressive phase (probably an inflammatory phase) and a latter chronic phase, although some patients showed acute/subacute onset and rapid progression.