Serum irisin and apelin levels and markers of atherosclerosis in patients with subclinical hypothyroidism

ABSTRACT Objective: In this study, we aimed to evaluate serum irisin and apelin levels in patients with subclinical hypothyroidism (SCH) when they were subclinical hypothyroid and become euthyroid after levothyroxine therapy and association of these adipokines with markers of atherosclerosis such as serum homocysteine levels and carotid intima-media thickness (IMT). Subjects and methods: The study included 160 patients with newly diagnosed subclinical hypothyroidism due to Hashimoto's thyroiditis and 86 euthyroid healty subjects. Serum glucose and lipid profile, insulin, HOMA, TSH, free T3, free T4, anti-thyroperoxidase and anti-thyroglobulin antibodies, homocysteine, apelin and irisin levels were measured in all study subjects. Thyroid and carotid ultrasound examinations were performed. The subclinical hypothyroid group was reevaluated after 12-weeks of levothyroxine therapy when they became euthyroid. Results: Clinical characteristics of the patient and control group were similar. Glucose, insulin and HOMA levels, lipid parameters and free T3 were similar between the two groups.. Serum homocystein was higher and apelin was lower in patients with SCH, but irisin levels were similar between the two groups. While thyroid volume was lower, carotid IMT was significantly greater in patients with SCH (pCarotidIMT:0,01). After 12-weeks of levothyroxine therapy, all the studied parameters remained unchanged except, serum freeT4, TSH, homocystein and apelin. While homocystein decreased (p: 0,001), apelin increased significantly (p = 0,049). In multivariate analysis, low apelin levels significantly contributed to carotid IMT (p = 0,041). Conclusions: Apelin-APJ system may play a role in vascular and cardiac dysfunction in patients with SCH and treatment of this condition may improve the risk of cardiovascular disease.

Conversion to Graves disease from Hashimoto thyroiditis: a study of 24 patients

ABSTRACT Objective: The conversion of Hashimoto's thyroiditis (HT) to hyperthyroidism due to thyrotropin receptor antibodies is intriguing and considered rare. The contribution of TSH receptor blocking antibodies (TRAb), which may be stimulators (TSAb) or blockers (TBAb), is suspected. We describe clinical and biological variables in a series of patients switching from Hashimoto's thyroiditis to Grave's disease. Subjects and methods: Retrospective case study of 24 patients with Hashimoto's thyroiditis followed during 48 ± 36 months that developed later Graves' disease (GD). These variables were analysed in the hypo and hyperthyroid phase: age, sex, initial TSH, free triiodothyronine (fT3), free thyroxine (fT4), anti-TPO, TBII antibodies, parietal cell autoantibodies, time between hypo and hyperthyroidism, thyroid volume and levothyroxine doses (LT). Results: In HT, mean TSH was 9.4 ± 26.1 UI/L and levothyroxine treatment was 66.2 ± 30.8 µg/day. The switch to GD was observed 38 ± 45 months after HT diagnosis. As expected, we found significant differences on TSH, FT3, FT4 and TBAb levels. Three out of 14 patients had parietal cell autoantibodies. In two of these three cases there was an Helicobacter pylori infection. There were no significant differences between HT and GD groups with respect to thyroid volume. Conclusions: To our knowledge, large series documenting the conversion of HT to GD are scarce. Although rare, this phenomenon should not be misdiagnosed. Suspicion should be raised whenever thyroxine posology must be tapered down during the follow-up of HT patients. Further immunological and genetic studies are needed to explain this unusual autoimmune change.

Encefalitis autoinmunes: Un nuevo diagnóstico para una antigua enfermedad / Autoimmune encephalitis. New diagnosis for an old condition

Las encefalitis autoinmunes son un nuevo grupo de enfermedades de gran trascendencia clínica y terapéutica debido a la buena respuesta en gran parte de los casos a la terapia inmunomoduladora indicada, con un gran porcentaje de curación, sin secuelas neurológicas importantes (cognitivo, motor, crisis o movimientos involuntarios). En el año 2007 se demostró la presencia de auto anticuerpos neuronales en la patogenia de este grupo de enfermedades, con síntomas psicóticos y de movimientos involuntarios como indicadores de la enfermedad. La presente revisión enfatiza el salto crucial y el cambio de paradigmas suscitados tras el descubrimiento de estas encefalitis asociadas a anticuerpos.

Autoimmune encephalitis is a new group of diseases of great clinical and therapeutic importance due to the good response in most cases to the immunomodulatory therapy indicated, with a large percentage of healing without significant neurological effects (cognitive, motor, seizures or involuntary movements). Since 2007, the presence of neuronal autoantibodies in the pathogenesis of this group of diseases has been demonstrated, with psychotic symptoms and involuntary movements as clinical markers of the disease. The present review emphasizes the crucial leap and change of paradigms arising after the discovery of these encephalitis associated with antibodies.

Influence of chronic lymphocytic thyroiditis on the risk of persistent and recurrent disease in patients with papillary thyroid carcinoma and elevated antithyroglobulin antibodies after initial therapy / Influência da tireoidite linfocítica crônica sobre o risco de doença persistente e recorrente em pacientes com carcinoma papilífero de tireoide e anticorpos antitireoglobulina elevados após a terapia inicial

Abstract Introduction In patients with papillary thyroid carcinoma who have negative serum thyroglobulin after initial therapy, the risk of structural disease is higher among those with elevated antithyroglobulin antibodies compared to patients without antithyroglobulin antibodies. Other studies suggest that the presence of chronic lymphocytic thyroiditis is associated with a lower risk of persistence/recurrence of papillary thyroid carcinoma. Objective This prospective study evaluated the influence of chronic lymphocytic thyroiditis on the risk of persistence and recurrence of papillary thyroid carcinoma in patients with negative thyroglobulin but elevated antithyroglobulin antibodies after initial therapy. Methods This was a prospective study. Patients with clinical examination showing no anomalies, basal Tg < 1 ng/mL, and elevated antithyroglobulin antibodies 8-12 months after ablation were selected. The patients were divided into two groups: Group A, with chronic lymphocytic thyroiditis on histology; Group B, without histological chronic lymphocytic thyroiditis. Results The time of follow-up ranged from 60 to 140 months. Persistent disease was detected in 3 patients of Group A (6.6%) and in 6 of Group B (8.8%) (p = 1.0). During follow-up, recurrences were diagnosed in 2 patients of Group A (4.7%) and in 5 of Group B (8%) (p = 0.7). Considering both persistent and recurrent disease, structural disease was detected in 5 patients of Group A (11.1%) and in 11 of Group B (16.1%) (p = 0.58). There was no case of death related to the disease. Conclusion Our results do not support the hypothesis that chronic lymphocytic thyroiditis is associated with a lower risk of persistent or recurrent disease, at least in patients with persistently elevated antithyroglobulin antibodies after initial therapy for papillary thyroid carcinoma.

Resumo Introdução Em pacientes com carcinoma papilífero de tireoide e com tireoglobulina sérica negativa após a terapia inicial, o risco de doença estrutural é maior entre aqueles com anticorpos antitireoglobulina elevados em comparação com pacientes sem anticorpos antitireoglobulina. Outros estudos sugerem que a presença de tireoidite linfocítica crônica está associada a um menor risco de persistência/recorrência do carcinoma papilífero de teireoide. Objetivo Este estudo prospectivo avaliou a influência da tireoidite linfocítica crônica sobre o risco de persistência e recorrência do carcinoma papilífero de tireoide em pacientes com tireoglobulina negativa, mas com anticorpos antitireoglobulinas elevados após a terapia inicial. Método Esse foi um estudo prospectivo, no qual foram selecionados pacientes com exame clínico sem anomalias; tireoglobulina basal < 1 ng/mL e anticorpos antitireoglobulina elevados 8-12 meses após ablação. Os pacientes foram divididos em dois grupos: Grupo A, com tireoidite linfocítica crônica no exame histológico; Grupo B, histologicamente sem tireoidite linfocítica crônica. Resultados O tempo de seguimento variou de 60 a 140 meses. Doença persistente foi detectada em 3 pacientes do Grupo A (6,6%) e em 6 do Grupo B (8,8%) (p = 1,0). Durante o seguimento, as recidivas foram diagnosticadas em 2 pacientes do Grupo A (4,7%) e em 5 do Grupo B (8%) (p = 0,7). Considerando tanto a doença persistente quanto a recorrente, doença estrutural foi detectada em 5 pacientes do Grupo A (11,1%) e em 11 do Grupo B (16,1%) (p = 0,58). Não houve nenhum caso de óbito relacionado à doença. Conclusão Nossos resultados não apoiam a hipótese de que a tireoidite linfocítica crônica esteja associada a um menor risco de doença persistente ou recorrente, pelo menos em pacientes com anticorpos antitireoglobulina persistentemente elevados após a terapia inicial do carcinoma papilífero de tireoide.

Elevated neutrophil-to-lymphocyte ratio in the diagnosis of Hashimoto's thyroiditis

Summary Objective: Hashimoto's thyroiditis (HT) is an autoimmune inflammatory disorder. The purpose of this study was to determine the neutrophil-to-lymphocyte ratio (NLR), a novel marker of inflammation, in patients with HT and to compare these values with those from healthy subjects. Method: A total of 154 participants were included in the study, 90 HT patients and 64 healthy volunteers. Retrospectively, demographic and laboratory data of the subjects were obtained from our institution's database. Patients with active infection, diabetes mellitus, malignancy, other chronic inflammatory diseases, hematologic disorders and patients on aspirin or steroid treatment were excluded from the study. Values for complete blood count (CBC) and serum laboratory parameters of HT patients were the baseline values obtained at the time of HT diagnosis. Control subjects consisted of healthy volunteers who visited our institution for a routine check-up. Results: Age, gender and CBC parameters were not different between the HT group and the control group; however, the NLR of HT group (2.1 [1.3-5.8]) was significantly higher than the control group (1.9 [0.6-3.3]), p=0.04. Conclusion: Increased NLR may be useful as an indicator of the presence of HT, especially in complicated cases. NLR is inexpensive and easy to determine. Larger, prospective studies are required to determine its usefulness in assessing diagnostic potential and treatment outcomes in HT patients.

Serum selenium and selenoprotein-P levels in autoimmune thyroid diseases patients in a select center: a transversal study

ABSTRACT Objective: Selenium (Se) supplementation has been used to help prevent the progression of Graves' ophthalmopathy (GO) and autoimmune thyroid diseases (AITD) patients. We investigated Se serum and selenoprotein P (SePP) levels in Graves' disease (GD) with and without GO, Hashimoto's thyroiditis (HT) patients and in 27 control individuals (C). Subjects and methods: We studied 54 female and 19 male patients: 19 with GD without GO, 21 GD with GO, 14 with HT and 19 with HT+LT4. Se values were measured using graphite furnace atomic absorption spectrophotometry. Serum SePP levels were measured by ELISA. Results: Median Se levels were similar among all groups; GD patients: 54.2 (46.5-61.1 μg/L), GO: 53.6 (43.5-60.0 μg/L), HT: 51.9 (44.6-58.5 μg/L), HT+LT4 54.4 (44-63.4) and C group patients: 56.0 (52.4-61.5 μg/L); P = 0.48. However, serum SePP was lower in GO patients: 0.30 (0.15-1.05 μg/mL) and in HT patients: 0.35 (0.2-1.17 μg/mL) compared to C group patients: 1.00 (0.564.21 μg/mL) as well as to GD patients: 1.19 (0.62-2.5 μg/mL) and HT+LT4 patients: 0.7 (0,25-1.95); P = 0.002. Linear regression analysis showed a significant relationship between SePP and TPOAb values (r = 0.445, R2 = 0.293; P < 0.0001). Multiple regression analysis found no independent variables related to Se or SePP. Conclusion: A serum Se concentration was lower than in some other countries, but not significantly among AITD patients. The low serum SePP levels in GO and HT patients seems to express inflammatory reactions with a subsequent increase in Se-dependent protein consumption remains unclear.

Prevalence of pancreatic autoantibodies in non-diabetic patients with autoimmune thyroid disease and its relation to insulin secretion and glucose tolerance

ABSTRACT Objective We evaluated the prevalence of glutamic acid decarboxylase (GADA) and tyrosine phosphatase-protein antibodies (IA2A), their titers and their relation to first phase insulin response (FPIR) and glucose tolerance in autoimmune thyroid diseases (ATDs) patients. Subjects and methods Graves' disease (GD; n = 181) and Hashimoto's thyroiditis (HT; n = 143) patients in addition to healthy controls (n = 93) were studied. Secondly, FPIR and oral glucose tolerance tests (OGTT) were performed in 11 anti-pancreatic islet-cell (+) and in 20 anti-pancreatic-cell (-) patients. Results There was a non significant trend for higher prevalence of GADA positivity in GD vs HT (7.2% vs 2% p = 0.06), but the GADA titers were higher in HT. We also did not find a significant difference in IA2 prevalence (0.7% vs 0.0%) between these two groups or compared to the control group. In the subsequent analysis, low FPIR was found in 10% of these patients but without statistical difference for OGTT between pancreatic antibody-positive and -negative patients. Conclusion A trend for greater prevalence of GADA was observed for GD patients than for HT or control. However, the titers of these autoantibodies were higher in HT patients, but there was no significant relation to insulin secretion and glucose tolerance at that moment and stage of autoimmune diseases.

Hypovitaminosis D in Children with Hashimoto’s Thyroiditis / Hipovitaminosis D en niños con tiroiditis de Hashimoto

Background: Vitamin D deficiency or insufficiency may play a role in the pathogenesis of certain autoimmune diseases. Aim: To measure vitamin D levels in children with Hashimoto’s thyroiditis (HT) (either with subclinical or marked hypothyroidism) and in healthy controls. Material and Methods: We included 68 children with HT aged 12 ± 4 years (39 females) from a pediatric outpatient clinic and 68 healthy children aged 10 ± 4 years (37 females). Calcium metabolism parameters, thyroid function tests and anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-TG) and 25 hydroxy vitamin D (25OHD) levels were measured. Results: Patients were older than controls but well matched by gender distribution. Mean 25OHD levels were significantly lower in HT patients than controls (16.8 ± 9.3 and 24.1 ± 9.4 ng/mL respectively, P < 0.01). Frequency of vitamin D deficiency was 76 and 35% in HT patients and controls, respectively (P < 0.001). Conclusions: Vitamin D deficiency is more common in children with HT than healthy controls.

Antecedentes: La deficiencia o insuficiencia de vitamina D puede tener un rol en la patogenia de enfermedades autoinmunes. Objetivo: Medir niveles de vitamina D en niños con tiroiditis de Hashimoto (TH) (con hipotiroidismo subclínico o marcado) y en controles sanos. Material y Métodos: Estudiamos 68 niños con TH, de 12 ± 4 años (39 mujeres) y 68 controles sanos de 10 ± 4 años (37 mujeres). Se les midió parámetros de metabolismo de calcio, pruebas de función tiroidea, anticuerpos anti peroxidasa y anti tiroglobulina y 25 hidroxi vitamina D (25 OH vit D). Resultados: Los pacientes eran mayores que los controles pero la distribución por género era homogénea en ambos grupos. Los niveles de 25 OH vit D en pacientes y controles fueron 16,8 ± 9,3 y 24,1 ± 9,4 ng/mL respectivamente, p < 0,01. La frecuencia de deficiencia de vitamina D fue de 76 y 35% en pacientes y controles, respectivamente. Conclusiones: La deficiencia de vitamina D es más común en niños con TH.

Circulating levels of irisin is elevated in hypothyroidism, a case-control study

Objective Our objective in this study was to determine the relationship between irisin hormone, which has a similar effect with thyroid hormones on adipose tissue and the metabolism, and the thyroid functions and the obesity secondary to thyroid disease. Subjects and methods Seventy-four patients were included in the study, of the patients, 37 were newly diagnosed with Hashimoto’s thyroiditis related hypothyroidism but not started on a treatment yet, and the remaining 37 were healthy volunteers without a known disease. Serum thyroid stimulating hormone (TSH), free thyroxin (fT4), anti-thyroglobulin and anti-thyroid peroxidase were measured and thyroid ultrasonography was performed in both groups. Serum irisin levels were measured using the commercially available ELISA kit. The hypothyroidism group had higher levels of irisin compared to the control group (2.77 ng/mL vs. 2.15 ng/mL respectively; p = 0.017). Results The hypothyroidism group had higher median levels of irisin in the obese patients than those in the control group (3.10 ng/mL vs. 2.10 ng/mL respectively; p = 0.013). Irisin level was negatively correlated with age in the whole population and patients with hypothyroidism (r = -0.255, p = 0.028; r = -0.346, p = 0.036 respectively). Irisin level was positively correlated with TSH (r = 0.247, p = 0.034) but negatively correlated with the fT4 (r = -0.316, p = 0.006) in the whole population. Obesity, fT4 and irisin levels were identified to be independent predictors in the diagnosis of hypothyroidism in the multivariable logistic regression analysis. Conclusion To the best of our knowledge, this study is the first in literature to identify that obesity, irisin level and fT4 level are independent risk factors for hypothyroidism.

The increased but non-predominant expression of Th17- and Th1-specific cytokines in Hashimoto’s thyroiditis but not in Graves’ disease

Hashimoto’s thyroiditis (HT) is considered to be mediated mainly by Th1 cells, but it is not known whether Graves’ disease (GD) is associated with Th1 or Th2 predominance. Th17 cells, a novel subset of Th cells, play a crucial role in the pathogenesis of various autoimmune disorders. In the present study, the expression of IL-17A and IFN-γ was investigated in patients with HT or GD. mRNA expression of IL-17A and IFN-γ in peripheral blood mononuclear cells (PBMC) from 43 patients with autoimmune thyroid disease (AITD) and in thyroid tissues from 40 AITD patients were measured by real-time qRT-PCR. The protein expression of IL-17A and IL-23p19 was examined by immunohistochemistry in thyroid tissues from 28 AITD patients. The mRNA levels of IL-17A and IFN-γ were higher in both PBMC and thyroid tissues of HT patients than in controls (mRNA levels are reported as the cytokine/β-actin ratio: IL-17 = 13.58- and 2.88-fold change and IFN-γ = 16.54- and 2.74-fold change, respectively, P < 0.05). Also, the mRNA levels of IL-17A and IFN-γ did not differ significantly in GD patients (P > 0.05). The high protein expression of IL-17A (IOD = 15.17 ± 4.8) and IL-23p19 (IOD = 16.84 ± 7.87) in HT was confirmed by immunohistochemistry (P < 0.05). The similar high levels of IL-17A and IFN-γ suggest a mixed response of Th17 and Th1 in HT, where both cells may play important roles in the destruction procedure by cell-mediated cytotoxicity.

Tiroiditis crónica de Hashimoto: Serie clínica / Hashimoto chronic thyroiditis: Retrospective analysis of 228 patients

Background: Chronic Hashimoto Thyroiditis (CHT) is the main cause of hypothyroidism. Aim: To report a series of patients with CHT. Material and Methods: Retrospective analysis of a series of 27 men aged 38 ± 14 years and 201 women aged 37 ± 16 years, evaluated in the private offces of two of the authors. Results: Fifty six percent of patients only had unspecifc symptoms at the moment of consultation, 50 percent had a family history of thyroid diseases and only 21 percent of women had a previous history of goiter. Eighty one percent of patients had clinical or subclinical hypothyroidism, 62 percent had both antithyroglobulin and antithyroid peroxidase positive antibodies and 13 percent had both antibodies negative. Only 1.4 percent of patients had a normal thyroid ultrasound examination. Patients were treated with levothyroxine at a mean dosage of 75 µg/day and 53 percent achieved an adequate TSH level. Six of ten patients operated due to nodules had a papillary carcinoma. Conclusions: CHT should be sought in the general population, especially those with a family history of thyroid disease. Thyroid ultrasound is seldom normal in patients with CHT. Thyroid substitution should be monitored periodically to achieve adequate TSH levels.

Frequency Of Pancreatic Beta-Cell Autoimmunity Markers In Patients With Autoimmune Thyroid Disease / Frecuencia de marcadores de autoinmunidad beta pancreática en pacientes con enfermedad tiroidea autoinmune

A total of 305 ambulatory patients recruited at the Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, with autoimmune thyroid disease (AITD) were studied to search for associations between autoimmune thyroid disease and presence of serum markers of autoimmune diabetes mellitus. Screening for markers of pancreatic beta-cell autoimmunity was performed by radioligand binding assays (RBA) as follows: autoantibodies to glutamic acid decarboxylase (GADA) and proinsulin (PAA) were determined in all sera, whereas autoantibodies to protein tyrosine phosphatase (IA-2A) and insulin (IAA) were additionally measured in 200 sera randomly selected from the total collection. In addition, every GADA positive serum among the remaining 105 sera was systematically tested for the presence of IA-2A and IAA. In the cohort of 305 AITD patients 22 (7.2%) were previously diagnosed as type 1, type 2 or insulin-requiring type 2 diabetics. Ten of these patients presented serum marker positivity specific for β-cell autoantigens and 12 were marker negative. On the other hand, considering the majority of non-diabetic AITD patients (n=283), β-cell marker positivity was detected in 17 individuals (6.0%). The prevalence of autoimmune diabetes markers was much higher in the studied population than in the general population utilized as a control group, and GADA was the most frequent marker.

Se investigó la asociación entre enfermedad tiroidea autoinmune y la presencia de marcadores séricos de diabetes mellitus en 305 pacientes ambulatorios con enfermedad tiroidea autoinmune reclutados en la División Endocrinología. La búsqueda de marcadores de autoinmunidad contra las células beta pancreáticas se realizó por la técnica de unión de radioligandos (RBA) como se detalla a continuación: se determinaron autoanticuerpos contra la decarboxilasa del ácido glutámico (GADA) y proinsulina (PAA) en todos los sueros, mientras que los anticuerpos contra la proteína tirosina fosfatasa (IA-2A) e insulina (IAA) fueron medidos en 200 de estos sueros tomados al azar de la colección total. Además, en los restantes 105 pacientes, la presencia de IA-2A y IAA fue evaluada en todos los sueros positivos para GADA. Del grupo de 305 pacientes con enfermedad tiroidea autoinmune 22 (7.2%) fueron diagnosticados previamente como diabéticos tipo 1, tipo 2 o tipo 2 insulino-requirientes. Diez de ellos presentaron positividad para marcadores específicos de autoantígenos de célula β, en tanto 12 fueron negativos. Por otra parte, en 17 de los 283 pacientes (6.0%) con enfermedad tiroidea autoimmune y sin diagnóstico previo de diabetes, se detectó positividad para marcadores de célula β. La prevalencia de marcadores de autoinmunidad asociados a diabetes fue mayor en la población estudiada que en la población general usada como grupo control, siendo GADA el marcador más frecuente.

Anti-thyroglobulin and anti-thyroid microsomal antibodies in thyroid disorders

High titers of antibodies to thyroglobulin [ATA] and thyroid microsomal antigen [ATMA] are the hallmarks of human autoimmune thyroid diseases. The clinical significance of these autoantibodies in other thyroid disorders is still unclear. The aim of this study was to analyze the prevalence and titres of these antibodies in Omani patients [mean age 32, range 5-81 years] with different thyroid disorders. This was done in order to investigate any correlation regarding clinical manifestations that may be unique to patients attending Sultan Qaboos University Hospital [SQUH]. Serum levels of ATA and ATMA in 400 cases involving four groups of thyroid disorders [one hundred each with Hashimoto's disease, Graves' disease, thyroid cancer and goitre] and 100 cases of non-thyroid disorders were studied. The antibodies were tested using a commercial haemagglutination assay [Thymune-T and Thymune-M]. The overall prevalence of ATA or ATMA antibodies with thyroid disease was 47% and in non-thyroid disorders was 8%. The ATA was positive in 27% of all the patients with thyroid disorders compared to only 4% of those in the non-thyroid groups while ATMA was positive in 42% and 8% respectively. Among all patients, ATA and ATMA were positive in 64% of patients with Graves's disease, 81% in those with Hashimoto's, 30% of goiter patients, and 20% of those with thyroid carcinoma. The prevalence according to the age within each group for the three ranges: less than 20 years, between 20-40 years and over 40 years, showed the following results: within Graves were 12, 49 and 39% respectively; in the goitre group: 23, 55 and 22%; in the Hashimotos' group: 18, 54 and 28% and 7, 56 and 37% among the patients with thyroid carcinoma. The female to male ratio prevalence was 68% and 32% in Graves disease, 92% and 8% in Hashimotos', 75% and 25% in thyroid cancer and 88% and 12% in goiter. This study confirms the prevalence of a high level of thyroid autoantibodies in these Omani patients as in Caucasians, and its correlation to age and gender. It also indicated the importance of screening for ATA and ATMA in non-autoimmune thyroid disorders. Their significance in thyroid cancers needs further elucidation