Microchimerism in Graves’ Disease

Microchimerism is the presence of cells from one individual in another genetically distinct individual. Pregnancy is the main cause of natural microchimerism through transplacental bidirectional cell trafficking between mother and fetus. The consequences of pregnancy-related microchimerism are under active investigation. However, many authors have suggested a close relationship linking fetal microchimerism and the development of autoimmune diseases. It has been more than ten years now since the demonstration of the presence of a significant high number of fetal microchimeric cells residing in thyroid glands from operated patients with Graves' disease. This intrathyroidal fetal microchimerism is an attractive candidate mechanism for the modulation of Graves' disease in pregnancy and the postpartum period

Manejo del hipertiroidismo subclínico

El manejo del hipertiroidismo subclínico (TSH baja asociado a hormo- nas tiroideas normales) esta sujeto a controversias. Es preciso conocer la causa, la morbilidad asociada y el contexto clínico. En el enfoque y tratamiento de esta alteración se deben seguir seis pasos: 1) confi rma- ción, 2) evaluar la intensidad, 3) determinar la causa, 4) estudiar las complicaciones, 5) decidir si es necesario el tratamiento y 6) en caso afi rmativo, elegir el más conveniente. Para su manejo se utilizan las mismas armas que en la alteración franca. INGLÉS: Management of subclinical hyperthyroidism (low TSH and normal thyroid hormones) is controversial. Knowledge of its causes, clinical context and associated morbidity is required. It is recommended to follow six steps in exploration and treatment: 1) confirmation, 2) estimation of severity, 3) cause assessment, 4) study of complications, 5) balance whether treatment is needed and 6) if necessary, choice of the most appropriate form. In its management, the same treatments are used as in overt hyperthyroidis

Marcadores de función tiroidea (II). Evaluación de la acción tisular

Advances in molecular medicine have increased our knowledge of the consequences of hormone action in target cells. We are currently able to determine to some extent the molecular thyroid hormone activity in different organs. The effects are related with a variety of factors, but their association with plasmatic hormone levels is only partially correlated. Recent advances indicate that there are several intermediate factors in thyroid tissue activity. The iodothyronine selenodeiodinases have a relevant role in this context. The clinical and biochemical methods currently available for thyroid function assessment do not permit us to explore many of these new elements. However, it is well known that thyroid hormones enhance the expression of a number of proteins, and some of these can be measured by simple methods. Accordingly, the plasmatic value of these proteins may be related with the effect of thyroid hormones in the target tissues, which is the result of thyroid function. The ability to determine the tissue activity of thyroid hormones will enable us to administrate the treatment dose more accurately, only to patients who require it, avoiding iatrogenis

Marcadores de función tiroidea (I). Evaluación de la actividad glandular

Las hormonas tiroideas desempeñan un papel fundamental en el meta- bolismo de todos los órganos y sistemas. La disfunción tiroidea (DT) es un importante problema de salud pública que afecta al 10% de la po- blación general. El diagnóstico actual de la DT se realiza de acuerdo con la concentración plasmática de hormonas determinadas en el labo- ratorio. El resultado permite clasificarla en clínica (TSH y hormonas tiroideas fuera del rango de normalidad) y subclínica (TSH alterada de forma aislada). El desarrollo de ensayos de tercera generación para la determinación de TSH ha supuesto un gran avance en el diagnóstico de la DT. Sin embargo ha aumentado el debate sobre el significado patoló- gico de la morbilidad asociada a la DT subclínica, hasta el punto de que los expertos mantienen posturas divergentes sobre el mejor método diag nóstico y las necesidades terapéuticas de esta situación tan prevalente 1-3 . Ello es así porque carecemos de la capacidad de conocer cuales son los pacientes con enfermedad tiroidea subclínica que desarrollarán las com- plicaciones propias de la disfunción clínica 4-7 . La consecuencia práctica de todo ello es que con toda probabilidad estamos tratando de forma inadecuada a pacientes con hipotiroidismo subclínico: en algunos ca- sos los sobretratamos, mientras que en otros no les proporcionamos la hormona que necesitan. INGLÉS: Advances in molecular medicine have increased our knowledge of the consequences of hormone action in target cells. We are currently able to determine to some extent the molecular thyroid hormone activity in different organs. The effects are related with a variety of factors, but their association with plasmatic hormone levels is only partially correlated. Recent advances indicate that there are several intermediate factors in thyroid tissue activity. The iodothyronine selenodeiodinases have a relevant role in this context. The clinical and biochemical methods currently available for thyroid function assessment do not permit us to explore many of these new elements. However, it is well known that thyroid hormones enhance the expression of a number of proteins, and some of these can be measured by simple methods. Accordingly, the plasmatic value of these proteins may be related with the effect of thyroid hormones in the target tissues, which is the result of thyroid function. The ability to determine the tissue activity of thyroid hormones will enable us to administrate the treatment dose more accurately, only to patients who require it, avoiding iatrogenism

Biología molecular del carcinoma de tiroides de estirpe folicular (II). Aplicaciones clínicas

The great advance of molecular medicine over the last few years gives us an attractive vision of the new possibilities in diagnosis and therapeutics of thyroid cancer and helps us to understand its biological behaviour. The clinical application of the growing understanding of gene alterations involved in thyroidal oncogenesis is becoming a reality. Such knowledge might contribute to greater diagnostic accuracy, by helping us characterise malignant or benign cells, predict tumour outcome or state its origin. Likewise it might be useful to know the response to conventional therapies or the future implications of pharmacogenetics. In addition molecular medicine applications ought to be considered in determining the prognosis of spontaneous and familiar carcinomas. Such information can significantly improve current clinical-pathologic prognostic methods

Biología molecular del carcinoma de tiroides de estirpe folicular. Bases moleculares en la oncogénesis tiroidea

Existen datos que nos permiten afirmar que probablemente, en gran parte de los casos, no existe una solución de continuidad entre las diferentes neoplasias tiroideas de estirpe folicular. Cabe pensar que el proceso evolutivo comienza con una serie de alteraciones moleculares que condicionan la aparición del adenoma folicular (AF). Cambios posteriores propiciarán el desarrollo de un carcinoma folicular (CF). La aparición del carcinoma papilar (CP) tiene probablemente un itinerario similar sin que esté demostrado que tenga su origen en AF. Ulteriores cambios genéticos, tanto en el CP como en el CF encaminarán hacia la indiferenciación celular y con ello el desarrollo del carcinoma indiferenciado (CI). Esta sucesión de alteraciones moleculares condiciona un empeoramiento en el pronóstico de la neoplasia tiroidea. Por ello, las neoplasias tiroideas constituyen un excelente modelo para el estudio de la cronología de los cambios moleculares que condicionan la evolución desde la benignidad a la malignidad. Se ha comprobado que en algunas neoplasias de tiroides existe inestabilidad genética que favorece dichos cambios moleculares. Como fenómeno inicial es frecuente observar alteraciones en los protooncogenes mientras que las mutaciones en los genes supresores de tumor suelen ser un evento tardío. La aparición de agresividad o invasividad de la neoplasia también se puede investigar mediante el estudio de cambios moleculares. La aplicación clínica de dichos hallazgos comienza a ser una realidad, lo que facilitará la precisión diagnóstica y con ello una terapéutica más eficaz.According to current data, it seems probable that there is no interruption in the evolution of different follicular thyroid neoplasm. Probably transforming events responsible for the transition from normal to tumor cells start with molecular changes that determine the appearance of follicular adenoma. Later changes propitiate the development of follicular cancer. It is likely that the generation of papillary carcinoma follows a different pathway without passing through a previous phase of follicular adenoma. Subsequently, genetic changes render the cell prone to a failure to differentiate, culminating in the development of anaplastic cancer. Those incidental molecular changes result in a dramatic worsening in the prognosis of thyroid cancer. Research into thyroid tumors is likely to be instructive in view of the spectrum they span, from benign adenomas to poorly differentiated carcinomas. It has been proven that molecular alterations in thyroid tumor cells are predisposed by genome instability. Usually changes of protooncogenes represent an early event whereas mutations of suppressant genes are usually a late phenomenon. The onset of aggressive or invasive behavior may be studied, and perhaps can be predicted in the future, by molecular changes. The clinical application of the growing understanding of gene alterations involved in thyroidal oncogenesis is becoming a reality. Such knowledge might contribute, in the near future, to greater diagnostic accuracy and effective treatment for thyroid malignancie

Intratumoral injection of bone-marrow derived dendritic cells engineered to produce interleukin-12 induces complete regression of established murine transplantable colon adenocarcinomas

Stimulation of the antitumor immune response by dendritic cells (DC) is critically dependent on their tightly regulated ability to produce interleukin-12 (IL-12). To enhance this effect artificially, bone marrow (BM)-derived DC were genetically engineered to produce high levels of functional IL-12 by ex vivo infection with a recombinant defective adenovirus (AdCMVIL-12). DC-expressing IL-12 injected into the malignant tissue eradicated 50-100% well established malignant nodules derived from the injection of two murine colon adenocarcinoma cell lines. Successful therapy was dependent on IL-12 transfection and was mediated only by syngeneic, but not allogeneic BM-derived DC, indicating that compatible antigen-presenting molecules were required. The antitumor effect was inhibited by in vivo depletion of CD8+ T cells and completely abrogated by simultaneous depletion with anti-CD4 and anti-CD8 mAbs. Mice which had undergone tumor regression remained immune to a rechallenge with tumor cells, showing the achievement of long-lasting systemic immunity that also was able to reject simultaneously induced concomitant untreated tumors. Tumor regression was associated with a detectable CTL response directed against tumor-specific antigens probably captured by DC artificially released inside tumor nodules. Our results open the possibility of similarly treating the corresponding human malignancies

Utility of recombinant human TSH stimulation test in the follow-up of patients with differentiated thyroid cancer depending on basal thyroglobulin results

Background: Thyroglobulin (Tg) is fundamental for differentiated thyroid cancer (DTC) monitoring. Tg detection can be enhanced using recombinant human thyroidstimulating hormone (TSH) (rhTSH). This study is aimed to evaluate the use of the rhTSH stimulation test when using a high-sensitivity Tg assay. Methods: We retrospectively studied 181 rhTSH tests from 114 patients with DTC and negative for antithyroglobulin antibodies (anti-TgAb). Image studies were performed in all cases. Serum Tg and anti-TgAb were measured using specific immunoassays. Results: rhTSH stimulation in patients with basal serum Tg (b-Tg) concentrations lower than 0.2 ng/mL always resulted in rhTSH-stimulated serum Tg (s-Tg) concentrations lower than 1.0 ng/mL and negative structural disease. In patients with bTg concentration between 0.2 and 1.0 ng/mL, s-Tg detected one patient (1/30) who showed biochemical incomplete response. Patients with negative images had lower s-Tg than thosewith nonspecific or abnormal findings (p<0.05).Receiver operating characteristic curve analysis of the s-Tg to detect altered images showed an area under the curve of 0.763 (p<0.05).With an s-Tg cutoff of 0.85 ng/mL, the sensitivity was 100%, decreasing to 96.15% with an s-Tg cutoff of 2 ng/mL. Conclusions: Patients with DTC with b-Tg concentrations equal or higher than 0.2 ng/mL can benefit from the rhTSH stimulation test

Circulating GDF11 levels are decreased with age but are unchanged with obesity and type 2 diabetes

Growth differentiation factor 11 (GDF11) is a member of the transforming growth factor β (TGFβ) superfamily which declines with age and exerts anti‐aging regenerative effects in skeletal muscle in mice. However, recent data in humans and mice are conflicting casting doubts about its true functional actions. The aim of the present study was to compare the circulating concentrations of GDF11 in individuals of different ages as well as body weight and glycemic status. Serum concentrations of GDF11 were measured by ELISA in 319 subjects. There was a significant increase in GDF11 concentrations in people in the 41‐50 y group and a decline in the elder groups (61‐70 and 71‐80 y groups, P=0.008 for the comparison between all age groups). However, no significant correlation between fat‐free mass index (FFMI), a formula used to estimate the amount of muscle mass in relation to height, and logGDF11 was observed (r=0.08, P=0.197). Moreover, no significant differences in circulating concentrations of GDF11 regarding obesity or glycemic status were found. Serum GDF11 concentrations in humans decrease in older ages being unaltered in obesity and T2D. Further studies should determine the exact pathophysiological role of GDF11 in aging

Clinical implications of changing thyroglobulin and antithyroglobulin antibodies analytical methods in the follow-up of patients with differentiated thyroid carcinoma

Background and aims: Patients’ response to treatment in differentiated thyroid cancer (DTC) is classified according to serum thyroglobulin concentrations (Tg), usually using the American Thyroid Association guidelines and considering potential interfering anti-thyroglobulin antibodies (Ab-Tg). We aim to evaluate the clinical implications of changing Tg and Ab-Tg quantification method. Material and methods: Tg and Ab-Tg were quantified in 82 serum samples (60 from DTC patients) by Elecsys and Access immunoassays. Results: Elecsys immunoassay rendered higher values of Tg than Access: mean bias 5.03 ng/mL (95%CI:- 14.14–24.21). In DTC patients, there was an almost perfect agreement for response classification (kappa index = 0.833). Discrepancies appeared in patients with undetermined response, with a more tendency to subclassification with Access. Ab-Tg showed a poor correlation (r = 0.5394). When Elecsys cut-off was reduced to 43 IU/ mL, agreement for positive/negative classification improved from a kappa index of 0.607 to 0.650. Prospective study with personalized follow-up showed that only 6.3% of Tg results required an analytical confirmation, being confirmed 93% of them. Conclusions: Despite the biases observed, clinical impact of an analytical change is minimal in patients’ management. However, cautious and personalized follow-up period after the change is still mandatory, especially in patients with Tg levels between 0.2 and 1 ng/mL