Endocrinopatías por inmunoterapia oncológica / Endocrinopathies by oncological immunotherapy

La relación entre inmunidad y cáncer es compleja. Las células tumorales desarrollan mecanismos de evasión a las respuestas del sistema inmunitario. Esta capacidad permite su supervivencia y crecimiento. La inmunoterapia ha transformado el tratamiento oncológico mejorando la respuesta inmunitaria contra la célula tumoral. Esta se basa en el bloqueo de los puntos de control inmunitario mediante anticuerpos monoclonales contra la molécula inhibidora CTLA-4 (antígeno 4 del linfocito T citotóxico [CTLA-4]) y la proteína 1 de muerte celular programada y su ligando (PD-1/PD-L1). Aunque los inhibidores de los puntos de control inmunitario (ICIs) son fármacos bien tolerados, tienen un perfil de efectos adversos conocido como eventos adversos inmunorrelacionados (EAI). Estos afectan varios sistemas, incluyendo las glándulas endocrinas. Los eventos adversos endocrinos más frecuentes son la disfunción tiroidea, la insuficiencia hipofisaria, la diabetes mellitus autoinmune y la insuficiencia suprarrenal primaria. El creciente conocimiento de estos efectos adversos endocrinos ha llevado a estrategias de tratamiento efectivo con el reemplazo hormonal correspondiente. El objetivo de esta revisión es reconocer la incidencia de estas nuevas endocrinopatías, la fisiopatología, su valoración clínica y el manejo terapéutico. (AU)

The relationship between immunity and cancer is complex. Tumor cells develop evasion mechanisms to the immune system responses. This ability allows their survival and progression. Immunotherapy has transformed cancer treatment by improving the immune response against tumor cells. This is achieved by blocking immune checkpoints with monoclonal antibodies against cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and programmed cell death protein 1 and its ligand (PD-1 / PD-L1). Although the immune checkpoint inhibitors (ICIs) are well tolerated drugs, they have a profile of adverse effects known as immune-related adverse events (irAES). These involve diverse systems, including the endocrine glands. The most frequent endocrine immune-related adverse events are thyroid and pituitary dysfunction, autoimmune diabetes mellitus and primary adrenal insufficiency. The increasing knowledge of these irAES has led to effective treatment strategies with the corresponding hormonal replacement. The objective of this review is to recognize the incidence of these new endocrinopathies, the physiopathology, their clinical evaluation, and therapeutic management. (AU)

Disfunción tiroidea y corazón / Thyroid dysfunction and heart

Los trastornos de la función tiroidea afectan profundamente al sistema cardiovascular. En esta revisión se presentan algunos aspectos fisiológicos de la interrelación entre tiroides y corazón, como también las consecuencias de la tirotoxicosis e hipotiroidismo sobre el aparato cardiovascular. Se analiza la influencia del hipertiroidismo en la gèc)nesis de la fibrilación auricular y del hipotiroidismo en el metabolismo de las lipoproteínas. Adicionalmente, el artículo se referirá a los potenciales efectos adversos del antiarrítmico amiodarona sobre la función tiroidea y cómo se investigan y tratan. Finalmente, se expone un caso clínico real para ilustrar con mayor claridad la enorme importancia que pueden alcanzar las relaciones fisiopatológicas entre el corazón y las afecciones de esta glándula endocrina.

Disorders of thyroid function profoundly affect the cardiovascular system. Inthisreviewsomephysiologicalaspectsoftherelationship between thyroid and the heart as well as the consequences of thyrotoxicosis and hypothyroidism on the cardiovascular system are presented. The influence of hyperthyroidism is analyzed in the genesis of atrial fibrillation and of hypothyroidism on lipoprotein metabolism. Furthermore, we refer to the potential adverse effects of the antiarrhythmic amiodarone on thyroid function and how they are investigated and treated. Finally, a real clinical case is exposed to more clearly illustrate the enormous importance that can reach the pathophysiological relationships between the heart and the diseases of the thyroid gland.

Incidence of and risk factors for thyroid dysfunction during peginterferon alpha and ribavirin treatment in patients with chronic hepatitis C

BACKGROUND/AIMS: Thyroid dysfunction (TD) is more likely to occur in patients with chronic hepatitis C (CHC) and is particularly associated with interferon (IFN) treatment. The purpose of this study was to investigate the incidence, outcomes, and risk factors for TD during pegylated interferon (PEG-IFN) and ribavirin (RBV) combined therapy in patients with CHC. METHODS: A total of 242 euthyroid patients with CHC treated with PEG-IFN/RBV were included. Thyroid function and autoantibodies were measured at baseline, and virologic response and thyroid function were assessed every 3 months during therapy. RESULTS: TD developed in 67 patients (27.7%) during the PEG-IFN/RBV treatment. The types of TD were subclinical hypothyroidism (50.7%), hypothyroidism (14.9%), thyroiditis (11.9%), subclinical hyperthyroidism (10.4%), and hyperthyroidism (10.4%). Most of the patients with TD recovered spontaneously; however, seven patients (10.4%) needed thyroid treatment. The sustained virological response rate was higher in patients with TD than those without (65.7% vs. 49.1%, p = 0.02). Baseline thyroid stimulating hormone (TSH) concentrations (odds ratio [OR], 2.09; 95% confidence interval [CI], 1.96 to 8.77; p < 0.001), presence of the thyroid peroxidase antibody (OR, 8.81; 95% CI, 1.74 to 44.6; p = 0.009), and PEG-IFNalpha-2b (OR, 3.01; 95% CI, 1.43 to 6.39; p = 0.004) were independent risk factors for the development of TD. CONCLUSIONS: TD developed in 27.7% of patients with CHC during PEG-IFN/RBV treatment, and 10.4% of these patients needed thyroid treatment. TD is associated with a favorable virologic response to PEG-IFN/RBV. Assessment of TSH and thyroid autoantibodies at baseline and close monitoring of thyroid function during PEG-IFN/RBV therapy are necessary for early detection and management of IFN-induced TD.

Thyroid dysfunction in Turkish patients with chronic hepatitis C receiving peginterferon plus ribavirin in the period of 2005-2010

Interferon-α based therapy for chronic hepatitis C (CHC) is associated with thyroiditis and thyroid dysfunction (TD). This study investigated whether TD during pegylated interferon-a (PEG-IFN) plus ribavirin treatment favors sustained viral response (SVR), and also the association between TD and PEG-IFN formulations. This retrospective study was performed in CHC patients who had received PEG-IFN plus ribavirin and had been followed for six months after treatment. Several factors were compared between patients with and without TD. 119 patients were included in the study. De novo incidence of TD was found to be 16.8%, and 16 of the 18 patients with TD achieved SVR. Although this rate was higher than patients without TD according to univariate analysis, logistic regression analysis revealed that there was not a significant association between TD and SVR, whereas baseline thyroperoxidase antibody (anti-TPO) positivity was the only significant predictor of TD. Moreover, TD was not associated with PEG-IFN type. Both interferon-a and hepatitis C virus (HCV) contribute to TD during antiviral therapy. It seems that there is no association between thyroid toxicity and viral clearance or type of PEG-IFN; however, anti-TPO positivity before treatment is the strongest predictor for TD during antiviral therapy.

Thyroid disorders in patients with chronic hepatitis C using interferon-alpha and ribavirin therapy

OBJECTIVE: To investigate the frequency of thyroid disorders (TD) in patients with chronic hepatitis C before and during interferon-alpha (IFN-α) and ribavirin (RIB) treatment. STUDY DESIGN: Prospective study. PATIENTS AND METHODS: We prospectively studied 65 anti-HCV and viral RNA positive patients. Free thyroxine, thyroid-stimulating hormone, and thyroid peroxidase antibodies (TPO-Ab) were systematically tested at entry (m0), week 12 (m3) and week 24 (m6) of treatment. RESULTS: Mean age of the 65 patients (38 females and 27 males) was 49.61 ± 11.83 years. Seven (10.76 percent) patients presented baseline thyroid disorders (m0), three had thyroid dysfunction, and four were TPO-Ab positive. Thyroid disorders occurred in the first 12 weeks of treatment in 11 (16.92 percent) patients, four with thyroid dysfunction, and seven with TPO-Ab positive (m3). A total of 18 patients (27.69 percent) developed TD after 24 weeks of treatment, 7 with thyroid dysfunction, and 11 with TPO-Ab positive (m6). The relative risk of developing hypothyroidism found in this study was 1.3 (95 percent CI: 1.1 to 1.6), hyperthyroidism 1.2 (95 percent CI: 1.1 to 1.4), and TPO-Ab positivity 7.6 (95 percent CI: 3.9 to 14.5). The study showed a significant association between female sex and thyroid disease (p = 0.009). CONCLUSION: Thyroid dysfunction and autoimmune TD were observed during IFN-α and RIB therapy.

Frequency of thyroid disorders during interferon and ribavirin therapy in chronic hepatitis C infection

The objective of this study was to assess the frequency of thyroid dysfunction in response to combination of interferon and ribavirin therapy in chronic hepatitis C [CHC] patients and HCV outcome. Descriptive study. This study was conducted at Outpatient Department of Liaquat University of Medical and Health Sciences, Jamshoro, Hyderabad from September 2005 to September 2007. One hundred cases of CHC, proven by anti-HCV and HCV RNA-positive with baseline TSH, FT[4] and FT[3] within the normal reference range, who were treated with interferon alpha-2b [3 million unit subcutaneously three times per week] and oral ribavirin [1000-1200 mg per day] were included in this study. All patients were assessed for TSH, FT[4], FT[3] levels at 12 weeks and 24 weeks during therapy. Among the 100 patients, overt thyroid disease developed in 13 [13%] and sub-clinical thyroid disease in 5 [5%]. Out of 13 patients of overt thyroid disorders, 11 [84.6%] had hypothyroidism and 02 [15.3%] hyperthyroidism. Four [80%] patients were of sub-clinical hypothyroidism and 01 [20%] patient was of sub-clinical hyperthyroidism. Overall, thyroid disorders developed in 18 [18%] both as overt and sub-clinical thyroid disorders. Ninety one [91%] patients became negative by HCV RNA. Treatment of HCV with IFN-alpha and ribavirin can be safely continued in patients with over and sub clinical hypothyroidism because thyroid disease responds well to treatment

Disfunção tireoidiana e conduta dos cardiologistas em pacientes usando amiodarona / Thyroid dysfunction and cardiological management in patients receiving amiodarone

OBJETIVO: Determinar a prevalência de disfunção tireoidiana em pacientes usando amiodarona e os possíveis fatores associados. Verificar através de questionário aplicado a cardiologistas, a importância do fármaco causar alterações na função tireoidiana. MÉTODO: Avaliados 56 pacientes em uso crônico (> 3 meses) de amiodarona com dosagens séricas de TSH, T4 livre, T3 total e Anti-TPO e definidos como portadores de disfunção tireoidiana (DT) pacientes com TSH alterado. RESULTADOS: A prevalência de disfunção tireoidiana foi de 33,9 por cento. Não houve diferença entre este grupo e os pacientes sem disfunção, exceto em relação à prevalência de anti-TPO positivo maior nos pacientes com DT (p=0,02). Hipotireoidismo subclínico foi diagnosticado em 10 (17,9 por cento) pacientes e hipotireoidismo clínico em 6 (10,7 por cento). A prevalência de hipertireoidismo subclínico foi de 3,6 por cento e de hipertireoidismo clínico de 1,8 por cento. Anticorpos anti-TPO foram positivos em 5 (8 por cento) pacientes (dos quais 4 apresentavam disfunção). Quando comparados aos doentes sem anti-TPO positivo este grupo teve maior prevalência de disfunção (80 por cento vs 29,4 por cento; p=0,04). Verificado que apenas 49,2 por cento dos cardiologistas faziam acompanhamento da função tireoidiana rotineiramente e a prevalência de disfunção referida na experiência da maioria era de 1 a 10 por cento. CONCLUSAO: A prevalência de disfunção tireoidiana na nossa população foi elevada, mostrando a necessidade de implementação de uma rotina laboratorial. Houve grande divergência entre os cardiologistas em relação ao tipo de acompanhamento utilizado nos pacientes em uso de amiodarona.

Disfunción tiroidea inducida por amiodarona / Thyroid dysfunction induced by amiodarone

La amiodarona (2-n-butil-3,4'-dietilaminoetoxi-3'5'-diyodobenzoil-benzofurano) es un fármaco ampliamente utilizado en el tratamiento de las arritmias cardiacas. Debido a su alto contenido de yodo y similitud estructural con la tiroxina, produce alteraciones en el metabolismo de las hormonas tiroideas y, en algunos casos, da lugar a disfunción tiroidea clínica. En esta comunicación se informa sobre 18 pacientes, 11 mujeres y 7 hombres con edades de 13 a 64 años, que desarrollaron enfermedad tiroidea durante el tratamiento con amiodarona (A). En 5 había antecedente familiar de enfermedad tiroidea y 3 pacientes presentaban crecimiento tiroideo antes del tratamiento con ella. Quince pacientes tenían arritmias auriculares y 3 ventriculares. Las dosis diarias de A fluctuaron entre 200 y 800 mg. Las alteraciones tiroideas aparecieron entre 1 y 29 meses después de iniciado el tratamiento. Nueve pacientes tuvieron manifestaciones clínicas y datos de laboratorio de tirotoxicosis; 3 pacientes desarrollaron crecimiento difuso de la glándula tiroides con aumentos de la T4 total y del IT4L, T3 normal y sin datos clínicos de hipertiroidismo; los otros 6 pacientes presentaron cuadro clínico de hipofunción tiroidea con valores bajos de T4 total y del IT4L y elevación de la TSH sérica. No hubo relación entre la dosis de A o la duración del tratamiento con la aparición o gravedad de la disfunción tiroidea. Excepto por 2 pacientes con bocio simple, el cuadro de distiroidismo desapareció entre 1 y 8 meses después de suspender la administración de A e instituir el tratamiento apropiado. Nuestras observaciones confirman el potencial de la A para inducir anormalidades tiroideas en pacientes con o sin enfermedad tiroidea previa. Es importante destacar que el hipertiroidismo asociado al uso de A puede ser un problema grave, puesto que los pacientes que reciben el fármaco pueden tener enfermedad isquémica y/o arritmias potencialmente letales que podrían ser exacerbadas por el exceso de hormonas tiroideas. Por lo tanto, es necesario que los pacientes tratados con esta droga sean revisados periodicamente y practicar determinaciones hormonales cuando existan manifestaciones clínicas sugestivas de disfunción tiroidea (AU) &P