Cardiovascular mortality in subclinicalhyperthyroidism: an ongoing dilemma.

The association of endogenous subclinical hyperthyroidism (SHyper) with cardiovascular mortality is controversial. This may reflect the different causes of endogenous SHyper in the population studied due to differences in iodine intake, and different selection criteria, e.g. sex, age, and race, the cutoff for serum TSH level, the duration of follow-up, and the presence of co-morbidities. A small sample size of SHyper patients could have caused a low statistical power in some of these studies. In other studies, the results were not adjusted for relevant confounders. Importantly, various meta-analyses have also given conflicting result

The Clinical Significance of Subclinical Thyroid Dysfunction.

Subclinical thyroid disease (SCTD) is defined as serum free T(4) and free T(3) levels within their respective reference ranges in the presence of abnormal serum TSH levels. SCTD is being diagnosed more frequently in clinical practice in young and middle-aged people as well as in the elderly. However, the clinical significance of subclinical thyroid dysfunction is much debated. Subclinical hyper- and hypothyroidism can have repercussions on the cardiovascular system and bone, as well as on other organs and systems. However, the treatment and management of SCTD and population screening are controversial despite the potential risk of progression to overt disease, and there is no consensus on the thyroid hormone and thyrotropin cutoff values at which treatment should be contemplated. Opinions differ regarding tissue effects, symptoms, signs, and cardiovascular risk. Here, we critically review the data on the prevalence and progression of SCTD, its tissue effects, and its prognostic implications. We also examine the mechanisms underlying tissue alterations in SCTD and the effects of replacement therapy on progression and tissue parameters. Lastly, we address the issue of the need to treat slight thyroid hormone deficiency or excess in relation to the patient's ag

Thyroid-hormone therapy and thyroid cancer: a reassessment.

Experimental studies and clinical data have demonstrated that thyroid-cell proliferation is dependent on thyroid-stimulating hormone (TSH), thereby providing the rationale for TSH suppression as a treatment for differentiated thyroid cancer. Several reports have shown that hormone-suppressive treatment with the L-enantiomer of tetraiodothyronine (L-T(4)) benefits high-risk thyroid cancer patients by decreasing progression and recurrence rates, and cancer-related mortality. Evidence suggests, however, that complex regulatory mechanisms (including both TSH-dependent and TSH-independent pathways) are involved in thyroid-cell regulation. Indeed, no significant improvement has been obtained by suppressing TSH in patients with low-risk thyroid cancer. Moreover, TSH suppression implies a state of subclinical thyrotoxicosis. In low-risk patients, the goal of L-T(4) treatment is therefore to obtain a TSH level in the normal range (0.5-2.5 mU/l). Only selected patients with high-risk papillary and follicular thyroid cancer require long-term TSH-suppressive doses of L-T(4). In these patients, careful monitoring is necessary to avoid undesirable effects on bone and heart

Levothyroxine and the Heart

n/

Effects of thyroid hormone on the cardiovascular system

Increased or reduced action of thyroid hormone on certain molecular pathways in the heart and vasculature causes relevant cardiovascular derangements. It is well established that overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular (LV) systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias - namely, atrial fibrillation - whereas overt hypothyroidism is characterized by the opposite changes. However, whether changes in cardiac performance associated with overt thyroid dysfunction are due mainly to alterations of myocardial contractility or to loading conditions remains unclear. Extensive evidence indicates that the cardiovascular system responds to the minimal but persistent changes in circulating thyroid hormone levels, which are typical of individuals with subclinical thyroid dysfunction. Subclinical hyperthyroidism is associated with increased heart rate, atrial arrhythmias, increased LV mass, impaired ventricular relaxation, reduced exercise performance, and increased risk of cardiovascular mortality. Subclinical hypothyroidism is associated with impaired LV diastolic function and subtle systolic dysfunction and an enhanced risk for atherosclerosis and myocardial infarction. Because all cardiovascular abnormalities are reversed by restoration of euthyroidism ("subclinical hypothyroidism") or blunted by beta-blockade and L-thyroxine (L-T4) dose tailoring ("subclinical hyperthyroidism"), timely treatment is advisable in an attempt to avoid adverse cardiovascular effects. Interestingly, some data indicate that patients with acute and chronic cardiovascular disorders and those undergoing cardiac surgery may have altered peripheral thyroid hormone metabolism that, in turn, may contribute to altered cardiac function. Preliminary clinical investigations suggest that administration of thyroid hormone or its analogue 3,5-diiodothyropropionic acid greatly benefits these patients, highlighting the potential role of thyroid hormone treatment in patients with acute and chronic cardiovascular disease

Impact of resistance to thyroid hormone on thecardiovascular system in adults.

Sixteen untreated and asymptomatic RTH patients (eight males; aged 33 +/- 12 yr, range 21-45 yr) and 16 controls (nine males; aged 33 +/- 5 yr, range 24-42 yr) were enrolled. Clinical data, thyroid status, and echocardiographic results were recorded.Our results suggest the presence of cardiovascular alterations in asymptomatic and untreated RTH patients similar to those reported in hypothyroid patients. Our strict selection likely created a bias in the inclusion of a particular type of RTH patients, who could represent a minority of patients with RTH. However, no correlation was found between the type of mutation and cardiovascular characteristics of RTH patient

How do etiological factors can explain the different clinical features of patients with differentiated thyroid cancer and their histopathological findings?

Abstract The aim was to retrospectively analyse the clinical–histopathological characteristics of patients with newly diagnosis of differentiated thyroid cancer (DTC) referred to two Italian centres, one in Northern and the other in Southern Italy, between 2000 and 2013. 1081 patients were included and subdivided into two groups: group A (474 patients from Novara) and group B (607 patients from Naples). The group A came from the industrial area of Novara, while the Group B came from the areas around Vesuvius and Campi Flegrei. The two groups were comparable for iodine levels, body mass index, diagnostic timing and clinical procedures. For all patients, demographic and clinical data were collected. No difference was found in gender, whereas the age at diagnosis was later in the group A (group A 53.1 ± 15.16 years, group B 41.9 ± 14.25 years, p < 0.001). In both groups, the most frequent histotype was papillary thyroid cancer (PTC) with prevalence of follicular variant in group A (p < 0.0001) and classical variant in group B (p < 0.0001). Aggressive histological features were mainly seen in group A (bilaterality p < 0.0001, multifocality p < 0.0001 and thyroid capsular invasion p < 0.0001). Microcarcinomas were more frequent in group A (p < 0.0001) but mostly characterized by bilaterality (p < 0.001) and multifocality (p < 0.04). In both groups, tumour-associated thyroiditis showed a significant increase over the years (group A p < 0.05, group B p < 0.04). Environmental factors could justify the differences found in our study. These preliminary data should stimulate the need for an Italian Cancer Registry of DTC in order to allow an epidemiological characterization, allowing the identification of specific etiological factors and an improvement in the management of the diseas

Genotype-phenotype features of germline variants of the TMEM127 pheochromocytoma susceptibility gene: A 10-year update

Purpose: This work aimed to evaluate genotype-phenotype associations in individuals carrying germline variants of transmembrane protein 127 gene (TMEM127), a poorly known gene that confers susceptibility to pheochromocytoma (PHEO) and paraganglioma (PGL). Design: Data were collected from a registry of probands with TMEM127 variants, published reports, and public databases. Main Outcome Analysis: Clinical, genetic, and functional associations were determined. Results: The cohort comprised 110 index patients (111 variants) with a mean age of 45 years (range, 21-84 years). Females were predominant (76 vs 34, P <. 001). Most patients had PHEO (n = 94; 85.5%), although PGL (n = 10; 9%) and renal cell carcinoma (RCC, n = 6; 5.4%) were also detected, either alone or in combination with PHEO. One-third of the cases had multiple tumors, and known family history was reported in 15.4%. Metastatic PHEO/PGL was rare (2.8%). Epinephrine alone, or combined with norepinephrine, accounted for 82% of the catecholamine profiles of PHEO/PGLs. Most variants (n = 63) occurred only once and 13 were recurrent (2-12 times). Although nontruncating variants were less frequent than truncating changes overall, they were predominant in non-PHEO clinical presentations (36% PHEO-only vs 69% other, P <. 001) and clustered disproportionately within transmembrane regions (P <. 01), underscoring the relevance of these domains for TMEM127 function. Integration of clinical and previous experimental data supported classification of variants into 4 groups based on mutation type, localization, and predicted disruption. Conclusions: Patients with TMEM127 variants often resemble sporadic nonmetastatic PHEOs. PGL and RCC may also co-occur, although their causal link requires further evaluation. We propose a new classification to predict variant pathogenicity and assist with carrier surveillance.Fil: Armaiz Pena, Gustavo. University Of Texas Health Science Center At San Antonio;; Estados UnidosFil: Flores, Shahida K.. No especifíca;Fil: Cheng, Zi Ming. No especifíca;Fil: Zhang, Xhingyu. No especifíca;Fil: Esquivel, Emmanuel. No especifíca;Fil: Poullard, Natalie. No especifíca;Fil: Vaidyanathan, Anusha. No especifíca;Fil: Liu, Qianqian. No especifíca;Fil: Michalek, Joel. No especifíca;Fil: Santillan Gomez, Alfredo A.. No especifíca;Fil: Liss, Michael. No especifíca;Fil: Ahmadi, Sara. No especifíca;Fil: Katselnik, Daniel. No especifíca;Fil: Maldonado, Enrique. No especifíca;Fil: Salgado, Sarimar Agosto. No especifíca;Fil: Jimenez, Camilo. No especifíca;Fil: Fishbein, Lauren. No especifíca;Fil: Hamidi, Oksana. No especifíca;Fil: Else, Tobias. No especifíca;Fil: Lechan, Ron. Tufts Medical Center; Estados UnidosFil: Tischler, Art S.. Tufts Medical Center; Estados UnidosFil: Benn, Diana E.. No especifíca;Fil: Dwight, Trisha. University of Technology Sydney; AustraliaFil: Clifton Bligh, Rory. University of Technology Sydney; AustraliaFil: Sanso, Elsa Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Barontini, Marta Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Gobierno de la Ciudad de Buenos Aires. Centro de Investigaciones Endocrinológicas "Dr. César Bergada". Fundación de Endocrinología Infantil. Centro de Investigaciones Endocrinológicas "Dr. César Bergada"; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; ArgentinaFil: Vincent, Deepa. Massachusetts Institute of Technology; Estados UnidosFil: Aronin, Neil. Massachusetts Institute of Technology; Estados UnidosFil: Biondi, Bernadette. University of Naples Federico II; ItaliaFil: Koops, Maureen. University of Texas Health San Antonio; Estados UnidosFil: Bowhay Carnes, Elizabeth. No especifíca;Fil: Gimenez Roqueplo, Anne Paule. No especifíca;Fil: Alvarez Eslava, Andrea. No especifíca;Fil: Bruder, Jan M.. No especifíca;Fil: Kitano, Mio. No especifíca;Fil: Burnichon, Nelly. No especifíca;Fil: Ding, Yanli. No especifíca;Fil: Dahia, Patricia L. M.. No especifíca

Natural history, diagnosis and management of subclinical thyroid dysfunction

Subclinical thyroid dysfunction (STD) represents a condition of slight thyroid hormone excess or deficiency, which may be associated with important adverse effects. This review will focus on the natural history, diagnosis and management of subclinical thyroid dysfunction. Since STD is only detected as a thyroid stimulating hormone (TSH) abnormality, it is essential to exclude transient causes of abnormal serum TSH before treating this disorder. Treatment of subclinical hyperthyroidism (SHyper) is recommended in elderly patients with undetectable serum TSH for the increased risk of atrial fibrillation, osteoporosis and bone fractures and for the higher risk of progression to overt disease. Treatment of subclinical hypothyroidism should be considered in patients with serum TSH above 10 mU/L for the increased risk of progression to overt hypothyroidism and the increased risk of coronary heart disease and heart failure events, which have been documented in patients with TSH increase above 10 mU/L. About 75% of patients with STD have mild dysfunction. The mild form of STD (low but detectable serum TSH in SHyper and mild increased serum TSH between 5 and 9 mU/L in SHypo is associated with a minor risk of disease progression to overt dysfunction. The best treatment for STD remains controversial. Treatment of the mild form of STD should be considered after evaluating the patients' age, the adverse risk factors, the potential beneficial effects of treating this disorder and any underlying co-morbidities. Mild SHypo should be treated in infertile and pregnant women. (