Francesco S. Celi

Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement

BACKGROUNDnA number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment.nnnMETHODSnTask force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force.nnnRESULTSnWe reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones.nnnCONCLUSIONSnWe concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile.

Physiology and relevance of human adaptive thermogenesis response

In homoeothermic organisms, the preservation of core temperature represents a primal function, and its costs in terms of energy expenditure can be considerable. In modern humans, the endogenous thermoregulation mechanisms have been replaced by clothing and environmental control, and the maintenance of thermoneutrality has been successfully achieved by manipulation of the micro- and macroenvironment. The rediscovery of the presence and activity of brown adipose tissue in adult humans has renewed the interest on adaptive thermogenesis (AT) as a means to facilitate weight loss and improve carbohydrate metabolism. The aim of this review is to describe the recent advancements in the study of this function, and to assess the potential and limitations of exploiting AT for environmental/behavioral, and pharmacological interventions.

Thyroid Hormone Mediated Modulation of Energy Expenditure

Thyroid hormone (TH) has diverse effects on mitochondria and energy expenditure (EE), generating great interest and research effort into understanding and harnessing these actions for the amelioration and treatment of metabolic disorders, such as obesity and diabetes. Direct effects on ATP utilization are a result of TH’s actions on metabolic cycles and increased cell membrane ion permeability. However, the majority of TH induced EE is thought to be a result of indirect effects, which, in turn, increase capacity for EE. This review discusses the direct actions of TH on EE, and places special emphasis on the indirect actions of TH, which include mitochondrial biogenesis and reduced metabolic efficiency through mitochondrial uncoupling mechanisms. TH analogs and the metabolic actions of T2 are also discussed in the context of targeted modulation of EE. Finally, clinical correlates of TH actions on metabolism are briefly presented.

Changes in Resting Energy Expenditure in Relation to Body Weight and Composition Following Gastric Restriction: A Systematic Review.

In comparison to gastric bypass surgery, gastric restriction without malabsorption more closely simulates dietary adherence while still producing durable weight loss. The latter is achieved despite considerable reductions in resting energy expenditure (REE), and whether REE is adjusted for body weight/composition using ratio- or regression-based methods could influence understanding of how these procedures affect energy balance. This systematic review identified studies that reported REE before and after gastric restriction in order to compare changes using each method. Ratio assessments revealed increases and decreases when REE was expressed per kilogram of body weight and per kilogram of fat-free mass, respectively. In comparison, measured REE tended to be less than predicted from linear regression after surgery. Explanations for these seemingly disparate findings and future directions are discussed.

Midkine concentrations in fine-needle aspiration of benign and malignant thyroid nodules

The primary preoperative method for distinguishing malignant from benign thyroid nodules is fine‐needle aspiration (FNA) cytology, but it is frequently inconclusive. Midkine (MDK) is a heparin‐binding growth factor, which is overexpressed in papillary thyroid carcinoma (PTC).

The role of adipose tissue in cancer-associated cachexia:

Adipose tissue (fat) is a heterogeneous organ, both in function and histology, distributed throughout the body. White adipose tissue, responsible for energy storage and more recently found to have endocrine and inflammation-modulatory activities, was historically thought to be the only type of fat present in adult humans. The recent demonstration of functional brown adipose tissue in adults, which is highly metabolic, shifted this paradigm. Additionally, recent studies demonstrate the ability of white adipose tissue to be induced toward the brown adipose phenotype – “beige” or “brite” adipose tissue – in a process referred to as “browning.” While these adipose tissue depots are under investigation in the context of obesity, new evidence suggests a maladaptive role in other metabolic disturbances including cancer-associated cachexia, which is the topic of this review. This syndrome is multifactorial in nature and is an independent factor associated with poor prognosis. Here, we review the contributions of all three adipose depots – white, brown, and beige – to the development and progression of cancer-associated cachexia. Specifically, we focus on the local and systemic processes involving these adipose tissues that lead to increased energy expenditure and sustained negative energy balance. We highlight key findings from both animal and human studies and discuss areas within the field that need further exploration. Impact statement Cancer-associated cachexia (CAC) is a complex, multifactorial syndrome that negatively impacts patient quality of live and prognosis. This work reviews a component of CAC that lacks prior discussion: adipose tissue contributions. Uniquely, it discusses all three types of adipose tissue, white, beige, and brown, their interactions, and their contributions to the development and progression of CAC. Summarizing key bench and clinical studies, it provides information that will be useful to both basic and clinical researchers in designing experiments, studies, and clinical trials.

Increased Pleiotrophin Concentrations in Papillary Thyroid Cancer

Background Thyroid nodules are common, and approximately 5% of these nodules are malignant. Pleiotrophin (PTN) is a heparin-binding growth factor which is overexpressed in many cancers. The expression of PTN in papillary thyroid cancer (PTC) is unknown. Method and Findings 74 subjects (age 47 ± 12 y, 15 males) who had thyroidectomy with a histological diagnosis: 79 benign nodules and 23 PTCs (10 classic, 6 tall cell, 6 follicular variant and 1 undetermined). Fine-needle aspiration (FNA) samples were obtained ex vivo from surgically excised tissue and assayed for PTN and thyroglobulin (Tg). Immunohistochemistry (IHC) was performed on tissue sections. In FNA samples, PTN concentration normalized to Tg was significantly higher in PTC than in benign nodules (16 ± 6 vs 0.3 ± 0.1 ng/mg, p < 0.001). In follicular variant of PTC (n = 6), the PTN/Tg ratio was also higher than in benign nodules (1.3 ± 0.6 vs 0.3 ± 0.1 ng/mg, P < 0.001, respectively). IHC showed cytoplasmic localization of PTN in PTC cells. Conclusion In ex vivo FNA samples, the PTN to thyroglobulin ratio was higher in PTCs, including follicular variant PTC, than in benign thyroid nodules. The findings raise the possibility that measurement of the PTN to Tg ratio may provide useful diagnostic and/or prognostic information in the evaluation of thyroid nodules.

Terapia sostitutiva combinata con L-T4 e L-T3 nell'ipotiroidismo

La L-tiroxina (L-T4) e attualmente utilizzata come terapia a lungo termine dell’ipotiroidismo [1, 2]. Le linee guida dell’American Thyroid Association (ATA) e della European Thyroid Association (ETA) hanno raccomandato la LT4 come monoterapia di prima scelta per il trattamento dell’ipotiroidismo persistente sia conclamato che subclinico, quando il TSH e ≥10 mU/L [3, 4]. Non pochi pazienti ipotiroidei lamentano la persistenza di sintomi durante la monoterapia con L-T4 a dispetto

Improving temporal accuracy of human metabolic chambers for dynamic metabolic studies

Metabolic chambers are powerful tools for assessing human energy expenditure, providing flexibility and comfort for the subjects in a near free-living environment. However, the flexibility offered by the large living room size creates challenges in the assessment of dynamic human metabolic signals—such as those generated during high-intensity interval training and short-term involuntary physical activities—with sufficient temporal accuracy. Therefore, this paper presents methods to improve the temporal accuracy of metabolic chambers. The proposed methods include 1) adopting a shortest possible step size, here one minute, to compute the finite derivative terms for the metabolic rate calculation, and 2) applying a robust noise reduction method—total variation denoising—to minimize the large noise generated by the short derivative term whilst preserving the transient edges of the dynamic metabolic signals. Validated against 24-hour gas infusion tests, the proposed method reconstructs dynamic metabolic signals with the best temporal accuracy among state-of-the-art approaches, achieving a root mean square error of 0.27 kcal/min (18.8 J/s), while maintaining a low cumulative error in 24-hour total energy expenditure of less than 45 kcal/day (188280 J/day). When applied to a human exercise session, the proposed methods also show the best performance in terms of recovering the dynamics of exercise energy expenditure. Overall, the proposed methods improve the temporal resolution of the chamber system, enabling metabolic studies involving dynamic signals such as short interval exercises to carry out the metabolic chambers.

STAT3 suppresses Wnt/β-catenin signaling during the induction phase of primary Myf5+ brown adipogenesis

HighlightsSTAT3 is required during the induction phase for differentiation of primary brown pre‐adipocytes.Deletion of STAT3 after the induction period does not affect UCP1 protein levels and differentiation.STAT3 KO cells can be rescued through inhibition of the canonical Wnt/&bgr;‐Catenin pathway or by knock down of &bgr;‐catenin.STAT3 KO cells upregulate Wnt ligands during the induction phase. Abstract Thermogenic fat is a promising target for new therapies in diabetes and obesity. Understanding how thermogenic fat develops is important to develop rational strategies to treat obesity. Previously, we have shown that Tyk2 and STAT3, part of the JAK‐STAT pathway, are necessary for proper development of classical brown fat. Using primary preadipocytes isolated from newborn mice we demonstrate that STAT3 is required for differentiation and robust expression of Uncoupling Protein 1 (UCP1). We also confirm that STAT3 is necessary during the early induction stage of differentiation and is dispensable during the later terminal differentiation stage. The inability of STAT3−/− preadipocytes to differentiate can be rescued using Wnt ligand secretion inhibitors when applied during the induction stage. Through chemical inhibition and RNAi, we show that it is the canonical &bgr;‐catenin pathway that is responsible for the block in differentiation; inhibition or knockdown of &bgr;‐catenin can fully rescue adipogenesis and UCP1 expression in the STAT3−/− adipocytes. During the induction stage, Wnts 1, 3a, and 10b have increased expression in the STAT3−/− adipocytes, potentially explaining the increased levels and activity of &bgr;‐catenin. Our results for the first time point towards an interaction between the JAK/STAT pathway and the Wnt/&bgr;‐catenin pathway during the early stages of in‐vitro adipogenesis.