MANAGEMENT OF ENDOCRINE DISEASE: Pitfalls on the replacement therapy for primary and central hypothyroidism in adults.

Hypothyroidism is one of the most common hormone deficiencies in adults. Most of the cases, particularly those of overt hypothyroidism, are easily diagnosed and managed, with excellent outcomes if treated adequately. However, minor alterations of thyroid function determine nonspecific manifestations. Primary hypothyroidism due to chronic autoimmune thyroiditis is largely the most common cause of thyroid hormone deficiency. Central hypothyroidism is a rare and heterogeneous disorder characterized by decreased thyroid hormone secretion by an otherwise normal thyroid gland, due to lack of TSH. The standard treatment of primary and central hypothyroidism is hormone replacement therapy with levothyroxine sodium (LT4). Treatment guidelines of hypothyroidism recommend monotherapy with LT4 due to its efficacy, long-term experience, favorable side effect profile, ease of administration, good intestinal absorption, long serum half-life and low cost. Despite being easily treatable with a daily dose of LT4, many patients remain hypothyroid due to malabsorption syndromes, autoimmune gastritis, pancreatic and liver disorders, drug interactions, polymorphisms in DIO2 (iodothyronine deiodinase 2), high fiber diet, and more frequently, non-compliance to LT4 therapy. Compliance to levothyroxine treatment in hypothyroidism is compromised by daily and fasting schedule. Many adult patients remain hypothyroid due to all the above mentioned and many attempts to improve levothyroxine therapy compliance and absorption have been made.

Genetics of non-syndromic childhood obesity and the use of high-throughput DNA sequencing technologies.

BACKGROUND: Childhood obesity is a serious public health problem associated with the development of several chronic diseases, such as type 2 diabetes mellitus, dyslipidemia, and hypertension. The elevated prevalence of obesity is mostly due to inadequate diet and lifestyle, but it is also influenced by genetic factors. OBJECTIVES: To review recent advances in the field of the genetics of obesity. We summarize the list of genes associated with the rare non-syndromic forms of obesity, and explain their function. Furthermore, we discuss the technologies that are available for the genetic diagnosis of obesity. RESULTS: Several studies reported that single gene variants cause Mendelian forms of obesity, determined by mutations of major effect in single genes. Rare, non-syndromic forms of obesity are a result of loss-of-function mutations in genes that act on the development and function of the hypothalamus or the leptin-melanocortin pathway. These variants disrupt enzymes and receptors that play a role in energy homeostasis, resulting in severe early-onset obesity and endocrine dysfunctions. Different approaches and technologies have been used to understand the genetic background of obesity. Currently, whole genome and whole exome sequencing are important diagnostic tools to identify new genes and variants associated with severe obesity, but other approaches are also useful at individual or population levels, such as linkage analysis, candidate gene sequencing, chromosomal microarray analysis, and genome-wide association studies. CONCLUSIONS: The understanding of the genetic causes of obesity and the usefulness and limitations of the genetic diagnostic approaches can contribute to the development of new personalized therapeutic targets against obesity.

Role of the IL-1 Pathway in Dopaminergic Neurodegeneration and Decreased Voluntary Movement.

Interleukin-1 (IL-1), a proinflammatory cytokine synthesized and released by activated microglia, can cause dopaminergic neurodegeneration leading to Parkinson's disease (PD). However, it is uncertain whether IL-1 can act directly, or by exacerbating the harmful actions of other brain insults. To ascertain the role of the IL-1 pathway on dopaminergic neurodegeneration and motor skills during aging, we compared mice with impaired [caspase-1 knockout (casp1-/-)] or overactivated IL-1 activity [IL-1 receptor antagonist knockout (IL-1ra-/-)] to wild-type (wt) mice at young and middle age. Their motor skills were evaluated by the open-field and rotarod tests, and quantification of their dopamine neurons and activated microglia within the substantia nigra were performed by immunohistochemistry. IL-1ra-/- mice showed an age-related decline in motor skills, a reduced number of dopamine neurons, and an increase in activated microglia when compared to wt or casp1-/- mice. Casp1-/- mice had similar changes in motor skills and dopamine neurons, but fewer activated microglia cells than wt mice. Our results suggest that the overactivated IL-1 pathway occurring in IL-1ra-/- mice in the absence of inflammatory interventions (e.g., intracerebral injections performed in animal models of PD) increased activated microglia, decreased the number of dopaminergic neurons, and reduced their motor skills. Decreased IL-1 activity in casp1-/- mice did not yield clear protective effects when compared with wt mice. In summary, in the absence of overt brain insults, chronic activation of the IL-1 pathway may promote pathological aspects of PD per se, but its impairment does not appear to yield advantages over wt mice.

Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomized, double-blind, crossover study.

OBJECTIVE: To compare the effects of a unique fixed combination levothyroxine/liothyronine (LT4/LT3) therapy in patients with primary hypothyroidism. SUBJECTS AND METHODS: This is a randomized, double-blind, crossover study. Adults with primary hypothyroidism (n = 32, age 42.6 ± 13.3, 30 females) on stable doses of LT4 for ≥ 6 months (125 or 150 µg/day) were randomized to continue LT4 treatment (G1) or to start LT4/LT3 therapy (75/15 µg/day; G2). After 8 weeks, participants switched treatments for 8 more weeks. Thyroid function, lipid profile, plasma glucose, body weight, electrocardiogram, vital signs, and quality of life (QoL) were evaluated at weeks 0, 8 and 16. RESULTS: Free T4 levels were significantly lower while on LT4/LT3 (G1: 1.07 ± 0.29 vs. 1.65 ± 0.46; G2: 0.97 ± 0.26 vs. 1.63 ± 0.43 ng/dL; P < 0.001). TSH and T3 levels were not affected by type of therapy. More patients on LT4/LT3 had T3 levels above the upper limit (15% vs. 3%). The combination therapy led to an increase in heart rate, with no significant changes in electrocardiogram or arterial blood pressure. Lipid profile, body weight and QoL remained unchanged. CONCLUSIONS: The combination therapy yielded significantly lower free T4 levels, with no changes in TSH or T3 levels. More patients on LT4/T3 had elevated T3 levels, with no significant alterations in the evaluated outcomes. No clear clinical benefit of the studied formulation could be observed. Future trials need to evaluate different formulations and the impact of the combined therapy in select populations with genetic polymorphisms.

Treatment of hypothyroidism with levothyroxine plus liothyronine: a randomized, double-blind, crossover study

ABSTRACT Objective To compare the effects of a unique fixed combination levothyroxine/liothyronine (LT4/LT3) therapy in patients with primary hypothyroidism. Subjects and methods This is a randomized, double-blind, crossover study. Adults with primary hypothyroidism (n = 32, age 42.6 ± 13.3, 30 females) on stable doses of LT4 for ≥ 6 months (125 or 150 μg/day) were randomized to continue LT4 treatment (G1) or to start LT4/LT3 therapy (75/15 μg/day; G2). After 8 weeks, participants switched treatments for 8 more weeks. Thyroid function, lipid profile, plasma glucose, body weight, electrocardiogram, vital signs, and quality of life (QoL) were evaluated at weeks 0, 8 and 16. Results Free T4 levels were significantly lower while on LT4/LT3 (G1: 1.07 ± 0.29 vs. 1.65 ± 0.46; G2: 0.97 ± 0.26 vs. 1.63 ± 0.43 ng/dL; P < 0.001). TSH and T3 levels were not affected by type of therapy. More patients on LT4/LT3 had T3 levels above the upper limit (15% vs. 3%). The combination therapy led to an increase in heart rate, with no significant changes in electrocardiogram or arterial blood pressure. Lipid profile, body weight and QoL remained unchanged. Conclusions The combination therapy yielded significantly lower free T4 levels, with no changes in TSH or T3 levels. More patients on LT4/T3 had elevated T3 levels, with no significant alterations in the evaluated outcomes. No clear clinical benefit of the studied formulation could be observed. Future trials need to evaluate different formulations and the impact of the combined therapy in select populations with genetic polymorphisms.

The Effects of Leptin Replacement on Neural Plasticity.

Leptin, an adipokine synthesized and secreted mainly by the adipose tissue, has multiple effects on the regulation of food intake, energy expenditure, and metabolism. Its recently-approved analogue, metreleptin, has been evaluated in clinical trials for the treatment of patients with leptin deficiency due to mutations in the leptin gene, lipodystrophy syndromes, and hypothalamic amenorrhea. In such patients, leptin replacement therapy has led to changes in brain structure and function in intra- and extrahypothalamic areas, including the hippocampus. Furthermore, in one of those patients, improvements in neurocognitive development have been observed. In addition to this evidence linking leptin to neural plasticity and function, observational studies evaluating leptin-sufficient humans have also demonstrated direct correlation between blood leptin levels and brain volume and inverse associations between circulating leptin and risk for the development of dementia. This review summarizes the evidence in the literature on the role of leptin in neural plasticity (in leptin-deficient and in leptin-sufficient individuals) and its effects on synaptic activity, glutamate receptor trafficking, neuronal morphology, neuronal development and survival, and microglial function.

Association between circulating adipocytokine concentrations and microvascular complications in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of controlled cross-sectional studies.

BACKGROUND: The adipocytokines leptin and adiponectin have been variously associated with diabetic microvascular complications. No comprehensive clinical data exist examining the association between adipocytokines and the presence of these complications. METHODS: This is a systematic review of cross-sectional studies comparing circulating adipocytokines in patients with type 2 diabetes mellitus (T2DM), with and without microvascular complications. Studies were retrieved from MEDLINE, EMBASE, Scopus and Cochrane databases. Study quality was evaluated using a modified Newcastle-Ottawa Scale. Meta-analysis was performed using an inverse-variance model, providing standardised mean differences (SMD) and 95% confidence intervals (CI). Heterogeneity was determined by I(2) statistic. RESULTS: Amongst 554 identified studies, 28 were included in the review. Study quality range was 3.5-9 (maximum 11). Higher leptin levels were associated with microalbuminuria (SMD=0.41; 95% CI=0.14-0.67; n=901; p=0.0003), macroalbuminuria (SMD=0.68; 95% CI=0.30-1.06; n=406; p=0.0004), and neuropathy (SMD=0.26; 95% CI=0.07-0.44; n=609; p=0.008). Higher adiponectin levels were associated with microalbuminuria (SMD=0.55; 95% CI=0.29-0.81, n=274; p<0.001), macroalbuminuria (SMD=1.37; 95% CI=0.78-1.97, n=246; p<0.00001), neuropathy (SMD=0.25; 95% CI=0.14-0.36; n=1516; p<0.00001), and retinopathy (SMD=0.38; 95% CI=0.25-0.51; n=1306; p<0.00001). Meta-regression suggested no influence of body mass index and duration of diabetes on effect size, and a weak trend in terms of age on effect size. DISCUSSION: Our meta-analysis suggests leptin and adiponectin levels are higher in T2DM patients with microvascular complications. Studies were limited by cross-sectional design. Large prospective analyses are required to validate these findings.

TSH levels are associated with increased risk of thyroid carcinoma in patients with nodular disease.

INTRODUCTION: Several studies have shown an increased risk of thyroid malignancies in patients with elevated TSH levels, even if these levels fell within the normal range. The aim of this study was to evaluate the relationship between TSH and risk of malignancy in patients with thyroid nodules. MATERIAL AND METHODS: We included 622 patients with thyroid nodules evaluated by fine needle aspiration and/or thyroidectomy and diagnosed by cytology or histology. Clinical and laboratory data, such as gender, weight, ultrasound findings, serum TSH, and free T4, were obtained from medical records or collected during each patient's first visit to our centre, prior to any intervention. RESULTS: Thyroid cancer was more prevalent in males (p = 0.012) and in patients with a solitary nodule (p < 0.01). Malignant tumours were predominantly solid, whereas benign tumours were solid or mixed (p = 0.053). The carcinoma risk in patients with thyroid nodules increased with increasing serum TSH concentration, with a significant elevation in patients with serum TSH levels above 1.64 mU/L (p < 0.001). This relationship persisted even when the subgroup of patients undergoing thyroidectomy was analysed separately. Patients with follicular lesions presented with significantly higher TSH levels compared to patients with benign cytology (p < 0.001). We also found correlation between elevated TSH and tumour size (p = 0.005). CONCLUSIONS: Our results suggest that in patients with nodular thyroid disease the carcinoma risk rose in parallel with serum TSH concentration, with significant increases evident in patients with serum TSH greater than 1.64 mU/L.

New advances in the treatment of generalized lipodystrophy: role of metreleptin.

Recombinant methionyl human leptin or metreleptin is a synthetic leptin analog that has been trialed in patients with leptin-deficient conditions, such as leptin deficiency due to mutations in the leptin gene, hypothalamic amenorrhea, and lipodystrophy syndromes. These syndromes are characterized by partial or complete absence of adipose tissue and hormones derived from adipose tissue, most importantly leptin. Patients deficient in leptin exhibit a number of severe metabolic abnormalities such as hyperglycemia, hypertriglyceridemia, and hepatic steatosis, which can progress to diabetes mellitus, acute pancreatitis, and hepatic cirrhosis, respectively. For the management of these abnormalities, multiple therapies are usually required, and advanced stages may be progressively difficult to treat. Following many successful trials, the US Food and Drug Administration approved metreleptin for the treatment of non-HIV-related forms of generalized lipodystrophy. Leptin replacement therapy with metreleptin has, in many cases, reversed these metabolic complications, with improvements in glucose-insulin-lipid homeostasis, and regression of fatty liver disease. Besides being effective, a daily subcutaneous administration of metreleptin is generally safe, but the causal association between metreleptin and immune complications (such as lymphoma) is still unclear. Moreover, further investigation is needed to elucidate mechanisms by which metreleptin leads to the development of anti-leptin antibodies. Herein, we review clinical aspects of generalized lipodystrophy and the pharmacological profile of metreleptin. Further, we examine studies that assessed the safety and efficacy of metreleptin, and outline some clinical perspectives on the drug.

The use of dried blood spot sampling for the measurement of HbA1c: a cross-sectional study.

BACKGROUND: The use of dried blood spot (DBS) sampling is an alternative to traditional venous blood collection, and particularly useful for people living in rural and remote areas, and for those who are infirm, house-bound or time-poor. The objective of this study was to assess whether the measurement of glycated haemoglobin A1c (HbA1c) in DBS samples provided comparative and acceptably precise results. METHODS: Venous and capillary blood samples were collected from 115 adult participants. After proper instruction, each participant punctured his/her own finger and collected capillary blood samples on pieces of a proprietary cellulose filter paper. Each filter paper was subsequently placed inside a breathable envelope, stored at room temperature, and processed on the same day (D0), four (D4), seven (D7) and fourteen (D14) days after collection. HbA1c was measured in duplicates/triplicates in whole venous blood (WB), capillary blood (capDBS) and venous blood placed on the matrix paper (venDBS), by turbidimetric inhibition immunoassay. Intra-assay coefficients of variation (CV) were calculated. DBS values were compared to WB results using linear regression, Bland-Altman plots and cross-validation models. RESULTS: Eleven and 56 patients had type 1 and type 2 diabetes mellitus, respectively. Mean HbA1c levels were 6.22 ± 1.11 % for WB samples (n = 115). The median intra-assay CV was lower than 3 % for WB and capDBS on all days. Results from capDBS and venDBS showed high correlation and agreement to WB results, with narrow 95 % limits of agreement (except for results from D14 samples), as observed in Bland-Altman plots. When capDBS values were applied to equations derived from regression analyses, results approached those of WB values. A cross-validation model showed that capDBS results on D0, D4 and D7 were close to the WB results, with prediction intervals that were narrow enough to be clinically acceptable. CONCLUSIONS: The measurement of HbA1c from DBS samples provided results that were comparable to results from WB samples, if measured up to seven days after collection. Intra-assay coefficients of variation were low, results were in agreement with the gold-standard, and prediction intervals were clinically acceptable. The measurement of HbA1c through DBS sampling may be considered in situations where traditional venipuncture is not available. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ID ACTRN12613000769785.

Temporal gene expression in the hippocampus and peripheral organs to endotoxin-induced systemic inflammatory response in caspase-1-deficient mice.

OBJECTIVES: Caspase-1 (casp1), a key protease involved in the systemic inflammatory response syndrome (SIRS), controls the brain expression of a set of eight genes: Nos2 and Ptgs2 (nitric oxide synthase 2 and prostaglandin-endoperoxide synthase 2, two inducible enzymes), Cxcl1 and Cxcl10 (C-X-C motif chemokine ligand 1 and ligand 10), Tgtp and Gbp2 (T cell-specific GTPase 1 and guanylate-binding protein 2, two GTPases), Adamts1 (a disintegrin-like and metallopeptidase with thrombospondin type 1 motif, 1, a metalloprotease) and Il1rn (interleukin-1 receptor antagonist). Our objective was to ascertain whether casp1 also controlled the peripheral expression of these genes and, if so, to compare their central versus peripheral patterns of gene expression in immune and endocrine tissues during SIRS. METHODS: Wild-type (wt) and casp1 knockout (casp1(-/-)) mice were injected with either saline or a high dose of endotoxin/lipopolysaccharide (LPS; 800 µg/mice i.p.). Saline-injected mice were immediately euthanized after injection, whereas LPS-injected mice were sacrificed 6 and 12 h after LPS administration. Hippocampal, splenic and adrenal gene expressions were determined by real-time PCR. RESULTS: Overall, casp1(-/-) mice showed a lower inflammatory response than wt mice. The expression levels of powerful proinflammatory factors such as Nos2 and Ptgs2 was reduced in casp1(-/-) mice. Moreover, a hierarchical clustering analysis aimed at studying patterns of gene coexpression revealed large alterations in the hippocampal pattern of casp1(-/-) mice. Surprisingly, the expression of Adamts1 was increased in the hippocampus and adrenals of casp1(-/-) mice. CONCLUSIONS: The resilience of casp1(-/-) mice to SIRS lethality is associated with a lower inflammatory response, loss of hippocampal gene coexpression patterns, and increased hippocampal Adamts1 gene expression. The latter might be beneficial for casp1(-/-) mice, since ADAMTS1 is likely to play a role in neuronal plasticity. The mechanisms described here may help the development of either novel biomarkers or therapeutic targets against SIRS/sepsis.

Leptin treatment: facts and expectations.

Leptin has key roles in the regulation of energy balance, body weight, metabolism, and endocrine function. Leptin levels are undetectable or very low in patients with lipodystrophy, hypothalamic amenorrhea, and congenital leptin deficiency (CLD) due to mutations in the leptin gene. For these patients, leptin replacement therapy with metreleptin (a recombinant leptin analog) has improved or normalized most of their phenotypes, including normalization of endocrine axes, decrease in insulin resistance, and improvement of lipid profile and hepatic steatosis. Remarkable weight loss has been observed in patients with CLD. Due to its effects, leptin therapy has also been evaluated in conditions where leptin levels are normal or high, such as common obesity, diabetes (types 1 and 2), and Rabson-Mendenhall syndrome. A better understanding of the physiological roles of leptin may lead to the development of leptin-based therapies for other prevalent disorders such as obesity-associated nonalcoholic fatty liver disease, depression and dementia.

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints.

The clinical manifestations of lipodystrophy syndromes (LS) are hypoleptinemia, hyperglycemia, insulin resistance, dyslipidemia and hepatic steatosis. Leptin replacement therapy (LRT) is effective at improving these pathologies. Currently, there are no data compiling the evidence from the literature, and demonstrating the effect of LRT in LS patients. A systematic review of the MEDLINE and Cochrane Library databases was conducted to identify studies assessing the effect of LRT on metabolic and hepatic endpoints in patients with LS not associated with highly active antiretroviral therapy (HAART) use. Standardized mean differences (SMD) and 95% confidence intervals of pooled results were calculated for overall changes in glucose homeostasis, lipid profile, and hepatic physiology, using an inverse-variance random-effects model. After screening, 12 studies were included for review. Meta-analysis of results from 226 patients showed that LRT decreased fasting glucose [0.75 SMD units (range 0.36-1.13), p=0.0001], HbA1c [0.49 (0.17-0.81), p=0.003], triglycerides [1.00 (0.69-1.31), p<0.00001], total cholesterol [0.62 (0.21-1.02), p=0.003], liver volume [1.06 (0.51-1.61), p=0.0002] and AST [0.41 (0.10-0.73) p=0.01]. In patients with non-HAART LS, LRT improves the outcome of several metabolic and hepatic parameters. Studies were limited by small populations and therefore large prospective trials are needed to validate these findings.

Evaluation of percutaneous ethanol injections in benign thyroid nodules / Avaliação do tratamento com injeção percutânea com etanol em nódulos benignos de tireoide

Objective The objective of this study was to evaluate the efficacy and safety of percutaneous ethanol injection (PEI) in the treatment of benign thyroid nodules. Subjects and methods We evaluated 120 patients with benign thyroid nodules. Patients underwent evaluation of serum TSH and free T4, cervical ultrasound, and thyroid scintigraphy (in those with suppressed TSH levels). The application of sterile ethanol 99% was guided by ultrasound, with the injected volume amounting to one-third of the nodule volume. Response was considered complete (reduction of 90%); partial (reduction between 50 and 90%); or none (reduction of < 50%). Autonomous nodules were evaluated for normalization of TSH levels. Results Among the nodules studied, 30.8% were solid, 56.7% were mixed, 12.5% were cystic, and 21.6% were hyperfunctioning. The initial volume of the treated nodules ranged from 0.9 to 74.8 mL (mean 13.1 ± 12.4 mL). We performed 1-8 sessions of PEI, applying an average of 6.2 mL of ethanol for patient. After 2 years of follow-up, 17% of patients achieved a complete response (94% reduction); 53%, a partial response (70% reduction); and 30%, no response. A reduction in the volume of autonomous nodules was noted in 70% of cases, and 54% had a normalized value of TSH. The main side effect is local pain, lasting less than 24 hours in most cases. Conclusion This study showed that PEI is a safe and effective procedure for treatment of benign, solid or mixed thyroid nodules. Most cases resulted in significant reduction in nodule volume, with normalization of thyroid function. Arq Bras Endocrinol Metab. 2014;58(9):912-7 .

Objetivo O objetivo deste estudo foi avaliar a eficácia e segurança da injeção percutânea de etanol (IPE) no tratamento de nódulos tireoidianos benignos. Sujeitos e métodos Foram avaliados 120 pacientes com nódulos benignos de tireoide. Todos realizaram dosagens de TSH, T4 livre, ecografia cervical (US) e cintilografia de tireoide (em pacientes com TSH suprimido). A aplicação de etanol estéril a 99% foi guiada por US e o volume de etanol injetado correspondeu a um terço do volume nodular calculado. A resposta foi considerada completa (redução de 90%); parcial (redução entre 50 e 90%) ou ausência de resposta (redução menor que 50%). Nos nódulos autônomos, foi avaliada a normalização do TSH. Resultados Entre os nódulos estudados, 30,8% eram sólidos, 56,7% eram mistos, 12,5% eram císticos e 21,6%, nódulos hiperfuncionantes. O volume inicial dos nódulos tratados variou de 0,9 a 74,8 mL (média 13,1 ± 12,4 mL). Foram realizadas de 1 a 8 sessões de IPE (média 2,8), com aplicação média de 6,2 mL de etanol por paciente. Após dois anos de seguimento, 17% dos pacientes obtiveram resposta completa (redução de 94%), 53% obtiveram resposta parcial (redução de 70%) e 30% não responderam. Houve redução de volume nos nódulos autônomos em 70% dos casos, e 54% normalizaram o valor do TSH. Os efeitos colaterais registrados foram decorrentes apenas do desconforto no local de aplicação. Conclusão Este trabalho mostrou que a IPE é um procedimento seguro e eficaz para tratamento de nódulos benignos, sólidos ou mistos de tireoide. ...

Leptin replacement therapy for the treatment of non-HAART associated lipodystrophy syndromes: a meta-analysis into the effects of leptin on metabolic and hepatic endpoints / Terapia de reposição de leptina para o tratamento de síndromes lipodistróficas não associadas ao uso de antirretrovirais: uma metanálise dos efeitos da leptina em parâmetros metabólicos e hepáticos

The clinical manifestations of lipodystrophy syndromes (LS) are hypoleptinemia, hyperglycemia, insulin resistance, dyslipidemia and hepatic steatosis. Leptin replacement therapy (LRT) is effective at improving these pathologies. Currently, there are no data compiling the evidence from the literature, and demonstrating the effect of LRT in LS patients. A systematic review of the MEDLINE and Cochrane Library databases was conducted to identify studies assessing the effect of LRT on metabolic and hepatic endpoints in patients with LS not associated with highly active antiretroviral therapy (HAART) use. Standardized mean differences (SMD) and 95% confidence intervals of pooled results were calculated for overall changes in glucose homeostasis, lipid profile, and hepatic physiology, using an inverse-variance random-effects model. After screening, 12 studies were included for review. Meta-analysis of results from 226 patients showed that LRT decreased fasting glucose [0.75 SMD units (range 0.36‐1.13), p=0.0001], HbA1c [0.49 (0.17‐0.81), p=0.003], triglycerides [1.00 (0.69‐1.31), p<0.00001], total cholesterol [0.62 (0.21‐1.02), p=0.003], liver volume [1.06 (0.51‐1.61), p=0.0002] and AST [0.41 (0.10‐0.73) p=0.01]. In patients with non-HAART LS, LRT improves the outcome of several metabolic and hepatic parameters. Studies were limited by small populations and therefore large prospective trials are needed to validate these findings.

As manifestações clínicas das síndromes lipodistróficas (SL) incluem hipoleptinemia, hiperglicemia, resistência insulínica, dislipidemia e esteatose hepática. A terapia de reposição de leptina (TRL) melhora tais parâmetros, mas atualmente não há dados compilados demonstrando tal efeito. Uma revisão sistemática dos bancos de dados MEDLINE e Cochrane Library identificou estudos avaliando os efeitos da TRL sobre parâmetros metabólicos e hepáticos em pacientes com SL não associadas ao uso de antirretrovirais. Diferenças médias padronizadas (DMP) e intervalos de confiança de 95% foram calculados a partir dos resultados, para os efeitos da TRL sobre a homeostase da glicose, perfil lipídico, e morfologia/função hepática, usando um modelo de variação inversa e efeitos randômicos. Após a triagem, 12 estudos foram incluídos para revisão. A metanálise dos resultados de 226 pacientes mostrou que a TRL reduziu a glicemia de jejum [0,75 DMP (amplitude 0,36‐1,13), p=0,0001], HbA1c [0,49 (0,17‐0,81), p=0,003], triglicerídeos [1,00 (0,69‐1,31), p<0,00001], colesterol total [0,62 (0,21‐1,02), p=0,003], volume hepático [1,06 (0,51‐1,61), p=0,0002] e AST [0,41 (0,10‐0,73), p=0,001]. Em pacientes com SL não associada ao uso de antirretrovirais, a TRL melhora vários parâmetros metabólicos e hepáticos. Os estudos avaliados foram limitados pelo pequeno número de pacientes. Maiores estudos clínicos prospectivos são necessários para validar tais achados.

Whole exome sequencing of extreme morbid obesity patients: translational implications for obesity and related disorders.

Whole-exome sequencing (WES) is a new tool that allows the rapid, inexpensive and accurate exploration of Mendelian and complex diseases, such as obesity. To identify sequence variants associated with obesity, we performed WES of family trios of one male teenager and one female child with severe early-onset obesity. Additionally, the teenager patient had hypopituitarism and hyperprolactinaemia. A comprehensive bioinformatics analysis found de novo and compound heterozygote sequence variants with a damaging effect on genes previously associated with obesity in mice (LRP2) and humans (UCP2), among other intriguing mutations affecting ciliary function (DNAAF1). A gene ontology and pathway analysis of genes harbouring mutations resulted in the significant identification of overrepresented pathways related to ATP/ITP (adenosine/inosine triphosphate) metabolism and, in general, to the regulation of lipid metabolism. We discuss the clinical and physiological consequences of these mutations and the importance of these findings for either the clinical assessment or eventual treatment of morbid obesity.

Evaluation of percutaneous ethanol injections in benign thyroid nodules.

OBJECTIVE: The objective of this study was to evaluate the efficacy and safety of percutaneous ethanol injection (PEI) in the treatment of benign thyroid nodules. SUBJECTS AND METHODS: We evaluated 120 patients with benign thyroid nodules. Patients underwent evaluation of serum TSH and free T4, cervical ultrasound, and thyroid scintigraphy (in those with suppressed TSH levels). The application of sterile ethanol 99% was guided by ultrasound, with the injected volume amounting to one-third of the nodule volume. Response was considered complete (reduction of 90%); partial (reduction between 50 and 90%); or none (reduction of < 50%). Autonomous nodules were evaluated for normalization of TSH levels. RESULTS: Among the nodules studied, 30.8% were solid, 56.7% were mixed, 12.5% were cystic, and 21.6% were hyperfunctioning. The initial volume of the treated nodules ranged from 0.9 to 74.8 mL (mean 13.1 ± 12.4 mL). We performed 1-8 sessions of PEI, applying an average of 6.2 mL of ethanol for patient. After 2 years of follow-up, 17% of patients achieved a complete response (94% reduction); 53%, a partial response (70% reduction); and 30%, no response. A reduction in the volume of autonomous nodules was noted in 70% of cases, and 54% had a normalized value of TSH. The main side effect is local pain, lasting less than 24 hours in most cases. CONCLUSION: This study showed that PEI is a safe and effective procedure for treatment of benign, solid or mixed thyroid nodules. Most cases resulted in significant reduction in nodule volume, with normalization of thyroid function.