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1.
Horm Metab Res ; 53(9): 575-587, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34496408

RESUMO

Global warming and the rising prevalence of obesity are well described challenges of current mankind. Most recently, the COVID-19 pandemic arose as a new challenge. We here attempt to delineate their relationship with each other from our perspective. Global greenhouse gas emissions from the burning of fossil fuels have exponentially increased since 1950. The main contributors to such greenhouse gas emissions are manufacturing and construction, transport, residential, commercial, agriculture, and land use change and forestry, combined with an increasing global population growth from 1 billion in 1800 to 7.8 billion in 2020 along with rising obesity rates since the 1980s. The current Covid-19 pandemic has caused some decline in greenhouse gas emissions by limiting mobility globally via repetitive lockdowns. Following multiple lockdowns, there was further increase in obesity in wealthier populations, malnutrition from hunger in poor populations and death from severe infection with Covid-19 and its virus variants. There is a bidirectional relationship between adiposity and global warming. With rising atmospheric air temperatures, people typically will have less adaptive thermogenesis and become less physically active, while they are producing a higher carbon footprint. To reduce obesity rates, one should be willing to learn more about the environmental impact, how to minimize consumption of energy generating carbon dioxide and other greenhouse gas emissions, and to reduce food waste. Diets lower in meat such as a Mediterranean diet, have been estimated to reduce greenhouse gas emissions by 72%, land use by 58%, and energy consumption by 52%.


Assuntos
Mudança Climática , Obesidade/etiologia , Agricultura/economia , Agricultura/tendências , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/patologia , Mudança Climática/história , Comorbidade , Disruptores Endócrinos/toxicidade , Meio Ambiente , Exposição Ambiental/história , Exposição Ambiental/estatística & dados numéricos , Gases de Efeito Estufa/toxicidade , História do Século XIX , História do Século XX , História do Século XXI , Humanos , Obesidade/epidemiologia , Obesidade/metabolismo , Pandemias , Fatores de Risco
2.
Front Endocrinol (Lausanne) ; 12: 653401, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34326811

RESUMO

Familial non-medullary thyroid cancer (FNMTC) is a form of endocrine malignancy exhibiting an autosomal dominant mode of inheritance with largely unknown germline molecular mechanism. Hereditary nonpolyposis colorectal cancer syndrome (HNPCC) is another hereditary autosomal dominant cancer syndrome which, if proven to be caused by germline mutations in mismatch repair genes (MMR)-MLHL, MSH2, MSH6, PMS2, and EPCAM-is called Lynch syndrome (LS). LS results in hereditary predisposition to a number of cancers, especially colorectal and endometrial cancers. Tumors in LS are characterized by microsatellite instability (MSI) and/or loss of MMR protein expression in immunohistochemistry (IHC). MSI is a rare event in thyroid cancer (TC), although it is known to occur in up to 2.5% of sporadic follicular TC cases. There are limited data on the role of germline MMR variants FNMTC. The goal of this study was to analyze the potential clinical and molecular association between HNPCC and FNMTC. We performed a cohort study analyzing the demographic, clinical, and pathologic data of 43 kindreds encompassing 383 participants (104 affected, 279 unaffected), aged 43.5 [7-99] years with FNMTC, and performed high-throughput whole-exome sequencing (WES) of peripheral blood DNA samples of selected 168 participants (54 affected by FNMTC and 114 unaffected). Total affected by thyroid cancer members per family ranged between 2 and 9 patients. FNMTC was more prevalent in women (68.3%) and characterized by a median tumor size of 1.0 [0.2-5.0] cm, multifocal growth in 44%, and gross extrathyroidal extension in 11.3%. Central neck lymph node metastases were found in 40.3% of patients at presentation, 12.9% presented with lateral neck lymph node metastases, and none had distant metastases. Family history screening revealed one Caucasian family meeting the clinical criteria for FNMTC and HNPCC, with five members affected by FNMTC and at least eight individuals reportedly unaffected by HNPCC-associated tumors. In addition, two family members were affected by melanoma. Genome Analysis Tool Kit (GATK) pipeline was used in variant analysis. Among 168 sequenced participants, a heterozygous missense variant in the MSH2 gene (rs373226409; c.2120G>A; p.Cys707Tyr) was detected exclusively in FNMTC- HNPCC- kindred. In this family, the sequencing was performed in one member affected by FNMTC, HPNCC-associated tumors and melanoma, one member affected solely by HNPCC-associated tumor, and one member with FNMTC only, as well as seven unaffected family members. The variant was present in all three affected adults, and in two unaffected children of the affected member, under the age of 18 years, and was absent in non-affected adults. This variant is predicted to be damaging/pathogenic in 17/20 in-silico models. However, immunostaining performed on the thyroid tumor tissue of two affected by FNMTC family members revealed intact nuclear expression of MSH2, and microsatellite stable status in both tumors that were tested. Although the MSH2 p.Cys707Tyr variant is rare with a minor allele frequency (MAF) of 0.00006 in Caucasians; it is more common in the South Asian population at 0.003 MAF. Therefore, the MSH2 variant observed in this family is unlikely to be an etiologic factor of thyroid cancer and a common genetic association between FNMTC and HNPCC has not yet been identified. This is the first report known to us on the co-occurrence of FNMTC and HNPCC. The co-occurrence of FNMTC and HNPCC-associated tumors is a rare event and although presented in a single family in our large FNMTC cohort, a common genetic background between the two comorbidities could not be established.

4.
J Clin Endocrinol Metab ; 106(5): 1501-1515, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33507248

RESUMO

BACKGROUND: Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. METHODS: We conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. RESULTS: Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ±â€…32.9 vs 42.8 ±â€…23.9; P = 0.002) and reduced adipo-IR (49.9 ±â€…45.9 vs 65.5 ±â€…43.8; P = 0.004), and HIRI (50.2 ±â€…38.7 vs 70.0 ±â€…44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or ß-cell glucose sensitivity. CONCLUSION: Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.


Assuntos
Tecido Adiposo/efeitos dos fármacos , Intolerância à Glucose/metabolismo , Resistência à Insulina , Mifepristona/farmacologia , Estado Pré-Diabético/metabolismo , Tecido Adiposo/metabolismo , Adulto , Idoso , Estudos Cross-Over , Método Duplo-Cego , Feminino , Intolerância à Glucose/tratamento farmacológico , Humanos , Resistência à Insulina/fisiologia , Secreção de Insulina/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Mifepristona/uso terapêutico , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Sobrepeso/tratamento farmacológico , Sobrepeso/metabolismo , Estado Pré-Diabético/tratamento farmacológico , Estados Unidos
5.
Geroscience ; 43(3): 1093-1112, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-32902818

RESUMO

We are in the midst of the global pandemic. Though acute respiratory coronavirus (SARS-COV2) that leads to COVID-19 infects people of all ages, severe symptoms and mortality occur disproportionately in older adults. Geroscience interventions that target biological aging could decrease risk across multiple age-related diseases and improve outcomes in response to infectious disease. This offers hope for a new host-directed therapeutic approach that could (i) improve outcomes following exposure or shorten treatment regimens; (ii) reduce the chronic pathology associated with the infectious disease and subsequent comorbidity, frailty, and disability; and (iii) promote development of immunological memory that protects against relapse or improves response to vaccination. We review the possibility of this approach by examining available evidence in metformin: a generic drug with a proven safety record that will be used in a large-scale multicenter clinical trial. Though rigorous translational research and clinical trials are needed to test this empirically, metformin may improve host immune defenses and confer protection against long-term health consequences of infectious disease, age-related chronic diseases, and geriatric syndromes.


Assuntos
COVID-19 , Doenças Transmissíveis , Metformina , Idoso , Doenças Transmissíveis/tratamento farmacológico , Humanos , Metformina/uso terapêutico , Estudos Multicêntricos como Assunto , RNA Viral , SARS-CoV-2
7.
J Diabetes Complications ; 35(1): 107584, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32331977

RESUMO

Mitochondrial disorders refer to the complex group of conditions affecting energy metabolism. A number of mitochondrial disorders can lead to the development of diabetes mellitus, and mitochondrial diabetes is thought to account for up to 3% of all diabetes mellitus cases. Depending on the degree of preservation of beta cell secretory capacity and peripheral muscle insulin sensitivity, the phenotype of mitochondrial diabetes may resemble that of type 1 or type 2 diabetes. Additionally, mitochondrial diabetes may rarely present with diabetic ketoacidosis, and can be distinguished from other forms of monogenic diabetes including maturity onset diabetes of the young by the presence of multi-organ involvement, particularly pre-senile sensorineural hearing loss, maternal transmission, and later-onset diagnosis, typically affecting adults over 35 years. Various guidelines on diabetes care do not address this important subset of cases, and this diagnosis is easily missed. Additionally, there is paucity of data on tailored diabetes therapies for mitochondrial diabetes, particularly in the era of novel therapies including glucagon-like peptide-1 receptor agonist and sodium glucose co-transporter-2 inhibitors. Here, we report three patients with mitochondrial diabetes who responded well to the addition of these novel agents and propose a new treatment algorithm for this condition.

8.
Lancet Oncol ; 21(11): e528-e537, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-33152312

RESUMO

Most primary thyroid tumours are of epithelial origin. Primary thyroid mesenchymal tumours are rare but are being increasingly detected. A vast majority of thyroid mesenchymal tumours occur between the fourth and seventh decades of life, presenting as progressively enlarging thyroid nodules that often yield non-diagnostic results or spindle cells on fine needle aspiration biopsy. Surgery is the preferred mode of treatment, with adjuvant chemoradiotherapy used for malignant thyroid mesenchymal tumours. Benign thyroid mesenchymal tumours have excellent prognosis, whereas the outcome of malignant thyroid mesenchymal tumours is variable. Each thyroid mesenchymal tumour is characterised by its unique histopathology and immunohistochemistry. Because of the rarity and aggressive nature of malignant thyroid mesenchymal tumours, a multidisciplinary team-based approach should ideally be used in the management of these tumours. Comprehensive guidelines on the management of thyroid mesenchymal tumours are currently lacking. In this Review, we provide a detailed description of thyroid mesenchymal tumours, their clinical characteristics and tumour behaviour, and provide recommendations for the optimal management of these tumours.


Assuntos
Biomarcadores Tumorais , Neoplasias de Tecido Conjuntivo e de Tecidos Moles , Neoplasias da Glândula Tireoide , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Tomada de Decisão Clínica , Humanos , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/química , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/genética , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/patologia , Neoplasias de Tecido Conjuntivo e de Tecidos Moles/terapia , Valor Preditivo dos Testes , Prognóstico , Neoplasias da Glândula Tireoide/química , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/terapia
9.
Lancet Diabetes Endocrinol ; 8(12): 978-986, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33128872

RESUMO

The risk factors for severe COVID-19 are diverse, yet closely resemble the clinical manifestations of catecholamine excess states (eg, hypertension, cardiovascular disease, immune dysregulation, and hyperglycaemia), suggesting a potentially common basis for disease. Unfortunately, severe illness (eg, respiratory failure, compromised cardiac function, and shock) incurred by COVID-19 hinders the direct study of catecholamines in these patients, especially among those on multiple medications or those on adrenaline or noradrenaline infusions, or both. Phaeochromocytoma and paraganglioma (PPGL) are tumours that secrete catecholamines, namely adrenaline and noradrenaline, often in excess. PPGL are well studied disease processes in which the effects of catecholamines are easily discernible and therefore their potential biochemical and physiological influences in patients with COVID-19 can be explored. Because catecholamines are expected to have a role in patients with critical illness, patients on vasopressor infusions, and patients who sustain some acute and chronic physical stresses, the challenges involved in the management of catecholamine excess states are directly relevant to the treatment of patients with COVID-19. In this Personal View, we discuss the complex interplay between catecholamines and COVID-19, and the management of catecholamine excess states, while referencing relevant insights derived from the study of PPGL.


Assuntos
COVID-19/epidemiologia , Catecolaminas/metabolismo , SARS-CoV-2/isolamento & purificação , COVID-19/metabolismo , COVID-19/virologia , Humanos , Fatores de Risco
10.
Cancers (Basel) ; 12(8)2020 Jul 29.
Artigo em Inglês | MEDLINE | ID: mdl-32751138

RESUMO

The knowledge on thyroid cancer biology has grown over the past decade. Thus, diagnostic and therapeutic strategies to manage thyroid cancer are rapidly evolving. With new insights into tumor biology and cancer genetics, several novel therapies have been approved for the treatment of thyroid cancer. Tyrosine kinase inhibitors (TKIs), such as lenvatinib and sorafenib, have been successfully utilized for the treatment of radioactive iodine (RAI)-refractory metastatic differentiated thyroid cancer (DTC). In addition, pretreatment with mitogen-activated protein kinase (MAPK) inhibitors (trametinib and selumetinib) has been shown to restore RAI avidity in previously RAI-refractory DTCs. Local therapies, such as external beam radiation and radiofrequency/ethanol ablation, have also been employed for treatment of DTC. Vandetanib and cabozantinib are the two TKIs currently approved by the Food and Drug Administration (FDA) for the treatment of medullary thyroid cancer (MTC). Other novel therapies, such as peptide receptor radionuclide therapy and carcinoembryonic antigen (CEA) vaccine, have also been utilized in treating MTC. Ongoing trials on selective rearranged-during-transfection (RET) protooncogene inhibitors, such as LOXO-292 and BLU-667, have demonstrated promising results in the treatment of metastatic MTC resistant to non-selective TKIs. The FDA-approved BRAF/MEK inhibitor combination of dabrafenib and trametinib has revolutionized treatment of BRAFV600E mutation positive anaplastic thyroid cancer. Several other emerging classes of medications, such as gene fusion inhibitors and immune checkpoint inhibitors, are being actively investigated in several clinical trials. In this review, we describe the molecular landscape of thyroid cancer and novel targeted therapies and treatment combinations available for the treatment of metastatic thyroid cancer.

11.
Endocrinology ; 161(10)2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32603424

RESUMO

The ongoing coronavirus disease 2019 (COVID-19) pandemic is caused by the novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Individuals with metabolic syndrome are at increased risk for poor disease outcomes and mortality from COVID-19. The pathophysiologic mechanisms for these observations have not been fully elucidated. A critical interaction between SARS-CoV-2 and the angiotensin-converting enzyme 2 (ACE2) facilitates viral entry into the host cell. ACE2 is expressed in pancreatic islets, vascular endothelium, and adipose tissue, and the SARS-CoV-2 -ACE2 interaction in these tissues, along with other factors, governs the spectrum and the severity of clinical manifestations among COVID-19 patients with metabolic syndrome. Moreover, the pro-inflammatory milieu observed in patients with metabolic syndrome may contribute toward COVID-19-mediated host immune dysregulation, including suboptimal immune responses, hyperinflammation, microvascular dysfunction, and thrombosis. This review describes the spectrum of clinical features, the likely pathophysiologic mechanisms, and potential implications for the management of metabolic syndrome in COVID-19 patients.


Assuntos
Infecções por Coronavirus/fisiopatologia , Síndrome Metabólica/fisiopatologia , Pneumonia Viral/fisiopatologia , Enzima de Conversão de Angiotensina 2 , Animais , Betacoronavirus/fisiologia , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Sistema Endócrino/metabolismo , Sistema Endócrino/fisiopatologia , Humanos , Sistema Imunitário/imunologia , Sistema Imunitário/fisiopatologia , Síndrome Metabólica/imunologia , Síndrome Metabólica/metabolismo , Microvasos/fisiopatologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/imunologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , SARS-CoV-2
12.
Am J Physiol Endocrinol Metab ; 318(5): E736-E741, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32228322

RESUMO

The pandemic of coronavirus disease (COVID-19), a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is causing substantial morbidity and mortality. Older age and presence of diabetes mellitus, hypertension, and obesity significantly increases the risk for hospitalization and death in COVID-19 patients. In this Perspective, informed by the studies on SARS-CoV-2, Middle East respiratory syndrome (MERS-CoV), and the current literature on SARS-CoV-2, we discuss potential mechanisms by which diabetes modulates the host-viral interactions and host-immune responses. We hope to highlight gaps in knowledge that require further studies pertinent to COVID-19 in patients with diabetes.


Assuntos
Betacoronavirus , Infecções por Coronavirus , Diabetes Mellitus , Interações entre Hospedeiro e Microrganismos , Pandemias , Pneumonia Viral , Animais , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , COVID-19 , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/fisiopatologia , Infecções por Coronavirus/virologia , Diabetes Mellitus/imunologia , Diabetes Mellitus/mortalidade , Interações entre Hospedeiro e Microrganismos/imunologia , Humanos , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/fisiopatologia , Pneumonia Viral/virologia , Medição de Risco , SARS-CoV-2 , Incerteza , Estados Unidos/epidemiologia
13.
Cell Metab ; 32(1): 15-30, 2020 07 07.
Artigo em Inglês | MEDLINE | ID: mdl-32333835

RESUMO

Biological aging involves an interplay of conserved and targetable molecular mechanisms, summarized as the hallmarks of aging. Metformin, a biguanide that combats age-related disorders and improves health span, is the first drug to be tested for its age-targeting effects in the large clinical trial-TAME (targeting aging by metformin). This review focuses on metformin's mechanisms in attenuating hallmarks of aging and their interconnectivity, by improving nutrient sensing, enhancing autophagy and intercellular communication, protecting against macromolecular damage, delaying stem cell aging, modulating mitochondrial function, regulating transcription, and lowering telomere attrition and senescence. These characteristics make metformin an attractive gerotherapeutic to translate to human trials.

14.
Int J Eat Disord ; 53(5): 510-519, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32202658

RESUMO

OBJECTIVE: The aim of this study is to evaluate two questionnaires, an updated youth version of the questionnaire on eating and weight patterns (Questionnaire on Eating and Weight Patterns-5 Children/Adolescent [QEWP-C-5]) and the Loss-of-Control (LOC) Eating Disorder Questionnaire (LOC-ED-Q), against the Eating Disorder Examination (EDE) interview to assess the presence of LOC-eating among youth. METHOD: Two-hundred and eighteen youths (12.8 ± 2.7 years) completed the QEWP-C-5, LOC-ED-Q, and EDE, depressive and anxiety questionnaires, and adiposity assessment. Sensitivity, specificity, positive-predictive value, negative-predictive value, and diagnostic accuracy were calculated; Cochran's Q and McNemar's tests were used to compare measures. Receiver operating characteristic area under the curve (AUC) analyses were performed. Mood and adiposity based on LOC-eating presence and absence based on each measure were examined. RESULTS: The QEWP-C-5 and LOC-ED-Q demonstrated poor sensitivity (33%; 30%) and high specificity (95%; 96%) compared with the EDE. The AUCs suggested neither the QEWP-C-5 (0.64) nor the LOC-ED-Q (0.62) demonstrated acceptable diagnostic accuracy. Comparing distributions of LOC-eating presence between assessments, the QEWP-C-5 and EDE did not differ significantly (p = .10), while the LOC-ED-Q and EDE had significantly different distributions (p = .03). LOC-eating presence was associated with higher depressive and anxiety symptoms across all measures (ps < .02). Greater adiposity (ps < .02) was associated with LOC-eating presence on the EDE and LOC-ED-Q, and higher BMI z-score (p = .02) on the LOC-ED-Q. DISCUSSION: Neither the QEWP-C-5 nor the LOC-ED-Q was sensitive for identifying LOC-eating presence as determined by the EDE, although both were associated with greater mood symptoms. Research is needed to improve self-report questionnaires to better screen for LOC-eating presence among pediatric populations.


Assuntos
Comportamento Alimentar/psicologia , Transtornos da Alimentação e da Ingestão de Alimentos/complicações , Psicometria/métodos , Adolescente , Feminino , Humanos , Entrevista Psicológica , Masculino , Reprodutibilidade dos Testes , Inquéritos e Questionários
15.
J Endocr Soc ; 4(1): bvz022, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-32010873

RESUMO

Context and Objective: Leptin treatment has dramatic clinical effects on glucose and lipid metabolism in leptin-deficient patients with lipodystrophy. Further elucidation of metabolic effects of exogenous leptin therapy will shed light on understanding leptin physiology in humans. Our objective was to utilize metabolomic profiling to examine the changes associated with administration of short-term metreleptin therapy in patients with lipodystrophy. Study Design: We conducted a pre-post-treatment study in 19 patients (75% female) with varying forms of lipodystrophy (congenital generalized lipodystrophy, n = 10; acquired generalized lipodystrophy, n = 1; familial partial lipodystrophy, n = 8) who received daily subcutaneous metreleptin injections for a period of 16 to 23 weeks. A 3-hour oral glucose tolerance test and body composition measurements were conducted before and after the treatment period, and fasting blood samples were used for metabolomic profiling. The study outcome aimed at measuring changes in physiologically relevant metabolites before and after leptin therapy. Results: Metabolomic analysis revealed changes in pathways involving branched-chain amino acid metabolism, fatty acid oxidation, protein degradation, urea cycle, tryptophan metabolism, nucleotide catabolism, vitamin E, and steroid metabolism. Fold changes in pre- to post-treatment metabolite levels indicated increased breakdown of fatty acids, branched chain amino acids proteins, and nucleic acids. Conclusions: Leptin replacement therapy has significant effects on important metabolic pathways implicated in patients with lipodystrophy. Continued metabolomic studies may provide further insight into the mechanisms of action of leptin replacement therapy and provide novel biomarkers of lipodystrophy.Abbreviations: 1,5-AG, 1,5-anhydroglucitol; 11ßHSD1, 11-ß hydroxysteroid dehydrogenase 1; BCAA, branched-chain amino acid; FFA, free fatty acid; GC-MS, gas chromatography mass spectrometry; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-γ; m/z, mass to charge ratio; OGTT, oral glucose tolerance test; TDO, tryptophan 2,3-dioxygenase; TNF-α, tumor necrosis factor-α; UPLC-MS/MS, ultra-performance liquid chromatography-tandem mass spectrometry.

16.
Horm Metab Res ; 52(8): 562-577, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32040962

RESUMO

The diagnostic modalities, stratification tools, and treatment options for patients with thyroid cancer have rapidly evolved since the development of the American Thyroid Association (ATA) guidelines in 2015. This review compiles newer concepts in diagnosis, stratification tools and treatment options for patients with differentiated thyroid cancer (DTC), medullary thyroid carcinoma (MTC) and anaplastic thyroid cancer (ATC). Newer developments apply precision medicine in thyroid cancer patients to avoid over-treatment in low risk disease and under-treatment in high risk disease. Among novel patient-tailored therapies are selective RET inhibitors that have shown efficacy in the treatment of MTC with limited systemic toxicity compared with non-specific tyrosine kinase inhibitors. The combination of BRAF and MEK inhibitors have revolutionized management of BRAF V600E mutant ATC. Several immunotherapeutic agents are being actively investigated in the treatment of all forms of thyroid cancer. In this review, we describe the recent advances in the diagnosis and management of DTC, MTC, and ATC, with an emphasis on novel treatment modalities.


Assuntos
Biomarcadores Tumorais/antagonistas & inibidores , Biomarcadores Tumorais/genética , Mutação , Inibidores de Proteínas Quinases/uso terapêutico , Neoplasias da Glândula Tireoide/terapia , Tireoidectomia/métodos , Terapia Combinada , Gerenciamento Clínico , Humanos , Comunicação Interdisciplinar , Prognóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologia
17.
J Clin Endocrinol Metab ; 105(4)2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31903484

RESUMO

CONTEXT: Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumors that can secrete norepinephrine (NE). Brown adipose tissue (BAT) activation is mediated through the action of NE on ß-adrenoceptors (ß-ARs). In some malignancies, BAT activation is associated with higher cancer activity. OBJECTIVE: To study the relationship between BAT activation and PPGL clinical outcomes. DESIGN: A retrospective case-control study that included 342 patients with PPGLs who underwent 18F-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) imaging at the National Institutes of Health (NIH). We excluded all patients with parasympathetic tumors and those who underwent 18F-FDG PET/CT after PPGL resection. Scans of 205 patients were reviewed by 2 blinded nuclear medicine physicians; 16 patients had BAT activation on 18F-FDG PET/CT [7.80%; age 27.50 (15.00-45.50) years; 10 female/6 male; body mass index [BMI] 24.90 [19.60-25.35] kg/m2). From the remaining 189 patients, we selected 36 matched controls (age 34.4 [25.4-45.5] years; 21 female/15 male; BMI 25.0 [22.0-26.0] kg/m2). PRIMARY OUTCOME MEASURE: Overall survival. RESULTS: The presence of active BAT on 18F-FDG PET/CT was associated with decreased overall survival when compared with the control group (HRz 5.80; 95% CI, 1.05-32.05; P = 0.02). This association remained significant after adjusting for the SDHB mutation. Median plasma NE in the BAT group was higher than the control group [4.65 vs 0.55 times above the upper limit of normal; P < 0.01]. There was a significant association between higher plasma NE levels and mortality in PPGLs in both groups. CONCLUSIONS: Our findings suggest that the detection of BAT activity in PPGL patients is associated with higher mortality. We suggest that BAT activation could either be reflecting or contributing to a state of increased host stress that may predict poor outcome in metastatic PPGL.


Assuntos
Tecido Adiposo Marrom/patologia , Neoplasias das Glândulas Suprarrenais/mortalidade , Paraganglioma/mortalidade , Feocromocitoma/mortalidade , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos/metabolismo , Tecido Adiposo Marrom/diagnóstico por imagem , Adolescente , Neoplasias das Glândulas Suprarrenais/diagnóstico por imagem , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Estudos de Casos e Controles , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Paraganglioma/diagnóstico por imagem , Paraganglioma/patologia , Feocromocitoma/diagnóstico por imagem , Feocromocitoma/patologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
18.
Front Endocrinol (Lausanne) ; 11: 587065, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33551992

RESUMO

Background: Lutetium 177 (177Lu) - DOTATATE is a form of peptide receptor radionuclide therapy (PRRT) utilized in the treatment of neuroendocrine tumors. Data on 177Lu-DOTATATE-induced thyroid dysfunction is limited. Case Description: A 29-year-old male with SDHB positive metastatic paraganglioma enrolled under the 177Lu-DOTATATE trial (NCT03206060) underwent thyroid function test (TFT) evaluation comprised of thyroid stimulating hormone (TSH) and free thyroxine (FT4) immunoassay measurements per protocol prior to 177Lu-DOTATATE therapy. The TSH was suppressed [<0.01 µIU/ml (0.27-4.2 µIU/ml)], and FT4 was normal [1.3 ng/dl (0.9-1.7 ng/dl)]. The TSH receptor antibody and thyroid stimulating immunoglobulin index were undetectable [<1 IU/L (≤1.75 IU/L), and <1 (≤1.3) respectively], while the anti-thyroid peroxidase (anti-TPO) and anti-thyroglobulin (anti-Tg) antibodies were elevated [605 IU/ml (0.0-34.9 IU/ml), and 178 IU/ml (0.0-40.0 IU/ml) respectively]. Mass spectrometry on a stored (-80°C) plasma sample obtained one-month pre-PRRT revealed elevated total triiodothyronine (TT3) [235 ng/dl (65-193 ng/dl)] and FT4 [3.9 ng/dl (1.2-2.9 ng/dl)] levels. The patient was diagnosed with Hashimoto's thyrotoxicosis. However, the patient was asymptomatic. One month after the first dose of 200mCi 177Lu-DOTATATE, the patient noted fatigue and a 2.6 Kg weight gain. The TSH (73.04 µIU/ml), anti-TPO antibodies (>1,000 IU/ml), and anti-Tg antibodies (668 IU/ml) had substantially increased, with reductions in FT4 (0.3 ng/dl) and TT3 [54 ng/dl (87-169 ng/dl)]. Diagnostic gallium 68 - DOTATATE positron emission tomography-computed tomography performed prior to 177Lu-DOTATATE treatment revealed diffuse thyroid uptake. Post-therapy single-photon emission computed tomography also revealed diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Levothyroxine therapy was initiated, and the patient's symptoms resolved. Summary: We report, for the first time, a patient with asymptomatic primary hyperthyroidism who rapidly developed symptomatic primary hypothyroidism 1 month after 177Lu-DOTATATE therapy, accompanied by marked changes in TFTs and thyroid auto-antibody titers, with functional imaging evidence of diffuse uptake of 177Lu-DOTATATE in the thyroid gland. Conclusions: Thyroid dysfunction can be associated with PRRT. Thyroid uptake patterns on pre-treatment diagnostic somatostatin analog scans might predict individual susceptibility to PRRT-associated TFT disruption. Therefore, periodic evaluation of TFTs should be considered in patients receiving PRRT.


Assuntos
Hipotireoidismo/induzido quimicamente , Octreotida/análogos & derivados , Compostos Organometálicos/efeitos adversos , Paraganglioma/radioterapia , Compostos Radiofarmacêuticos/efeitos adversos , Adulto , Doenças Assintomáticas , Doença de Hashimoto/complicações , Doença de Hashimoto/diagnóstico , Humanos , Hipotireoidismo/diagnóstico por imagem , Hipotireoidismo/tratamento farmacológico , Masculino , Metástase Neoplásica/radioterapia , Octreotida/efeitos adversos , Octreotida/metabolismo , Compostos Organometálicos/metabolismo , Paraganglioma/complicações , Paraganglioma/metabolismo , Paraganglioma/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Compostos Radiofarmacêuticos/metabolismo , Succinato Desidrogenase/metabolismo , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/metabolismo , Glândula Tireoide/patologia , Tiroxina/uso terapêutico , Resultado do Tratamento
19.
Best Pract Res Clin Endocrinol Metab ; 33(6): 101371, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31866206

RESUMO

Hypophysitis is a heterogeneous condition that leads to inflammation of the sella and/or suprasellar region, potentially resulting in hormonal deficiencies and/or mass effects. A preponderance of hypophysitis subtypes have an underlying autoimmune aetiology. The overall incidence and prevalence of hypophysitis has dramatically increased over the past decade, mainly due to increased awareness of the condition in the medical community, improvements in imaging techniques, and a rise in the occurrence of certain forms of hypophysitis such as IgG4 hypophysitis (IgG4Hy) and immune checkpoint inhibitor induced hypophysitis (ICIHy). The clinical presentation varies from an asymptomatic condition to a fatal disease often as a result of electrolyte abnormalities due to glucocorticoid deficiency in the context of adrenal crisis from central adrenal insufficiency. Milder forms of hypophysitis are treated with replacement of deficient hormones while more acute presentations with mass effects require glucocorticoid therapy, immunosuppressive therapy or surgery. Timely diagnosis and interventions are keys to prevention of the lethal complications of this disease. In this review, we provide an update on the recent advances in the field of pituitary autoimmunity, with an emphasis on autoimmune hypophysitis and novel forms of hypophysitis such as anti-PIT1 hypophysitis, IgG4Hy and ICIHy.


Assuntos
Hipofisite , Hipofisite Autoimune/diagnóstico , Hipofisite Autoimune/terapia , Autoimunidade/fisiologia , Técnicas de Diagnóstico Endócrino/tendências , Humanos , Hipofisite/classificação , Hipofisite/diagnóstico , Hipofisite/terapia , Inflamação/diagnóstico , Inflamação/terapia , Doenças da Hipófise/classificação , Doenças da Hipófise/diagnóstico , Doenças da Hipófise/terapia , Terapias em Estudo/tendências
20.
Artigo em Inglês | MEDLINE | ID: mdl-31765326

RESUMO

Summary: Adrenococortical carcinoma (ACC) is a rare cancer, occurring at the rate of one case in two million person years. Cushing syndrome or a mixed picture of excess androgen and glucocorticoid production are the most common presentations of ACC. Other uncommon presentations include abdominal pain and adrenal incidentalomas. In the present report, a 71-year-old male presented with abdominal pain and was eventually diagnosed with ACC. He was found to have pulmonary thromboembolism following an investigation for hypoxemia, with the tumor thrombus extending upto the right atrium. This interesting case represents the unique presentation of a rare tumor, which if detected late or left untreated is associated with poor outcomes, highlighting the need for a low index of suspicion for ACC when similar presentations are encountered in clinical practice. Learning points: ACC is a rare but aggressive tumor. ACC commonly presents with rapid onset of hypercortisolism, combined hyperandrogenism and hypercortisolism, or uncommonly with compressive symptoms. Clinicians should have a low index of suspicion for ACC in patients presenting with rapid onset of symptoms related to hypercortisolism and/or hyperandrogenism. Venous thromboembolism and extension of the tumor thrombus to the right side of the heart is a very rare but serious complication of ACC that clinicans should be wary of. The increased risk of venous thromboembolism in ACC could be explained by direct tumor invasion, tumor thrombi or hypercoagulability secondary to hypercortisolism. Early diagnosis and prompt treatment can improve the long-term survival of patients with ACC.

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