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The Hypothalamus-pituitary-adrenocortical Response to Critical Illness: A Concept in Need of Revision. 下丘脑-垂体-肾上腺皮质对危重疾病的反应:一个需要修正的概念。
IF 20.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-09 DOI: 10.1210/endrev/bnad021
Lies Langouche, Arno Téblick, Jan Gunst, Greet Van den Berghe

Based on insights obtained during the past decade, the classical concept of an activated hypothalamus-pituitary-adrenocortical axis in response to critical illness is in need of revision. After a brief central hypothalamus-pituitary-adrenocortical axis activation, the vital maintenance of increased systemic cortisol availability and action in response to critical illness is predominantly driven by peripheral adaptations rather than by an ongoing centrally activated several-fold increased production and secretion of cortisol. Besides the known reduction of cortisol-binding proteins that increases free cortisol, these peripheral responses comprise suppressed cortisol metabolism in liver and kidney, prolonging cortisol half-life, and local alterations in expression of 11βHSD1, glucocorticoid receptor-α (GRα), and FK506 binding protein 5 (FKBP51) that appear to titrate increased GRα action in vital organs and tissues while reducing GRα action in neutrophils, possibly preventing immune-suppressive off-target effects of increased systemic cortisol availability. Peripherally increased cortisol exerts negative feed-back inhibition at the pituitary level impairing processing of pro-opiomelanocortin into ACTH, thereby reducing ACTH-driven cortisol secretion, whereas ongoing central activation results in increased circulating pro-opiomelanocortin. These alterations seem adaptive and beneficial for the host in the short term. However, as a consequence, patients with prolonged critical illness who require intensive care for weeks or longer may develop a form of central adrenal insufficiency. The new findings supersede earlier concepts such as "relative," as opposed to "absolute," adrenal insufficiency and generalized systemic glucocorticoid resistance in the critically ill. The findings also question the scientific basis for broad implementation of stress dose hydrocortisone treatment of patients suffering from acute septic shock solely based on assumption of cortisol insufficiency.

基于过去十年获得的见解,对危重疾病反应的激活下丘脑-垂体-肾上腺皮质轴的经典概念需要修订。在短暂的中枢下丘脑-垂体-肾上腺皮质轴激活后,增加的全身皮质醇可用性和对危重疾病的反应的重要维持主要是由外周适应驱动的,而不是由持续的中央激活的几倍增加的皮质醇的产生和分泌驱动的。除了已知的增加游离皮质醇的皮质醇结合蛋白的减少外,这些外周反应还包括肝脏和肾脏中皮质醇代谢的抑制,皮质醇半衰期的延长,以及11βHSD1、糖皮质激素受体-α (GRα)和FK506结合蛋白5 (FKBP51)表达的局部改变,这些表达似乎会增加重要器官和组织中GRα的作用,同时降低中性粒细胞中GRα的作用。可能防止免疫抑制脱靶效应增加全身皮质醇可用性。外周升高的皮质醇在垂体水平上产生负反馈抑制,损害促肾上腺皮质激素的加工过程,从而减少促肾上腺皮质激素驱动的皮质醇分泌,而持续的中枢激活导致循环促肾上腺皮质激素的增加。这些变化似乎是适应性的,在短期内对宿主有益。然而,结果是,需要重症监护数周或更长时间的重症患者可能会出现中枢性肾上腺功能不全。新发现取代了早期的概念,如“相对”,而不是“绝对”,肾上腺功能不全和危重患者全身糖皮质激素抵抗。研究结果还质疑了仅仅基于皮质醇不足假设而广泛实施应激剂量氢化可的松治疗急性感染性休克患者的科学依据。
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引用次数: 0
Nicotinamide Adenine Dinucleotide in Aging Biology: Potential Applications and Many Unknowns. 烟酰胺腺嘌呤二核苷酸在衰老生物学中的潜在应用和许多未知。
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-09 DOI: 10.1210/endrev/bnad019
Shalender Bhasin, Douglas Seals, Marie Migaud, Nicolas Musi, Joseph A Baur

Recent research has unveiled an expansive role of NAD+ in cellular energy generation, redox reactions, and as a substrate or cosubstrate in signaling pathways that regulate health span and aging. This review provides a critical appraisal of the clinical pharmacology and the preclinical and clinical evidence for therapeutic effects of NAD+ precursors for age-related conditions, with a particular focus on cardiometabolic disorders, and discusses gaps in current knowledge. NAD+ levels decrease throughout life; age-related decline in NAD+ bioavailability has been postulated to be a contributor to many age-related diseases. Raising NAD+ levels in model organisms by administration of NAD+ precursors improves glucose and lipid metabolism; attenuates diet-induced weight gain, diabetes, diabetic kidney disease, and hepatic steatosis; reduces endothelial dysfunction; protects heart from ischemic injury; improves left ventricular function in models of heart failure; attenuates cerebrovascular and neurodegenerative disorders; and increases health span. Early human studies show that NAD+ levels can be raised safely in blood and some tissues by oral NAD+ precursors and suggest benefit in preventing nonmelanotic skin cancer, modestly reducing blood pressure and improving lipid profile in older adults with obesity or overweight; preventing kidney injury in at-risk patients; and suppressing inflammation in Parkinson disease and SARS-CoV-2 infection. Clinical pharmacology, metabolism, and therapeutic mechanisms of NAD+ precursors remain incompletely understood. We suggest that these early findings provide the rationale for adequately powered randomized trials to evaluate the efficacy of NAD+ augmentation as a therapeutic strategy to prevent and treat metabolic disorders and age-related conditions.

最近的研究揭示了NAD+在细胞能量生成、氧化还原反应中的广泛作用,并在调节健康寿命和衰老的信号通路中作为底物或共底物。本综述对NAD+前体治疗年龄相关疾病的临床药理学、临床前和临床证据进行了批判性评估,特别关注心脏代谢疾病,并讨论了当前知识的空白。NAD+水平在整个生命过程中下降;年龄相关的NAD+生物利用度下降被认为是许多年龄相关疾病的一个因素。通过给药NAD+前体提高模式生物的NAD+水平可改善糖脂代谢;减轻饮食引起的体重增加、糖尿病、糖尿病肾病和肝脂肪变性;减少内皮功能障碍;保护心脏免受缺血性损伤;改善心力衰竭模型左心室功能;减轻脑血管和神经退行性疾病;延长了健康寿命。早期的人体研究表明,口服NAD+前体可以安全地提高血液和某些组织中的NAD+水平,并表明在预防非黑色素皮肤癌、适度降低血压和改善肥胖或超重老年人的血脂水平方面有好处;预防高危患者肾损伤;抑制帕金森病和SARS-CoV-2感染的炎症。NAD+前体的临床药理学、代谢和治疗机制仍不完全清楚。我们认为,这些早期发现为充分有力的随机试验提供了理论依据,以评估NAD+增强作为预防和治疗代谢紊乱和年龄相关疾病的治疗策略的有效性。
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引用次数: 0
Treating the Side Effects of Exogenous Glucocorticoids; Can We Separate the Good From the Bad? 外源性糖皮质激素不良反应的治疗我们能区分好与坏吗?
IF 20.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-09 DOI: 10.1210/endrev/bnad016
Riccardo Pofi, Giorgio Caratti, David W Ray, Jeremy W Tomlinson

It is estimated that 2% to 3% of the population are currently prescribed systemic or topical glucocorticoid treatment. The potent anti-inflammatory action of glucocorticoids to deliver therapeutic benefit is not in doubt. However, the side effects associated with their use, including central weight gain, hypertension, insulin resistance, type 2 diabetes (T2D), and osteoporosis, often collectively termed iatrogenic Cushing's syndrome, are associated with a significant health and economic burden. The precise cellular mechanisms underpinning the differential action of glucocorticoids to drive the desirable and undesirable effects are still not completely understood. Faced with the unmet clinical need to limit glucocorticoid-induced adverse effects alongside ensuring the preservation of anti-inflammatory actions, several strategies have been pursued. The coprescription of existing licensed drugs to treat incident adverse effects can be effective, but data examining the prevention of adverse effects are limited. Novel selective glucocorticoid receptor agonists and selective glucocorticoid receptor modulators have been designed that aim to specifically and selectively activate anti-inflammatory responses based upon their interaction with the glucocorticoid receptor. Several of these compounds are currently in clinical trials to evaluate their efficacy. More recently, strategies exploiting tissue-specific glucocorticoid metabolism through the isoforms of 11β-hydroxysteroid dehydrogenase has shown early potential, although data from clinical trials are limited. The aim of any treatment is to maximize benefit while minimizing risk, and within this review we define the adverse effect profile associated with glucocorticoid use and evaluate current and developing strategies that aim to limit side effects but preserve desirable therapeutic efficacy.

据估计,目前有2%至3%的人接受全身或局部糖皮质激素治疗。糖皮质激素的有效抗炎作用提供治疗效益是毫无疑问的。然而,与它们的使用相关的副作用,包括中心体重增加、高血压、胰岛素抵抗、2型糖尿病(T2D)和骨质疏松症,通常统称为医源性库欣综合征,与重大的健康和经济负担相关。支持糖皮质激素驱动理想和不理想效果的不同作用的精确细胞机制仍未完全了解。面对未满足的临床需求,限制糖皮质激素诱导的不良反应,同时确保保持抗炎作用,已经采取了几种策略。现有许可药物的共同处方治疗偶发不良反应可能有效,但检查预防不良反应的数据有限。新的选择性糖皮质激素受体激动剂和选择性糖皮质激素受体调节剂已经被设计出来,目的是特异性和选择性地激活基于它们与糖皮质激素受体相互作用的抗炎反应。其中一些化合物目前正在进行临床试验,以评估其疗效。最近,通过11β-羟基类固醇脱氢酶的同工型来开发组织特异性糖皮质激素代谢的策略已经显示出早期的潜力,尽管来自临床试验的数据有限。任何治疗的目标都是在最小化风险的同时最大化获益,在本综述中,我们定义了与糖皮质激素使用相关的不良反应概况,并评估了当前和正在开发的旨在限制副作用但保持理想治疗效果的策略。
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引用次数: 0
Reevaluating the Role of Progesterone in Ovarian Cancer: Is Progesterone Always Protective? 重新评估黄体酮在卵巢癌中的作用:黄体酮是否总是有保护作用?
IF 22 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-11-09 DOI: 10.1210/endrev/bnad018
Laura J Mauro, Angela Spartz, Julia R Austin, Carol A Lange

Ovarian cancer (OC) represents a collection of rare but lethal gynecologic cancers where the difficulty of early detection due to an often-subtle range of abdominal symptoms contributes to high fatality rates. With the exception of BRCA1/2 mutation carriers, OC most often manifests as a post-menopausal disease, a time in which the ovaries regress and circulating reproductive hormones diminish. Progesterone is thought to be a "protective" hormone that counters the proliferative actions of estrogen, as can be observed in the uterus or breast. Like other steroid hormone receptor family members, the transcriptional activity of the nuclear progesterone receptor (nPR) may be ligand dependent or independent and is fully integrated with other ubiquitous cell signaling pathways often altered in cancers. Emerging evidence in OC models challenges the singular protective role of progesterone/nPR. Herein, we integrate the historical perspective of progesterone on OC development and progression with exciting new research findings and critical interpretations to help paint a broader picture of the role of progesterone and nPR signaling in OC. We hope to alleviate some of the controversy around the role of progesterone and give insight into the importance of nPR actions in disease progression. A new perspective on the role of progesterone and nPR signaling integration will raise awareness to the complexity of nPRs and nPR-driven gene regulation in OC, help to reveal novel biomarkers, and lend critical knowledge for the development of better therapeutic strategies.

卵巢癌(OC)是一种罕见但致命的妇科癌症,由于腹部症状通常很微妙,难以早期发现,导致死亡率高。除BRCA1/2突变携带者外,卵巢癌最常表现为绝经后疾病,在此期间卵巢退化,循环生殖激素减少。黄体酮被认为是一种“保护性”激素,可以在子宫或乳房中观察到雌激素的增殖作用。与其他类固醇激素受体家族成员一样,核孕激素受体(nPR)的转录活性可能依赖于配体或独立,并与癌症中经常改变的其他普遍存在的细胞信号通路完全整合。在OC模型中出现的新证据挑战了黄体酮/nPR的单一保护作用。在此,我们将黄体酮在OC发生和发展中的历史观点与令人兴奋的新研究发现和关键解释结合起来,以帮助描绘黄体酮和nPR信号在OC中的作用的更广泛的图景。我们希望能够减轻围绕黄体酮作用的一些争议,并深入了解nPR在疾病进展中的重要性。关于孕激素和nPR信号整合作用的新视角将提高对OC中nPR和nPR驱动基因调控复杂性的认识,有助于揭示新的生物标志物,并为开发更好的治疗策略提供关键知识。
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引用次数: 0
AMPK and the Endocrine Control of Metabolism. AMPK与代谢的内分泌控制。
IF 20.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-15 DOI: 10.1210/endrev/bnad012
Logan K Townsend, Gregory R Steinberg

Complex multicellular organisms require a coordinated response from multiple tissues to maintain whole-body homeostasis in the face of energetic stressors such as fasting, cold, and exercise. It is also essential that energy is stored efficiently with feeding and the chronic nutrient surplus that occurs with obesity. Mammals have adapted several endocrine signals that regulate metabolism in response to changes in nutrient availability and energy demand. These include hormones altered by fasting and refeeding including insulin, glucagon, glucagon-like peptide-1, catecholamines, ghrelin, and fibroblast growth factor 21; adipokines such as leptin and adiponectin; cell stress-induced cytokines like tumor necrosis factor alpha and growth differentiating factor 15, and lastly exerkines such as interleukin-6 and irisin. Over the last 2 decades, it has become apparent that many of these endocrine factors control metabolism by regulating the activity of the AMPK (adenosine monophosphate-activated protein kinase). AMPK is a master regulator of nutrient homeostasis, phosphorylating over 100 distinct substrates that are critical for controlling autophagy, carbohydrate, fatty acid, cholesterol, and protein metabolism. In this review, we discuss how AMPK integrates endocrine signals to maintain energy balance in response to diverse homeostatic challenges. We also present some considerations with respect to experimental design which should enhance reproducibility and the fidelity of the conclusions.

复杂的多细胞生物需要多个组织的协调反应来维持整个身体在面对能量压力(如禁食、寒冷和运动)时的稳态。通过进食和肥胖引起的慢性营养过剩来有效地储存能量也很重要。哺乳动物已经适应了几种调节新陈代谢的内分泌信号,以应对营养可利用性和能量需求的变化。这些包括通过禁食和再喂养改变的激素,包括胰岛素、胰高血糖素、胰高血糖素样肽-1、儿茶酚胺、胃饥饿素和成纤维细胞生长因子21;脂肪因子,如瘦素和脂联素;细胞应激诱导的细胞因子,如肿瘤坏死因子α和生长分化因子15,最后是运动因子,如白细胞介素-6和鸢尾素。在过去的20年里,人们发现许多内分泌因子通过调节AMPK(单磷酸腺苷活化蛋白激酶)的活性来控制代谢。AMPK是营养平衡的主要调节因子,磷酸化超过100种不同的底物,这些底物对控制自噬、碳水化合物、脂肪酸、胆固醇和蛋白质代谢至关重要。在这篇综述中,我们讨论了AMPK如何整合内分泌信号来维持能量平衡,以应对各种稳态挑战。我们还提出了一些关于实验设计的考虑,这应该提高结论的可重复性和保真度。
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引用次数: 4
Syndrome of Inappropriate Antidiuresis: From Pathophysiology to Management. 不适当抗利尿综合征:从病理生理到治疗。
IF 20.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-15 DOI: 10.1210/endrev/bnad010
Annabelle M Warren, Mathis Grossmann, Mirjam Christ-Crain, Nicholas Russell

Hyponatremia is the most common electrolyte disorder, affecting more than 15% of patients in the hospital. Syndrome of inappropriate antidiuresis (SIAD) is the most frequent cause of hypotonic hyponatremia, mediated by nonosmotic release of arginine vasopressin (AVP, previously known as antidiuretic hormone), which acts on the renal V2 receptors to promote water retention. There are a variety of underlying causes of SIAD, including malignancy, pulmonary pathology, and central nervous system pathology. In clinical practice, the etiology of hyponatremia is frequently multifactorial and the management approach may need to evolve during treatment of a single episode. It is therefore important to regularly reassess clinical status and biochemistry, while remaining alert to potential underlying etiological factors that may become more apparent during the course of treatment. In the absence of severe symptoms requiring urgent intervention, fluid restriction (FR) is widely endorsed as the first-line treatment for SIAD in current guidelines, but there is considerable controversy regarding second-line therapy in instances where FR is unsuccessful, which occurs in around half of cases. We review the epidemiology, pathophysiology, and differential diagnosis of SIAD, and summarize recent evidence for therapeutic options beyond FR, with a focus on tolvaptan, urea, and sodium-glucose cotransporter 2 inhibitors.

低钠血症是最常见的电解质紊乱,影响到医院15%以上的患者。不适当抗利尿综合征(SIAD)是低渗性低钠血症的最常见原因,由精氨酸抗利尿素(AVP,以前称为抗利尿激素)的非渗透性释放介导,其作用于肾脏V2受体促进水潴留。SIAD的病因多种多样,包括恶性肿瘤、肺部病理和中枢神经系统病理。在临床实践中,低钠血症的病因往往是多因素的,治疗方法可能需要在单个发作的治疗过程中不断发展。因此,定期重新评估临床状况和生物化学是很重要的,同时对潜在的潜在病因保持警惕,这些病因可能在治疗过程中变得更加明显。在没有需要紧急干预的严重症状的情况下,液体限制(FR)在当前指南中被广泛认可为SIAD的一线治疗,但在FR不成功的情况下,二线治疗存在相当大的争议,约有一半的病例发生。我们回顾了SIAD的流行病学、病理生理学和鉴别诊断,并总结了除FR之外的治疗选择的最新证据,重点是托伐普坦、尿素和钠-葡萄糖共转运蛋白2抑制剂。
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引用次数: 3
Signaling Pathways of the Insulin-like Growth Factor Binding Proteins. 胰岛素样生长因子结合蛋白的信号通路。
IF 20.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-15 DOI: 10.1210/endrev/bnad008
Robert C Baxter

The 6 high-affinity insulin-like growth factor binding proteins (IGFBPs) are multifunctional proteins that modulate cell signaling through multiple pathways. Their canonical function at the cellular level is to impede access of insulin-like growth factor (IGF)-1 and IGF-2 to their principal receptor IGF1R, but IGFBPs can also inhibit, or sometimes enhance, IGF1R signaling either through their own post-translational modifications, such as phosphorylation or limited proteolysis, or by their interactions with other regulatory proteins. Beyond the regulation of IGF1R activity, IGFBPs have been shown to modulate cell survival, migration, metabolism, and other functions through mechanisms that do not appear to involve the IGF-IGF1R system. This is achieved by interacting directly or functionally with integrins, transforming growth factor β family receptors, and other cell-surface proteins as well as intracellular ligands that are intermediates in a wide range of pathways. Within the nucleus, IGFBPs can regulate the diverse range of functions of class II nuclear hormone receptors and have roles in both cell senescence and DNA damage repair by the nonhomologous end-joining pathway, thus potentially modifying the efficacy of certain cancer therapeutics. They also modulate some immune functions and may have a role in autoimmune conditions such as rheumatoid arthritis. IGFBPs have been proposed as attractive therapeutic targets, but their ubiquity in the circulation and at the cellular level raises many challenges. By understanding the diversity of regulatory pathways with which IGFBPs interact, there may still be therapeutic opportunities based on modulation of IGFBP-dependent signaling.

6种高亲和力胰岛素样生长因子结合蛋白(igfbp)是通过多种途径调节细胞信号传导的多功能蛋白。它们在细胞水平上的典型功能是阻碍胰岛素样生长因子(IGF)-1和IGF-2进入其主要受体IGF1R,但igfbp也可以通过其自身的翻译后修饰(如磷酸化或有限的蛋白质水解)或通过与其他调节蛋白的相互作用来抑制或有时增强IGF1R信号。除了调节IGF1R活性外,igfbp还通过似乎不涉及IGF-IGF1R系统的机制调节细胞存活、迁移、代谢和其他功能。这是通过与整合素、转化生长因子β家族受体和其他细胞表面蛋白以及作为多种途径中间体的细胞内配体直接或功能性地相互作用来实现的。在细胞核内,igfbp可以调节II类核激素受体的多种功能,并通过非同源末端连接途径在细胞衰老和DNA损伤修复中发挥作用,从而可能改变某些癌症治疗药物的疗效。它们还能调节某些免疫功能,并可能在类风湿性关节炎等自身免疫性疾病中发挥作用。igfbp已被认为是有吸引力的治疗靶点,但它们在循环和细胞水平上的普遍存在带来了许多挑战。通过了解igfbp相互作用的调节途径的多样性,可能仍然存在基于igfbp依赖性信号调节的治疗机会。
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引用次数: 4
Biochemical Assessment of Pheochromocytoma and Paraganglioma. 嗜铬细胞瘤和副神经节瘤的生化评价。
IF 20.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-15 DOI: 10.1210/endrev/bnad011
Graeme Eisenhofer, Christina Pamporaki, Jacques W M Lenders

Pheochromocytoma and paraganglioma (PPGL) require prompt consideration and efficient diagnosis and treatment to minimize associated morbidity and mortality. Once considered, appropriate biochemical testing is key to diagnosis. Advances in understanding catecholamine metabolism have clarified why measurements of the O-methylated catecholamine metabolites rather than the catecholamines themselves are important for effective diagnosis. These metabolites, normetanephrine and metanephrine, produced respectively from norepinephrine and epinephrine, can be measured in plasma or urine, with choice according to available methods or presentation of patients. For patients with signs and symptoms of catecholamine excess, either test will invariably establish the diagnosis, whereas the plasma test provides higher sensitivity than urinary metanephrines for patients screened due to an incidentaloma or genetic predisposition, particularly for small tumors or in patients with an asymptomatic presentation. Additional measurements of plasma methoxytyramine can be important for some tumors, such as paragangliomas, and for surveillance of patients at risk of metastatic disease. Avoidance of false-positive test results is best achieved by plasma measurements with appropriate reference intervals and preanalytical precautions, including sampling blood in the fully supine position. Follow-up of positive results, including optimization of preanalytics for repeat tests or whether to proceed directly to anatomic imaging or confirmatory clonidine tests, depends on the test results, which can also suggest likely size, adrenal vs extra-adrenal location, underlying biology, or even metastatic involvement of a suspected tumor. Modern biochemical testing now makes diagnosis of PPGL relatively simple. Integration of artificial intelligence into the process should make it possible to fine-tune these advances.

嗜铬细胞瘤和副神经节瘤(PPGL)需要及时考虑和有效的诊断和治疗,以尽量减少相关的发病率和死亡率。一旦考虑,适当的生化检测是诊断的关键。对儿茶酚胺代谢的理解取得了进展,阐明了为什么测量o甲基化儿茶酚胺代谢物而不是儿茶酚胺本身对有效诊断很重要。这些代谢物,去甲肾上腺素和肾上腺素分别由去甲肾上腺素和肾上腺素产生,可在血浆或尿液中测量,可根据现有方法或患者的表现进行选择。对于有儿茶酚胺过量体征和症状的患者,两种检测方法都能确定诊断,而对于因偶发瘤或遗传易感性而筛查的患者,特别是小肿瘤或无症状患者,血浆检测比尿肾上腺素检测灵敏度更高。血浆甲氧基酪胺的额外测量对于某些肿瘤(如副神经节瘤)和有转移性疾病风险的患者的监测可能是重要的。避免假阳性测试结果的最佳方法是采用适当的参考间隔和分析前预防措施进行血浆测量,包括完全仰卧位采血。阳性结果的随访,包括优化重复检查的预分析,或是否直接进行解剖成像或确证性可乐定检查,取决于检查结果,这也可以提示可能的大小、肾上腺与肾上腺外的位置、潜在的生物学,甚至可疑肿瘤的转移性累及。现代生化检测使PPGL的诊断相对简单。将人工智能整合到这一过程中,应该可以对这些进步进行微调。
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引用次数: 4
Medullary Thyroid Cancer: Updates and Challenges. 甲状腺髓样癌:最新进展和挑战。
IF 20.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-15 DOI: 10.1210/endrev/bnad013
Matti L Gild, Roderick J Clifton-Bligh, Lori J Wirth, Bruce G Robinson

A personalized approach to the management of medullary thyroid cancer (MTC) presents several challenges; however, in the past decade significant progress has been made in both diagnostic and treatment modalities. Germline rearranged in transfection (RET) testing in multiple endocrine neoplasia 2 and 3, and somatic RET testing in sporadic MTC have revolutionized the treatment options available to patients. Positron emission tomography imaging with novel radioligands has improved characterization of disease and a new international grading system can predict prognosis. Systemic therapy for persistent and metastatic disease has evolved significantly with targeted kinase therapy especially for those harboring germline or somatic RET variants. Selpercatinib and pralsetinib are highly selective RET kinase inhibitors that have shown improved progression-free survival with better tolerability than outcomes seen in earlier multikinase inhibitor studies. Here we discuss changes in paradigms for MTC patients: from determining RET alteration status upfront to novel techniques for the evaluation of this heterogenous disease. Successes and challenges with kinase inhibitor use will illustrate how managing this rare malignancy continues to evolve.

个性化的方法来管理甲状腺髓样癌(MTC)提出了几个挑战;然而,在过去十年中,在诊断和治疗方式方面取得了重大进展。多种内分泌肿瘤2型和3型的生殖系重排转染(RET)检测以及散发性MTC的体细胞RET检测彻底改变了患者的治疗选择。新型放射配体的正电子发射断层成像改善了疾病的表征,新的国际分级系统可以预测预后。持续性和转移性疾病的全身治疗随着靶向激酶治疗的发展而显著发展,特别是对于那些携带种系或体细胞RET变异的疾病。Selpercatinib和pralsetinib是高度选择性的RET激酶抑制剂,与早期的多激酶抑制剂研究相比,它们已显示出改善的无进展生存期和更好的耐受性。在这里,我们讨论了MTC患者模式的变化:从预先确定RET改变状态到评估这种异质性疾病的新技术。使用激酶抑制剂的成功和挑战将说明如何管理这种罕见的恶性肿瘤继续发展。
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引用次数: 2
Molecular and Clinical Spectrum of Primary Hyperparathyroidism. 原发性甲状旁腺功能亢进的分子和临床谱。
IF 20.3 1区 医学 Q1 ENDOCRINOLOGY & METABOLISM Pub Date : 2023-09-15 DOI: 10.1210/endrev/bnad009
Smita Jha, William F Simonds

Recent data suggest an increase in the overall incidence of parathyroid disorders, with primary hyperparathyroidism (PHPT) being the most prevalent parathyroid disorder. PHPT is associated with morbidities (fractures, kidney stones, chronic kidney disease) and increased risk of death. The symptoms of PHPT can be nonspecific, potentially delaying the diagnosis. Approximately 15% of patients with PHPT have an underlying heritable form of PHPT that may be associated with extraparathyroidal manifestations, requiring active surveillance for these manifestations as seen in multiple endocrine neoplasia type 1 and 2A. Genetic testing for heritable forms should be offered to patients with multiglandular disease, recurrent PHPT, young onset PHPT (age ≤40 years), and those with a family history of parathyroid tumors. However, the underlying genetic cause for the majority of patients with heritable forms of PHPT remains unknown. Distinction between sporadic and heritable forms of PHPT is useful in surgical planning for parathyroidectomy and has implications for the family. The genes currently known to be associated with heritable forms of PHPT account for approximately half of sporadic parathyroid tumors. But the genetic cause in approximately half of the sporadic parathyroid tumors remains unknown. Furthermore, there is no systemic therapy for parathyroid carcinoma, a rare but potentially fatal cause of PHPT. Improved understanding of the molecular characteristics of parathyroid tumors will allow us to identify biomarkers for diagnosis and novel targets for therapy.

最近的数据显示甲状旁腺疾病的总体发病率有所增加,原发性甲状旁腺功能亢进症(PHPT)是最常见的甲状旁腺疾病。PHPT与发病率(骨折、肾结石、慢性肾病)和死亡风险增加有关。PHPT的症状可能是非特异性的,可能会延迟诊断。大约15%的PHPT患者具有潜在的遗传性PHPT,可能与甲状旁腺外表现相关,需要积极监测这些表现,如1型和2A型多发性内分泌肿瘤。对于多腺疾病、复发性PHPT、年轻发病PHPT(年龄≤40岁)和有甲状旁腺肿瘤家族史的患者,应提供遗传形式的基因检测。然而,大多数遗传性PHPT患者的潜在遗传原因仍然未知。区分散发和遗传形式的PHPT在甲状旁腺切除术的手术计划中是有用的,并对家族有影响。目前已知与遗传性PHPT相关的基因约占散发性甲状旁腺肿瘤的一半。但是大约一半散发性甲状旁腺肿瘤的遗传原因仍不清楚。此外,甲状旁腺癌是一种罕见但可能致命的PHPT病因,目前尚无系统性治疗方法。提高对甲状旁腺肿瘤分子特征的理解将使我们能够确定诊断的生物标志物和新的治疗靶点。
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引用次数: 1
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Endocrine reviews
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