New Approaches to the Evaluation and Treatment of Acromegaly

描述(申请人提供)：肢端肥大症是一种罕见的疾病，其特征是GH和IGF-I过多及其多系统不良反应。流行病学数据表明，肢端肥大症主要由心血管原因引起的发病率和死亡率增加，通常归因于肢端肥大症相关的代谢异常，包括胰岛素抵抗。然而，这些异常的病因和对心血管风险增加的贡献不一定与其他人群中类似的代谢综合征成分相同。相反，正如我们新的初步数据显示的那样，我们假设GH-IGF-I过度特异的脂肪组织调节失调(AT)和脂肪营养不良发生。我们认为，这种脂肪营养不良包括中央AT库减少但肌肉AT增加，导致胰岛素抵抗、脂肪因子和食欲激素失调、内皮细胞功能障碍，并最终增加活动期肢端肥大症的心血管风险。对肢端肥大症的生化控制应能逆转这些异常。然而，我们已经确定了一些患者的缓解伴随着显著的体重增加和C反应蛋白的升高。在他们中，我们假设随着GH/IGF-I的正常化，脂营养不良的逆转显著增加了中央AT、巨噬细胞的浸润和AT的炎症以及全身炎症。炎症是否持续，这些患者的最终身体成分，以及治疗后Ghrelin水平增加在刺激体重增加中的作用，需要确定。我们将通过在治疗前和治疗期间研究活动期肢端肥大症患者来验证这些假设，利用研究肢端肥大症和GH/IGF-I轴的新技术，包括通过MRI和1HMRS检查肌肉脂肪，通过1HMRS检查肝脏脂肪，检查脂肪组织中巨噬细胞的浸润和炎症，以及活检的内皮细胞的功能。我们还将把这些临床终点与我们的肢端肥大症的现代生化标记物联系起来，从而为肢端肥大症的治疗建立临床有效的生化指南。了解这种脂肪营养不良的后果及其逆转是至关重要的，因为针对肢端肥大症的新的有效医学疗法现在允许我们将治疗滴定到特定的生化目标，甚至是正常范围内的IGF-I靶点，这可能对心血管结果具有长期的临床意义。这一建议因我们独特的、正在进行的肢端肥大症队列研究的继续而得到加强。这项研究是由美国国立卫生研究院资助的唯一一项关于肢端肥大症的研究，为肢端肥大症的许多方面提供了新的重要数据，特别是其生化标志物。目前应用中研究的终点和结果只能通过对一个独特的、连续的、特征良好的队列进行长期跟踪才能实现，我们已经很好地开展了这一工作。肢端肥大症提供了一个模型，通过它我们可以提高我们对GH和IGF-I过量对脂肪组织、全身炎症、内皮功能障碍和心血管风险的影响的了解，这也适用于我们对GH的使用和在其他临床环境中过度使用的影响的理解。公共卫生相关性：肢端肥大症是一种罕见的疾病，由一种产生生长激素的垂体瘤引起，与发病率和死亡率的增加有关。在这个项目中，我们将利用现代生化方法、新技术和一项独特的、正在进行的大型前瞻性肢端肥大症队列研究来描述肢端肥大症的新特征，包括可能导致其发病率和死亡率增加的异常脂肪分布。我们的研究将有助于了解GH和IGF-I对体成分、脂肪组织炎症、内皮功能障碍和心血管风险的影响，这也适用于我们理解GH在其他临床环境中的使用和过度使用的影响。

DESCRIPTION (provided by applicant): Acromegaly is a rare disease characterized by excess GH and IGF-I and their multi-system adverse effects. Epidemiological data associate acromegaly with increased morbidity and mortality primarily from cardiovascular causes, which are often attributed to acromegaly's associated metabolic abnormalities including insulin resistance. However, these abnormalities' etiology and contribution to increased CV risk cannot necessarily be equated with those of similar metabolic syndrome components in other populations. Rather, as our novel preliminary data suggest, we hypothesize that a GH-IGF-I excess specific dysregulation of adipose tissue (AT) and lipodystrophy occur. This lipodystrophy, we propose, includes reduced central AT depots yet increased AT in muscle and contributes to insulin resistance, adipokine and appetite hormone dysregulation, endothelial cell dysfunction and ultimately increased CV risk in active acromegaly. Biochemical control of acromegaly should reverse these abnormalities. However, we have identified some patients whose remission is accompanied by significant weight gain and a rise in crp. In them, we hypothesize that as GH/IGF-I normalize, reversal of the lipodystrophy markedly increases central AT, macrophage infiltration and inflammation in AT and systemic inflammation. Whether inflammation persists and these patients' ultimate body composition as well as the role of post-therapy increases in ghrelin levels in stimulating weight gain need to be determined. We will test these hypotheses by studying patients with active acromegaly before and during therapies utilizing techniques novel to the study of acromegaly and the GH/IGF-I axis including examinations of muscle lipid by MRI and 1HMRS, hepatic lipid by 1HMRS, adipose tissue for macrophage infiltration and inflammation and function of biopsied endothelial cells. We will also relate these clinical endpoints to our modern biochemical markers of acromegaly and thereby establish clinically validated biochemical guidelines for acromegaly therapy. Understanding the consequences of this lipodystrophy and its reversal are crucial because new potent medical therapies for acromegaly now allow us to titrate therapy to particular biochemical goals and even a target for IGF-I within the spectrum of the normal range which may have long term clinical significance with regard to cardiovascular outcomes. This proposal is strengthened by its continuation of our unique, ongoing prospective acromegaly cohort study. This study, the only one on acromegaly funded by the NIH, has provided novel important data on a number of aspects of acromegaly in particular its biochemical markers. The endpoints and outcomes studied in the current application can only be achieved with long term follow up of a uniquely large, consecutive, well-characterized cohort, which we have well underway. Acromegaly provides a model through which we can improve our knowledge about the effects of GH and IGF-I excess on adipose tissue, systemic inflammation, endothelial dysfunction and CV risk which is also applicable to our understanding of the effects of GH use and over-use in other clinical settings. PUBLIC HEALTH RELEVANCE: Acromegaly, a rare disease due to a growth hormone producing pituitary tumor, is associated with increased morbidity and mortality. In this project we will utilize modern biochemical methods, novel techniques and a uniquely large, ongoing prospective acromegaly cohort study to characterize novel features of acromegaly including an abnormal fat distribution that may contribute significantly to its increased morbidity and mortality. Our study will lead to important knowledge about the effects GH and IGF-I on body composition, adipose tissue inflammation, endothelial dysfunction and cardiovascular risk which is also applicable to our understanding of the effects of GH use and over-use in other clinical settings.