Characterization of the Pathogenesis of Lymphangioleiomyomatosis (LAM)

本研究的目的是确定成年女性TSC的临床表现和严重程度。在1995至2009年间，有79名年龄在18岁或以上的女性参加了这项研究。采用病史、体格检查、肺功能检查、胸部X光、腹部CT、高分辨率胸部CT和脑磁共振成像对患者进行评估。其中45名患者在成年后接受了TSC诊断。其中30人在儿童时期符合TSC的临床标准，但中位数为22年未被诊断，15人在表现出足够的疾病特征做出诊断之前超过18岁。与儿童时期诊断的人相比，成年外显者的主要TSC特征更少，皮肤损害更少，不太可能发生癫痫，更有可能出现肺淋巴管肌瘤病或血管肌脂肪瘤。没有纳入男性，患者偏向于患有肺淋巴管肌瘤病的患者。在这项研究中，成年后接受TSC诊断的女性要么在晚年表现出TSC症状，要么经历了显著的延迟诊断，但仍有发生危及生命的肺和肾TSC表现的风险。在首次出现症状时未能认识到TSC，会增加发病率和死亡率，因为筛查和干预被推迟了，早期诊断可以为个人及其家人提供做出知情生育决定的机会。 我们研究的目的是评估西罗莫司对患有快速进展性或严重肺部疾病的LAM患者以及乳糜液和淋巴管肌瘤患者的疗效，这些患者中西罗莫司尚未进行测试。由于大多数患者参与了美国国立卫生研究院的自然病史研究，我们有大多数患者在西罗莫司治疗前几年的生理学和放射学数据，因此能够比较治疗前和治疗后的数据。 在西罗莫司治疗前和治疗期间测量肺功能、乳糜液和淋巴管肌瘤。在西罗莫司治疗前的平均2.5年中，第一秒用力呼气量(FEV1)和肺弥散能力(DLCO)分别下降了2.80.8%和4.80.9%。相比之下，在西罗莫司治疗的平均2.6年期间，预计FEV1和DLCO每年分别增加1.80.5%和0.80.5%(p&lt；0.001)。12例乳糜性积液和11例淋巴管肌瘤患者的这些异常症状几乎完全消失。在12名患者中的两名患者中，西罗莫司治疗使胸腔积液停止引流。西罗莫司的治疗与改善或稳定肺功能以及减少淋巴管肌瘤病患者的乳糜液和淋巴管肌瘤的大小有关。

The purpose of this study was to determine the clinical presentation and severity of TSC in adult women. Seventy-nine women, age eighteen or older were enrolled between 1995 and 2009. Patients were evaluated using history, physical examination, pulmonary function testing, chest X-ray, abdominal computed tomography, high-resolution chest computed tomography and brain magnetic resonance imaging. Forty-five of the patients received a TSC diagnosis in adulthood. Thirty of these met clinical criteria for TSC in childhood but remained undiagnosed for a median of 22 years, and fifteen were greater than 18 years old before manifesting sufficient disease characteristics to make the diagnosis. Compared to those diagnosed in childhood, individuals with adult penetrance had fewer major TSC features, fewer skin lesions, were less likely to have seizures, and were more likely to present with pulmonary lymphangioleiomyomatosis or angiomyolipomas. No males were included and patients were biased towards those having pulmonary lymphangioleiomyomatosis. In this study, women who received a TSC diagnosis in adulthood either manifested TSC symptoms later in life or experienced a significant delay to diagnosis, but were still at risk for developing life-threatening pulmonary and renal TSC manifestations. Failure to recognize TSC when manifestations first appear contributes to increased morbidity and mortality because screening and interventions are delayed and early diagnosis can offer individuals and their families an opportunity to make informed childbearing decisions. The aim of our study was to evaluate the effect of sirolimus in LAM patients with rapidly progressive or severe lung disease and those with chylous effusions and lymphangioleiomyomas, a population in whom sirolimus has not been tested. Because most patients were participating in a natural history study at National Institutes of Health, we had physiologic and radiologic data preceding sirolimus therapy for several years for most patients and, therefore, were able to compare pre- and post-therapy data. Lung function, chylous effusions, and lymphangioleiomyomas before and during sirolimus therapy were measured. During a mean of 2.5 years before sirolimus therapy, forced expiratory volume in the first second (FEV1) and lung diffusion capacity (DLCO) declined, respectively, 2.80.8 and 4.80.9 % predicted per year. In contrast, during a mean of 2.6 years of sirolimus therapy, FEV1 and DLCO, increased, respectively, 1.80.5 and 0.80.5 % predicted per year (p<0.001). Twelve patients with chylous effusions and 11 with lymphangioleiomyomas experienced almost complete resolution of these abnormalities. In two of the 12 patients, sirolimus therapy enabled discontinuation of pleural fluid drainage. Sirolimus therapy is associated with improvement or stabilization of lung function and reduction of the size of chylous effusions and lymphangioleiomyomas in patients with lymphangioleiomyomatosis.