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年至2009年间，79名年龄在18岁及以上的女性参加了这项研究。通过病史、体格检查、肺功能检查、胸部x线、腹部计算机断层扫描、高分辨率胸部计算机断层扫描和脑磁共振成像对患者进行评估。45例患者在成年期接受了TSC诊断。其中30例符合儿童期TSC的临床标准，但中位时间为22年未被诊断，15例在18岁以上才表现出足够的疾病特征以进行诊断。与儿童期诊断的患者相比，具有成年外显率的个体具有更少的TSC主要特征，更少的皮肤病变，更不容易发作，更容易出现肺淋巴管平滑肌瘤病或血管平滑肌脂肪瘤。没有男性纳入，患者偏向于肺淋巴管平滑肌瘤病。在本研究中，在成年期接受TSC诊断的女性，要么在生命后期表现出TSC症状，要么在诊断时明显延迟，但仍有发展危及生命的肺部和肾脏TSC表现的风险。未能在症状首次出现时识别出TSC会导致发病率和死亡率增加，因为筛查和干预措施被推迟，而早期诊断可以为个人及其家庭提供做出知情生育决定的机会。

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.