Characterization of the Pathogenesis of Lymphangioleiomy

Heart, Lung, And Blood Institute

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Abstract

Lymphangioleiomyomatosis (LAM) is a multisystem disorder characterized by cystic lung disease and abdominal tumors (lymphangiomyomas and angiomyolipomas). The disease, which presents in middle-aged women, is characterized by the proliferation of abnormal smooth muscle containing premelanosomal structures similar to those found in melanoma cells. A clinical protocol has enabled the Branch to assemble a large cohort of patients with LAM and to document the natural history of the disease, the histopathological findings, the radiographic appearance, characteristic pulmonary function abnormalities, and the association with an inherited disorder, tuberous sclerosis complex. Gene expression and cell regulatory pathways have been examined in tissue samples. We have found that lung diffusion (DLCO) and/or forced expiratory volume in the first second (FEV1) are decreased, but, frequently, not in parallel with each other. Cardiopulmonary exercise testing (CPET) uncovers the presence of exercise-induced hypoxemia and assists in grading the severity of disease and determining supplemental oxygen requirements. LAM appears to be exacerbated by estrogens. Hence, hormonal therapy with progesterone is frequently employed; however, efficacy has not been demonstrated. Our aim was to determine whether progesterone administration slowed the decline in lung function in LAM. The study population comprised 348 patients with LAM participating in our longitudinal research protocol. Declines in DLCO and FEV1 were measured in 275 patients followed for approximately four years. The declines in DLCO and FEV1 of patients treated with progesterone, orally (n=67) or intramuscularly (n=72), were compared with those of untreated patients (n=136). Overall yearly rates of decline in DLCO and FEV1 were, respectively, 2.4?0.4 (0.69?0.07 ml/min/mmHg) and 1.7?0.4 (75?9 ml) percent- predicted. The most significant predictors of functional decline were initial lung function and age. After adjusting for initial FEV1, age, and duration of disease, patients treated with intramuscular progesterone tended to have lower rates of decline in FEV1 than patients treated orally (1.9?0.6 versus 3.2?0.8 percent-predicted, respectively, p=0.081). However, there was no significant difference in rates of decline in FEV1 between patients treated with intramuscular progesterone and untreated patients (1.9?0.6 versus 0.8?0.5 percent-predicted, respectively, p=0.520), and patients treated with oral progesterone and untreated patients (3.2?0.8 versus 0.8?0.5 percent-predicted, respectively, p=0.064). After adjusting for initial DLCO, rates of decline in DLCO were significantly higher in patients treated with oral (3.6?0.7 percent-predicted, p=0.002) and intramuscular (2.8?0.5 percent-predicted, p=0.022) progesterone, than in untreated patients (1.6?0.6 percent-predicted). Within the limitations of a retrospective study, our data suggest that progesterone therapy does not slow the decline in lung function in LAM. Estrogen deficiency and pulmonary diseases are associated with bone mineral density (BMD) loss. Lymphangioleiomyomatosis (LAM) is frequently treated with anti-estrogen therapy, i.e., progesterone and/or oophorectomy. Therefore, we evaluated BMD yearly in 211 LAM patients to determine the prevalence of BMD abnormalities, whether anti-estrogen therapy decreased BMD, and if treatment with bisphosphonates prevented bone loss. Abnormal BMD, found in 70% of the patients, was correlated with severity of lung disease and age. Greater severity of lung disease, menopause and oophorectomy were associated with greater decline in BMD. After adjusting for differences in initial lung function and BMD, similar rates of BMD decline were found in progesterone-treated (n=122) and untreated patients (n=89). After similar adjustments we found that bisphosphonate-treated patients (n=98) had lower rates of decline in lumbar spine BMD (---00...004?0.003 vs. -0.015?0.003 gm/cm 2, p=0.036) and T-scores (-0.050?0.041 vs. -0.191? 0.041, p<0.001), than untreated patients (n=113). Thus, abnormal BMD was frequent in LAM. Progesterone therapy was not associated with changes in BMD; bisphosphonate therapy was associated with lower rates of bone loss. Based on these observations we recommend systematic evaluation of BMD and early treatment with bisphosphonates for patients with LAM.