Bone mineral density in lymphangioleiomyomatosis.
ABSTRACT Estrogen deficiency and pulmonary diseases are associated with bone mineral density (BMD) loss. Lymphangioleiomyomatosis (LAM), a disorder affecting women that is characterized by cystic lung lesions, is frequently treated with antiestrogen therapy, i.e., progesterone and/or oophorectomy. Therefore, we evaluated BMD yearly in 211 LAM patients to determine the prevalence of BMD abnormalities, whether antiestrogen therapy decreased BMD, and if treatment with bisphosphonates prevented bone loss. Abnormal BMD was found in 70% of the patients and 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, we found similar rates of BMD decline 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 (-0.004 +/- 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). We conclude that 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. We recommend systematic evaluation of BMD and early treatment with bisphosphonates for patients with LAM.
- SourceAvailable from: Branko Pevec
Article: [Lymphangioleiomyomatosis].[Show abstract] [Hide abstract]
ABSTRACT: Lymphangioleiomyomatosis (LAM) is a progressive and usually fatal interstitial lung disease characterized by an abnormal smooth-muscle proliferation in the lung and axial lymphatics. It affects almost exclusively young women of childbearing age. The presenting features most commonly include dyspnea, symptoms of pneumothorax and cough. Less commonly patients can present with chest pain, pleural or pericardial effusion and lymphedema. Our patient, a 41-year-old woman, complained mainly of fatigue that had lasted for 2 months and finally became febrile and dispneic, especially when lying down. Pulmonary diagnostic procedures revealed several multicystic destruction of lung parenchyma. There was also respiratory insufficiency with O2 saturation of 87% and lung diffusion capacity reduced to 48%. The retroperitoneum was filled with neoplastic mass as shown on an abdominal CT scan. Pathohistologic analysis of retroperitoneal mass together with the radiologic finding of the lungs correlated with the diagnosis of LAM. The patient was prescribed corticosteroid therapy, which led to rapid clinical improvement. After making a definite diagnosis, the patient was recommended further treatment with medroxyprogesterone. This case shows that LAM, although rare, can present a diagnostic problem to clinicians and should always be considered as one of the diagnostic possibilities in young women with nonspecific pulmonary symptoms.Acta medica Croatica: c̆asopis Hravatske akademije medicinskih znanosti 02/2004; 58(3):233-6.
- [Show abstract] [Hide abstract]
ABSTRACT: Lymphangioleiomyomatosis (LAM) is a rare multisystemic disease of women of child-bearing age and affects mainly the lungs, promoting cystic destruction of lung parenchyma or leading to abdominal tumor formation (e.g., angiomyolipomas, lymphangioleiomyomas). LAM can arise sporadically or in association with tuberous sclerosis complex (TSC), an autosomal inherited syndrome characterized by hamartoma-like tumor growth and pathologic features that are distinct from manifestations of pulmonary LAM. A substantial body of evidence has now been gathered suggesting that the two diseases share a common genetic origin. TSC is caused by mutations in two genes, TSC1 on chromosome 9q34 and TSC2 on 16p13. Both of these genes are tumor suppressor genes encoding hamartin (TSC1) and tuberin (TSC2). Sporadic LAM is correlated with a mutation in the TSC2 gene and tuberin appears to play a central role in the pathogenesis of the disease. A TSC2 loss or mutation leads to disruption of the tuberin-hamartin heteromer and dysregulation of S6K1 activation leading to aberrant cell proliferation seen in LAM disease. The extremely diverse clinical and radiologic features of the disease and the complex therapeutic approach are reviewed in detail. Although new therapeutic agents have been tested, to date no effective treatment has been proposed and the prognosis of patients with LAM remains poor. As long as newer therapeutic agents do not change this picture, lung transplantation remains the last hope for patients with respiratory failure at the advanced stage of the disease.Beiträge zur Klinik der Tuberkulose 01/2008; 186(4):197-207. · 2.06 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Lymphangioleiomyomatosis is a rare and progressive lung cystic disease, caused by the infiltration of lung parenchyma by mesenchymal cells characterized by co-expression of contractile proteins and melanocytic markers. The pathogenesis of lymphangioleiomyomatosis is determined by mutations affecting tuberous sclerosis complex (TSC) genes, with eventual deregulation of the Rheb/mTOR/p70S6K pathway, and the potential therapeutic activity of mTOR inhibitors is currently under investigation. To better understand the molecular mechanisms involved in the pathogenesis of lymphangioleiomyomatosis, we investigated the expression of cathepsin-k (a papain-like cysteine protease with high matrix-degrading activity). The rationale of this choice was based on the recent demonstration that mTOR inhibitors can regulate major functional activities of osteoclasts, including the expression of cathepsin-k. The immunohistochemical study included 12 cases of lymphangioleiomyomatosis. Twelve angiomyolipomas and several lung diseases (sarcoidosis, organizing pneumonia, usual interstitial pneumonia, emphysema) were investigated as controls. In all lymphangioleiomyomatosis cases, strong cathepsin-k immunoreactivity was demonstrated, restricted to lymphangioleiomyomatosis cells. Similar expression levels were observed in renal angiomyolipomas. These observations extend the knowledge regarding the immunophenotypic profile of lymphangioleiomyomatosis cells, and provide a useful new marker for diagnosis in difficult cases (eg, in small transbronchial biopsies). The strong expression of such a potent papain-like cysteine protease in lymphangioleiomyomatosis cells can significantly contribute to the progressive remodelling of lung parenchyma observed in this deadly disease, with eventual formation of lung cysts. It is possible to speculate that mTOR inhibitors may exert part of their action by limiting the destructive remodelling of lung structure.Modern Pathology 01/2009; 22(2):161-6. · 5.25 Impact Factor
BONE MINERAL DENSITY IN LYMPHANGIOLEIOMYOMATOSIS (LAM).
Angelo M. Taveira-DaSilva, M.D., Ph.D.1, Mario P. Stylianou, Ph.D.2, Carolyn J. Hedin,
C.R.N.P.1, Olanda Hathaway C.R.N.P.1 , and Joel Moss, M.D., Ph.D.1
Pulmonary-Critical Care Medicine Branch 1 and Office of Biostatistics Research 2,
National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD
Corresponding author: Angelo M. Taveira-DaSilva, M.D., Ph.D.: Pulmonary-Critical
Care Medicine Branch, National Heart, Lung, and Blood Institute, National Institutes of
Health, Building 10, Room 6D05, MSC 1590, Bethesda, MD 20892-1590; Telephone:
301-496-1117; Fax: 301-496-2363; E-mail: email@example.com.
Subject code: 75.
Running Head: Bone mineral density in LAM.
Word count: 3540.
Supported by NHLBI Intramural Research.
AJRCCM Articles in Press. Published on October 1, 2004 as doi:10.1164/rccm.200406-701OC
Copyright (C) 2004 by the American Thoracic Society.
Estrogen deficiency and pulmonary diseases are associated with bone mineral
density (BMD) loss. Lymphangioleiomyomatosis (LAM), a disorder affecting women
that is characterized by cystic lung lesions, 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, we found
similar rates of BMD decline 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 (-0.004±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). We conclude that 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. We
recommend systematic evaluation of BMD and early treatment with bisphosphonates
for patients with LAM.
Word count: 199
Key words: Interstitial lung disease; bone mineral density; lung function; progesterone;
Lymphangioleiomyomatosis (LAM), a disease affecting primarily women, is
characterized by cystic lung lesions, recurrent pneumothorax, chylous effusions,
lymphatic abnormalities, and abdominal tumors, i.e., angiomyolipomas,
lymphangioleiomyomas (1-4). LAM occurs sporadically in patients with no evidence
of genetic disease and in about one third of women with tuberous sclerosis complex
(TSC) (5-7). Generally, the pulmonary manifestations dominate the clinical features
of LAM. The severity of lung disease, as measured by oxygen requirements,
roentgenographic abnormalities, and exercise tolerance, correlates with the severity
of the lung function abnormalities (8,9). These abnormalities, characterized by
airflow obstruction and decreased diffusion capacity (DLCO), may cause respiratory
failure, requiring oxygen therapy and may result in lung transplantation, or death.
The rate of progression of disease however, is variable, and some patients have a
chronic course lasting more than 20 years (8,9).
There is evidence suggesting that LAM may be influenced by hormonal factors.
Indeed, not only does LAM affect primarily women (1-4), but the disease appears to
progress during pregnancy (10,11), or following the administration of estrogens (12-
14). In addition, there is evidence for the co-localization of estrogen and
progesterone receptors in LAM cells (15-18). Consequently, hormonal manipulations
that reduce the production of estrogens, such as treatment with progesterone and/or
oophorectomy, have been employed in the treatment of LAM. Since estrogen
deficiency is a recognized cause of osteoporosis (19), we hypothesized that anti-
estrogen therapy in the presence of lung disease could adversely affect bone
mineral density (BMD) in patients with LAM. To test this hypothesis, we measured
BMD yearly in a large group of women with LAM followed for more than three years.
The aims of our study were three fold: 1) to determine the prevalence and factors
associated with BMD abnormalities; 2) to determine whether treatment with
progesterone is associated with an accelerated loss of bone; and 3) to determine
whether treatment with bisphosphonates is associated with lower rates of decline in
Some of the results of this study have been previously reported in the form of an
MATERIAL AND METHODS Word count: 716
Study Population. The study population consisted of 305 patients with LAM referred to NIH
since 1995 for participation in a natural history longitudinal study (NHLBI Protocol 95-H-0186)
approved by the Institutional Review Board of the National Heart, Lung, and Blood Institute. In
addition to self-referral or referral through individual physicians, subjects were informed of the
study by the LAM Foundation and the Tuberous Sclerosis Alliance. All subjects gave informed
consent before enrollment. Sixty-three patients who had only one set of BMD studies and 31
patients who had lung transplantation were excluded. Complete data for analysis were
available from 211 patients. The diagnosis of LAM was made by lung or intra-abdominal tissue
biopsy, or by clinical and roentgenographic data (9). Patients were considered to have reached
menopause when menopause had occurred naturally (low estradiol levels and elevated follicle-
stimulating hormone levels) or was surgically induced (bilateral oophorectomy). A patient was
defined as postmenopausal if hormonal levels, as well as history, were consistent with a
menopausal state for most of the duration of the study. The decision to initiate progesterone
therapy and the choice of route of administration were made, independently, by the patients’
physicians and was not part of the NHLBI protocol. The majority of the progesterone-treated
patients were on this therapy for the duration of the study. Patients with osteoporosis were
advised to take bisphosphonates but the final decision for implementation of this therapy was
left up to the patient and her family physician. However, in the majority of the patients,
bisphosphonate therapy was started after the first abnormal BMD test, and continued
thereafter. Hormonal replacement therapy was discontinued after the first visit. Compliance with