What is LAM?
Lymphangioleiomyomatosis (LAM) is a rare, cystic lung disease that primarily affects young women. Lymphangioleiomyomatosis (pronounced lim-fan-gee-o-ly-o-my-o-ma-to-sis) causes progressive shortness of breath and recurrent pneumothoraces. LAM is caused by mutations in tuberous sclerosis genes. Other manifestations of LAM include renal angiomyolipomas, chylous effusions (chylothorax and chylous ascites), lymphangioleiomyomas and abdominal/retroperitoneal lymphadenopathy.
Characteristics of LAM
LAM is most often characterized by progressive dyspnea after exertion, recurrent pneumothoraces and an abundance of chylous fluid.
- Lung function often declines at approximately two- to three-fold times rate of those without LAM. This is based on an annual drop in forced expiratory volume in one second (FEV1) of 75-120 cc in various reported series.
- LAM occurs in two settings: in the disease tuberous sclerosis complex (TSC-LAM) and in a sporadic form, in women who do not have TSC (sporadic LAM or S-LAM).
- More than 1,400 U.S. women have been diagnosed with LAM. However, scientists estimate that as many as 250,000 women worldwide may have LAM, but are currently undiagnosed or misdiagnosed with asthma, emphysema or pulmonary bronchitis.
Expert radiologists can diagnose pulmonary LAM using a high resolution CT scan with a reasonable degree (greater than 80%) of certainty.
In the presence of compatible CT scan findings, the presence of any one of the following can obviate the need for a lung biopsy:
- Tuberous Sclerosis Complex
- Chylous effusions
- Histologically confirmed LAM from enlarged lymph nodes
- Elevated serum vascular endothelial growth factor – D (VEGF-D) greater than 800pg/ml
In the absence of the above mentioned confirmatory features, the diagnosis of LAM requires a lung biopsy for confirmation.
Treatment strategies presently available for LAM are based on inhibition of the mechanistic target of rapamycin (mTOR) pathway. The use of sirolimus (also called rapamycin) is now FDA approved for treatment of LAM.
- Long-term treatment with an mTOR inhibitor is generally recommended for patients who have abnormal lung function and evidence of progressive lung function decline. mTOR therapy is also effective in patients with refractory chylous effusions.
- A trial of bronchodilators is often used with LAM patients who have a reversible airflow obstruction based on pulmonary function testing.
- Pleurodesis should be performed after the patient’s initial pneumothorax in each hemithorax (the rate of ipsilateral recurrence is more than 70%).
- Angiomyolipomas that exceed 4 cm in size are more likely to bleed and should be evaluated for possible initiation of mTOR inhibitors..
- Lung transplantation is an important option for women with LAM and can be safely performed by experienced surgeons despite prior unilateral or bilateral pleurodesis in most patients.
Research and treatment progress
Researchers and health care professionals have made great strides in the basic science of LAM in the past 20 years, due in large part to a confluence of scientific discoveries from the tuberous sclerosis and signaling biology fields and remarkably effective grass roots patient advocacy from organizations, such as The LAM Foundation.
- Recent major scientific breakthroughs include:
- First evidence of a genetic link to LAM
- Identification of a LAM gene
- A molecular explanation for abnormal smooth muscle cell growth in LAM
- First LAM treatment trials
- Discovery and development of VEGF-D as a biomarker that can reduce the need for a lung biopsy
- Approval of the first FDA approved treatment for LAM
Multicenter LAM clinical trials based on several well-defined molecular targets are currently underway or have recently concluded in the United States, Europe, Canada, and Japan.
Click here to read more about current and recent trials and studies.
Next steps in LAM research include determining whether early and low dose mTOR inhibitors, such as sirolimus, can be administered to patients with early disease, preventing progression to symptomatic stages and converting LAM from a death sentence to a chronic, manageable disease.
The Institute of Medicine has cited the MILES trial as an exemplar of success in their report on CTSAs and the New England Journal of Medicine, Lancet Respiratory Medicine, the Clinical Research Forum, the National Organization of Rare Diseases, and the Wall Street Journal have all heralded the synergies between patients and investigators that have lead to these remarkable advances.