Lymphangioleiomyomatosis (LAM) is a rare and progressive disease that primarily affects the lungs, often leading to respiratory failure. This condition involves the abnormal growth of smooth muscle-like cells (LAM cells) throughout the lungs and sometimes in other organs, such as the kidneys and the lymphatic system. LAM almost exclusively affects women, typically those of childbearing age, with the average age of diagnosis around 35. The proliferation of these abnormal cells gradually destroys healthy lung tissue, leading to the formation of numerous air-filled cysts, which severely impede normal breathing function.
Defining Lymphangioleiomyomatosis and Its Underlying Cause
The biological mechanism driving LAM involves a genetic change that disrupts a fundamental cellular growth regulator. The disease is caused by mutations in the TSC2 gene, which provides instructions for making a protein called tuberin. Tuberin normally works with another protein to form the TSC1-TSC2 complex, which acts as a major suppressor of cell growth. When the TSC2 gene is mutated, the function of this complex is lost, leading to uncontrolled growth.
The loss of this regulatory complex results in the overactivation of the mammalian target of rapamycin (mTOR) signaling pathway. In healthy cells, the mTOR pathway controls cell growth, metabolism, and survival, but its hyperactivation in LAM cells promotes uncontrolled proliferation. These rapidly dividing LAM cells accumulate along the airways, blood vessels, and lymphatics, causing the destructive cystic changes seen in the lungs. This molecular defect explains why LAM is considered a neoplastic disorder, characterized by the growth of cells similar to low-grade tumors.
Recognizing the Symptoms and Complications
The initial presentation of LAM can often be subtle, frequently mimicking common respiratory conditions like asthma or bronchitis, which can delay diagnosis. The most frequent pulmonary symptom is progressive shortness of breath (dyspnea), particularly during physical exertion, which worsens as the lung cysts multiply and destroy tissue. This deterioration in lung structure also predisposes patients to a life-threatening complication known as a pneumothorax, or collapsed lung.
A pneumothorax occurs when a lung cyst ruptures, allowing air to leak into the space between the lung and the chest wall, and this event is often the first symptom that leads to a diagnosis of LAM. Another significant complication involves the lymphatic system, where LAM cell growth can cause chylothorax, a fluid accumulation around the lungs. This chyle fluid, rich in lymph and fat, compresses the lungs and impairs breathing. Many women with LAM also develop benign kidney growths called angiomyolipomas (AMLs). Large AMLs can cause flank pain or, rarely, spontaneous bleeding requiring urgent medical intervention.
The Process of Diagnosis
Diagnosing LAM requires combining clinical suspicion with specific imaging and laboratory tests due to the non-specific nature of early symptoms. The first step involves a High-Resolution Computed Tomography (HRCT) scan of the chest, which reveals characteristic thin-walled, diffuse cysts distributed throughout both lungs. These cystic changes are highly suggestive of LAM, but imaging alone is not sufficient for a definitive diagnosis.
Confirmation is frequently achieved non-invasively through a blood test that measures the level of Vascular Endothelial Growth Factor-D (VEGF-D). VEGF-D is a growth factor secreted by the abnormal LAM cells, and an elevated serum level (generally 800 pg/mL or higher) is considered diagnostically specific for LAM in a patient with typical HRCT findings. Utilizing this biomarker allows physicians to confirm the diagnosis without resorting to more invasive procedures for most patients. However, if the VEGF-D level is not elevated or the imaging is atypical, a lung biopsy may still be necessary for microscopic confirmation of the LAM cells.
Current Treatment and Management Options
Treatment for LAM focuses on slowing the progression of the disease and managing its complications, as there is currently no cure. The main therapeutic agent is the drug sirolimus, also known as rapamycin, which is an inhibitor of the hyperactive mTOR signaling pathway. By blocking this pathway, sirolimus slows the growth and proliferation of the LAM cells, stabilizing lung function and often reducing the size of kidney angiomyolipomas and lymphatic fluid collections. This drug is now considered the first-line treatment for patients with abnormal or declining lung function.
Supportive care measures are also important for managing the effects of LAM on the lungs. For patients who experience a collapsed lung, procedures such as pleurodesis may be used to prevent recurrence by adhering the lung to the chest wall. Individuals with advanced disease and low oxygen levels often require supplemental oxygen therapy. When lung function declines severely despite medical therapy, a lung transplant becomes the final treatment consideration.