Lymphangioleiomyomatosis (LAM): Symptoms, Causes, and Treatment

Some lung diseases can begin with nonspecific symptoms such as fatigue, shortness of breath, coughing, or chest pain. Because these symptoms can resemble asthma or other respiratory conditions, the underlying disease may not be immediately recognized. One such condition is lymphangioleiomyomatosis (LAM), a rare lung disease that occurs almost exclusively in women, particularly those of reproductive age.

LAM causes abnormal cells to grow and accumulate in the lungs, gradually damaging healthy lung tissue and leading to the formation of numerous cysts. As the disease progresses, lung function may decline. Some people may also develop complications such as a collapsed lung or fluid accumulation around the lungs.

Although there is currently no cure for LAM, appropriate diagnosis, regular monitoring of lung function, and certain treatments can help control the disease, slow the decline in lung function, and reduce complications in appropriate patients.

What Is Lymphangioleiomyomatosis (LAM)?

Lymphangioleiomyomatosis, or LAM, is a rare disease caused by the abnormal growth of cells with characteristics similar to smooth muscle cells. These cells can occur in the lungs, lymphatic system, kidneys, and certain other organs.

When LAM cells multiply in the lungs, they gradually damage normal lung tissue and cause multiple thin-walled cysts to develop throughout the lungs. These cysts interfere with normal lung function and gas exchange, potentially making breathing increasingly difficult as the disease progresses.

LAM can generally be divided into two main types:

• TSC-LAM: Occurs in people with tuberous sclerosis complex (TSC), a genetic disorder associated with abnormalities in the TSC1 or TSC2 genes.
• Sporadic LAM (S-LAM): Occurs in people who do not have TSC. In these cases, genetic changes develop in certain cells of the body and are generally not inherited by their children.

LAM occurs almost exclusively in women and is commonly diagnosed during the reproductive years.

Why Is LAM Important?

LAM is a chronic, progressive disease that can cause lung function to decline over time. However, the rate of progression varies considerably from person to person. Some people may experience only mild symptoms for many years, while others may experience a more continuous decline in lung function.

One important complication is pneumothorax, or a collapsed lung. This can occur when a lung cyst ruptures, allowing air to leak into the space between the lung and chest wall. It may cause sudden chest pain and difficulty breathing and requires prompt medical evaluation.

LAM can also affect the lymphatic system, potentially causing lymphatic fluid containing fat to accumulate around the lungs. Abnormal masses may also develop within the lymphatic system.

Some patients may develop a noncancerous kidney tumor known as an angiomyolipoma. Larger angiomyolipomas may carry a risk of bleeding.

What Causes LAM?

LAM is associated with abnormalities involving the TSC1 and TSC2 genes, which play an important role in regulating cell growth and proliferation.

When these genes do not function normally, mechanisms that regulate cell growth can become disrupted, allowing LAM cells to multiply and spread to tissues, including the lungs.

Estrogen is also believed to play a role in the progression of LAM. This is partly because the disease occurs almost exclusively in women and is commonly diagnosed before menopause. Changes in the disease may also occur during periods of hormonal change, such as pregnancy.

Symptoms of LAM to Watch For

LAM symptoms can vary between individuals, and some people may have only mild symptoms during the early stages of the disease. Possible symptoms include:

• Shortness of breath or difficulty breathing, particularly during physical activity
• Becoming tired or breathless more easily than usual
• Chronic cough
• Wheezing
• Chest pain or tightness
• Dizziness or lightheadedness
• Coughing up blood in some cases
• Sudden chest pain or difficulty breathing caused by a collapsed lung

During the early stages, symptoms may occur only during physical activities such as walking quickly or climbing stairs. As lung function declines, patients may begin to experience breathlessness during normal daily activities.

Because these symptoms overlap with those of other respiratory diseases, including asthma, diagnosis of LAM may sometimes be delayed.

When Should You Seek Emergency Medical Care?

People diagnosed with LAM, or those suspected of having the disease, should seek immediate medical attention if they experience:

• Sudden chest pain, particularly sharp pain that begins unexpectedly
• Sudden shortness of breath or severe difficulty breathing
• Rapid worsening of breathing difficulties
• Coughing up blood
• Bluish discoloration of the lips, fingertips, or nails
• Fainting, severe dizziness, or unusual weakness

How Is LAM Diagnosed?

Because LAM is rare and its symptoms can resemble those of other lung diseases, diagnosis usually involves several types of evaluation. Doctors may use the following tests:

• High-Resolution Computed Tomography (HRCT): HRCT of the chest is an important test for evaluating suspected LAM. It can reveal the characteristic thin-walled cysts distributed throughout the lungs in considerable detail.
• Pulmonary Function Tests: These tests evaluate how effectively the lungs move air in and out and can be used to monitor changes in lung function over time.
• Blood VEGF-D Test: Vascular endothelial growth factor-D (VEGF-D) may be elevated in many patients with LAM. In patients whose CT findings are consistent with LAM, measuring VEGF-D can help support the diagnosis and, in some cases, may reduce the need for a lung biopsy.
• Evaluation for Associated Conditions: Doctors may examine the kidneys, abdomen, or other organs to identify associated abnormalities such as angiomyolipomas. Patients may also be evaluated for signs of tuberous sclerosis complex.
• Biopsy: If other investigations cannot provide a definitive diagnosis, a tissue biopsy may be considered. However, not every patient suspected of having LAM requires a biopsy.

Treatment for LAM

There is currently no cure for LAM, but treatments are available to help control disease progression, preserve lung function, and manage complications.

One of the most important medications used to treat LAM is sirolimus, an mTOR inhibitor. Sirolimus targets a pathway involved in the abnormal growth of LAM cells.

Evidence shows that sirolimus can help stabilize or slow the decline in lung function in appropriate patients. It may also help control certain lymphatic abnormalities and angiomyolipomas.

Other approaches to treatment may include:

• Bronchodilators for some patients with airflow obstruction
• Supplemental oxygen when blood oxygen levels are low
• Pulmonary rehabilitation to improve exercise capacity and quality of life
• Treatment for pneumothorax or fluid accumulation around the lungs
• Monitoring and treatment of kidney angiomyolipomas when appropriate
• Lung transplantation for selected patients with advanced disease

The appropriate treatment plan depends on the severity of the disease, lung function, complications, other medical conditions, and the individual patient’s overall health.

Living With LAM

Regular medical follow-up is an important part of managing LAM because doctors need to monitor changes in lung function and identify potential complications over time. Patients with LAM should:

• Attend scheduled medical appointments and undergo lung function testing as recommended
• Avoid smoking and exposure to secondhand smoke
• Exercise or remain physically active at a level considered appropriate by their healthcare provider
• Maintain overall health and receive vaccinations relevant to respiratory health as recommended
• Take medications according to the treatment plan and avoid changing or stopping medication without medical advice
• Inform their doctor about new or worsening shortness of breath, chest pain, or other unusual symptoms
• Consult their doctor before using medications or products containing estrogen

Patients who are planning a pregnancy should discuss this with their healthcare team in advance. Pregnancy may involve additional risks for people with LAM, and certain medications may require special consideration.

Who Should Consult a Doctor?

Medical evaluation, particularly by a pulmonologist, should be considered for people with unexplained chronic breathing difficulties or other findings that may be associated with LAM, including:

• Persistent shortness of breath or becoming unusually breathless with activity
• A history of unexplained pneumothorax, particularly in women of reproductive age
• Multiple lung cysts detected on a CT scan
• Tuberous sclerosis complex
• Kidney angiomyolipoma accompanied by lung abnormalities
• Lung symptoms that have not been clearly explained by another condition

People who have already been diagnosed with LAM should ideally receive follow-up care from healthcare professionals experienced in managing rare lung diseases or LAM.

Summary

Lymphangioleiomyomatosis, or LAM, is a rare lung disease that occurs almost exclusively in women, particularly during the reproductive years. It is caused by the abnormal proliferation of cells that can damage lung tissue and lead to the formation of numerous lung cysts. Patients may experience shortness of breath, fatigue, coughing, or chest pain and may be at risk of complications such as pneumothorax.

Because the symptoms of LAM can resemble those of other respiratory diseases, diagnosis may involve HRCT, pulmonary function testing, VEGF-D measurement, and other assessments.

Although there is currently no cure for LAM, treatment with an mTOR inhibitor such as sirolimus in appropriate patients, together with regular monitoring of lung function and management of complications, can help control the disease and maintain quality of life. Early medical evaluation when unusual respiratory symptoms develop and continued follow-up after diagnosis are therefore important parts of LAM care.

Prepared by: Punyanooch Angkanawin, Pharm.D.

References

1. National Heart, Lung, and Blood Institute (NHLBI). Lymphangioleiomyomatosis (LAM)
2. American Thoracic Society (ATS). Diagnosis and Management of Lymphangioleiomyomatosis (LAM)
3. American Lung Association. Lymphangioleiomyomatosis (LAM)