Lymphangioleiomyomatosis (LAM) is a rare and progressive lung disease that primarily affects women during their childbearing years, causing abnormal smooth muscle-like cells to grow out of control in the lungs, lymphatic system, and kidneys, leading to cyst formation and potentially serious breathing problems.
Epidemiology
Lymphangioleiomyomatosis is an extremely rare condition that affects only a small number of women worldwide. The disease is so uncommon that estimates suggest only three to seven women per million are diagnosed with the sporadic form of LAM. However, a more recent study conducted in four European countries in 2023 suggests the actual number may be higher, with at least 21 cases per million women, which is substantially more than previous estimates had indicated.[3]
What makes LAM particularly distinctive is that it almost exclusively affects women, with only a handful of men ever having received a diagnosis in medical history. In fact, there is only one documented case of a man diagnosed with the sporadic form of LAM. The disease typically strikes women during their reproductive years, with most diagnoses occurring between the ages of 20 and 40, or more specifically, between puberty and menopause. The average age at diagnosis is approximately 35 years old.[1][3]
LAM can also occur in women who have a genetic condition called tuberous sclerosis complex (TSC), which is a rare inherited disorder. Studies show that anywhere between 30% to 80% of women with tuberous sclerosis also develop LAM. The risk increases with age—about 27% of TSC patients develop LAM by age 21, but this number rises dramatically to 81% for those over 41 years old.[1][6]
One of the challenges with LAM is that it often goes unrecognized for years. Most women with LAM experience symptoms for several years before ultimately receiving a correct diagnosis. The diagnosis is typically delayed by five to six years from the time symptoms first appear. This happens because LAM is frequently mistaken for more common respiratory conditions such as asthma, bronchitis, or emphysema (a chronic lung condition that causes shortness of breath).[6][8]
Causes
Lymphangioleiomyomatosis is caused by changes, called mutations, in genes that normally help control how cells grow and divide. Two specific genes are involved in LAM: TSC1 and TSC2. These genes are known as tumor suppressor genes because their normal job is to prevent certain cells from multiplying when they shouldn’t. When one of these genes has a mutation, smooth muscle cells begin to grow out of control, even though they normally wouldn’t.[1][11]
This uncontrolled growth of smooth muscle-like cells leads to several problems in the body. In the lungs, these abnormal cells form cysts, which are fluid-filled sacs that damage healthy lung tissue and block airways. The cells can also cause benign tumors called angiomyolipomas to develop in the kidneys. These are non-cancerous growths made up of smooth muscle and fat. Additionally, LAM cells can affect the lymphatic system, which is the network of vessels that carries lymph fluid throughout the body.[1][2]
The way these genetic mutations occur determines which type of LAM a person has. There are two main forms of the disease. In TSC-LAM, a person inherits an abnormal copy of either the TSC1 or TSC2 gene from a biological parent who carries the mutation. This inherited form causes tuberous sclerosis complex, and more than 30% of women with this condition will also develop LAM.[1]
The second form is called sporadic LAM, which occurs when changes to the TSC2 gene happen spontaneously during a person’s lifetime for reasons scientists don’t yet fully understand. These spontaneous mutations are not inherited from parents and cannot be passed on to children. Sporadic LAM appears without the other symptoms of tuberous sclerosis complex.[1][2]
Risk Factors
Being female is by far the most significant risk factor for developing LAM. The disease affects women almost exclusively, and this pattern is so strong that medical experts believe the hormone estrogen or having a uterus may play an important role in how cysts develop in the lungs. Estrogen is a hormone that is produced in higher amounts in women, especially during the reproductive years.[1]
Women who have tuberous sclerosis complex face the greatest risk of developing LAM. Roughly three out of every ten women with TSC will be affected by LAM, making this genetic condition a major risk factor. The connection between TSC and LAM is so strong that doctors routinely monitor women with tuberous sclerosis for signs of lung disease.[5]
Pregnancy and the use of medications containing estrogen can worsen LAM in women who already have the disease. Some reports have suggested that symptoms may become more severe during pregnancy, possibly due to hormonal changes. Similarly, taking birth control pills or hormone replacement therapy that contains estrogen may accelerate disease progression. For these reasons, women with LAM are often advised to discuss their options carefully with their doctors before becoming pregnant or taking hormone-based medications.[1][6]
Symptoms
The symptoms of LAM can vary widely from one woman to another. Some women experience very mild symptoms at first, while others notice more significant problems right from the beginning. The disease often develops slowly over time, which means symptoms may gradually worsen as the cysts in the lungs multiply and damage more healthy tissue.[3]
The most common symptom of LAM is shortness of breath, also called dyspnea. Women often notice they become breathless during physical activity or exercise, and this breathlessness tends to get worse over time as the disease progresses. What might start as mild difficulty breathing during exertion can eventually become a problem even during everyday activities like walking or climbing stairs.[1][2]
Chest pain is another frequent symptom. This pain can range from mild discomfort to sharp, stabbing sensations, particularly during breathing. Many women also develop a chronic cough that doesn’t go away. In some cases, this cough may produce thick, sticky mucus. Occasionally, women may cough up blood or a milky white substance called chyle, which is lymph fluid from the digestive system. Wheezing is also common, as the abnormal cells block the airways.[1][3]
For many women with LAM, a collapsed lung, also known as pneumothorax, is actually the first sign that something is wrong. This serious complication occurs when a cyst bursts and air leaks into the space between the lung and the chest wall. A collapsed lung causes sudden, severe chest pain and a rapid increase in breathlessness. About three-quarters of women with LAM will experience at least one collapsed lung during the course of their disease, and it often happens repeatedly. In fact, the first pneumothorax precedes the diagnosis of LAM in 82% of patients, meaning many women don’t know they have LAM until their lung collapses.[1][3][6]
Beyond respiratory symptoms, LAM can cause problems in other parts of the body. Women may experience fatigue and a general feeling of tiredness that doesn’t improve with rest. Some women develop abdominal bloating, swelling, or discomfort due to fluid buildup in the abdomen or pelvis. If kidney tumors are present, they may cause blood in the urine or, if they bleed, sudden pain and low blood pressure.[3][6]
Prevention
Unfortunately, because LAM is caused by genetic mutations that either occur spontaneously or are inherited, there is no known way to prevent the disease from developing. The mutations happen at a cellular level, and scientists have not yet discovered methods to stop these genetic changes from taking place.[1]
However, women who have been diagnosed with LAM or who have tuberous sclerosis complex can take steps to prevent complications and slow the progression of lung damage. Avoiding cigarette smoke is crucial, as smoking can worsen lung function and accelerate damage to the respiratory system. Women with LAM should not smoke and should avoid environments where they are exposed to secondhand smoke.[17]
Staying up to date with vaccinations is another important preventive measure. Women with LAM should receive a yearly flu vaccine to protect against influenza, which can be particularly dangerous for people with compromised lung function. The pneumonia vaccine is also recommended, as is the COVID-19 vaccine. These vaccinations help prevent respiratory infections that could lead to serious complications.[10][17]
For women with LAM, it’s generally advised to avoid taking medications that contain estrogen, such as certain birth control pills or hormone replacement therapy. Since estrogen may contribute to the growth of LAM cells, limiting exposure to this hormone may help slow disease progression. Women should work closely with their doctors to find alternative treatments or contraceptive methods that don’t involve estrogen.[1][5]
Air travel and travel to high altitudes may pose risks for women with LAM because changes in air pressure can increase the likelihood of a collapsed lung. Before traveling by plane or to mountainous regions, women should check with their doctors to ensure it is safe. In some cases, doctors may advise against certain types of travel depending on the severity of the disease.[19]
Regular monitoring and early diagnosis are also key to managing LAM effectively. Women with tuberous sclerosis should undergo routine lung screenings to detect LAM early, even if they have no symptoms. Early detection allows for timely treatment that can help preserve lung function and improve quality of life.[17]
Pathophysiology
To understand how LAM affects the body, it’s helpful to first understand how healthy lungs work. When you breathe in, oxygen passes through the airways and reaches tiny air sacs in the lungs called alveoli. Oxygen then moves from these air sacs into the blood through very small blood vessels called capillaries. This oxygen-rich blood is then carried throughout the body to keep organs and tissues functioning properly.[3]
In LAM, abnormal smooth muscle-like cells, known as LAM cells, begin to grow and spread throughout the lungs. These cells infiltrate the walls of airways, blood vessels, and lymph vessels. As they grow, they form clusters and create fluid-filled cysts that replace healthy lung tissue. Over time, these cysts damage the delicate structure of the lungs and reduce the amount of healthy tissue available for breathing.[6][2]
The presence of LAM cells and cysts causes several mechanical and physical problems in the lungs. First, the cysts block the small airways, making it harder for air to flow in and out of the lungs. This obstruction reduces airflow and leads to shortness of breath, especially during physical activity. Second, the cysts can compress nearby blood vessels, which interferes with blood flow and reduces the amount of oxygen that reaches the bloodstream. As a result, oxygen levels in the blood drop, a condition known as hypoxemia, and the body’s organs don’t receive enough oxygen to function properly.[3][6]
The cysts also make the lungs more fragile and prone to rupture. When a cyst bursts, air escapes from the lung and leaks into the space between the lung and the chest wall. This causes the lung to collapse, a condition called pneumothorax. Collapsed lungs are a common and serious complication of LAM and often require immediate medical treatment.[1][3]
LAM cells can also invade and block the lymphatic system, which is a network of vessels that carries lymph fluid throughout the body. When lymph vessels become blocked, fluid accumulates in places where it shouldn’t. This can lead to a buildup of lymph fluid around the lungs, a condition called chylothorax, or in the abdomen, known as chylous ascites. The fluid buildup can cause discomfort, swelling, and difficulty breathing. Some women may even cough up chyle, which appears as a thick, whitish substance.[3][6]
In the kidneys, LAM cells contribute to the formation of angiomyolipomas, which are benign tumors made up of blood vessels, smooth muscle, and fat. Most of these kidney tumors are small and don’t cause symptoms, but larger ones can bleed, especially if they grow beyond four centimeters in diameter. When these tumors bleed, they can cause sudden pain, blood in the urine, and potentially dangerous drops in blood pressure.[3][6]
At a biochemical level, LAM is driven by mutations in the TSC1 or TSC2 genes, which normally control a cellular pathway called mTOR (mechanistic target of rapamycin). The mTOR pathway regulates cell growth, division, and survival. When the TSC genes are mutated, the mTOR pathway becomes overactive, allowing LAM cells to grow and multiply uncontrollably. This is why treatments that target the mTOR pathway, such as the drug sirolimus, have been found to be effective in managing LAM.[10][12]
As the disease progresses, more and more healthy lung tissue is replaced by cysts and scar tissue. Lung function gradually declines, and many women eventually require supplemental oxygen to maintain adequate oxygen levels in their blood. In advanced cases, the lungs can become so damaged that a lung transplant may be necessary to restore breathing function.[2][3]
