Lymphangioleiomyomatosis

What is lymphangioleiomyomatosis?

Lymphangioleiomyomatosis – abbreviated to LAM – is a very rare lung disease that almost exclusively affects women. Atypical smooth muscle cells form in the walls of the bronchi and pulmonary vessels, which multiply excessively and form connective tissue. As a result, the neighboring structures in the lungs become increasingly thickened and scarred and can block the bronchi and blood vessels. In addition, the scarred tissue displaces and destroys more and more healthy lung tissue and cavities (cysts) form. As a result, the people affected ultimately lack vital oxygen.

Researchers link a defect in the so-called TSC gene to LAM. Affected individuals either acquire this genetic mutation sporadically in the course of their lives or they inherit it. In the latter case, it develops as part of another hereditary disease, tuberous sclerosis.

Women with LAM suffer from increasing shortness of breath and reduced physical performance. Over time, the lung disease can lead to a lack of oxygen. However, there are treatments that alleviate the symptoms and improve the quality of life. In rare cases, only a lung transplant can help.

LAM is a chronic disease that progresses during a woman’s fertile phase and becomes much milder after the menopause. There is currently no cure, but it is treatable. However, scientists have been conducting intensive research into the lung disease for several years in order to gain more knowledge about it and develop new therapies.

Lymphangioleiomyomatosis – frequency and age

LAM is a very rare disease that occurs almost exclusively in women. Experts therefore also suspect hormonal causes in which the female sex hormones play a role.

The sporadic form of LAM affects around three to five women in a million. In contrast, the inherited form of the lung disease, which occurs as part of tuberous sclerosis, is around four times more common: it affects around 19 out of every million women. Tuberous sclerosis is a very complex disease that can be associated with tumors in various organs, skin changes and epilepsy, among other things. Worldwide, there are around 200,000 women with tuberous sclerosis who also have LAM. In contrast, only around 30,000 women have sporadic LAM.

Lymphangioleiomyomatosis usually first appears in middle age at around 35 years. However, the diagnosis of LAM is difficult and lengthy. Because the lung disease is so rare, it is hardly ever seen by doctors, which is why the initial diagnosis is often delayed for years.

Lymphangioleiomyomatosis: causes probably lie in the genes

The causes of lymphangioleiomyomatosis are not yet fully understood. But they are probably located in a defective gene, more precisely in the TSC1 or TSC2 gene. These genes are responsible for the production of two proteins that provide the “building instructions” for hamartin in TSC1 and for tuberin in TSC2. The genetic mutation means that one of the two proteins, tuberin or hamartin, is not normally formed in the LAM tissue. These proteins normally slow down the growth of LAM cells.

Doctors recognize two forms of lymphangioleiomyomatosis: A person can develop LAM without another disease (sporadic) or in connection with another disease – tuberous sclerosis (inherited).

Sporadic LAM

The change (mutation) in a TSC gene occurs spontaneously and a person acquires it in the course of their life. It is therefore not inherited and is not passed on to offspring. The benign cell growths only affect the lungs. In addition, benign kidney tumors (angiomyolipomas) occur more frequently.

Hormones probably also play a role. The “diseased” LAM cells carry docking sites (receptors) for female sex hormones, the oestrogens, on their surface. When the hormones bind to these, growth stimuli are transmitted to the cells. They multiply excessively and the LAM begins. This may also be the reason why almost only women are affected.

Inherited LAM

LAM occurs as part of another disease, the hereditary disease “tuberous sclerosis”. Children inherit the altered TSC gene from their parents. For the disease to break out, it is sufficient for one of the two gene copies (maternal or paternal) to carry the mutation (autosomal dominant inheritance). If one parent is ill, the risk of the child becoming ill is 50 percent. If both parents are affected, the probability of developing the disease is 75 to 100 percent.

In this case, the benign cell growths affect not only the lungs, but also other organs such as the skin, kidneys and brain. Around 30 percent of patients with tuberous sclerosis develop LAM of the lungs.

In addition, some general risk factors are known that can have an unfavorable influence on the course of LAM. These include smoking and infections of the lungs with viruses or bacteria.

Symptoms: Lymphangioleiomyomatosis mainly affects the lungs

The symptoms of lymphangioleiomyomatosis vary and are not equally pronounced in every woman. In addition, the symptoms are not very characteristic and can also occur with other lung diseases, such as bronchial asthma, bronchitis or pulmonary emphysema. This is why LAM is not easy for us to diagnose.

The following symptoms are most common in LAM:

• Shortness of breath and shortness of breath during physical exertion
• Declining physical performance due to lack of oxygen
• Chest pain
• Cough (blood may also be present)

Some complications may arise later on:

• Pneumothorax (collapsed lung): One or both lungs collapse because air enters the pleural cavity – the space between the lungs and the chest wall.
• Chylothorax: An accumulation of lymph fluid in the pleural cavity (a cavity around the lungs) – the lungs can then no longer expand properly when breathing.

LAM symptoms in tuberous sclerosis

If LAM develops as part of tuberous sclerosis, tissue changes and symptoms are not limited to the lungs. The following additional symptoms are possible:

• Skin changes: white spots, cobblestone birthmarks
• Tumors: Mostly skin, kidneys (angiomyolipomas), brain, heart, liver or the retina in the eye are affected
• Epilepsy and mental disabilities due to brain tumors
• Behavioral problems, autism
• sudden internal bleeding

Diagnosis of lymphangioleiomyomatosis

The diagnosis of LAM is also a challenge for us. This is because LAM is rare and we hardly ever have to deal with the lung disease here. In addition, the symptoms are often so unspecific that other lung diseases may also be the cause. These include bronchial asthma, chronic obstructive pulmonary disease (COPD) and bronchitis. Therefore, it often takes some time before affected people receive the correct diagnosis of LAM. We will start by asking you a few questions about your medical history (anamnesis), for example:

• What exactly are your symptoms?
• When did the complaints first appear?
• How pronounced are the symptoms?
• Do you have any known diseases? If yes: Which ones?
• Are there any diseases in your family? If yes: Which ones?

Your answers to these and other questions will help us to make an initial assessment. This is followed by further examinations to diagnose LAM.

The most important tests for diagnosing LAM

• Lung function test: This includes, for example, spirometry, body plethysmography and peak flow measurement. They provide information on the condition of the airways and the performance of the lungs.
• Blood gas analysis: A reduced oxygen content in the blood can be detected. The more advanced the lymphangioleiomyomatosis, the greater the oxygen deficiency.
• Computed tomography (CT) of the lungs: An X-ray examination in which radiologists can detect thickening, scarring and cysts in the lungs. CT provides detailed sectional images and we can usually make a diagnosis of “LAM” based on the images.
• Blood test: If very high concentrations of the protein called “vascular endothelial growth factor D” (VEGF-D) are detected in the blood, this may indicate lymphangioleiomyomatosis.
• Tissue sample (lung biopsy): We take tissue samples from the suspicious areas of the lungs if the diagnosis is inconclusive. The pathology specialist then examines the cell material under a microscope in the laboratory. This allows the altered smooth muscle cells to be detected, as well as an altered architecture of the lung tissue.

We also look for other abnormalities and indications of tuberous sclerosis, for example:

• Kidney, skin and brain tumors
• Lymphatic effusion in the lung or abdominal cavity (chylothorax)
• Altered lymph nodes
• Skin changes

If necessary, we use other imaging techniques such as magnetic resonance imaging (MRI = magnetic resonance imaging) or ultrasound (sonography).

According to the guidelines of the European Respiratory Society (ERS), the following criteria must be met for the diagnosis of LAM:

• • Computed tomography, which detects lung cysts
  • as well as other evidence, such as tuberous sclerosis, a kidney tumor or a chylothorax.

Lymphangioleiomyomatosis: prevention, early detection, prognosis

The causes of lymphangioleiomyomatosis appear to lie primarily in the genes. In addition, female sex hormones such as oestrogen play a role because LAM is almost exclusively contracted by women. You have little or no influence on either – genes and hormones. For this reason, there are no measures for the early detection and prevention of lymphangioleiomyomatosis. As a general rule, please visit us promptly if you have any respiratory complaints.

Course and prognosis of lymphangioleiomyomatosis

LAM is a chronic disease that progresses without treatment. It increasingly restricts breathing and reduces physical resilience. However, the course and prognosis of LAM cannot be predicted in general – they vary from person to person. Some women develop only mild symptoms and have a good quality of life for many years, even without treatment. They can cope well with their everyday life and job. Others, however, are more severely affected by LAM and their lung function continuously declines. The joy of life also usually suffers as a result.

Complications are also possible during the course of LAM. These include lung collapse(pneumothorax) or chylothorax – an accumulation of lymph fluid in the pleural cavity.