lungsSome people with TSC, especially women, may have signs of TSC in their lungs. The most common sign is lymphangioleiomyomatosis (LAM). Most of these people will not have any symptoms but it is still recommended for all women to have a scan of their chest to look for signs of TSC in their lungs.

Terms used by health professionals for things to do with the lungs are respiratory and pulmonary. Doctors who specialize in lungs and lung disease can be called respiratory physicians.

Signs and Symptoms

Signs of TSC in the lungs are much more commonly found in women, usually only in adulthood. There have only been a small number of cases of TSC affecting the lungs in men.

The lungs can be affected by TSC in two different ways:

  • Lymphangioleiomyomatosis (LAM)
  • Multifocal micronodular pneumocyte hyperplasia (MMPH)

People with TSC can be affected with many other lung diseases, just like everyone else in the community. These include infections such as influenza and pneumonia as well as asthma.

Lymphangioleiomyomatosis (LAM)

Lymphangioleiomyomatosis (LAM) is a lung disease that affects exclusively women, usually between the onset of puberty and menopause. LAM has also been reported in older women with TSC, but it is not clear when the disease developed in these individuals.

It is hard to estimate the number of women with TSC who have LAM. Some studies have estimated 30-40% of women with TSC also have LAM, but only 4% of women with TSC will show symptoms of LAM.

When a person has LAM, an unusual type of muscle cell is found in their lungs, airways, and blood and lymph vessels. Over time, these muscle cells destroy the lungs and make it difficult for oxygen to get across the wall of the airway and into the blood cells. This prevents the lungs from providing oxygen to the rest of the body.

The word lymphangioleiomyomatosis can be broken down into its parts to help explain what the disease is. Lymph- and angio- refer to the lymphatic and blood vessels in the body, respectively. The lymph nodes and lymphatic vessels are involved in the lung, and the cysts that form in the lung may contain lymph fluid. Leiomyomatosis refers to the formation of the unusual muscle cells in the lung.

Pulmonary LAM has a distinctive appearance. The lungs of a person with TSC who has LAM contain many cysts, varying in size from a few millimeters to several centimeters. These cysts take the place of the normal fine lacy pattern of the normal lung. The cysts are usually empty, but they may contain lymph fluid, referred to as chylous fluid. The walls of the person’s airways become infiltrated with muscle cells, and become thickened and distorted, resulting in cyst formation.

Symptoms of LAM

Most women with TSC and LAM never have symptoms. For a smaller proportion LAM can be a disease that gradually worsens.

Single cysts in the lungs may rupture, which can cause a collection of air or gas in the space surrounding the lungs. This is a very serious condition called pneumothorax or lung collapse. This may lead to abnormal or uncomfortable breathing for that person, which is called dyspnoea. It may also lead to coughing up blood from the respiratory tract, a condition called haemoptysis.

Multiple cysts in the lungs can be a sign of severe LAM. Sometimes the lungs cannot take in sufficient oxygen or expel sufficient carbon dioxide to meet the needs of the cells of the body. Doctors call this respiratory insufficiency. The person may also be diagnosed with pulmonary hypertension (PHT). This is high blood pressure in the arteries that supply blood to the lungs. Once PHT has been diagnosed, often more medical care is needed, including regular follow-up with a respiratory physician or a cardiologist specializing in caring for individuals with PHT.

Sporadic LAM

Some people have LAM without having TSC and this is called sporadic LAM, or S-LAM. When LAM is diagnosed in a person with TSC, health professionals refer to this as TSC-LAM.

Some people with sporadic LAM also have kidney tumours, but no other signs of TSC.

Researchers have identified mutations in the TSC2 gene in individuals with sporadic LAM, indicating that LAM is caused by mutations in the same gene(s) as TSC.

The number of individuals who have LAM is not known. Scientists estimate that there may be up to 300,000 women with the disease worldwide if both individuals who have TSC-LAM and sporadic LAM are included.

Multifocal micronodular pneumocyte hyperplasia (MMPH)

Multifocal micronodular pneumocyte hyperplasia (MMPH) consists of overgrowth (hyperplasia) of the pneumocytes (a specific type of cell found in the lining of the air sacs in the lung) into small nodules. An individual with TSC who has MMPH may have a few or many nodules in their lungs. This condition occurs with equal frequency in men and women with TSC and does not usually produce any symptoms or cause any problems.

Surveillance

Surveillance is important because it can lead to early detection and treatment. Each person with TSC should have an individual management plan developed with their medical team that uses these guidelines as a starting point.

  • Females should have a high resolution chest computerized topography (HRCT) scan at least once after reaching 18 years of age
  • Lung function tests, such as spirometry and lung volumes as well as measurement of gas transfer, can be performed every 1-3 years
  • HRCT scans may be repeated at regular intervals in women with TSC

It is recommended that females seek advice from a doctor with experience in TSC before commencing the oral contraceptive pill or planning a pregnancy. This is because doctors believe that oestrogen might make LAM worse.

Tests used to diagnose LAM
The diagnosis of the lung features of TSC can be difficult because many of the early symptoms are similar to those of other lung diseases such as asthma, emphysema, or pulmonary bronchitis. Often, the first signs of LAM are chest pain and shortness of breath, but many individuals with TSC who are diagnosed with LAM will be completely free of any symptoms.

There are a number of tests that doctors can do to diagnose LAM in TSC:

  • Chest X-ray: This is a simple procedure that produces a picture of the lungs and other tissues in the chest. The chest x-ray is used to diagnose a pneumothorax or the presence of fluid in the chest cavity. The cysts that are suggestive of LAM can be difficult to see on a chest x-ray, and the results of this test are usually not diagnostic.
  • Lung function tests: To perform lung (or respiratory) function tests (RFTs), the individual breathes through a mouthpiece into a spirometer. A spirometer is a machine that measures the volume of air in the lungs, the movement of air into and out of the lungs, and the movement of oxygen from the lungs into the blood. This test can be used to determine the effects that lung involvement in TSC have on lung performance over time, but cannot be used to make a diagnosis. More sophisticated lung function tests will pick up earlier disease and can be useful for measuring change.
  • Blood tests: A blood sample from the individual with TSC is analysed to determine whether the lungs are providing an adequate supply of oxygen to the blood. This is also a useful test to use to follow the progression of LAM in individuals with TSC.
  • Computed tomography: High resolution computed tomography (CT) is the most useful imaging test for diagnosing LAM or MMPH in individuals with TSC. The presence of thin-walled cysts and/or nodules can be observed using a CT scan of the lungs.
  • Thoracoscopy and video-assisted (VATS) thoracoscopic biopsy: Thoracoscopy is used to obtain lung tissue. In this procedure, tiny incisions are made in the chest wall and a small lighted tube (endoscope) is inserted so that the interior of the lung can be viewed, and small pieces of tissue removed. This procedure is be done in a hospital under general anaesthetic. Recovery from thoracoscopy is usually quicker than with the more invasive lung biopsy.
  • Open lung biopsy: An open lung biopsy is nowadays only performed only as a last resort to diagnose LAM, if there are good reasons why a less invasive procedure is not safe. In this procedure, a few small pieces of lung tissue are removed through an incision made in the chest wall between the ribs. This procedure must be done in the hospital under general anaesthetic.
  • Transbronchial biopsy: This procedure can be used to obtain a small piece of lung tissue through a long, narrow, flexible, lighted tube (bronchoscope) that is inserted down the trachea (windpipe) and into the lungs. Bits of lung tissue are sampled using tiny forceps. This procedure is done in a hospital on an outpatient basis under local anesthetic. However, the amount of tissue that can be sampled is often inadequate for diagnostic purposes in individuals with LAM.

The symptoms of LAM, such as lung collapse, fluid in the lungs, shortness of breath and chest pain can also aid in the diagnosis of LAM or other lung signs of TSC.

Researchers are exploring other tests that may help diagnose LAM. These tests include blood tests for the LAM cells or a blood vessel growth factor called VEGF-D

Treatment

Severe LAM is a serious illness, but treatment is available and there is a large amount of research being done to identify and trial new treatments for LAM.

Most treatments for LAM are aimed at easing symptoms and preventing complications. The main treatments are:

  • Medicines to improve air flow in the lungs and reduce wheezing
  • Oxygen therapy
  • Procedures to remove fluid from the chest or abdomen and stop it from building up again
  • Hormone therapy
  • Lung transplantation
  • Research medicines which aim to prevent progression of the disease

None of these treatments work well on everyone with LAM. Each individual with LAM will work with their doctor to decide the best treatments for them.

Vaccinations for influenza and pneumonia should also be considered because these infections can be very serious in individuals with LAM. Supplemental oxygen during air travel and avoiding low oxygen environment such as high altitude and unpressurised aeroplane cabins may also be recommended for some individuals with LAM.

New treatments
A few clinical trials of mTOR inhibiting drugs have shown that they may slow or stop the growth of LAM cell clusters in the lungs. These trials have also shown that the medicine only works in some individuals and not all. These medicines also can have serious side effects.

There has also been one trial of the use of an antibiotic that may have a positive effect on LAM.

Oral Contraceptives and Pregnancy
Researchers believe that oestrogen may play a part in LAM. This means that doctors usually recommend that women with LAM avoid oestrogen containing oral contraceptive pills, and post menopausal hormone replacement therapy. However, there is little information in this area and individualised management is required. Women with LAM should also discuss a possible pregnancy with their doctor as the hormones produced during pregnancy might worsen LAM.

 

About this article

Prepared by: Clare Stuart, The Australasian Tuberous Sclerosis Society

Reviewed by: A/Prof Deborah Yates, Respiratory Physician, St Vincent’s Hospital

References:

  1. Kwiatkowski D.J., Whittemore V.H. & Thiele E.A. (2010) Tuberous Sclerosis Complex: Genes, Clinical Features, and Therapeutics. Weinheim: Wiley-Blackwell
  2. Lung Involvement in TSC, Tuberous Sclerosis Alliance, viewed 6th April 2012, http://tsalliance.org/pages.aspx?content=593
Parts of this web page have been adapted with permission from copyrighted content developed by the Tuberous Sclerosis Alliance (www.tsalliance.org)