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Lung involvement in tuberous sclerosis complex (TSC) has been recognized for many years, but until recently it was thought to be a very rare manifestation of the disease. In older studies, the incidence of lung involvement was estimated to be between 1 and 2.3% of all individuals with TSC. Recently, it has been reported that between 26% and 34% of women with a definite diagnosis of TSC have evidence of lymphangioleiomyomatosis (LAM) (see below) (Costello et al., 2000; Franz et al., 2001; Moss et al., 2001; Ryu et al., 2006). These findings indicate that the frequency of lung involvement in individuals with TSC, especially women, is much higher than previously suspected. In most of these women, the disease does not cause respiratory symptoms. These findings support the recommendation from the TSC Consensus Conference report (Roach et al., 1999) that all women with TSC should have a computerized tomography (CT) scan of the chest.
Lung involvement in TSC is almost exclusively found in women, generally aged 30 years or older. There have been a few case reports of men with TSC who have lymphangioleiomyomatosis, but this is very rare. Two forms of lung involvement in TSC have been described:
- lymphangioleiomyomatosis (LAM)/pulmonary cysts; and
- multifocal micronodular pneumocyte hyperplasia (MMPH).
These manifestations of TSC are described below.
Lymphangioleiomyomatosis (LAM) is a lung disease that affects almost 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. The precise 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 you include both individuals who have TSC and LAM and those with sporadic LAM (60% of these individuals have kidney tumors, but no other manifestations of TSC). Smolarek and colleagues (1998) 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.
LAM is characterized by an unusual type of muscle cell that invades the 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 an individual with TSC who has LAM contains a multitude of cysts, varying in size from a few millimeters to several centimeters, that 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 airways become infiltrated with muscle cells and cysts, and become thickened and distorted.
Pulmonary cysts are the hallmark of LAM and may be single or multiple in the lungs of individuals with TSC. Single cysts may remain clinically silent or they may rupture, resulting in pneumothorax (a collection of air or gas in the space surrounding the lungs). The pneumothorax may produce dyspnea (abnormal or uncomfortable breathing in the context of what is normal for a person according to his or her level of fitness and exertional threshold for breathlessness) and hemoptysis (coughing up blood from the respiratory tract).
If an individual has many cystic lesions, as is the case with severe LAM, they may have respiratory insufficiency and/or pulmonary hypertension (PHT; high blood pressure in the arteries that supply the lungs). Once PHT has been diagnosed, often more medical care is needed, including regular follow-up with a cardiologist or pulmonologist trained in caring for individuals with PHT.
This is a serious illness, but treatment is available. You may be treated with oxygen, agents to help your heart pump better, diuretics, anticoagulants (blood thinners), and medications to lower your PHT. Sometimes lung transplants also are performed.
Pregnancy and delivery produce dramatic changes that can seriously endanger your life if you have PHT. Thus, avoid pregnancy by practicing a safe and effective method of contraception. Avoid oral contraceptives; they can aggravate PHT.
Additional precautions are often taken with individuals with PHT. These include supplemental oxygen during air travel, antibiotic therapy for significant respiratory tract infections, pneumococcal pneumonia vaccine and yearly flu vaccines (since pneumonia can be very serious with individuals with PHT). Also avoid conditions in which the ambient oxygen concentration may be decreased, such as high altitude and travel in unpressurized airplane cabins. Before starting an exercise program, ask your physician what activities are appropriate for you.
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 clinical symptoms.
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 the physician can do to diagnose lung manifestations of 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 often not diagnostic.
- Pulmonary function tests: To perform pulmonary function tests (PFT), the individual breathes through a mouthpiece into a spirometer (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.
- Blood tests: A blood sample from the individual with TSC is analyzed 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. CT scans of the abdomen that images the kidneys will also provide information about the presence of kidney tumors (angiomyolipomas) in both individuals with TSC and those with sporadic LAM.
- Manifestations of LAM: Such as lung collapse, fluid in the lungs, shortness of breath, chest pain can all aid in the diagnosis of LAM or other lung manifestations of TSC.
- Lung biopsy: An open lung biopsy should be performed only as a last resort to diagnose LAM. 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 anesthesia.
- Thoracoscopy: Thoracoscopy is also 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 should also be done in a hospital under general anesthesia. Recovery from thoracoscopy is usually shorter than with the more invasive lung biopsy.
- 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 usually done in a hospital on an outpatient basis under local anesthesia. However, the amount of tissue that can be sampled is usually inadequate for diagnostic purposes in individuals with LAM.
Because LAM affects women of childbearing age, physicians have thought that the hormone estrogen might be involved in the abnormal muscle cell growth that characterizes the disease. Although there is no direct evidence that there is a relationship between estrogen and LAM, treatment of LAM has focused on reducing the production or effects of estrogen. The response to treatment has been highly individual, and no therapy has been found to be effective for all individuals with LAM. Treatments vary in effectiveness from one individual to the next, and none have been scientifically proven. Oxygen therapy may become necessary if the disease continues to worsen and lung function is impaired. Some individuals will require surgery following a pneumothorax to help prevent future occurrences. Lung transplantation is considered as a last resort to treat LAM.
A multicenter clinical trial is presently being conducted at several sites in the U.S.A. and an additional trial is underway in Europe. An initial pilot clinical trial with rapamycin in individuals with TSC and/or LAM showed promising results, so additional clinical trials are now underway.
Some women and men with TSC and LAM may be eligible to participate in clinical studies at the Clinical Center at the National Institutes of Health in Bethesda, MD. Contact information for this study is included in Information Sheet about Current Clinical Trials and Studies.
Costello LC, Hartman TE, Ryu JH (2000) High frequency of pulmonary lymphangioleiomyomatosis in women with tuberous sclerosis complex. Mayo Clin Proc 75:591-4
Franz DN, Brody A, Meyer C, Leonard J, Chuck G, Dabora S, Sethuraman G, Colby TV, Kwiatkowski DJ, McCormack, FX (2001)
Mutational and radiographic analysis of pulmonary disease consistent with lymphangioleiomyomatosis and micronodular pneumocyte hyperplasia in women with tuberous sclerosis. Am J Respir Crit Care Med 164(4):661-8.
Moss J, Avila NA, Barnes PM, Litzenberger RA, Bechtle J, Brooks PG, Hedin CJ, Hunsberger S, Kristof AS (2001) Prevalence and clinical characteristics of lymphangioleiomyomatosis (LAM) in patients with tuberous sclerosis complex. Am J Respir Crit Care Med 164(4):669-71
Roach ES, Gomez MR, Northrup H (1998) Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 13:624-628
Ryu JH, Moss J, Beck GJ, Lee JC, Brown KK, Chapman JT, Finlay GA, Olson EJ, Ruoss SJ, Maurer JR, Raffin TA, Peavy HH, McCarthy K, Taveira-Dasilva A, McCormack FX, Avila NA, Decastro RM, Jacobs SS, Stylianou M, Fanburg BL, NHLBI LAM Registry Group (2006)
The NHLBI lymphangioleiomyomatosis registry: characteristics of 230 patients at enrollment. Am J Respir Crit Care Med 173(1):105-11
Smolarek TA, Wessner LL, McCormack FX, Mylet JC, Menon AG, Henske EP (1998) Evidence that lymphangiomyomatosis is caused by TSC2 mutations: chromosome 16p13 loss of heterozygosity in angiomyolipomas and lymph nodes from women with lymphangiomyomatosis. Am J Human Genetics 62:810-15
American Heart Association
National Center
7272 Greenville Avenue
Dallas, TX 75231
Phone: 1-800-AHA-USA-1
or 1-800-242-8721
www.americanheart.org
American Lung Association
Phone: 1-800-LUNGUSA (1-800-586-4872)
To speak to a lung health professional, contact the American Lung Association Lung HelpLine at 1-800-548-8252
www.lungusa.org
American Thoracic Association
61 Broadway, 4th Floor
New York, NY 10006
Phone: 212-315-8600
www.thoracic.org
The LAM Foundation
10105 Beacon Hills Drive
Cincinnati, OH 45241
Phone: 513-777-6889
www.thelamfoundation.org
LAM Treatment Alliance
16 Stearns Street
Cambridge, MA 02138
Phone: 617-460-7339
info@lamtreatmentalliance.org
www.lamtreatmentalliance.org
Pulmonary Hypertension Association
801 Roeder Rd. Ste 400
Silver Spring, MD 20910
Office: (301) 565-3004 Fax: (301) 565-3994
Toll-Free Helpline: 1-800-748-7274
www.phassociation.org
candibleifer@earthlink.net
Reviewed and revised by Frank McCormack, M.D., University of Cincinnati and Joel Moss, M.D., Ph.D., National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD.
**Tuberous Sclerosis Alliance Information Sheets are intended to provide basic information about TSC. They are not intended to, nor do they, constitute medical or other advice. Readers are warned not to take any action with regard to medical treatment without first consulting a physician. The TS Alliance does not promote or recommend any treatment, therapy, institution or health care plan.