August 20, 2007

The Lonely Disease: LAM
By Kim M. Norton
For The Record
Vol. 19 No. 17 P. 32

Striking women in their childbearing years, lymphangioleiomyomatosis—which has no cure or treatment protocol—often goes misdiagnosed as asthma, emphysema, or chronic bronchitis.

Lymphangioleiomyomatosis (LAM) is a progressive lung disease that affects women from puberty through menopause. Abnormal smooth muscle cell growth in the lungs and cyst formation decrease oxygen capacity, which ultimately suffocates the patient. With no treatment protocol other than oxygen therapy, a LAM patient’s only option is a lung transplant, which brings about a different set of issues.

It is estimated that 250,000 women worldwide have LAM but are unaware of it. To date, researchers have identified 2,500 women who have been diagnosed with the disease. LAM researcher Elizabeth Henske, MD, of Philadelphia’s Fox Chase Cancer Center, says, “Other than diseases of the genitals, LAM affects women almost exclusively. Of the documented diagnoses, 99.5% are female, which is higher than even breast cancer with 98% female diagnoses.” This exclusivity toward females could be linked to increased estrogen during a woman’s childbearing years, Henske says.

Although the research cannot prove a link between estrogen and LAM, there is reason to believe that pregnancy exacerbates its effects. There have been three documented cases where LAM was diagnosed in men, but it is believed that the disease is suppressed in males due to androgens. LAM was first documented in the 1940s, but it was not until the mid-1990s that research began, thanks in part to the LAM Foundation and Susan Byrnes, the foundation’s director of research programs and the mother of a LAM patient.

LAM is considered a lonely disease because its victims don’t appear sick, but in reality, their lungs are slowly deteriorating. Before Byrnes established the LAM Foundation in 1995, many women suffered alone through the effects of the disease, but now there is a national registry that provides a support network. The foundation also offers hope to LAM sufferers through dedicated research funded by the National Institutes of Health and conferences discussing advancements and pertinent issues.

Types of LAM
There are two clinical manifestations of LAM: sporadic LAM and tuberous sclerosis complex (TSC) LAM. In both forms, smooth muscle cells invade the airways and blood and lymph vessels of both lungs, causing them to become obstructed. As the disease progresses, the cell growth blocks the air flow to the rest of the body, says Henske.

“Sporadic LAM behaves in many ways like a cancer, although it is not considered a cancer,” she says. It is usually exacerbated by pregnancy and with vague, asthmalike symptoms that are often difficult to diagnose. “We have found that TSC, a genetic disorder that causes tumors to form in different organs throughout the body, primarily in the brain, eyes, heart, kidney, skin, and lungs, is present in the LAM cells of sporadic LAM patients but not in the other cells of the body. It is this link that leads us to believe that there is a correlation between TSC and LAM,” says Henske.

TSC LAM is an inheritable disorder in 50% of patients that with TSC, says Henske. Contrary to sporadic LAM patients, there is a TSC mutation in every cell in the body, not just in the LAM cells, she says. Determining if a woman has TSC would be a logical first step in identifying if she is at risk for developing LAM, but at present, there is no definitive TSC screening available, explains Frank McCormack, MD, scientific director of the LAM Foundation and director of the division of pulmonary and critical care at the University of Cincinnati.

As the research evolves, there will be greater understanding about both LAM and TSC and their influence on each other. As the body of research grows and drugs such as Sirolimus (rapamycin) move through clinical trials, physicians must rely on patient symptoms and diagnostic tools to diagnose and prescribe palliative care such as oxygen therapy, according to McCormack.

Signs and Symptoms
Diagnosing LAM is arduous since the symptoms are generally nonspecific and commonly associated with asthma, emphysema, pulmonary bronchitis, or simply being out of shape, says Henske. “It is especially difficult to consider LAM as a possible diagnosis while the woman is pregnant because shortness of breath is common during pregnancy, especially the further along the woman is,” she says.

“Primary spontaneous lung collapse is a common symptom of LAM, but it is also a fairly common occurrence, so it is not enough to make a diagnosis of LAM with a collapse,” says McCormack. “Most physicians will order a chest x-ray to have a look at the lungs, but the smooth muscle cells are not visible on an x-ray and is not definitive in diagnosing LAM.”

The first steps most physicians take in diagnosing a pulmonary problem are ordering lung x-rays, pulmonary function tests to measure the volume of air in the patient’s lungs, and blood tests to determine if the patient has an adequate supply of oxygen in his or her blood. Being able to evaluate the amount of oxygen in the patient’s lungs and blood supply are helpful but not enough to diagnose LAM.

Currently, the only way to definitively diagnose LAM is with a lung biopsy or CT scan. A lung biopsy is generally only performed as a last resort, with a CT scan being the preferred diagnostic tool. The 2-D CT image enables the physician to detect the presence of the thin-walled cysts in the lungs. Scans of the abdomen and kidneys are also recommended to detect the presence of rare, benign kidney tumors called angiomyolipoma. In 50% of patients with LAM, angiomyolipoma coupled with symptoms such as lung collapse, fluid in the lungs, shortness of breath, and chest pain makes for a more definitive diagnosis, says Henske.

Treatment Options
Once a LAM diagnosis has been made, there is little that can be done as far as a cure. In some women, the progression of the cell growth in the lungs is slow and in others, rapid. “Every patient is different in how the disease progresses, but currently, the only treatment protocol is using oxygen to assist the patient to increase the amount of oxygen the lungs take in,” says Henske. Depending on how the disease progresses, the only other option for the patient is a bilateral lung transplant.

Lung Transplant
If it is determined that a LAM patient would benefit from a lung transplant, she is put on the national transplant list. Lung transplantation for a LAM patient is more about improving the quality of life rather than curing the disease. As LAM progresses, the patient will likely be unable to walk or eat without constant oxygen use. Even tethered to an oxygen tank, she may still have extreme shortness of breath due to the muscle cell growth, which makes the lungs appear more like a honeycomb rather than normal lung tissue, says Henske.

“Some of the LAM cells may return after a lung transplant, but not enough will return to threaten the viability of the transplanted lungs,” says McCormack. With the threat of LAM removed, the transplant patient now faces a new set of issues. Lung transplants are among the most difficult and delicate organs to transplant, with the five-year survival rate currently at 55% due to exposure to outside elements that can damage the lungs.

“A lung transplant is not the ideal solution—yet a welcome one—for LAM patients because although she is gaining time and quality of life with the new lungs, she is inheriting a new set of issues relating to the transplant,” says Henske. Rejection rates are high with lung transplants, and the amount of medicine necessary to reduce the risk of rejection and infection is staggering, she adds.

With lung transplants being the only viable option for those with aggressive LAM, researchers are exploring other possible treatment options to control the growth of LAM cells. One possibility is the drug Sirolimus, an immunosuppressant. The drug is currently FDA approved to prevent kidney transplant rejection, but researchers have found it could also work for controlling the growth of LAM cells. “It is not likely that rapamycin will ever be a cure for LAM as a single agent. There is discussion that with a second agent it could possibly be a cure, but right now, it is the hope of scientists for LAM to be similar to that of diabetes in that we can control it,” says Henske.

Hope for the Future
The fact that LAM afflicts women in their reproductive years ,just as many are starting their careers and families, is a strong reason for investigating this rare disease. Byrnes founded the LAM Foundation when her daughter was diagnosed with sporadic LAM in 1994. Although her daughter is among the fortunate who have a relatively slow progressing form of the disease, she knows others are not so lucky. Her goal is to help ignite interest in the disease and develop a national registry. To date, she has accomplished both goals, but there are still hurdles to overcome.

The LAM Foundation’s mission is to educate and advise healthcare professionals in using CT scans instead of x-rays and increase the body of knowledge physicians have about LAM, says Byrnes. “There are more and more rare diseases out there, and physicians need to be educated about their existence and how best to diagnose and treat them,” she says.

However, the reality is that LAM is a rare disease, and CT imaging is an expensive diagnostic tool to use when it is not always warranted, explains McCormack. “Most physicians practice evidenced-based medicine, and if through our research we are able to provide the evidence necessary to warrant a CT for a woman presenting with shortness of breath and a collapsed lung, we may be able to push for more scans at the ER [emergency room] level,” he says.

— Kim M. Norton is a New Jersey-based freelance writer specializing in healthcare-related topics for various trade and consumer publications.

Resources
The LAM Foundation
www.theLAMfoundation.org

Tuberous Sclerosis Alliance
www.TSAlliance.org

10 Facts about LAM
1. Symptoms may include shortness of breath, cough, a collapsed lung, chest pain, or fatigue.

2. Approximately 40% of women with lymphangioleiomyomatosis (LAM) have a benign kidney tumor called angiomyolipoma.

3. LAM usually does not appear on an x-ray. A high-resolution CT scan of the chest, and often the abdominal area, is required for accurate diagnosis.

4. LAM results in progressive destruction of healthy lung tissue caused by cyst formation and abnormal growth of smooth muscle cell not usually found in the lungs.

5. Lung capacity can decline, resulting in the need for oxygen therapy.

6. Women often go undiagnosed for years and are frequently misdiagnosed with asthma, bronchitis, or emphysema.

7. The discovery of a genetic link between LAM and tuberous sclerosis, another rare disease, leads scientists to estimate that more than 250,000 women worldwide are unaware they have LAM.

8. Since LAM occurs almost exclusively in women, the disease is thought to be hormonally related.
9. Many doctors think pregnancy accelerates the disease.

10. There is no cure and no treatment proven effective at this time, but a treatment trial to test a drug called Sirolimus (rapamycin) is underway.

— Source: The LAM Foundation

Surviving LAM
Being diagnosed with any disease is devastating. Being diagnosed with a little-known disease with no effective treatment and no cure is not only devastating but can seem hopeless. When Tish Davey, then 37, of Pelham Manor, N.Y., was pregnant with her third child, she started having extreme shortness of breath that her doctor attributed to her pregnancy. However, after her son was born in October 1992, she had no relief from her acute shortness of breath.

By April 1993, she started investigating what could be behind her continued breathing problems. She convinced herself that it was exercise-induced asthma because although she was an avid tennis player, her trouble seemed to peak after a few sets. “I went to a local internist and had a chest x-ray done to determine what was going on. I was put on a series of inhalers, which made no difference,” says Davey. It was not until a friend recommended that she see an allergist that she came closer to a diagnosis.

“The allergist had me do a breathing test and determined that I had some sort of obstruction in my lungs. Because my FEV/FVC [forced expiratory volume/forced vital capacity] numbers were so low, he called a pulmonologist at Columbia Hospital and made an appointment for me. It was not until this point that I realized that it was probably more serious than asthma,” says Davey. In June 1993, she met with the pulmonologist, and after a series of tests, he finally diagnosed her with sporadic lymphangioleiomyomatosis (LAM).

Since the initial pulmonologist had only seen one other patient with LAM, he referred Davey to a colleague with more experience. “The new doctor was very forthcoming and told me that he had had several other LAM patients, but they had all died within a year of their diagnosis,” she says. At the time Davey was diagnosed, there was no research being done on LAM; there was, and still is, no treatment protocol; and there were no support groups to spearhead research. Her only option was oxygen. If her disease progressed rapidly—which it did—her only viable option was a lung transplant.

Because this was before the current grading system for transplants was implemented, Davey originally went on the transplant list in New York. Unfortunately for her, after more than two years on the regional waiting list, her name had made hardly any progress.

At this point, Davey was so ill, she weighed roughly 100 pounds and, even with continuous oxygen, was confined to a wheelchair and unable to take more than a few steps before becoming winded. “My doctors recommended that I try to get on a list in another region that afforded a better chance of receiving a transplant. Fortunately, Barnes Jewish Medical Center in St. Louis was willing to accept me on their waiting list. But in order for me to be on their list, I had to live in the area,” she says.

Davey could not have fathomed the events that transpired over the next 18 months. Leaving her family behind in New York, Davey and her father headed to St. Louis to await her transplant. After four months in St. Louis without her husband and children, she decided that she needed to be home. But, as fate would have it, once she got back to New York, a match came up in St. Louis. But because of the quick turnaround time required for a lung transplant, she missed the call. “I was crushed that I missed it. But the hospital decided to work with me because they knew I had young children at home and were willing to push the time necessary for the transplant,” she says.

Davey stayed in New York with her family for 14 months hoping for a phone call from Barnes. With time running out, Davey and her husband decided to drive back to St. Louis in August 2000 to wait it out. “I had this intense claustrophobic feeling when we were in the car, and I thought we should stay home, but we went ahead with our plans. It was not until we arrived in Indiana that night that I called home to check in with my family that I found out that I missed another call while driving back to St. Louis,” she says.

At this point, Davey stayed in St. Louis, relying on her friends to take turns flying out to stay with her. In December 2000, with her family and friends thinking she was just days away from death, Davey received the call, and this time, she was in the right place at the right time.

Today, six years after her lung transplant, Davey is doing well. She is spending time with her family, playing tennis, and recently went back to work. Despite everything that Davey and her family went through while waiting for the transplant, she is one of the lucky ones. She has had more time with her family, and for that, she is extremely grateful. But she will be the first to say that lung transplantation is not the answer for LAM.

Survival rates for lung transplant patients lag behind those of most other transplant patients. And LAM cells grow back after a lung transplant, although doctors say that not enough grow back to be a threat. “My doctors have assured me that it is not going to be LAM that gets me; it is going to be the principal enemy of lung transplantation—chronic rejection,” Davey says. “I’ve already had one miracle. To survive long term, I need another miracle—new drugs that will effectively battle chronic rejection and extend the lung transplantation timeline. And two miracles in one lifetime may be too much to ask.”

— KMN