Caring for Patients with LAM
Caring for Patients with Lymphangioleiomyomatosis (LAM)
Although patients with LAM have been managed empirically with antiestrogen therapies, there is no proof that these strategies are effective. Many clinicians do not treat asymptomatic LAM patients. Progestins can cause fluid retention and mood swings, and the benefits of Gonadotropin-releasing hormone agonists are unproven. Induction of early menopause is distressing and morbid in young women. There is no proven role for corticosteroids, immunomodulatory cytoxic agents or ovarian irradiation in the treatment of LAM. Oophorectomy is no longer recommended because the benefits are unknown and the risk of bone and heart disease is increased. In the face of therapeutic uncertainty, the patient and physician should make all treatment decisions jointly, after thorough discussion of the risks and limited available data.
Role of Hormones in Women with LAM
Since LAM occurs almost exclusively in women of reproductive age, researchers believe 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, the treatment of LAM has focused on reducing the production or effects of estrogen. This could include progestins or other hormone suppressing drugs. Additionally, doctors believe pregnancy may accelerate the progression of LAM. However, the risk of pregnancy in LAM has not been rigorously studied. The physician and patient should discuss the risks of pregnancy carefully and decisions should be made on an individual basis.
Current treatments for LAM are primarily based on antagonism of estrogen action and are empiric and unproven. The most commonly employed treatment is IM progesterone, which became the standard of care following a dramatic case report in 1987. Enthusiasm for the use of progestins has waned over time. In a recent retrospective analysis, Dr. Taveira-DaSilva et al found that progesterone treatment did not slow the decline in FEV1, and in fact, appeared to accelerate the rate of decline in diffusing capacity compared to untreated patients. Use of oral progestins or GnRh agonists has also been reported in case studies and small series, but neither has been assessed in clinical trials. There is no evidence that bilateral oophorectomy slows the rate of progression in LAM, and this therapy is much less commonly recommended than in the past. A trial of bronchodilator therapy should be considered for the 17% of patients with LAM who exhibit reversible airflow limitation. Although abnormal bone density is common in women with LAM, progesterone therapy does not appear to accelerate the development of osteoporosis and bisphosphonates are effective for this population.
Other Pulmonary Management Issues
Patients with LAM should avoid exposure to tobacco smoke.
A trial of bronchodilators should be considered in patients with LAM. Based on extrapolation from the COPD populations, the use of oxygen may prolong life in hypoxic patients with LAM. Oxygen should be administered to maintain oxyhemoglobin saturations of greater than 90% with rest, exercise and sleep.
Pleural Complications in LAM
Pneumothoraces ultimately occur in approximately 60-70% of patients with LAM and the rate of recurrence is over 70%; the highest among all chronic lung diseases. The average number of subsequent pneumothoraces for those who have had a sentinel pneumothorax is 4.4. The average lifetime pneumothorax-related burden for LAM patients with a history of pneumothorax who responded to a LAM Foundation questionnaire was approximately 3.5 events, 5 interventions, one month in the hospital and $75,000 in estimated hospital costs. The recurrence rate following conservative therapy such as aspiration or chest tube drainage is about 66%, and following chemical or surgical pleurodesis are 27% and 32%, respectively. It is unclear why the recurrence rate following pleural fusion is so much higher for LAM than for other cystic lung diseases, such as Langerhan's cell histiocytosis, but it is possible that the remarkable profusion of cysts on the surface of the LAM lung prevents apposition and fusion of the lung and the parietal pleura. The LAM Foundation Pleural Disease Consensus Committee recommended ipsilateral pleurodesis with the initial pneumothorax in each hemithorax, although when surveyed patients often preferred a more conservative approach. Chylous pleural effusions occur in about one third of patients and may be unilateral or bilateral. Pleurodesis is generally an effective approach for chylothorax, but less invasive treatments such as thoracentesis or observation may suffice in some cases.
Lung Transplantation in LAM
The cumulative survival for LAM patients transplanted in the United States is 65% at five years, which is equal to or better than the rate for other lung disease groups who had transplantation during the same period. Some patients with LAM develop marked dyspnea on exertion, hypoxemia and reduced DLCO in the absence of marked airflow obstruction; this subset of LAM may require transplantation evaluation before FEV1 reaches the typical threshold of 30% of predicted. Prior pleurectomy or talc pleurodesis can create difficulties with tissue plane dissection and bleeding during removal of the native lung. In the Almoosa study, 45 of 80 transplanted patients had a prior pleural fusion procedure and 13 of the 14 pleura-related postoperative bleeding events occurred in patients with a prior pleurodesis. However, these perioperative complications are generally manageable, and most centers do not consider even bilateral prior pleurodesis to be a contraindication to lung transplantation. Although there is no LAM specific data available, many centers prefer double over single lung transplantation for LAM patients despite similar 1,3 and 5 year survival and quality of life outcomes, because double lung transplantation is typically associated with lower rates of bronchiolitis obliterans and higher airflows (FEV1).
Renal Disease in LAM
About 93% of patients with TSC-LAM and 30-50% of patients with Sporadic LAM (S-LAM) have renal angiomyolipomas, benign renal tumors composed of dysplastic blood vessels, smooth muscle and variable amounts of fat. Interestingly, angiomyolipomas are the only known neoplastic lesions in which the intratumoral blood vessels are composed of the cells containing transforming mutations. In most patients, angiomyolipomas are clinically silent, however flank pain, hydronephrosis, hematuria and loss of renal function can all occur. In S-LAM, angiomyolipomas are usually unilateral, small, solitary, and restricted to the kidney while in TSC-LAM they are more often larger, bilateral, multiple, multiorgan involving the spleen or liver, and prone to hemorrhage. The risk of renal hemorrhage from angiomyolipomas is associated with large size and with profusion of aneurysms. Patients with lesions approaching 4 cm in size should be followed with periodic ultrasonography or CT scanning, and intervention should be considered when the tumor exceeds this threshold. Selective, nephron sparing techniques such as embolization, enucleation, radioablation, electrocautery or partial nephrectomy, rather than total nephrectomy, are recommended. Many LAM patients have had prior resections of angiomyolipomas which were initially suspected to be renal cell carcinomas by clinicians who were unfamiliar with the diagnostic implications of radiographic fat density within a renal tumor. Atypical angiomyolipomas with malignant potential and frank renal cell carcinomas are uncommon in TSC but should be considered when solid renal masses with little fat are detected by MRI or CT.
Bone Disease Management
Bone densitometry should be considered in all patients who are immobilized and/or on antiestrogen therapies. Calcium and bisphosphonate therapy should be considered in osteoporotic patients. Proper attention should be paid to cardiovascular health in patients who are rendered menopausal by therapy.
LAM and Airtravel
Many LAM patients have been advised to avoid air travel because of the theoretical risk of lung cyst rupture associated with atmospheric pressure changes during flight. In a questionnaire study of 276 patients who had taken 454 flights, Pollock-Bar Ziv et al found that air travel is generally well tolerated by most patients with LAM. Symptoms of anxiety, chest pain, shortness of breath, cyanosis or hemoptysis occurred in 10-20% of flights. Pneumothorax occurred in 10 flights, including eight episodes that were radiographically documented, but in five cases symptoms suggestive of pneumothorax were present prior to boarding. There have been no airtravel-associated incidents requiring hospitalization among the over 500 LAM patients who have participated in the decade-long NHLBI protocol, which has encouraged visits every six months. Airtravel, however, was not recommended to all patients (personal communication, Joel Moss).
The MILES Trial
The Multicenter International LAM Efficacy of Sirolimus (MILES) Trial will test the effectiveness of sirolimus (rapamycin) in preservation of lung function in patients with LAM. Sirolimus is currently approved for kidney transplantation, to prevent rejection of the graft. Sirolimus benefit in the first trial to treat benign kidney tumors known as angiolipomas. The MILES Trial is now enrolling patients. For more information about this study click here.
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