NORD gratefully acknowledges Feriel Rahmani, MDCM Candidate, McGill University School of Medicine, and Nishant Gupta MD, MS, Associate Professor, The LAM Foundation Professor for LAM Research, Director, Interstitial and Rare Lung Disease Program, Division of Pulmonary, Critical Care and Sleep Medicine, University of Cincinnati, for assistance in the preparation of this report.
Lymphangioleiomyomatosis (LAM) is a rare progressive multisystem disorder that predominantly impacts women of reproductive age. It is estimated to affect 3.4-7.8/1,000,000 women worldwide. There are two main types of LAM: sporadic LAM (that occurs spontaneously) and LAM associated with tuberous sclerosis complex (TSC), an inheritable genetic condition. LAM is characterized by the spread and uncontrolled growth (proliferation) of specialized cells (smooth muscle-like LAM cells) in certain organs of the body, especially the lungs, kidneys and lymphatics. The most common symptom associated with LAM is difficulty breathing (dyspnea), especially on exertion. Affected individuals may also experience complications including lung collapse (pneumothorax) or fluid accumulation around the lungs (pleural effusion) and in the abdomen, and benign kidney tumors called angiomyolipomas. The disorder is progressive and, in some patients, may result in chronic respiratory failure. Fortunately, treatment with sirolimus allows for a slower progression of disease and better management of complications. Further research leading to better understanding of this rare disease promises improved therapeutic options in the future.
The symptoms of LAM vary depending on the organs affected.
The abnormal LAM cells infiltrate tissues, form cysts and obstruct the affected airways (breathing tubes), blood vessels and lymphatic vessels. Consequently, pulmonary LAM can present with shortness of breath upon exertion, cough, wheezing and chest pain. Sometimes, individuals may cough up small amounts of blood (hemoptysis) and have bleeding in their lungs (pulmonary hemorrhage) due to obstructed blood vessels. Infiltration of the lung with LAM cells results in progressive breathing difficulties, lung collapse and interference with the lung’s ability to deliver oxygen to the rest of the body.
About 50-60% of individuals with LAM experience a lung collapse (pneumothorax) at some point in their life. In about one third of these patients, the pneumothorax may be the first manifestation that brings the diagnosis of LAM to light. The symptoms of a collapsed lung may include sudden, sharp chest pain, difficult, rapid breathing (tachypnea), rapid heartbeat (tachycardia), low blood pressure (hypotension), profuse sweating (diaphoresis), dizziness and/or lack of normal chest movement on the affected side of the chest. This complication tends to recur in LAM, therefore management with a medicine or surgical technique that adheres lungs to the chest wall (pleurodesis) is recommended.
About 10 to 30% of people with LAM experience fluid (e.g. chyle) accumulation in the chest cavity around the lungs (pleural effusion). Chyle is a fat-laden cloudy fluid that is absorbed during digestion by the lymphatic vessels located around the intestine. Chyle normally flows through lymphatic vessels into the upper chest (thoracic duct) and is then deposited into veins, where it mixes with blood. In some people with LAM, the lymphatic vessels may rupture or become blocked (obstructed) due to the infiltration of LAM cells, causing chyle to accumulate in the chest cavity (chylothorax). In some patients, chyle may accumulate in the abdomen causing an increase in girth, a condition called chylous ascites. Involvement of the axial lymphatics may also lead to formation of chyle-filled lymphatic cysts called lymphangioleiomyomas within the chest and abdomen.
Approximately 30% of individuals with sporadic LAM and up to 80% of individuals with TSC-LAM develop angiomyolipomas, which are benign tumors made up of fat, blood vessels and smooth muscle-like cells. These tumors most commonly affect the kidneys and often do not cause symptoms. In some patients, they may cause flank pain, blood in the urine (hematuria) or bleeding into the abdomen.
Symptoms of LAM may become progressively worse as LAM cell proliferation continues and may result in chronic life-threatening respiratory failure.
LAM is associated with the rare genetic disorder known as tuberous sclerosis complex (TSC) as both diseases are caused by changes (mutations) in one of two genes known as the TSC1 gene or TSC2 gene. There are two main types of LAM: sporadic LAM (called S-LAM that may occur without TSC) and LAM associated with TSC (called TSC-LAM). In both cases, abnormal LAM cells circulate in blood and lymphatic vessels and deposit in the lungs, causing cysts and lung damage. In S-LAM, mutations are thought to be somatic mutations (e.g., mutations that occur in peripheral tissues after conception and are not inherited). These mutations are not found in the blood or the normal lung or normal kidney cells of affected individuals. On the contrary, in TSC-LAM, these mutations may occur spontaneously (sporadically) for unknown reasons or be inherited in an autosomal dominant pattern. Most cases represent new (sporadic) gene mutations, with no family history of the disease.
Approximately one-third of women with TSC show evidence of pulmonary LAM; however, the prevalence of LAM in women with TSC increases with age and by the age of 40 years almost 80% of women with TSC have cystic changes consistent with LAM. Consequently, the TSC Guidelines recommend that females with TSC be screened for LAM at least once on reaching adulthood.
Other factors affect the disease process in LAM but are not completely understood. For example, researchers have observed that estrogen and progesterone receptors are commonly expressed on LAM cells. In addition, LAM symptoms flare up during surges of female hormones, such as during pregnancy, with hormonal contraception, or during menstruation, and then symptoms stabilize post-menopause. The mechanism of action of female hormones in LAM on a molecular level is still not fully understood.
LAM is a rare disorder that is estimated to affect approximately 3.4-7.8/1,000,000 women worldwide. The US LAM clinic network follows ~1,500 patients with LAM and there are ~3,000 patients with LAM registered with The LAM Foundation. Current estimates suggest that there are roughly 8,000–21,000 patients with sporadic LAM and 80,000–160,000 patients with TSC-LAM worldwide. However, many researchers believe that the disorder is under-diagnosed making it difficult to determine the true frequency in the general population.
LAM predominantly affects women of reproductive age, with an average age at symptom onset of 33 years of age. Two thirds of people who first present with symptoms of LAM are in their thirties or forties, but the age range can extend from pre-adolescent to elderly.
The diagnosis of LAM may be confirmed by a thorough clinical evaluation that includes a detailed patient history and a variety of specialized tests.
High resolution CT scan (HRCT) shows characteristic thin-walled cysts in the lungs consistent with LAM and can help rule out other pulmonary conditions. HRCT may also reveal angiomyolipomas or lymphangioleiomyomas in the abdomen that support a diagnosis of LAM. Chest x-rays are not diagnostic for LAM and are often normal early in the disease course.
VEGF-D blood test is elevated in ~60-70% of individuals with LAM. In combination with a characteristic CT scan, the finding of elevated VEGF-D can establish the diagnosis of LAM without the need of a surgical lung biopsy, which is the gold standard for diagnosis but comes with its risks and complications.
Lung function tests are useful to obtain a baseline of the individual’s lung function and facilitate monitoring over time.
Currently, no test can accurately predict the course of the disease (prognosis) and progression seems to vary greatly from one person to another, though there has been a significant improvement in our understanding of LAM in the past decade. Patients with LAM have a favorable life expectancy with a transplant-free survival of more than 20 years from the time of diagnosis.
Individuals with LAM are encouraged to lead a normal life with a healthy lifestyle as LAM is generally a chronic disease with slow progression over decades. LAM is a progressive disease with no cure but, in recent years, a medication called sirolimus has been shown to slow the decline in lung function in LAM. Sirolimus has been shown to slow the disease process, resolve fluid accumulation in the lungs (chylous effusions) and regress renal masses (angiomyolipomas). Sirolimus is approved by the U.S. Food and Drug Administration (FDA) as well as by the regulatory agencies in the European Union and 15 other countries across the world to treat LAM.
Fluid accumulation in the lungs (pleural effusion) should be first managed with a trial of sirolimus, and invasive procedures such as drainage should only be employed in patients where sirolimus doesn’t have a satisfactory response. It is worth noting that it can sometimes take a few months for sirolimus to take full effect in the resolution of chylous fluids. Lung collapse (pneumothorax) may require the placement of a chest tube. Due to the high risk of recurrence, it is recommended that patients with LAM undergo a procedure called pleurodesis (a technique that adheres lungs to the chest wall) early in order to reduce the number of future pneumothoraces.
Drugs that temporarily widen the bronchial tubes (bronchodilators) may help to alleviate breathing difficulties (asthma-like symptoms) in some patients. Influenza and pneumococcal vaccination are recommended due to the pulmonary vulnerability of individuals with LAM. Supplemental oxygen should be administered to qualifying patients as needed. As with other respiratory conditions, patients with LAM may benefit from pulmonary rehabilitation. In individuals with severe cases of LAM, lung transplantation may be considered.
Renal angiomyolipomas pose a risk for internal bleeding especially as they increase in size. Interventional radiology procedures such as embolization or treatment with sirolimus may be needed to reduce the risk of bleeding. Surgical resection is rarely needed and should be reserved as a last resort.
Because of the association between surges in female hormones and worsening of symptoms of LAM, estrogen-containing contraceptives are contraindicated. Postmenopausal patients and patients with reduced mobility should be tested for osteoporosis. Any loss of bone mineral density should be treated with vitamin D and calcium supplementation and/or bisphosphonates according to treatment guidelines for osteoporosis.
Although sirolimus is an effective treatment of LAM, drug toxicity and development of resistance are potential problems related to therapy. Research continues to determine when sirolimus should be initiated, what side effects might be expected in the long term, and what other medicines could offer a better side effects profile.
Scientists are also investigating the role of hormone therapy in the onset, development and treatment of LAM. No beneficial outcomes have been consistently demonstrated in patients with LAM who received hormonal therapy, although available studies are limited and provide low-quality evidence. Randomized controlled trials of hormonal agents, either alone or in combination with sirolimus, are needed to better assess the impact of hormonal manipulation on the course of LAM. Until then, routine use of hormonal treatment in patients with LAM is discouraged.
Hereditary factors are also being studied to help determine whether or not a genetic predisposition is essential to the development of LAM. Similarly, research is ongoing to identify better biomarkers to improve the non-invasive diagnosis of LAM.
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