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Lymphangioleiomyomatosis

Disease Details

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Description: Lymphangioleiomyomatosis is a rare, progressive lung disease characterized by the abnormal growth of smooth muscle-like cells, leading to the formation of cysts and obstruction of airways and lymphatic vessels.
Type: Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that falls under the category of interstitial lung diseases. It is genetically transmitted in an autosomal dominant manner, often associated with mutations in the TSC1 or TSC2 genes, which are also implicated in Tuberous Sclerosis Complex (TSC). In sporadic cases, the genetic mutation is somatic.
Signs And Symptoms: The average age of onset is the early-to-mid-30s. Exertional dyspnea (shortness of breath) and spontaneous pneumothorax (lung collapse) have been reported as the initial presentation of the disease in 49% and 46% of patients, respectively.Diagnosis is typically delayed 5 to 6 years. The condition is often misdiagnosed as asthma or chronic obstructive pulmonary disease. The first pneumothorax, or lung collapse, precedes the diagnosis of LAM in 82% of patients. The consensus clinical definition of LAM includes multiple symptoms:
Fatigue
Cough
Coughing up blood (rarely massive)
Chest pain
Chylous complications arising from lymphatic obstruction, including
Chylothorax
Chylous ascites
Chylopericardium
Chyloptysis
Chyluria
Chyle in vaginal discharge
Chyle in stool
Angiomyolipomas (fatty kidney tumors) are present in about 30% of patients with sporadic LAM and up to 90% of patients with TSC-LAM. Angiomyolipomas can sometimes spontaneously bleed, causing pain or low blood pressure.
Cystic lymphangiomas or lymph nodes with hypodense centers, which mimic necrotizing lymphomas, ovarian or renal cancers, or other malignancies can occur in the retroperitoneum, pelvis or mediastinum.Lung destruction in LAM is a consequence of diffuse infiltration by neoplastic smooth muscle-like cells that invade all lung structures including the lymphatics, airway walls, blood vessels and interstitial spaces. The consequences of vessel and airway obstruction include chylous fluid accumulations, hemoptysis, airflow obstruction and pneumothorax. The typical disease course displays progressive dyspnea on exertion, spaced by recurrent pneumothoraces and in some patients, chylous pleural effusions or ascites.Most people have dyspnea on exertion with daily activities by 10 years after symptom onset. Many patients require supplemental oxygen over that interval.
Prognosis: Survival estimates vary, dependent on mode of presentation or ascertainment, and have generally trended upward, probably due to earlier recognition through more widespread use of CT scanning. In a recent population-based cohort survey, median survival was found to be 29 years. Data from earlier, large case series indicated that 38% to 78% of patients were alive at 8.5 years from the time of disease onset.Patients typically develop progressive airflow obstruction. In a cohort of patients in the United Kingdom, 10 years after symptom onset, 55% of 77 patients were breathless walking on flat ground and 10% were housebound. The average annual rate of decline in FEV1 and DLCO in 275 patients studied in a single pulmonary function laboratory at the NHLBI was 75 ± 9 mL, and 0.69 ± 0.07 mL/min/mm Hg, respectively. In other series from Europe, the rate of decline in FEV1 was considerably higher, estimated at approximately 100 to 120 mL/yr. In the MILES trial, patients in the placebo group lost 134 cc/yr. There was some evidence in these studies that rate of decline in lung function correlates with initial DLCO, with menopausal status and high baseline VEGF-D.
Estimates of median survival vary from 10 to 30 years, depending on whether hospital-based or population-based cohorts are studied.
Onset: Lymphangioleiomyomatosis (LAM) typically has an onset in women of childbearing age, most commonly between the ages of 20 and 40 years. It is a rare, progressive lung disease characterized by the abnormal growth of smooth muscle-like cells, leading to cyst formation and complications in the lungs, lymphatics, and kidneys.
Prevalence: Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that primarily affects women of childbearing age. The prevalence is estimated to be about 1 in 1 million women in the general population.
Epidemiology: LAM is almost completely restricted to women. While lung cysts consistent with LAM are reported in some men with tuberous sclerosis, very few of these men develop symptoms. The prevalence of LAM is estimated using data from registries and patient groups and is between 3.4 and 7.8/million women. The number of new cases each year is between 0.23 and 0.31/million women/year in the US, UK and Switzerland. The variation between countries and between adjacent states in the US, suggest that a significant number of women with LAM remain either undiagnosed or their symptoms are attributed to other diseases. Adult women with tuberous sclerosis are more likely to develop LAM than women without tuberous sclerosis. Cohorts of patients with tuberous sclerosis have been screened for LAM using CT scanning. In a retrospective study of adults with tuberous sclerosis, CT demonstrated lung cysts in 42% of 95 women and 13% of 91 men. In general, lung cysts were larger and more numerous in women than in men. In a further retrospective study of women with TSC who underwent CT scanning to detect LAM, 25% of those in their 20s had lung cysts whereas 80% of women in their 40s were affected, suggesting that the development of LAM is age dependent at least in tuberous sclerosis-related LAM. Although the prevalence of tuberous sclerosis at 1 in 6,000 births is much greater than that of LAM, most pulmonary clinics see more cases of sporadic than tuberous sclerosis–LAM: probably due to a combination of low levels of screening for LAM in tuberous sclerosis and in many, the absence of symptoms.Female sex and tuberous sclerosis are the only known risk factors. Although use of supplemental estrogen is not associated with development of LAM, one study suggested that use of estrogen-containing contraceptive pills was associated with earlier onset.It occurs in more than 30% of women with tuberous sclerosis complex (TSC-LAM), a heritable syndrome that is associated with seizures, cognitive impairment and benign tumors in multiple tissues. Most LAM patients who present for medical evaluation have the sporadic form of the disease (S-LAM), however, which is not associated with other manifestations of tuberous sclerosis complex.
Mild cystic changes consistent with LAM have been described in 10–15% of men with TSC, but symptomatic LAM in males is rare. Sporadic LAM occurs exclusively in women, with one published exception to date. Both TSC-LAM and S-LAM are associated with mutations in tuberous sclerosis genes.
Intractability: Lymphangioleiomyomatosis (LAM) is considered a progressive and currently incurable disease. While treatment options, such as mTOR inhibitors (e.g., sirolimus) and supportive therapies, can help manage symptoms and slow disease progression, there is no definitive cure. Lung transplantation may be an option for advanced cases.
Disease Severity: Lymphangioleiomyomatosis (LAM) can vary significantly in disease severity. In mild cases, patients may have minimal symptoms and maintain normal daily activities. In severe cases, LAM can lead to progressive lung damage, respiratory failure, and complications such as pneumothorax (lung collapse) and chylothorax (accumulation of lymphatic fluid in the chest). Comprehensive evaluation and monitoring are essential for assessing and managing the severity of this disease in affected individuals.
Healthcare Professionals: Disease Ontology ID - DOID:3319
Pathophysiology: A variable percentage of cells within the LAM lesion contain mutational inactivation of the tuberous sclerosis complex (TSC1 or TSC2) tumor suppressor genes. TSC1 mutations cause a less severe clinical phenotype than TSC2 mutations. The discovery of TSC1/2 gene function as negative regulator of the mammalian target of rapamycin complex 1 (mTORC1) led to successful use of rapamycin analog sirolimus in clinical trials and FDA approval of sirolimus for treatment of LAM.
TSC1 and TSC2 form a tumor suppressor complex that regulates mammalian target of rapamycin (mTOR) signaling complex by directly controlling the activity of the small GTPase Rheb via the GTPase activating protein (GAP) domain of TSC2. Rheb binds to Raptor and controls the activity of mTOR complex 1 (mTORC1) that directly phosphorylates p70 S6 kinase (S6K1) and 4E-BP1. mTOR forms two physically and functionally distinct multiprotein complexes: the rapamycin-sensitive mTORC1 and the rapamycin-insensitive mTORC2. MTORC1 consists of five proteins including Raptor that positively regulate mTOR activity. MTORC2 consists of six proteins including mTOR and Rictor, which defines the activation level of mTORC2 and modulates the assembly of the actin cytoskeleton through Rho GTPases, and Rac1 is required for mTOR activation. In TSC2-null and human LAM cells, Rho GTPase activity is required for cell adhesion, motility, proliferation and survival. Loss of TSC1/TSC2 in LAM induces uncontrolled LAM cell growth and increases LAM cell viability. Upregulation of STAT1 and STAT3 and autophagy are known mediators of LAM cell viability and survival.
LAM cells behave, in many ways, like metastatic tumor cells. LAM cells appear to arise from an extrapulmonary source and migrate to the lung. Increased LAM cell migration and invasiveness is rescued by TSC2 re-expression. The cellular and molecular mechanisms of neoplastic transformation and lung parenchymal destruction by LAM cells remain unknown. Lung remodeling may be mediated by an imbalance between matrix degrading metalloproteinases (MMPs) and their endogenous inhibitors TIMPs. The invasive cell phenotype in LAM is associated with TIMP-3 downregulation and TSC2-dependent upregulation of MMPs.Clinical and histopathological evidence demonstrate the lymphatic involvement in LAM. The prevailing hypothesis is that LAM lesions secrete the lymphangiogenic factor VEGF-D, recruit lymphatic endothelial cells (LECs) that form lymphatic vessels and induce lung cysts. VEGF-D serum levels are increased in LAM compared to other cystic lung diseases, including pulmonary Langerhans cell histiocytosis, emphysema, Sjögren's syndrome, or Birt–Hogg–Dubé syndrome. VEGF-D levels correlate with the severity of LAM, evaluated as a measure of CT grade (the abundance of chylous effusions and lymphatic involvement). VEGF-D is a secreted homodimeric glycoprotein and a member of the VEGF family of growth factors, is known for its role in cancer lymphangiogenesis and metastasis. Proteolytic processing of VEGF-D affects cognate binding to VEGFR3. Histopathologically, LAM lesions are surrounded by cells that stain for VEGFR3, the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and podoplanin. VEGF-D binds to the receptor protein tyrosine kinases VEGFR-2 and VEGFR-349 in humans, and to VEGFR3 in mice. Surprisingly, knock-out of VEGF-D in mice has little effect on lymphatic system development. Nevertheless, during tumorigenesis VEGF-D promotes formation of tumor lymphatic vessels and facilitates metastatic spread of cancer cells. However, little is known about a role of abnormal lymphatics and VEGF-D in LAM pathogenesis.
Carrier Status: Lymphangioleiomyomatosis (LAM) is not typically associated with a carrier status. It is a rare, progressive lung disease that primarily affects women. It is often sporadic, but in some cases, it can be associated with tuberous sclerosis complex (TSC), an inherited genetic condition. In the context of TSC, LAM can be influenced by mutations in the TSC1 or TSC2 genes.
Mechanism: Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease that primarily affects women of childbearing age. In LAM, abnormal muscle-like cells, termed LAM cells, proliferate within the lungs and lymphatic system, leading to the formation of cysts, obstruction of airways, and destruction of lung tissue.

### Mechanism:
1. **Cell Proliferation and Infiltration**: LAM cells proliferate and infiltrate lung tissue, resulting in cyst formation and lung destruction.
2. **Lymphatic Involvement**: LAM cells also infiltrate the lymphatic system, causing lymphangioleiomyomas and chylous fluid accumulation.
3. **Airway Obstruction**: The proliferation of LAM cells can obstruct small airways, leading to reduced airflow and respiratory issues.

### Molecular Mechanisms:
1. **TSC Gene Mutations**: LAM is often associated with mutations in the TSC1 or TSC2 genes, which encode for hamartin and tuberin, respectively. These proteins form a complex that inhibits the mTOR (mechanistic target of rapamycin) signaling pathway.
2. **mTOR Pathway Activation**: Loss-of-function mutations in TSC1 or TSC2 lead to uncontrolled activation of the mTOR pathway. This, in turn, drives cell growth, proliferation, and survival.
3. **HIF-1α and VEGF**: Hyperactivation of mTOR can increase the expression of hypoxia-inducible factor 1-alpha (HIF-1α) and vascular endothelial growth factor (VEGF), promoting angiogenesis and lymphangiogenesis.
4. **Estrogen Sensitivity**: LAM cells express estrogen receptors, and estrogen may stimulate their growth and proliferation, explaining the disease's predilection for women.
5. **Migration and Metastasis**: LAM cells exhibit metastatic properties, similar to cancer cells, allowing them to spread within the lungs and lymphatic systems.

Understanding these mechanisms has therapeutic implications. For instance, mTOR inhibitors like sirolimus have been shown to slow disease progression by targeting the hyperactive mTOR pathway.
Treatment: An FDA-approved drug for treatment of LAM, the mTOR inhibitor sirolimus, is available for stabilization of lung function decline. Lung transplant remains the last resort for patients with advanced disease.
Compassionate Use Treatment: For lymphangioleiomyomatosis (LAM), compassionate use treatments and experimental therapies involve offerings outside standard approved treatments. Here are some notable options:

1. **Sirolimus (Rapamycin)**: This immunosuppressant drug, which inhibits mTOR (mechanistic target of rapamycin), has shown efficacy in stabilizing lung function, improving quality of life, and reducing the size of angiomyolipomas in LAM patients. Though it is an FDA-approved treatment, its use was initially considered experimental.

2. **Everolimus**: Another mTOR inhibitor similar to sirolimus, everolimus has been used off-label for LAM. Some studies suggest it may offer benefits similar to those of sirolimus.

3. **Anti-VEGF (Vascular Endothelial Growth Factor) Therapies**: These experimental treatments target angiogenesis. Bevacizumab (Avastin) has been studied for its potential to reduce lung cysts and improve lung function in LAM patients.

4. **Hormonal Therapies**: Drugs like progesterone and GnRH (gonadotropin-releasing hormone) analogs were historically used in LAM, given the disease's association with estrogen. However, their efficacy remains controversial, and they are not standard due to limited benefit and potential side effects.

5. **Autophagy Inhibitors**: Hydroxychloroquine, an autophagy inhibitor, has been explored in clinical trials for LAM due to its potential to interfere with cellular mechanisms promoting disease progression.

Given the rarity of LAM, patients often explore these options through clinical trials or programs for compassionate use. It's advisable for patients and healthcare providers to stay updated on evolving therapies through clinical research and professional guidelines.
Lifestyle Recommendations: Here are some lifestyle recommendations for individuals with lymphangioleiomyomatosis (LAM):

1. **Avoid Smoking**: Smoking can worsen lung function. It's critical for individuals with LAM to avoid smoking and exposure to secondhand smoke.

2. **Healthy Diet**: Maintain a balanced diet to support overall health. A nutritionist can help tailor a diet suitable for individual needs and existing conditions.

3. **Exercise**: Engage in regular, moderate exercise to strengthen respiratory muscles and improve overall fitness. It's best to consult a healthcare provider for a safe and suitable exercise routine.

4. **Oxygen Therapy**: Some individuals may require supplemental oxygen. Follow the health provider’s recommendations regarding oxygen use.

5. **Monitor Symptoms**: Keep track of symptoms and report any changes such as increased shortness of breath, coughing, or new chest pain to a healthcare provider immediately.

6. **Regular Check-ups**: Regular visits to a pulmonologist or a specialist familiar with LAM are important for monitoring disease progression and adjusting treatment as necessary.

7. **Avoid High-Altitude Exposure**: High altitudes can worsen respiratory symptoms; hence, avoid such environments if possible or use supplemental oxygen as prescribed when traveling by air or being in high altitudes.

8. **Manage Stress**: Stress can impact overall health, so engaging in stress-reducing activities like yoga, meditation, or other relaxation techniques may be beneficial.

9. **Infection Prevention**: Practice good hygiene, avoid close contact with people who are sick, and get regular vaccinations to prevent respiratory infections.

10. **Stay Hydrated**: Adequate hydration can help maintain lung health and overall well-being.

Always consult with healthcare professionals for personalized recommendations.
Medication: Sirolimus is an mTOR inhibitor that stabilizes lung function and improves some measures of life in LAM patients. It is approved by the FDA for use in LAM, based on the results of the Multicenter International LAM Efficacy and Safety of Sirolimus (MILES) Trial. MILES data supports the use of sirolimus in patients who have abnormal lung function (i.e. FEV1<70% predicted). Whether the benefits of treatment outweigh the risks for asymptomatic LAM patients with normal lung function is not clear, but some physicians consider treatment for declining patients who are approaching the abnormal range for FEV1. Sirolimus also appears to be effective for the treatment chylous effusions and lymphangioleiomyomatosis. The benefits of sirolimus only persist while treatment continues. The safety of long term therapy has not been studied.Potential side effects from mTOR inhibitors include swelling in the ankles, acne, oral ulcers, dyspepsia, diarrhea, elevation of cholesterol and triglycerides, hypertension and headache. Sirolimus pneumonitis and latent malignancy are more serious concerns, but occur infrequently. Sirolimus inhibits wound healing. It is important to stop therapy with the drug for 1–2 weeks before and after elective procedures that require optimal wound healing. Precautions must be taken to avoid prolonged sun exposure due to increased skin cancer risk.Treatment with another mTOR inhibitor, everolimus, was reported in a small, open-label trial to be associated with improvement in FEV1 and six-minute walking distance. Serum levels of VEGF-D and collagen IV were reduced by treatment. Adverse events were generally consistent with those known to be associated with mTOR inhibitors, although some were serious and included peripheral edema, pneumonia, cardiac failure and Pneumocystis jirovecii infection. Escalating doses of everolimus were used, up to 10 mg per day; higher than what is typically used clinically for LAM.
Serum VEGF-D concentration is useful, predictive and prognostic biomarker. Higher baseline VEGF-D levels predicts more rapid disease progression and a more robust treatment response.
Hormonal approaches to treatment have never been tested in proper trials. In the absence of proven benefit, therapy with progesterone, GnRH agonists (e.g., leuprorelin, goserelin) and tamoxifen are not routinely recommended. Doxycycline had no effect on the rate of lung function decline in a double blind trial.Sirolimus is often effective as first-line management for chylothorax. If chylous leakage or accumulations persist despite treatment, imaging with heavy T2 weighted MRI, MRI lymphangiography or thoracic duct lymphangiography can be considered. Pleural fusion procedures can be considered in refractory cases.
Repurposable Drugs: Lymphangioleiomyomatosis (LAM) is a rare lung disease that can lead to the formation of cysts and the destruction of healthy lung tissue. Repurposable drugs for LAM include:

1. **Sirolimus (Rapamycin)**: Originally used as an immunosuppressant for organ transplant recipients, sirolimus has shown efficacy in reducing lung decline in LAM patients by inhibiting the mTOR pathway.
2. **Everolimus**: Similar to sirolimus, everolimus is an mTOR inhibitor and is used in some cases to manage LAM symptoms.
3. **Doxycycline**: An antibiotic with anti-inflammatory properties, it has been investigated for its potential to reduce lung damage in LAM, though its efficacy is still under study.
Metabolites: Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease characterized by the abnormal growth of smooth muscle-like cells, which can lead to the formation of cysts in the lungs. Important metabolites involved in LAM include:

1. **VEGF-D (Vascular Endothelial Growth Factor-D)**: Elevated levels of VEGF-D are commonly found in LAM patients and are used as a biomarker for diagnosis and disease monitoring.

2. **mTOR Pathway Metabolites**: Since LAM cells show activation of the mTOR pathway, metabolites such as phosphorylated S6 kinase and 4EBP1 are significant, as they reflect pathway activity. These metabolites are targeted by treatments like sirolimus (an mTOR inhibitor).

3. **Glycolytic Pathway Metabolites**: LAM cells often exhibit higher rates of glycolysis, leading to increased levels of metabolites like lactate and pyruvate. Enhanced glycolysis supports the rapid cell growth and survival seen in LAM.

Understanding these metabolites is crucial for diagnosing and tailoring treatment strategies for LAM.
Nutraceuticals: For lymphangioleiomyomatosis, there is no established evidence supporting the use of nutraceuticals as an effective treatment. LAM is a rare, progressive lung disease that may benefit from management approaches like sirolimus or everolimus, which are mTOR inhibitors. Consultation with a healthcare provider is recommended for the most appropriate treatment options.
Peptides: Lymphangioleiomyomatosis (LAM) is a rare, progressive lung disease characterized by the abnormal growth of smooth muscle cells, especially in the lungs and lymphatic system. Currently, there is limited information on specific peptides directly involved in LAM treatment or pathogenesis.

However, potential experimental therapies looking into peptide inhibitors or targeting molecular pathways could be under investigation. Nanotechnology applications in LAM research focus on developing targeted drug delivery systems to improve the effectiveness and reduce the side effects of therapeutics. Nanoparticles can be designed to deliver drugs specifically to the abnormal smooth muscle cells, potentially enhancing treatment efficacy and minimizing damage to healthy tissues.