What is lymphangioleiomyomatosis (LAM)
Lymphangioleiomyomatosis (LAM): Symptoms, Causes Treatment, pulmonary: Lymphangioleiomyomatosis (LAM) is one of the rare lung diseases and is caused by a spontaneously acquired or inherited genetic defect. As a result, excessive proliferation of smooth muscle cells in lymphatic vessels and bronchial pathways destroys healthy lung tissue.
This obstructs the vital oxygen uptake in the lungs. The research into the rare disease LAM has only been intensively pursued for a few years. Fortunately, some important discoveries have been made in recent years to better understand the condition and improve treatment options.
LYMPHANGIOLEIOMYOMATOSIS (LAM): DEVELOPMENTAL MECHANISMS
A defect in the TSC gene causes atypical smooth muscle cells to form in the wall structures of the bronchi and pulmonary vessels. These cell progenies multiply rapidly and produce abundant connective tissue mass. Thickening of the structures occurs in the affected area, as a result of which the bronchi and vessels, ie the air, lymph and blood flow paths, can be laid. The progressive tissue scarring displaces healthy lung tissue. It forms cavity structures (cysts), which lead to a lung overinflation and a reduced guest exchange.
Forms of Lymphangioleiomyomatosis (LAM)
- Sporadic form: Patients have a spontaneously acquired gene defect in the TSC gene. Only the lungs are affected by the cell changes.
form: An inherited defect of the TSC gene leads to the clinical picture of tuberous sclerosis (TSC). It comes to benign cell proliferation in various organs of the body. Particularly affected are skin and brain as well as the kidneys. About 30 percent of TSC patients develop LAM of the lungs.
Although the inherited form is approximately four times more common than the sporadic LAM (sLAM), sLAM represents the majority of patients in treatment. The reasons for this are not conclusively clarified, discussed are different degrees of severity of the disease depending on their shape. In addition, pulmonary symptoms in TSC could be suppressed by other organ complications.
Symptoms of Lymphangioleiomyomatosis (LAM)
The patients feel shortness of breath and report a reduced physical capacity. Often there
If the LAM occurs as part of tuberous sclerosis, associated tissue malformations are present: Almost all patients carry nodular skin symptoms. The cell tumors of the organs (most commonly affected next to the skin are brain and kidney) can cause other symptoms such as epileptic seizures and sudden internal bleeding.
HOW COMMON IS LYMPHANGIOLEIOMYOMATOSIS?
Sporadic lymphangioleiomyomatosis affects about five out of every one million women. In addition, LAM occurs in about 30 percent of patients with tuberous sclerosis (about another 19 out of 1 million women).
Although the TSC-LAM is much more common, most patients in treatment show the sLAM. (see also forms of the LAM ). The disease almost exclusively breaks out in women. So far, only five cases have been reported in male patients, four of which have not been confirmed.
This is probably due to hormonal causes (see also risk factors of the LAM ). The LAM begins in middle age (about 35 years), but it is often diagnosed later due to a long diagnostic process.
lymphangioleiomyomatosis Risk Factors
The sporadic form of LAM leads to a spontaneous gene mutation in the TSC gene. The disease-specific cells of LAM carry on their surface estrogen receptors. It is believed that the binding of female hormones stimulates growth, and thus the disease is set in motion. So the female sex alone is a risk factor for the disease.
Inheritance of the TSC gene defect is an autosomal dominant inheritance. That is, it comes to disease outbreak, if one of the two gene copies (alleles) carries the mutation. For a parent who is ill, the risk of having a baby is 50 percent. If both parents are affected, the risk increases to 75 to 100 percent. In a disease of tuberous sclerosis, about 30 percent of female patients develop LAM.
Other risk factors that can adversely affect the disease are smoking and bacterial or viral lung infections.
LYMPHANGIOLEIOMYOMATOSIS (LAM): DIAGNOSIS
HR (High Resolution) computed tomography of the lungs provides more detailed information in the next step: To identify a LAM, there are defined radiological criteria, such as the wall thickness of the alveoli or the presence of cystic structures (cavities), which indicate pulmonary hyperinflation ( Emphysema ) are.
If a LAM is suspected, a lung biopsy ( tissue sample ) is usually carried out. Under the microscope, the typical growths of smooth muscle cells, the regular lung architecture appears destroyed by
For the reliable diagnosis of LAM, a typical findings in lung CT and tissue biopsy or a typical findings in lung CT and another of the following criteria are necessary: renal tumor (angiomyolipoma), lung or abdominal lymphathlon (chylothorax, chylous ascites) , Lymph node involvement, confirmed disease of tuberous sclerosis.
If there is no already known tuberous sclerosis, the diagnosis of a LAM should be followed by further symptoms of a TSC: presentation to the dermatologist, cMRT (cranial MRI) for the exclusion / detection of brain tumors, ultrasound and CT abdomen (abdominal region) Exclusion / detection of renal mass.
Other useful investigations
LAM is associated with osteoporosis. Therefore, patients, especially menopause, should undergo regular bone density measurements. In addition, an echocardiogram (ultrasound of the heart) is always important in lung diseases to detect sequelae, such as pulmonary hypertension or heart failure.
LYMPHANGIOLEIOMYOMATOSIS (LAM) Therapy & TREATMENT
LAM therapy consists of three pillars: symptom-oriented therapy, drug therapy to control cell growth, and lung transplantation.
The most commonly used therapy is the treatment of the symptoms. The supply of oxygen, also in the form of long-term oxygen therapy plays thereby the largest role. In addition, bronchodilators are used individually, which lead to an expansion of the bronchial pathways and alleviate respiratory distress. Complications of LAM require additional procedures.
In cases of frequent lymphatic spasm or pulmonary collapse, pleurodesis (bonding of the pleura) should be considered. In patients with TSC, further complications may occur which also need to be treated: surgical removal or obliteration in angiomyolipoma, antiepileptic drugs in epilepsy due to brain tumors.
Drug Therapy to control cell growth
In order to prevent the unrestrained cell growth, one uses specific acting drugs, which intervene in well-known molecular processes of the LAM.
- Hormone therapy:The proliferating smooth muscle cells carry estrogen receptors on their cell surface. Binding female hormones to the receptor causes a growth stimulus on the cells. To prevent this, the receptor is to be blocked by antiestrogens medicen. So far, however, all study results are disappointing. With respect to LAM, no significant slowing of the disease process was observed, with significant side effects for the patients due to disruption of the hormone cycle throughout the body. Therefore, the hormone therapy is currently not generally recommended. In some patients with a rapidly developing clinical picture, the hormone progesterone can benefit because it has anti-estrogenic properties, that is, can weaken the estrogen-mediated growth stimulus on the cells. According to the guideline of the European Respiratory Society, therapy can be attempted on a case by case basis, whereby progesterone is not routinely used. If the patients take hormone supplements for other reasons (birth control pills, hormone replacement therapy), the disease can progress faster. Special care is therefore needed with hormone substances.
- immunosuppression:Another promising approach is the use of immunosuppressants, so-called mTOR inhibitors. The substance sirolimus (= rapamycin) inhibits the mTOR-mediated signaling pathway, which promotes cell growth and is overactivated by the gene defect in LAM. Results of a clinical trial showed significant improvement in lung function when administered with sirolimus. In addition, the patients found a stable cell population and reduced levels of messenger substances that promote cell growth. However, when treatment was stopped, the disease progressed again, suggesting that long-term therapy with sirolimus is necessary, considering the numerous side effects of immunosuppressive therapy. The European Respiratory Society guideline recommends that patients undergoing aggressive disease undergo treatment with sirolimus following assessment of the individual risk profile for immunosuppressive therapy. Regular checkups should check the effect and possible side effects of the substance. If possible, the therapy should be accompanied by a study center. In particular, current clinical trials are investigating the long-term efficacy and drug safety of sirolimus in order to provide a long-term overall recommendation for the drug. See also Regular checkups should check the effect and possible side effects of the substance. If possible, the therapy should be accompanied by a study center. In particular, current clinical trials are investigating the long-term efficacy and drug safety of sirolimus in order to provide a long-term overall recommendation for the drug. See also Regular checkups should check the effect and possible side effects of the substance. If possible, the therapy should be accompanied by a study center. In particular, current clinical trials are investigating the long-term efficacy and drug safety of sirolimus in order to provide a long-term overall recommendation for the drug.
The lung transplantation is currently the only option for cure LAM. However, only a few patients come into question and the capacity of the donor organs is limited. In the case of successful transplantation, according to the current study situation, recurrence of LAM is rarely expected.
In order to improve the quality of life, there are a number of measures that can be taken in the case of chronic lung disease LAM in consultation with the attending physician. These include respiratory physiotherapy exercises to promote lung capacity, abstinence from nicotine or vaccines against influenza and pneumococci.
LYMPHANGIOLEIOMYOMATOSIS (LAM) other RESEARCH APPROACHES
Research into LAM has only been intensively pursued for a few years. Fortunately, some important discoveries have been made in recent years to better understand the condition and improve treatment options.
Efficacy of sirolimus
An important contribution is made by clinical studies on the efficacy of various medications. Since studies on hormone therapies have not been successful, there is great hope in the treatment with the immunosuppressant sirolimus (rapamycin).
Sirolimus inhibits cell growth via the mTOR signaling pathway (see also LAM Therapy)). A study published in the New England Journal of Medicine in 2010/2011 on 89 patients confirmed the substance’s effectiveness. Compared with the placebo group, sirolimus-treated participants showed significantly improved lung function, fewer symptoms and a higher quality of life. In addition, the number of smooth muscle cells was stable due to inhibited growth, for growth-promoting messenger substances (VEGF), reduced blood levels were measured.
The therapy with sirolimus was carried out over 12 months, then the participants were observed for a further 12 months without therapy. Critics had previously feared that it could come to a dramatic deterioration of the disease after the therapy, a so-called rebound. Fortunately, this fear did not materialize, but after discontinuing therapy, the disease progressed again, but only to a stage similar to that in the comparison group. The values of lung function matched those of the comparison group. However, the results indicate that long-term therapy with sirolimus is needed to stabilize lung function and halt the disease.
Patients report various side effects with sirolimus, especially mucosal inflammation, diarrhea, elevated blood lipid levels, acne-like lesions and leg swelling. However, in the placebo group of the study an almost comparable number of side effects occurred, in particular pulmonary complications were even more frequent.
The authors of the study see a positive effect for therapy with sirolimus in patients with moderate LAM. Whether a therapy really comes into question, remains currently an individual decision, depending on the disease severity and risk profile of the patient.
Mouse model for basic research
Researchers hope to gain the latest findings from a mouse model that has just been developed for further research on LAM. A working group in Philadelphia has managed to introduce cells with missing TSC gene into the lungs of mice. The affected animals then developed LAM-like lung disease. The researchers now want to use this model to investigate molecular changes caused by the genetic defect and, above all, to carry out therapy studies.
Initial results of drug testing in this mouse model confirm the good efficacy of sirolimus. In addition, an added benefit of combination therapy with simvastatin, a cholesterol-lowering agent, was observed. Simvastatin itself has an anti-inflammatory and growth-inhibiting effect. In addition, it counteracts elevated blood lipid levels – an undesirable side effect of sirolimus.