Clinical Representation and Course of LAM

General Facts about the Clinical Representation and Course of LAM:

• Average age at diagnosis: 35 years old, although the age range can vary from teenagers to octogenarians
• Average symptomatic period prior to diagnosis: 3 to 5 years
• Most common complaints: Dyspnea on exertion (~75%), fatigue (~65-70%), cough (~20%), chest pain (~15%), hemoptysis (~5%), and chyloptysis (less than 5%)
• Pneumothorax occurs in approximately 60% of patients at some point in the course of their illness. Recurrence after an initial pneumothorax is very common and occurs in more than 70% of patients.
• Chylothorax occurs in about 20% of LAM patients.
• Angiomyolipomas are present in most (80-90%) of patients with TSC-LAM and about one-third of patients with sporadic LAM (S-LAM).
• Rarely, LAM presents as retroperitoneal masses or adenopathy which mimic lymphoma, ovarian or renal cancer, or other malignancy.
• Large lymph-filled abdominal lymphangiomyomas have also been described and may vary in size with gravitational influences in supine and erect patients.

Pulmonary physiology of LAM

Lung function may be normal in about one-third of patients, especially early in the disease course or in TSC patients whose LAM is identified through screening and have no pulmonary symptoms. The most common abnormality detected on spirometry is the presence of airflow obstruction, seen in >50% of patients. Reversible airflow obstruction is present in up to 20-25% of patients. Air trapping and/or hyperinflation are frequently observed. Restrictive or mixed physiologic defects can be seen in ~20-25% of patients. Diffusion capacity for carbon monoxide (DLCO) is frequently reduced, and in some cases may be reduced out of proportion to the obstructive defect. Impaired gas exchange and hypoxemia occur, but hypercapnea is rare even in end-stage disease.

Natural history of disease progression

Lung Function Decline

LAM is a gradually progressive disease and roughly half of patients with LAM develop dyspnea while walking on flat ground by ten years following the onset of symptoms. Spontaneous pneumothorax is a common manifestation and can often be the presenting manifestation that leads to the diagnosis of LAM. Most patients with LAM experience a pneumothorax in their 3^rd –5^th decades, with a very high (>70%) risk of recurrence.

The average rate of decline in FEV1 in patients with LAM has been variably reported to range between 75 – 120mls/year, with a recent NHLBI LAM Registry analysis reporting an average FEV1 decline of ~90ml/year. Premenopausal women with LAM tend to decline faster than postmenopausal women with LAM.

The average survival in women with LAM is greater than 25 years from the time of diagnosis, with estimated 5-, 10-, 15-, and 20-year transplant-free survival rates of 94%, 85%, 75%, and 64%, respectively.

Renal Angiomyolipomas

Kidney tumors called angiomyolipomas, unusual hamartomas containing fat, smooth muscle and blood vessels, are present in about 80-90% of patients with TSC-LAM and 30-40% of patients with S-LAM (Table 1). In S-LAM, angiomyolipomas are usually unilateral, small, solitary, and restricted to the kidney. In TSC-LAM they are more often larger, bilateral, multiple, and can involve other organs such as the spleen or liver.

Angiomyolipomas, especially those greater than 4cm in size or with high profusion of aneurysms, can result in hemorrhage-producing symptoms ranging from chronic intermittent flank pain to acute abdomen with hypovolemic shock.

Embolization or cauterization may be required to prevent bleeding. Treatment with mTOR inhibitors such as everolimus and sirolimus can shrink the angiomyolipomas and help prevent bleeding.

Tuberous Sclerosis Complex-LAM (TSC-LAM) vs. Sporadic LAM (S-LAM)

Most women presenting with LAM do not have TSC. Frequently, people with TSC have mild symptoms, so the diagnosis may be overlooked into adulthood. Genetic tests may be required to ensure they do not have a mild form of TSC in association with LAM. The inherited nature of TSC is very relevant when considering pregnancy since 50% of children will inherit TSC. Comparison of S-LAM and TSC-LAM in the chart below.

 Living with LAM and Pregnancy

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