Lymphangioleiomyomatosis

We describe a case of a 37-year-old female ex-smoker with lymphangioleiomyomatosis and SZ [[alpha].sub.1]-antitrypsin disease who underwent successful bilateral sequential lung transplantation. While this disease combination has not been described previously, we recommend vigilance for the possibility of such combinations in patients with chronic lung disease. The possible mechanisms of interaction resulting from both disease processes are discussed.

Key words: chylothorax; COPD: lymphangioleiomyomatosis: matrix metalloproteinase: SZ [[alpha].sub.1]-antitrypsin disease

Abbreviations: A1AT = [[alpha].sub.1]-antitrypsin: LAM = lymphangioleiomyomatosis

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[[alpha].sub.1]-Antitrypsin (A1AT) deficiency is the most common inherited metabolic disorder causing lug disease. (1) Although the ZZ phenotype, of A1AT deficiency has been clearly linked to an increased risk of emphysema, the clinical significance of the SZ phenotype has been less evident. (1) Some studies have suggested an increased risk of obstructive lung disease, (1,2) while others have not. (3,4) SZ heterozygosity appears to result in minimal, if any, clinical sequelae in nonsmokers with intermediate levels of A1AT. (3) However, exposure to cigarette smoke confers a significant risk of developing COPD in such patients, presumably by further accentuating the inherent elastase/ A1AT imbalance within the lung. (5) A1AT deficiency has been reported (6) in association with idiopathic pulmonary fibrosis. We describe the first report, to our knowledge, of biopsy-proven lymphangioleimyomatosis (LAM) in the setting of A1AT heterozygosity with the SZ phenotype. The possibility that the SZ phenotype may have further contributed to this patient's pulmonary pathology in the setting of LAM is intriguing, especially as their association has not been described previously.

CASE REPORT

A 37-year-old white woman was referred for consideration of lung transplantation. A presumptive diagnosis of LAM had been made 2 years prior, based on her clinical, physiologic, and radiologic findings.

Her history included 6 years of progressive dyspnea, exertional wheezing, and chest tightness, a 15-lb unplanned weight loss, and a chronic cough productive of milky sputum for 3 months. She smoked 1 cigarette daily from age 17 to 22 years. There was no personal or family history of seizures, mental retardation, or skin lesions, although a vague history of it sister having a low A1AT level was reported but could not be subsequently confirmed.

Physical examination revealed an alert woman with a BP of 100/80 mm Hg, a heart rate of 86 heats/min, a respiratory rate of 16 breaths/min, and a resting oxygen saturation level of 95% breathing room air. Abnormal physical findings included mild nasal congestion, a widened anterior/posterior thoracic diameter, depressed diaphragms with a diaphragmatic excursion of 2 cm, labored respirations, and use of accessory muscles of respiration with minor exertion. On chest auscultation, breath sounds were diminished, and expiration was prolonged with audible wheezing. No finger clubbing, cyanosis, peripheral edema, or cutaneous manifestations of tuberous sclerosis were noted. There were no cardiac murmurs, gallops, or parasternal heaves. The remainder of the physical examination findings was normal.

A summary of her pertinent laboratory data included the following. Arterial blood gas levels while breathing room air showed a pH of 7.46, a PC[O.sub.2], of 29 mm Hg, and a P[O.sub.2] of 65 mm Hg. The hematocrit was 43%, hemoglobin level was 15.1 g/dL, and a WBC count was 6,100 cells/[micro]L. The WBC differential count was normal, with 1% eosinophils. The IgE level was 23 U/mL, (normal range, 0 to 110 U/mL), Antinuclear antibody and rheumatoid antibody assays were negative. The lactate dehydrogenase level was elevated at 829 IU/L (normal range, 313 to 618 IU/L).

An ECG showed sinus rhythm and was consistent with a diagnosis of Wolff-Parkinson-White syndrome. An echocardiogram demonstrated normal-sized cardiac chambers, with normal left ventricular systolic function. A quantitative ventilation-perfusion scan of the lungs demonstrated matched, symmetric bilateral mid-zone ventilation and perfusion defects, with 50% perfusion to each lung.

A CT scan of the sinuses was normal. Posteroanterior and lateral chest radiographs demonstrated hyperinflation and increased interstitial marking with evidence of bilateral bullous disease. A high-resolution CT scan of the chest revealed multiple bilateral, diffuse, thin-walled cystic air spaces, ranging in size from a few millimeters to 3.5 cm in diameter, throughout the entire lung. In addition, there were some scattered linear scarring changes. The pulmonary arteries were of normal size (Fig 1).

[FIGURE 1 OMITTED]

Pulmonary function tests revealed an [FEV.sub.1] of 0.62 L (22% of predicted), an FVC of 2.0 L (61% of predicted), all [FEV.sub.1]/FVC ratio of 31%, a total lung capacity of 5.66 L (116% of predicted), mid a diffusing capacity of the lung carbon monoxide of 8.0 mL/min/mm Hg (42% of predicted). This was interpreted as being consistent with severe airflow obstruction. No significant bronchodilator response was noted. A 6-min walk test showed significant oxygen desaturation while breathing air from a resting baseline of 96% to a nadir of 85% during exercise. The total distance walked was 1,584 feet. Because of the persistent wheezing and a family history of possible A1AT deficiency, an A1AT level was measured, revealing an abnormally low value of 66 mg/dL (normal range, 90 to 180 mg/dL). Subsequent testing confirmed the presence of an SZ phenotype in this patient.

The patient's clinical course was complicated by bilateral pneumothoraces, requiring bilateral tube thoracostomies and, finally, bilateral surgical pleurodeses to close bilatera bronchopleural fistulas. During this latter procedure, a subpleural wedge biopsy of the left lung was performed, and the specimen showed lung parenchyma with multiple cystic spaces, occasionally lined by cells with plump avoid-to-round nuclei and moderate amounts of cytoplasm (Fig 2). These cells strongly stained with immunohistochemical markers for actin and HMB-45, and were diagnostic for LAM (Fig 3). Seventeen months ago, the patient underwent uncomplicated bilateral sequential lung transplantation and has since returned to full-time employment.

[FIGURE 2-3 OMITTED]

DISCUSSION

LAM is a rare interstitial lung disease that is characterized by an abnormal proliferation of smooth muscle-like cells, resulting in the progressive obstruction of airways, blood vessels, and lymphatics. Clinical features of LAM include progressive dyspnea, spontaneous pneumothoraces, and cough. Hemoptysis, chest pain, and chylothorax may be present. (7) The etiology of LAM is not known.

Among the pathology hallmarks of LAM are diffuse cystic changes with proliferation of smooth muscle cells. (8) Previous authors have hypothesized that these cystic lesions may develop as a result of airflow obstruction secondary to bronchiole and bronchiolar narrowing by the proliferating smooth muscle. (9,10) More recently, it has been noted that, at the periphery of the smooth muscle infiltrate. the degradation of elastic fibers and intense remodeling activity occur. These are likely related to an imbalance in the elastase/A1AT system similar to the probable pathogenesis of emphysema. (11) Indeed, Fukuda et al (12) proposed that the cystic lesions found in patients with LAM were the result of such degradation of elastic fibers from the mechanism outlined above. They observed that the proliferating smooth muscle cells contained electron-dense granules in the cytoplasm that, when released, may have contributed to the development of emphysema via the elastase pathway. Hayashi et al (13) showed increased immunoreactivity in the LAM cells of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-1. As MMPs are capable of cleaving extracellular elastins and collagens, the authors suggested that it was an imbalance of MMPs and their inhibitors that was responsible for the cystic lesions in patients with LAM. Of note, Ohnishi et al (14) reported increased immunoreactivity to some MMPs, including MMP-2, in the lungs of non-LAM patients with emphysema, suggesting a significant role for the MMP-mediated extracellular matrix degradation pathway in the pathogenesis of emphysema.

Although A1AT is all inhibitor mainly of serine proteases, and does not inhibit MMP-2 and MMP-9 per se, (13) it is possible that MMPs may cleave a variety of nonextracellular matrix proteins including A1AT. (15) The inactivation of A1AT by LAM cell-derived MMPs in this ex-minimal smoker with a low serum A1AT level possibly could hasten parenchymal destruction and the development of emphysema.

While the current literature does not support a common etiology or genetic linkage between LAM and A1AT deficiency, the presence of these two conditions in our patient could produce severe airflow obstruction and cystic lung disease. It is also unclear whether A1AT augmentation therapy at this stage would be of benefit. (16) Further understanding of the genetic, biochemical, and molecular pathways in both LAM and A1AT deficiency may enable future novel therapies for these patients.

* From the University of California (Drs. Chan and Kwack), Davis Medical Center, Sacramento, CA; University of California (Dr. Jones), San Francisco, CA: University of Miami (Dr. Glassberg), Miami, FL; and Kaiser Permanente Medical Center (Dr. Gherman), San Francisco, CA.

Manuscript received December 18, 2002; revision accepted February 12, 2003.

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Correspondence to: Andrew Chan, MB, FCCP, 4150 V St, Suite 3400, Sacramento. CA 95817; e-mail: alchan@ucdavis.edu

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