We report the results of therapy with alglucerase in two patients with severe hypoxemia and intrapulmonary vascular dilatations that appeared on agitated saline contrast echocardiography [4].

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Patient 1

A previous article [3] and two case series [2, 5] described patient 1. We first evaluated this patient in 1984 when she was 23 years of age. Progressive dyspnea began when the patient was about 20 years of age; by 1990, she would become breathless after walking a few steps. The patient was small (height, 159 cm; weight, 40 kg) and deeply cyanotic with clubbing of the fingers and a large liver. Bronchoalveolar lavage fluid and transbronchial lung biopsy specimens showed no Gaucher cells. Results of studies of lung function are shown in Table 1.

Therapy with alglucerase began in January 1990. The patient initially received alglucerase, 30 U/kg of body weight per month at 3.3 U/kg twice weekly. After 7 months, the dose was reduced to 2.3 U/kg twice weekly. After 33 months, the patient no longer needed administration of oxygen and was working full-time, but chest radiography showed enlarged pulmonary arteries (Figure 1, left and middle). Because the patient had no tricuspid regurgitation, we could not estimate pulmonary artery pressure from the echocardiogram [7]. After 6 years of therapy, no further progression of pulmonary hypertension has been seen on physical examination or chest radiography.

View larger version (91K): [in this window] [in a new window]   Figure 1. Left. Chest radiograph of patient 1 after 12 months of therapy with alglucerase. Middle. Chest radiograph of patient 1 after 36 months of therapy with alglucerase. Increased prominence of the main pulmonary artery and an increase in the diameter of the right pulmonary artery from 12.5 mm to 16.5 mm can be seen (arrows). Right. Lung biopsy specimen of patient 2 obtained 3 years before treatment. A small pulmonary artery in the region of a terminal bronchiole shows medial hypertrophy. (Hematoxylin-eosin stain; original magnification, x 250.).

Patient 2

Patient 2 was 41 years of age at his first evaluation. He had had splenectomy at 13 years of age but remained otherwise asymptomatic for Gaucher disease until 38 years of age, at which time vertebral osteomyelitis, hypoxemia, and a cerebral abscess developed. Thoracotomy with ligation of a suspected arteriovenous malformation did not alleviate hypoxemia. Examination of open lung biopsy specimens showed no Gaucher cells in the lungs. However, medial hypertrophy of small muscular arteries and arterioles was seen (Figure 1, right), and some large pulmonary arteries showed intimal proliferation of the type occurring in the early stages of pulmonary hypertension.

Patient 2 was thin and muscular (height, 178 cm; weight, 68.5 kg) and had moderate finger clubbing and a markedly enlarged liver. Results of studies of lung function are shown in Table 1.

Therapy with alglucerase (120 U/kg per month for 7 months as part of a dose-ranging protocol, followed by 30 U/kg per month) was started in September 1991. After 20 months of treatment (total dose, 1230 U/kg), the patient had no symptoms and was following a vigorous exercise program. His chest radiograph showed an increase in the size of the main pulmonary artery, and progressive pulmonary hypertension was seen after catheterization of the right side of the heart.

Discussion

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We describe two patients with type 1 Gaucher disease who presented with hepatomegaly, severe hypoxemia, and intrapulmonary vascular dilatations. Therapy with alglucerase decreased the size of the liver and almost completely eliminated the hypoxemia. However, the patients then developed pulmonary hypertension.

Until recently, pulmonary involvement has been considered to be a rare complication of Gaucher disease. When lung tissue is available, examination of the tissue frequently shows that the lungs are infiltrated with Gaucher cells [8, 9]. Pulmonary hypertension has occasionally been reported with Gaucher disease; in some cases, the pulmonary capillaries were obstructed by Gaucher cells [9, 10]. In one patient, however, few Gaucher cells were found in the lungs, and the pathologic findings resembled those of primary pulmonary hypertension [11].

More recent studies have shown pulmonary involvement in Gaucher disease. In a large autopsy series [12] that included patients with type 2 and type 3 Gaucher disease, more than one third of the cases had interstitial infiltration, plugging of the capillaries, or filling of the air spaces with Gaucher cells. Kerem and colleagues [13] found that 68% of patients in a clinic for Gaucher disease had some abnormality of lung function.

Our patients had no evidence of parenchymal lung infiltration with Gaucher cells. No Gaucher cells were seen in patient 1 on examinations of transbronchial biopsy specimens of the lung or bronchoalveolar lavage fluid. Patient 2 had an open lung biopsy, and no Gaucher cells were found on examination of the specimens. No lung infiltrates were seen on the chest radiograph of either patient. The hypoxemia thus seemed to be caused by intrapulmonary vascular dilatations.

The hepatopulmonary syndrome is defined as the triad of liver disease, hypoxemia, and intrapulmonary vascular dilatations [14]. Our patients had little evidence of hepatocellular dysfunction, but both had a very enlarged liver. Improvement in the hypoxemia and disappearance of the intrapulmonary vascular dilatations were presumably related to the decreased liver size seen with treatment. Severe hypoxemia has been reversed after successful liver transplantation and with medical therapy; in some cases, intrapulmonary vascular dilatations are reversible if the underlying liver disease is treated [15].

Pelini and colleagues [16] described a patient with type 1 Gaucher disease and severe hypoxemia that showed remarkable improvement after therapy with alglucerase. Although this patient may have had the hepatopulmonary syndrome, Pelini and colleagues did not test for intrapulmonary vascular dilatations. The abnormalities in the patient's lung function and the time taken to respond to treatment were similar to those of our patients.

It is difficult to account for the progression of pulmonary hypertension in our patients, whose response to alglucerase was otherwise favorable. Pulmonary hypertension does not seem to be a feature of the hepatopulmonary syndrome. In fact, patients with severe hypoxemia and liver disease usually have low pulmonary artery pressure and pulmonary vascular resistance [17] that tend to increase after such patients receive liver transplants [18].

Patient 2 developed pulmonary hypertension when his intrapulmonary vascular dilatation decreased. Patient 1 had moderate pulmonary hypertension after treatment, but evidence that her pulmonary artery pressure increased after therapy is somewhat unconvincing. The size of the main pulmonary artery in patient 1 definitely increased, but only one catheterization of the right side of the heart was done for confirmation.

The increase in pulmonary artery pressure may be partly explained by diminished dilatation of intrapulmonary vessels in a vascular bed that was already abnormally restricted. This explanation was suggested by the appearance of the small vessels in the lung biopsy specimens of patient 2 and by the low diffusing capacity that remained diminished after therapy in both patients. Decreased intrapulmonary vascular dilatation in patient 2 cannot be the only cause of pulmonary hypertension because his pulmonary artery pressure continued to increase after hypoxemia resolved. Progressive infiltration of the lung with Gaucher cells, leading to obstruction of small pulmonary arteries, also does not seem to explain the worsening pulmonary hypertension because the severe hepatomegaly improved remarkably after alglucerase therapy. Treatment of severe hypoxemia may have allowed patient 2 to survive long enough for progressive changes in the pulmonary vascular bed to become clinically evident. We also cannot exclude the possibility that alglucerase therapy aggravates pulmonary hypertension despite its beneficial effect on other manifestations of Gaucher disease. We cannot explain the reappearance of intrapulmonary vascular dilatation in patient 2, but the dilatation must have been relatively minor because the arterial oxygen tension remained normal.

Alglucerase saved the lives of these two patients and allowed them to return to a normal lifestyle. The increase in pulmonary artery pressure seen in these patients was not expected. Our first suspicion of increasing pressure was based on changes in the physical examination findings and the chest radiograph; therefore, screening does not have to be expensive. For these reasons, we believe that patients treated for Gaucher disease should be carefully examined for signs of pulmonary hypertension.

Dr. Garver: Department of Radiology, Scripps Clinic and Research Foundation, 10666 North Torrey Pines Road, La Jolla, CA 92037.

Dr. Kay: Sandoz Pharmaceutical Corporation, Building 419, Room 2111, 59 Route 10, East Hanover, NJ 07936.

Dr. Bloor: Department of Pathology (8320), University of California at San Diego Medical Center, 225 Dickinson Street, San Diego, CA 92103.

Dr. Beutler: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037.