Case Report

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A 42-year-old woman was first diagnosed with Gaucher disease at the age of 19 years. She eventually required splenectomy for symptomatic massive splenomegaly. Progressive dyspnea subsequently developed. After the patient was evaluated at the National Institutes of Health, Gaucher disease with pulmonary involvement was diagnosed. Initial treatment consisted of home oxygen delivered at 4 L/min. Evaluation in September 1991 showed a middle-aged white woman with conversational dyspnea while breathing room air and with severe exercise limitation despite supplemental oxygen. Breath sounds were normal, the cardiac examination was notable only because of a prominent second heart sound, and the liver was markedly enlarged. No cyanosis or clubbing was present. A chest radiograph was normal. Pulmonary function test results and room-air arterial blood gas analysis Table 1 showed normal expiratory flow rates, a severely reduced single-breath diffusing capacity for carbon monoxide, and severe hypoxemia with a widened alveolar-arterial oxygen gradient.

Enzyme replacement therapy was started with mannose-terminated glucocerebrosidase (Ceredase; Genzyme, Boston, Massachusetts) at 60 U/kg every 2 weeks. By April 1992, the patient's dyspnea had substantially improved, and she no longer required home oxygen. A repeat room-air arterial blood gas analysis Table 1 showed a markedly improved oxygen saturation and narrowed alveolar-arterial oxygen gradient. An integrated cardiopulmonary exercise stress test showed a minimally decreased breathing reserve, elevated ventilatory equivalents for CO₂ and O₂ at the anaerobic threshold, a low O₂ pulse, and a decrease in oxygen saturation with exercise that was consistent with pulmonary vascular disease.

Discussion

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Pulmonary involvement in Gaucher disease is common and is seen in one third of patients [2]. However, it is infrequent in the adult (type I) form and suggests an unfavorable prognosis [1]. Two distinct patterns of pulmonary involvement in patients with type I Gaucher disease have been described: interstitial infiltration with Gaucher cells in the perivascular, peribronchial, and septal regions with fibrosis and capillary plugging with Gaucher cells that occlude small capillaries and cause pulmonary hypertension [2, 3]. In the latter pattern, chest radiographs tend to be normal, and death is usually secondary to pulmonary hypertension with severe hypoxemia and cor pulmonale [3-5]. This pattern is consistent with the clinical characteristics of our patient. Both right-to-left shunting and a reduced pulmonary capillary volume have been postulated as the cause of the hypoxemia [1, 4, 6].

Recently, severe pulmonary hypertension was identified in a patient with Gaucher disease without apparent capillary plugging [4]. The cause of pulmonary hypertension in this patient is unknown, although several authors have postulated a circulating chemical or humoral substance that damages the pulmonary vasculature [1, 4]. Angiotensin II has been shown to induce pulmonary hypertension in animal models. Gaucher cells contain large amounts of angiotensin-converting enzyme [3], and levels of this enzyme decrease with enzyme replacement [6]. The precise relation between pulmonary hypertension and angiotensin II, however, remains uncertain.

The dramatic improvement this patient showed after glucocerebrosidase treatment has not been previously reported. Beutler and colleagues [6] described two patients with hypoxemia who were followed for 5 to 11 months while they received enzyme replacement therapy. As in our patient, both oxygenation and diffusing capacity improved during therapy, although gains were modest. The more substantial gains in our patient may be related to a longer duration of therapy (23 months compared with 11 months), the pattern and duration of pulmonary involvement, or the glucocerebrosidase dosing schedule. The increase in diffusing capacity without change in lung volumes or flow rates and the results of cardiopulmonary exercise testing in our patient are consistent with capillary obstruction or clearance of a circulating humoral vasoconstrictor as the cause of the hypoxemia, although resolution of right-to-left shunting secondary to improved hepatic function cannot be excluded.

Although the response of our patient to 60 U/kg of glucocerebrosidase every 2 weeks is heartening, optimal therapy has not yet been determined. Studies of the hematologic and hepatic responses to different dosing schedules have yielded conflicting results [6-9]. Given the cost (estimated to be $382 000 for the first year for a 70-kg patient receiving 60 U/kg every 2 weeks [7]) and limited treatment experience, more data are needed to determine optimal dosing and to predict which patients with pulmonary involvement would most likely benefit from this extremely expensive therapy.