Gaucher's disease

Gaucher's disease is a rare disorder characterized by a deficiency of lysosomal [Beta]-glucosidase. Pulmonary hypertension, the etiology of which is unclear, has been reported to occur in association with Gaucher's disease. We report the use of continuous intravenous epoprostenol (prostacyclin), which has been used to treat other forms of pulmonary hypertension, in a patient with pulmonary hypertension associated with Gaucher's disease. Although its mechanism of action remains unknown, epoprostenol may be an effective form of therapy for chronic pulmonary hypertension due to a variety of conditions, one of which is Gaucher's disease.

(CHEST 1999; 116:1127-1129)

Key words: epoprostenol; Gaucher's disease; pulmonary hypertension

Abbreviations: PA = pulmonary artery; PPH = primary pulmonary hypertension; PVR = pulmonary vascular resistance

Gaucher's disease is a rare disorder in which the activity of lysosomal [Beta]-glucosidase is genetically deficient, resulting in the accumulation of glucocerebroside in reticuloendothelial cells. The typical manifestations include hepatosplenomegaly and bone marrow infiltration with dysfunctional monocytes. pulmonary hypertension has been described, although the etiology is unclear. We describe a patient with Gaucher's disease and pulmonary hypertension who has been successfully treated with long-term continuous IV epoprostenol. This is the first report of the successful treatment of pulmonary hypertension associated with Gaucher's disease, and it may have important implications for other patients with this condition.

CASE REPORT

A 47-year-old white woman was diagnosed with type I Gaucher's disease in 1958 at 8 years of age, presenting with hepatomegaly and bone disease. pulmonary hypertension was diagnosed in 1990 when she developed progressive dyspnea. She was started on replacement therapy with aglucerase in 1991 with improvement of her symptoms and a marked reduction in liver size.

In 1993, she presented with progressive exertional dyspnea and chest pain, and right heart catheterization was performed (Table 1). Based on the absence of an acute response (luring a vasodilator trial, she was started on continuous IV infusion of epoprostenol and oral anticoagulants in August 1993. Right heart catheterization was repeated in March 1994 (Table 1).

Table 1--Right Heart Catheterization Data(*)

(*) CVP = central venous pressure; PAS/D = pulmonary artery systolic pressure/diastolic pressure; PAM = mean pulmonary artery pressure; PCW = pulmonary capillary wedge pressure; CO = cardiac output; [PGI.sub.2], = epoprostenol.

In May 1995, a repeat right heart catheterization (Table 1) demonstrated that the mean pulmonary artery (PA) pressure had decreased from 34 to 25 mm Hg and the pulmonary vascular resistance (PVR) had decreased from 363 to 176 dvnes.s.[cm.sup.-5]. During the catheterization, the epoprostenol infusion was discontinued, resulting in a prompt increase in PA pressure and a reduction in cardiac output. Hemodynamic measurements were also evaluated during exercise (Table 2).

(*) All data was collected on May 2, 1995. See Table 1 for abbreviations.

Her most recent catheterization in May 1997 demonstrated a PA pressure of 45/12 mm Hg (mean, 23), a right atrial pressure of 2 mm Hg, and a cardiac output of approximately 9 L/min.

The patient is presently asymptomatic with normal activities. Current medications include aglucerase, 2,400 U IV every 10 days, epoprostenol, 61 ng/kg/min, heparin, 5,000 U subcutaneously every other day, furosemide, 160 mg/d, spironolactone, 25 mg twice daily, levothyroxine, 0.1 mg daily, and alendronate, 10 mg daily.

Her past medical history includes a splenectomy in 1963, aseptic necrosis of the left femoral head requiring total hip replacement in 1990, disseminated actinomycosis in 1986 with a recurrence in 1991, a partial gastrectomy in 1990, and Grave's disease.

DISCUSSION

Lung involvement in Gaucher's disease has been reported to occur in the following three distinct patterns:[1] (1) interstitial infiltrates of Gaucher cells with associated fibrosis; (2) alveolar consolidation by Gaucher cells filling alveolar spaces; and (3) pulmonary hypertension. Several possible mechanisms for the pulmonary hypertension have been suggested: (1) One possible mechanism is capillary plugging by Gaucher cells. Boss et al[2] recovered Gaucher cells from a sample of pulmonary capillary blood aspirated from a PA catheter during balloon occlusion in the wedged position. (2) In another report, however, few Gaucher cells were found in the lungs, and the pathologic findings resembled those of primary pulmonary hypertension (PPH).[3] (3) A clinical pattern similar to the pulmonary hypertension associated with liver disease has also been observed.[4] Some authors have suggested that, in those patients without infiltration of the lung by Gaucher cells, the pulmonary hypertension may be related to either the possible presence of contaminants in the enzyme replacement therapy[5] or to closure of intrapulmonary vascular dilatations (arterial-venous shunting) following the reduction of hepatomegaly by enzymatic treatment, resulting in increased blood flow through a pre-existing restricted pulmonary vascular bed.[4] Using echocardiography to estimate pulmonary arterial systolic pressure, Elstein and colleagues[6] found an unexpectedly high rate (7%) of pulmonary hypertension in 134 patients with type 1 Gaucher's disease and recommended routine echocardiographic monitoring of all treated and untreated patients. Some reports have suggested that enzyme replacement therapy may aggravate pulmonary hypertension despite its beneficial effect on other manifestations of the disease. It is unclear, however, whether pulmonary hypertension can be reversed, stabilized, or worsened by enzyme replacement therapy.[2,4,6]

In addition to improving hemodynamics and exercise tolerance, continuous IV infusion of epoprostenol therapy prolongs life in severe (New York Heart Association functional classes III and IV) PPH.[7] Preliminary reports suggest that epoprostenol also produces improvement in hemodynamics and exercise tolerance in pulmonary hypertension secondary to connective tissue diseases.[8] However, there have been no reports on its use in patients with pulmonary hypertension secondary to Gaucher's disease. The decision to use epoprostenol in our patient was based on her symptoms and the lack of a favorable acute response to vasodilators during catheterization.

The pulmonary vascular bed can be injured by various different stimuli that, in the susceptible host, result in the following characteristic pathologic findings that combine to produce increased PVR: smooth muscle cell hypertrophy, intimal proliferation, and in situ thrombosis. Therefore, irrespective of the cause of the pulmonary hypertension, be it PPH from anorexigens, portopulmonary hypertension, or pulmonary hypertension associated with systemic sclerosis, the pathologic injury pattern is indistinguishable and may be amenable to the beneficial effects of epoprostenol. In addition to its vasodilatory and antiplatelet properties, epoprostenol may have effects on vascular growth and remodeling, which could facilitate the restoration of endothelial-dependent functions that normally serve to maintain the low-resistance state of the pulmonary vascular bed. The response of our patient to epoprostenol supports the impression that epoprostenol can decrease PVR in patients unresponsive to acute vasodilatory challenges, regardless of the nature of the stimulus or the vascular injury pattern.

In conclusion, the frequency of pulmonary hypertension complicating Gaucher's disease, coupled with our observations that epoprostenol may be useful in treating this disorder, suggest that all patients (treated and untreated) may benefit from echocardiographic screening.

REFERENCES

[1] Lee RE, Yousem SA. The frequency and type of lung involvement in patients with Gaucher's disease [abstract]. Lab Invest 1988; 58:54A

[2] Ross DJ, Spira S, Buchbinder NA. Gaucher Cells in pulmonary-capillary blood in association with pulmonary hypertension. N Engl J Med 1997; 336:379-381

[3] Theise ND, Ursell PC. Pulmonary hypertension and Gaucher's disease: logical association or mere coincidence? Am J Pediatr Hematol Oncol 1990; 12:74-76

[4] Dawson A, Elias DJ, Rubenson D, et al. pulmonary hypertension developing after aglucerase therapy in two patients with type 1 Gaucher disease complicated by the hepatopulmonary syndrome. Ann Intern Med 1996; 125:901-904

[5] Harats D, Pauzner B, Elstein D, et al. pulmonary hypertension in two patients with type 1 Gaucher disease while on aglucerase therapy. Acta Haematol 1997; 98:47-50

[6] Elstein D, Klutstein MW, Lahad A, et al. Echocardiographic assessment of pulmonary hypertension in Gaucher's disease. Lancet 1998; 351:1544-1546

[7] Barst RJ, Rubin LJ, Long WA, et al. A comparison of continuous intravenous prostacyclin versus conventional therapy in primary pulmonary hypertension. N Engl J Med 1996; 334:296-301

[8] Badesch D, et al. A comparison of continuous intravenous epoprostenol with conventional therapy for pulmonary hypertension secondary to scleroderma spectrum of diseases (in press)

(*) From the Department of Medicine, Division of pulmonary and Critical Care Medicine, University of Maryland, Baltimore, MD.

Manuscript received January 12, 1999; revision accepted May 12, 1999.

Correspondence to: Lewis J. Rubin, MD, FCCP, Division of pulmonary and Critical Care Medicine, University of California, San Diego, 200 W. Arbor Dr, San Diego, CA 921033

COPYRIGHT 1999 American College of Chest Physicians
COPYRIGHT 2000 Gale Group