Pulmonary hypertension in Gaucher's disease
Authors: Gregory M Pastores, Albert Miller
Journal: The Lancet (1998)

Deborah Elstein and co-workers (May 23, p 1544)1Elstein D Klustein MW Lahad A et al.Echocardiographic assessment of pulmonary hypertension in Gaucher's disease.Lancet. 1998; 351: 1544-1546Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar report a 7% incidence of pulmonary hypertension in patients with type 1 Gaucher's disease. Although we have not undertaken echocardiography and pulmonary function tests on all our patients with Gaucher's diease, our experience is different from that reported by Elstein. We have followed 180 patients on enzyme-replacement therapy.Of 150 patients, baseline pulmonary hypertension was recorded in only three patients (splenectomised, with severe systemic disease and interstitial lung disease). We have not found any indicaton of progressive pulmonary disease in these patients. Five patients with interstitial lung disease and three with pulmonary hypertension had substantial haematological and hepatic responses on enzyme-replacement therapy. Two patients died from unrelated causes. Necropsy showed histological changes indicative of a response to therapy—ie, minimum accumulations of Gaucher cells were seen in the lung interstitium, along with many normal macrophages, which contrasts with the findings from an open-lung biopsy performed before enzyme-replacement therapy.Since we did not screen all the patients, there may be some with subclinical increase in pulmonary pressures, but, if this is true, none of the patients showed any signs of progression to the point of developing symptoms. Our patients may differ from those in Elstein's study, perhaps in their concurrent or inter-current medical disorders. Interpretation of the data reported by Elstein and colleagues is complicated since only limited information on patients is provided. The patients in their study may have comorbidities that might predispose them to pulmonary hypertension, which tends to occur with severe extrapulmonary manifestations in patients with Gaucher's disease.Our therapeutic outcomes may be different from those of Elstein because of the treatment regimens. Our patients received higher doses of enzyme (100–120 U/kg per month),2Pastores GM Sibille AR Grabowski GA Enzyme replacement therapy in Gaucher disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months.Blood. 1993; 82: 408-416Crossref PubMed Google Scholar whereas most of Elstein's patients received 30 U/kg per month. The lung, like the brain, and perhaps bone, may represent sequestered sites not readily accessible to circulating enzyme. In this scenario, a low-dose regimen may not be sufficient to overcome a threshold and allow an adequate enzyme concentration at the site of pathology, especially if there are fibrotic or necrotic regions. Although not reported for Gaucher's disease, due to the absence of a long-term surviving animal model, the observations in other models of storage diseases show a tissue dose-response gradient.3Kikuchi T Yang HW Pennybacker M et al.Clinical and metabolic correction of Pompe disease by enzyme therapy in acid maltase-deficient quail.J Clin Invest. 1998; 101: 827-833Crossref PubMed Scopus (144) Google Scholar, 4Sands MS Vogler C Torrey A et al.Murine mucopolysaccharidosis type VII: long-term therapeutic effects of enzyme replacement and enzyme replacement followed by bone marrow transplantation.J Clin Invest. 1998; 99: 1596-1605Crossref Scopus (114) Google ScholarEnzyme therapy is expensive. However, patients with symptomatic Gaucher's disease on enzyme-replacement therapy have shown significant improvements in health-related quality of life.5Damiano AM Pastores GM Ware JE The health-related quality of life in adults with Gaucher disease receiving enzyme replacement: results from a retrospective study.Qual Life Res. 1998; 7: 373-386Crossref PubMed Scopus (75) Google Scholar Although lysosomal accumulation of under-graded substrate may represent the initiating insult, other mechanisms may promote the various clinical expressions of Gaucher's disease. Treatment may alter the natural history of the disease, with unpredictable long-term outcomes and even adverse effects, which underlines the need for careful monitoring. We strongly disagree with the recommendation to withdraw treatment in symptomatic patients, because it would increase the risk of disease progression without definitive evidence of the relation between treatment and pulmonary hypertension. Deborah Elstein and co-workers (May 23, p 1544)1Elstein D Klustein MW Lahad A et al.Echocardiographic assessment of pulmonary hypertension in Gaucher's disease.Lancet. 1998; 351: 1544-1546Summary Full Text Full Text PDF PubMed Scopus (89) Google Scholar report a 7% incidence of pulmonary hypertension in patients with type 1 Gaucher's disease. Although we have not undertaken echocardiography and pulmonary function tests on all our patients with Gaucher's diease, our experience is different from that reported by Elstein. We have followed 180 patients on enzyme-replacement therapy. Of 150 patients, baseline pulmonary hypertension was recorded in only three patients (splenectomised, with severe systemic disease and interstitial lung disease). We have not found any indicaton of progressive pulmonary disease in these patients. Five patients with interstitial lung disease and three with pulmonary hypertension had substantial haematological and hepatic responses on enzyme-replacement therapy. Two patients died from unrelated causes. Necropsy showed histological changes indicative of a response to therapy—ie, minimum accumulations of Gaucher cells were seen in the lung interstitium, along with many normal macrophages, which contrasts with the findings from an open-lung biopsy performed before enzyme-replacement therapy. Since we did not screen all the patients, there may be some with subclinical increase in pulmonary pressures, but, if this is true, none of the patients showed any signs of progression to the point of developing symptoms. Our patients may differ from those in Elstein's study, perhaps in their concurrent or inter-current medical disorders. Interpretation of the data reported by Elstein and colleagues is complicated since only limited information on patients is provided. The patients in their study may have comorbidities that might predispose them to pulmonary hypertension, which tends to occur with severe extrapulmonary manifestations in patients with Gaucher's disease. Our therapeutic outcomes may be different from those of Elstein because of the treatment regimens. Our patients received higher doses of enzyme (100–120 U/kg per month),2Pastores GM Sibille AR Grabowski GA Enzyme replacement therapy in Gaucher disease type 1: dosage efficacy and adverse effects in 33 patients treated for 6 to 24 months.Blood. 1993; 82: 408-416Crossref PubMed Google Scholar whereas most of Elstein's patients received 30 U/kg per month. The lung, like the brain, and perhaps bone, may represent sequestered sites not readily accessible to circulating enzyme. In this scenario, a low-dose regimen may not be sufficient to overcome a threshold and allow an adequate enzyme concentration at the site of pathology, especially if there are fibrotic or necrotic regions. Although not reported for Gaucher's disease, due to the absence of a long-term surviving animal model, the observations in other models of storage diseases show a tissue dose-response gradient.3Kikuchi T Yang HW Pennybacker M et al.Clinical and metabolic correction of Pompe disease by enzyme therapy in acid maltase-deficient quail.J Clin Invest. 1998; 101: 827-833Crossref PubMed Scopus (144) Google Scholar, 4Sands MS Vogler C Torrey A et al.Murine mucopolysaccharidosis type VII: long-term therapeutic effects of enzyme replacement and enzyme replacement followed by bone marrow transplantation.J Clin Invest. 1998; 99: 1596-1605Crossref Scopus (114) Google Scholar Enzyme therapy is expensive. However, patients with symptomatic Gaucher's disease on enzyme-replacement therapy have shown significant improvements in health-related quality of life.5Damiano AM Pastores GM Ware JE The health-related quality of life in adults with Gaucher disease receiving enzyme replacement: results from a retrospective study.Qual Life Res. 1998; 7: 373-386Crossref PubMed Scopus (75) Google Scholar Although lysosomal accumulation of under-graded substrate may represent the initiating insult, other mechanisms may promote the various clinical expressions of Gaucher's disease. Treatment may alter the natural history of the disease, with unpredictable long-term outcomes and even adverse effects, which underlines the need for careful monitoring. We strongly disagree with the recommendation to withdraw treatment in symptomatic patients, because it would increase the risk of disease progression without definitive evidence of the relation between treatment and pulmonary hypertension.