Pulmonary hypertension in Gaucher's disease
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes
The Lancet, Volume 352, Issue 9127, Page 580, 15 August 1998
doi:10.1016/S0140-6736(05)79295-3
Sir
Deborah Elstein and co-workers (May 23, p 1544)1
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),2
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.3, 4
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.5
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.
References
1 Echocardiographic assessment of pulmonary hypertension in Gaucher's disease. . Lancet 1998; 351: 1544-1546. Summary | Full Text | PDF(74KB) | CrossRef | PubMed2 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: 408-416. PubMed
3 Clinical and metabolic correction of Pompe disease by enzyme therapy in acid maltase-deficient quail. . J Clin Invest 1998; 101: 827-833. CrossRef | PubMed
4 Murine mucopolysaccharidosis type VII: long-term therapeutic effects of enzyme replacement and enzyme replacement followed by bone marrow transplantation. . J Clin Invest 1998; 99: 1596-1605. CrossRef | PubMed
5 The health-related quality of life in adults with Gaucher disease receiving enzyme replacement: results from a retrospective study. . Qual Life Res 1998; 7: 373-386. CrossRef | PubMed
a Neurology, Pediatrics, and Human Genetics, New York University School of Medicine, New York, NY 10018, USA; and Community Medicine Mount Sinai School of Medicine, New York