Type 1 Gaucher's disease (GD) is recognized for striking but unexplained phenotypic diversity. Rarely, severe pulmonary hypertension (PH) may occur in GD but its clinical spectrum, determinants or its response to enzyme replacement therapy (ERT) ± vasodilators is not known. One hundred and thirty-four consecutive patients with Type 1 GD were screened to estimate right ventricular systolic pressure (RVSP) by Doppler echocardiography. Ninety-four patients were on ERT and 40 were untreated. Eight additional GD patients were studied that represented consecutive tertiary referrals with severe PH. Angiotensin converting enzyme (ACE) gene polymorphisms and acid β-glucosidase gene (GBA) mutations were determined by DNA analysis. Mild, asymptomatic PH (RVSP > 35 < 50 mm Hg) was prevalent in Type 1 GD: 30% in untreated patients and 7.4% among patients receiving ERT (P < 0.001). Splenectomy was strongly associated with severe, life-threatening PH: all patients with severe PH (RVSP 50-130 mm Hg) were asplenic compared to only 31% of patients with RVSP < 50 mm Hg (Odds ratio [OR] 28.8, 95% CI 1.6-531.6, P < 0.001). Other characteristics of patients presenting with severe PH were poor compliance to ERT (4/9 patients) or no ERT (5/9 patients), a family history of a sib with GD and PH (2/2 patients), an excess of ACE I allele (OR 2.3, 95% CI 1.1-4.9, P = 0.034) and an excess of non-N370S GBA mutation (OR 6.0, 95% CI 1.1-33, P = 0.003). Severe PH was ameliorated by ERT ± vasodilators during 4.6 ± 4.0 yr (range 1-12 yr) follow-up; three patients were initially considered for lung transplantation but improved such that they are no longer active transplant candidates. Our study reveals a remarkable predisposition for PH in type 1 GD. Progression to severe, life-threatening PH occurs in the presence of additional genetic factors (non-N370S GBA mutation, positive family history, and ACE I gene polymorphism) and epigenetic modifiers (i.e., asplenia and female sex). Splenectomy should be avoided and in high-risk patients, ERT ± vasodilators/coumadin should be initiated.
Bibliographical noteFunding Information:
We express our gratitude to the patients and their families who participated in these studies. We thank Dr. H.I. Palevsky for providing right heart catheter data on patient 6 ( Table 1 ) and Drs. S. Wallenstein and K. Katz for statistical advice. We thank Drs. Robert J. Desnick, Jane Morse, and James L. Boyer for critical review of the manuscript. Assistance of Helen Chung, Karen Lim, Whitney Lomazow, and Nursing staff of the General Clinical Research Center in executing the study is gratefully acknowledged. The study was funded in part by the National Institutes of Health Grant 5 MO1 RR00071 to the Mount Sinai General Clinical Research Center and in part by a grant from Genzyme Corporation, Boston.
- Angiotensin converting enzyme
- Enzyme replacement therapy
- Gaucher's disease
- Pulmonary hypertension