Differential effects of enzyme supplementation therapy on manifestations of type 1 gaucher disease

BACKGROUND: In type 1 Gaucher disease (GD), the accumulation of glucocerebroside in macrophages, caused by deficient activity of glucocerebrosidase, results in a variety of disease manifestations. In addition to the characteristic features of hepatosplenomegaly, cytopenia, and bone abnormalities, resting energy expenditure (REE) and glucose production are increased. In this study the effects of enzyme supplementation therapy on metabolic parameters in relation to other disease manifestations in type 1 GD patients are investigated. PATIENTS AND METHODS: In 12 adult type 1 GD patients, measurements of REE (by indirect calorimetry), liver and spleen volume (by spiral computerized axial tomography [CT]) and hemoglobin and platelet count were obtained before and after 6 months of alglucerase therapy (15 U/kg per month). In 7 of the 12 patients hepatic glucose production was measured by infusing 3-3H glucose. For comparison, REE and glucose metabolism were studied in 7 weight- and age-matched healthy subjects. RESULTS: REE and glucose production were increased in GD patients as compared with controls (REE: 29.8 kcal/kg/24 h +/- 3.6 and 23.1 +/- 2.3 kcal/kg/24 h, respectively, P <0.05; glucose production: 14.00 mumol/kg/min +/- 0.51 and 10.77 mumol/kg/min +/- 0.26, respectively, P <0.03). There were no differences in plasma glucose concentrations. Whereas the elevated REE decreased after 6 months of alglucerase therapy from 129% to 120% of predicted values (P <0.01), the increase in hepatic glucose production did not change. An increase in weight occurred after 6 months of treatment (1.7 +/- 0.8 kg, P <0.001), which was accounted for by an increase in fat mass of 1.6 +/- 1.5 kg (P <0.02). Hemoglobin levels increased from 11.2 mg/dL to 12.1 mg/dL (P = 0.05) and platelet counts rose from 84 x 10(9)/L to 113 x 10(9)/L (P <0.05). Although liver and spleen volumes decreased by approximately 10% and approximately 20%, respectively, there was no correlation between the decrease in organ volumes and the decrease in REE. CONCLUSIONS: Treatment with alglucerase improves hypermetabolism and organomegaly in GD, whereas the increase in glucose production persists. Therefore, the dose-response effects of alglucerase are variable for the different manifestations of type 1 GD