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01.12.2014 | Research | Ausgabe 1/2014 Open Access

Orphanet Journal of Rare Diseases 1/2014

Modeling changes in biomarkers in Gaucher disease patients receiving enzyme replacement therapy using a pathophysiological model

Orphanet Journal of Rare Diseases > Ausgabe 1/2014
Marie Vigan, Jérôme Stirnemann, Catherine Caillaud, Roseline Froissart, Anne Boutten, Bruno Fantin, Nadia Belmatoug, France Mentré
Wichtige Hinweise

Electronic supplementary material

The online version of this article (doi:10.​1186/​1750-1172-9-95) contains supplementary material, which is available to authorized users.

Competing interests

FM had consulting fees and INSERM UMR1137 received a grant from Sanofi. JS had travel fees from Sanofi-Genzyme. NB had travel fees, consulting fees, fees for speaking and received grants (Genzyme, Shire, Actelion, Pfizer) donated to the Department of Clinical Research of the Assistance-Publique Hôpitaux de Paris. The other authors declared no financial disclosures.

Authors’ contributions

MV, JS and FM designed the research and analyzed and interpreted the data. MV, JS and FM wrote the first draft of the paper, which was then corrected and approved by all authors.



Gaucher disease (GD) is a rare recessively inherited disorder caused by deficiency of a lysosomal enzyme, glucocerebrosidase. Accumulation of glucosylceramide or glucosylsphingosine in macrophages leads to increased production of ferritin and chitotriosidase and to decreases in hemoglobin concentration and platelet count, which are used as blood biomarkers. GD is treated by enzyme replacement therapy (ERT) or, sometimes by substrate reduction therapy. However, no physiological model for analysis of biomarkers change during ERT has been proposed. We aimed to develop a pathophysiological model to analyze biomarker’s response to ERT and several covariates impact.


Changes in blood ferritin, chitotriosidase, hemoglobin and platelets were analyzed in French GD Registry patients receiving imiglucerase/alglucerase as ERT. We used simplified exponential pathophysiological model, with initial concentration, biomarkers amplitude of variation and rate constant of normalization during ERT. Changes in four biomarkers were analyzed separately and then all four together from initiation to discontinuation of ERT, or until the end of follow-up. Several covariates were tested, including age at ERT initiation, splenectomy, sex, genotype (N370S/N370S), and ERT dose.


An exponential model gave a good data fit. The four biomarkers analysis showed that the rate of nomalization was the same for all biomarkers, with a half-life of 0.5 years. Predicted values of biomarkers at ERT’s steady state were 40% and 10% of initial concentrations, for ferritin and chitotriosidase, respectively, and 120% and 200% for hemoglobin and platelets, respectively. We found that 3 covariates had an effect on initial concentration or on amplitude of variation in ferritin, hemoglobin and platelets: women and patients under 15 years of age had lower ferritin and hemoglobin concentrations, and patients under 15 years of age had higher platelet count. Splenectomized patients had higher ferritin concentrations and platelet count and lower amplitude of variation of hemoglobin.


We report the first dynamic model of biomarker changes in GD. It enabled us to estimate that 95% of biomarker response to ERT was achieved in 2 years, but with high inter-patient variability. We also found that with the current treatment, normalization of chitotriosidase and ferritin will occur in about 65% of patients.
Additional file 1:Equation describing change in chitotriosidase level.(DOCX 39 KB)
Additional file 2:Goodness-of-fit plots.(DOCX 199 KB)
Authors’ original file for figure 1
Authors’ original file for figure 2
Authors’ original file for figure 3
Authors’ original file for figure 4
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