Nadia Belmatoug

Ferritinemia during type 1 Gaucher disease: mechanisms and progression under treatment.

BACKGROUNDnEarlier results highlighted hyperferritinemia during type-1 Gaucher disease (GD), but its potential mechanisms and long-term progression remained unexamined.nnnMETHODSnWe analyzed the clinical, biological and iron characteristics of type-1 GD patients, before and after starting enzyme-replacement therapy (ERT). Iron parameters under ERT were subjected to linear-regression analyses.nnnRESULTSnSerum ferritin (median 739 [46-2371] μg/L) was determined for 54 patients (21 (39%) males; median age 32 [range 12-73] years) before ERT; it exceeded 300 μg/L in 47 (87%), while the other iron parameters always remained normal: transferrin saturation coefficient (26 [16-42]), serum iron at 13 [6-22] mmol/L and transferrin at 2.4 [2,3] g/L. Four patients had mild elevation of liver transaminases, with C-reactive protein >20mg/l in two. The absence of hemolysis was accompanied by a median bilirubin of 9 μmol/L and lactate dehydrogenase at 250 IU/L; diabetes and lipid anomalies were not observed. Clinical, biological and iron parameters at GD diagnosis were comparable for the 12 and 42 patients with ferritinemia ≤400 and >400 μg/L, respectively. Ferritinemia was measured at least once for 46 patients after ERT onset (median treatment duration 90 [3-204] months). At study closure, median serum ferritin was 187.5 [11-1560] μg/L, exceeding 300 μg/L in 15 (33%) patients, while the other iron parameters were normal. Among the latter, only the mean±SD ferritinemia slope decreased significantly under ERT (-1.9±0.3%/month; p<0.001).nnnCONCLUSIONnHyperferritinemia is a specific GD characteristic and serum ferritin monitoring could be informative during follow-up.

Bone events and evolution of biologic markers in Gaucher disease before and during treatment.

IntroductionKnown biomarkers of Gaucher-disease activity are platelets, chitotriosidase, angiotensin-converting enzyme (ACE), tartrate-resistant acid phosphatase (TRAP) and ferritin. The aim of this study was to retrospectively evaluate the frequency of bone events (BE) and biomarker changes during two periods: diagnosis to first enzyme-replacement therapy (ERT) and the latter to the closing date.MethodsBE of 62 treated patients, among the 73-patient cohort followed at Beaujon Hospital, Clichy, France, were described with Kaplan-Meier curves, and linear-mixed models were used to analyze their biomarker changes and the influence of several covariates (splenectomy, diagnosis year, genotype, age at diagnosis and sex).ResultsBE occurred before (54 events in 21 patients), but also during, ERT (12 events in 10 patients), with respective frequencies (95% confidence interval) at 10 years of 22.4% (13.3 to 36.3) and 20.0% (10.2 to 36.9). Biomarker slope changes before and during ERT differed significantly for platelets (+190/mm3/year and 7,035/mm3/year, respectively; P < 0.0001) and ferritin (+4% and -14%; P < 0.0001). High ferritin levels and low platelet counts at ERT onset were significantly associated with BE during ERT (P = 0.019 and 0.039, respectively). Covariates significantly influenced biomarker changes (baseline and/or slope): splenectomy affected platelets (baseline and changes), TRAP changes and chitotriosidase changes; diagnosis date influenced ACE and TRAP baseline values; and genotype influenced chitotriosidase baseline and changes.ConclusionsPlatelet counts and ferritin levels and their slope changes at ERT onset seem to predict BE during treatment. Biomarker baseline values and changes are dependent on several covariables.

Impact of imiglucerase on the serum glycosylated-ferritin level in Gaucher disease

Gaucher disease (GD) is a lysosomal storage disorder, caused by deficient activity of the enzyme glucocerebrosidase, which can be treated by enzyme-replacement therapy (ERT). No prognostic marker can predict long-term complications of GD but several markers are used in therapeutic monitoring: chitotriosidase, total serum ferritin (TSF), angiotensin-converting enzyme (ACE) and tartrate-resistant acid phosphatase (TRAP). They all increase with disease progression and generally decrease under ERT. This study was undertaken to investigate ferritin glycoforms, i.e., glycosylated ferritin (GF) and non-glycosylated ferritin (NGF) concentrations, as potential markers for the follow-up of GD therapy. GF and NGF determinations for GD patients followed in a single center between 1996 and 2007 were analyzed using two approaches: (1) the serum levels of 12 untreated patients were compared with those of 10 patients after 48 months on ERT; (2) the evolution of serum levels under ERT in 15 patients were analyzed using linear/logarithmic mixed models. TSF and NGF levels did not differed significantly between untreated patients and those on ERT (TSF: 524.5 (range 221.0-2045.0) μg/L vs. 410.5 (range 115.0-1587.0) μg/L, respectively, p=0.72; NGF: 340.0 (range 182.8-1717.8) μg/L vs. 199.9 (range 77.1-649.8) μg/L, p=0.09). The percent GF was significantly lower in untreated patients than in those on ERT (27.0% (range 8.0-51.0) vs. 43.5% (range 22.0-80.0) respectively; p=0.02). The percent GF increased significantly during ERT (slope=0.156% [95% confidence interval (CI), 0.03; 0.29] per month, p=0.01) regardless of whether NGF and TSF significantly decreased during ERT (slope=-1.4% per month [95%CI, -1.9%; -1.0%], p<0.0001; slope=-1.1% [95%CI, -1.6%; -0.6%] per month, p<0.0007, respectively). Thus, GF is low in untreated GD patients. GF and NGF changed significantly under ERT and might be of clinical value for GD management under treatment.

Efficacité du miglustat dans la maladie de Gaucher : à propos de l’analyse du suivi de 8 patients suivi au Centre de Référence des Maladies Lysosomales

ormale (1 %) et qu’il n’existait pas de signes d’hémophagocytose. Le taux de -glucocérébrosidase sérique était significativement abaissé (17 %). Le taux de hitotriosidase sérique était normal (101 nmol/h/ml). Sur le scanner abdominal, e foie et la rate avaient un volume normal. L’IRM montrait une diminution du issu graisseux dans la moelle osseuse. Le taux sérique de FG mesuré après sépaation par chromatographie avec la conconavalin A était abaissé à 26 % (normal 7 à 88 %). Les taux de LDH (350 UI/l) et de triglycérides sériques (1,35 g/l) taient normaux. Aucun traitement spécifique n’a été prescrit. Avec 5 ans de ecul, la situation clinique et biologique était stable. iscussion.– Dans de nombreuses situations pathologiques, en particulier ’inflammation et la surcharge en fer, l’hyperferritinémie s’accompagne habiuellement d’un taux normal de FG. Cependant, dans le syndrome d’activation acrophage ou la maladie de Still de l’adulte, l’hyperferritinémie est associée une FG abaissée reflétant l’activation macrophagique. Au cours de la MG, ’hyperferritinémie est très fréquente (jusqu’à 90 % des cas) mais de significaion équivoque. La réalisation de biopsie hépatique a permis d’écarter l’existence ’une surcharge ferrique. À notre connaissance, il s’agit du premier cas rapporté ’abaissement de la FG chez un patient atteint de MG. onclusion.– Cette observation souléve l’hypothèse d’une activation macrophaique chronique dans la genèse de l’hyperferritinémie au cours de la MG. Dans ette situation, l’abaissement de la FG reflèterait une accélération de la synthèse e la ferritine par les macrophages surchargés en céramide.