Page 50 - Haematologica-April 2018

594
T. Lefebvre et al.
ABC
DE
Figure 6. Impact of ERT on iron metabolism. Paired comparison of the levels of ferritin (A), TS (B) and hemoglobin (C) in patients before (pre-ERT) and after initiation of enzyme replacement treatment (ERT) (from 6 months at least). (D) The hepcidin level was measured in untreated (NT) and treated patients during different peri- ods of time. Each group was compared with the NT group. The hepcidin level was transiently increased during the first five years of ERT (<5). (E) Comparison of the levels of serum soluble transferrin receptor in untreated (n=24) versus treated (ERT; n=22) patients. (A-C) A paired Wilcoxon test was used; (D and E) an unpaired Mann-Whitney test was used.
in GD patients are increased independently of the hep- cidin levels and inflammation. Indeed, our measures of hepcidin were analyzed in a larger cohort of untreated GD1 patients (n=34) and interpreted in the context of other iron metabolism parameters.
Previous reports have documented that GD may trigger pro-inflammatory and anti-inflammatory pathways including IL-6 coming from monocytes/macrophages line- ages, and pathways due to glucocerebroside accumula- tion.34-36 These pathways could lead to high ferritin levels and increased hepcidin transcription. However, the patho- logical manifestations of GD are highly variable, leading to different levels of accumulated glucocerebroside among patients and individually within organs. Thus, one may speculate that the management of our patients was per- formed before the critical threshold of glucosylceramide storage was reached, leading to the absence of systemic inflammation in these patients. Moreover, the appearance of local inflammation around Gaucher cells cannot be excluded. Indeed, Gaucher cells have been shown to exhibit a phenotype resembling activated M2 macrophages not expressing pro-inflammatory cytokines; however, they are surrounded by macrophages with an M1 signature.37
Under steady-state conditions, the serum ferritin concen- tration is well correlated with total body iron stores.38 The sequestration of iron in Gaucher cells may then account for the increased production and secretion of ferritin. Of inter- est, iron accumulation in the macrophage compartment has already been described in GD.39-41 Herein, using Perl’s staining of a spleen biopsy and medullar smear from one GD patient, we confirmed a significant iron overload in
Gaucher cells. The origin of this iron accumulation is not fully elucidated, but evidence for increased erythrophago- cytic activity in Gaucher cells with the ingestion of mainly mature erythrocytes has already been provided.42,43 Our data suggested that iron efflux is also affected in these cells. Indeed, the expression of FPN, the sole iron exporter, was significantly diminished upon glucocerebrosidase inhibi- tion and accumulation of glucocerebroside into J774 macrophage cells. Because hepcidin transcripts were also enhanced, we postulate that one of the mechanisms involved in this FPN downregulation may be the induction of local hepcidin in this in vitro system. Macrophages have already been shown to be able to express endogenous hep- cidin.29 Our data confirmed these reports and also suggest- ed that, in Gaucher cells, the hepcidin/ferroportin axis may be active via an autocrine/paracrine pathway. Whether hepcidin is induced via a local inflammatory state or direct- ly via lipid-mediated pathways remains to be determined. However, one cannot exclude the possibility that FPN may also be directly affected by lipid-mediated pathways in addition to local hepcidin effect.
Enzyme replacement therapy was associated with a notable reversal of hyperferritinemia that appeared to cor- relate with iron release from Gaucher cells. Indeed, longi- tudinal monitoring of 10 patients under ERT showed the opposite time course of ferritin and rates of TS. This improvement in iron availability occurred under the con- trol of systemic hepcidin as evidenced by the moderate elevation in TS compared to the strong decrease in fer- ritinemia. This is also reinforced by the improvement in the correlation between serum hepcidin and ferritinemia post ERT. We postulate that the recovery of hemoglobin
haematologica | 2018; 103(4)