Hepcidin Dysregulation in Patients with Type 1 Gaucher’s Disease.

Gaucher’s Disease is a glycosphingolipid storage disorder where accumulation of glucosylceramide within reticuloendothelial cells results in diverse systemic manifestations. Patients often present with multifactorial anaemia and elevated ferritin which in the context of chronic inflammation may not truly represent their iron status.

We have investigated the iron status and the role of of hepcidin, a negative regulator of iron absorption, in our cohort of patients with type 1 Gaucher Disease. Analysis of haematological indices and haematinic parameters of 57 patients with type 1 Gaucher disease revealed 31% males and 29% females to be anaemic. Of these haematinic parameters were consistent with iron deficiency or anaemia of chronic disease in 45.5% and 27.3% of patients respectively. Measurement of the soluble transferrin receptor (sTFR), which is elevated in iron deficiency and reduced in iron overload, allowed the iron status of patients to be further classified. Of 17 patients in whom the sTFR was measured 64.7% where found to have normal levels, 11.7% had elevated levels indicative of iron deficiency, and 23.5% reduced levels indicating iron overload. The mean ferritin was 79ug/l and 547ug/l in these groups respectively. Levels of serum prohepcidin, the 84 amino acid precursor of hepcidin, were measured using a competitive elisa (DRG diagnostics). Levels of prohepcidin in those patients with normal sTFR were comparable to levels in control subjects: 387.2 +/− 305ng/ml compared to 357 +/1 120 ng/ml. In those patients with elevated sTFR and iron deficiency the prohepcidin level was appropriately suppressed to 112.5 +/− 17.6 ng/ml. Similarly levels in anaemic Gaucher patients were lower than those in patients with normal haemoglobin. However, in those patients with low sTFR and high ferritin the prohepcidin measuring 225 +/−35.3 ng/ml was not appropriately elevated compared to control subjects or Gaucher patients with normal iron status. We hypothesize that storage of glucosylceramide within lysosomes of macrophages interferes with their iron sensing mechanisms and secretion of regulatory cytokines. Iron overload is not appropriately detected and hepatocyte synthesis of hepcidin not upregulated. Progressive accumulation of iron may therefore occur.