Hepcidin Contributes to Anemia of Malignancy by Causing Sequestration of Iron in Hepatic Stores.

The iron regulatory hormone hepcidin is presumed to be the central mediator of anemia of inflammation (AI, anemia of chronic disease). Hepcidin is an acute phase protein which restricts iron absorption and release of iron from stores. Patients with hepatic adenomas producing large amounts of hepcidin had severe AI that resolved when the tumors were resected (Weinstein et al, 2002). In order to study the effects of hepcidin in anemia of malignancy, we created tumor xenografts in SCID mice, some of which were engineered to secrete large amounts of hepcidin (33 mice with control tumors, 30 with hepcidin producing tumors). Hepcidin producing tumors expressed 2000-times more hepcidin mRNA which also correlated with increased levels of hepcidin peptide detected in urine of these mice. Mice with hepcidin producing tumors were significantly more anemic (median hemoglobin = 10.4 vs. 8.4 g/dL, p=0.02) and had significantly lower serum iron values (median serum iron = 242 vs. 96 mg/dL, p<0.001). Liver iron was significantly higher in mice with hepcidin producing tumors (mean liver iron 199 vs. 142 mg/100 mg dry weight, p<0.001) even in the face of anemia and hypoferremia. Splenic and bone marrow iron levels were unchanged. Hepcidin contributes to the anemia of malignancy by sequestering iron predominately in hepatic stores, similar to the pattern seen in AI.