Our data indicate that hypoferremia in ACD may result from downregulation of ferroportin expression by hepcidin and cytokines with subsequent iron retention in monocytes.
Hepcidin, the pivotal regulator of iron metabolism, plays a critical role in multiple diseases including anemia of chronic disease and hemochromatosis.
The anaemia of chronic disease (ACD) results from inflammation-mediated up-regulation of the iron regulatory hormone hepcidin, with the consequent sequestration of iron limiting its availability for erythropoiesis.
In this review, we will summarize the role of hepcidin in iron homeostasis, its contribution to the pathophysiology of ACD, and novel strategies that modulate hepcidin and its target ferroportin for the treatment of ACD.
We speculated that the adipokine leptin might play a role in regulating iron metabolism in the overweight population because it shares a number of common biological features with IL-6, a major factor in the development of the anemia of chronic disease via its stimulatory actions on the production and release of the iron regulatory hormone hepcidin.
Hepcidin is the master inducer of iron accumulation during ACD, and its production is mainly regulated by IL-6 and the novel erythroid hormone erythroferrone (ERFE).
Hepcidin has emerged as the central regulatory molecule in systemic iron homeostasis, and its inhibition could be a favorable strategy for treating anemia of chronic disease (ACD).
This mechanism explains the central role of hepcidin and, indirectly, its regulator, hemojuvelin, in the pathogenesis of hemochromatosis but also in anemia of chronic disease.
Hepcidin is a proposed mammalian host defense peptide that was identified on the basis of its antimicrobial activity, but it was later shown to be a crucial regulator of iron homeostasis and a mediator of the anemia of chronic inflammation.
The concomitant presence of kidney failure, especially chronic kidney disease (CKD) and MM per se, leading to anaemia of chronic disease (ACD) in combination, provoked us to pose the question about their reciprocal dependence and relationship with specific biomarkers; namely, soluble transferrin receptor (sTfR), growth differentiation factor 15 (GDF15), hepcidin 25 and zonulin.
Treating anemia of chronic disease and anemia of chronic kidney disease may be limited by elevated levels of hepcidin and new promising treatments are still in pre-clinical and clinical trial phases.
Importantly, existing data illustrate that hepcidin may play a significant role in the development of several iron-related disorders, including the anemia of chronic disease and the iron dysregulation observed in obesity.
We conclude that hepcidin plays a major, causative role in the anemia observed in our subgroup of patients with hepatic adenomas, and we speculate that it is important in the pathogenesis of the anemia of chronic disease in general.
In conclusion, we developed a dose-dependent and safe approach for the direct suppression of hepcidin, resulting in prolonged iron mobilization to alleviate iron-restricted erythropoiesis that can address the root cause of ACD.
We conclude that serum hepcidin levels can predict the hematologic responsiveness to erythropoiesis-stimulating agent therapy in anemia of chronic disease.
Our results suggest that ferroportin expression in inflammatory monocytes is negatively affected by autocrine formation of hepcidin, thus contributing to iron sequestration within monocytes as found in ACD.
The pathogenesis of ACD had been poorly understood, but recently there has been important progress: upregulation of interleukin-6 (Il-6) secondary to the underlying chronic inflammatory disease upregulates expression of the protein hepcidin.