Dysregulated monocyte iron homeostasis and erythropoietin formation in patients with anemia of chronic disease.
Anemia of chronic disease (ACD) is frequently found in patients with chronic immune activation. Since most studies on ACD pathophysiology were performed with cell culture or animal models but not in humans, we examined 37 ACD patients suffering from autoimmune diseases or infections, 10 subjects with iron-deficiency anemia (IDA), 10 anemic patients with hereditary spherocytosis (HS), and 27 age-matched controls. Although hemoglobin concentrations were comparable between ACD and IDA patients, the latter presented with significantly higher serum erythropoietin concentrations than ACD patients. The significant negative correlation between erythropoietin and hemoglobin levels observed in IDA patients was also found in a group of anemic but not hypoferremic hereditary spherocytosis subjects, but not in ACD patients. Increased serum concentrations of the hepcidin precursor prohepcidin were paralleled by a decreased expression of the iron exporter ferroportin in circulating monocytes of ACD patients. In the latter cells, increased amounts of the iron storage protein ferritin and a reduced activity of iron-regulatory protein indicated monocyte iron accumulation. Our data indicate that hypoferremia in ACD may result from downregulation of ferroportin expression by hepcidin and cytokines with subsequent iron retention in monocytes. Together with a diminished erythropoietin formation, the impaired iron recirculation from monocytes may be central in the pathophysiology of ACD in humans.
Theurl
Igor
I
Department of General Internal Medicine, Clinical Immunology and Infectious Diseases, Medical University, Anichstrasse 35, A-6020 Innsbruck, Austria.
Mattle
Verena
V
Seifert
Markus
M
Mariani
Mariagabriella
M
Marth
Christian
C
Weiss
Günter
G
D000368:Aged; D000740:Anemia / Q000097:blood* / Q000209:etiology; D001483:Base Sequence; D002097:C-Reactive Protein / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000097:blood; D017931:DNA Primers; D004921:Erythropoietin / Q000378:metabolism*; D005260:Female; D006706:Homeostasis; D006801:Humans; D007501:Iron / Q000097:blood*; D008297:Male; D008875:Middle Aged; D009000:Monocytes / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000235:genetics
D016207:Cytokines; D017931:DNA Primers; D012333:RNA, Messenger; D004921:Erythropoietin; D002097:C-Reactive Protein; D007501:Iron