title: Proinflammatory state and circulating erythropoietin in persons with and without anemia.
abstract: OBJECTIVE
  High circulating levels of proinflammatory cytokines cause anemia, perhaps by interacting with erythropoietin production or biological activity. We characterize the relationships of systemic inflammation, erythropoietin, and hemoglobin.
  
  
  METHODS
  Data are from the InCHIANTI (Invecchiare in Chianti, aging in the Chianti area) study population. A sample of 1270 persons aged 65 years or older and 30 men and 30 women from each age-decade 20 to 70 years were randomly selected from the residents in the Chianti, Italy, geographic area. Of the 1714 eligible persons, 1235 had complete data on inflammatory markers, erythropoietin, hemoglobin, potential causes of anemia, and other relevant covariates. Anemia was defined as hemoglobin less than 12 g/dL in women and less than 13 g/dL in men.
  
  
  RESULTS
  Independent of age, sex, and hemoglobin, the number of elevated inflammatory markers (C-reactive protein, interleukin-6, interleukin-1beta, and tumor necrosis factor-alpha) was associated with progressively higher erythropoietin in non-anemic participants but lower erythropoietin in anemic participants. Findings were consistent across different causes of anemia. The threshold at which the effect of inflammation on erythropoietin reversed was close to 13.0 g/dL of hemoglobin.
  
  
  CONCLUSIONS
  Our findings suggest that anemia of inflammation evolves from a "pre-anemic" stage characterized by a compensatory increment of erythropoietin that maintains normal hemoglobin levels to a stage of clinically evident anemia in which erythropoietin levels are not high enough to maintain normal hemoglobin, possibly because of the inhibitory effect of inflammation on erythropoietin production. This hypothesis requires testing in a longitudinal study.
authors.affiliation: Clinical Research Branch, National Institute on Aging, Longitudinal Studies Section Clinical Research Branch, ASTRA Unit, Harbor Hospital Baltimore, Md 21225, USA. ferruccilu@grc.nia.nih.gov
authors.forename: Luigi
authors.initials: L
authors.lastname: Ferrucci
authors.forename: Jack M
authors.initials: JM
authors.lastname: Guralnik
authors.forename: Richard C
authors.initials: RC
authors.lastname: Woodman
authors.forename: Stefania
authors.initials: S
authors.lastname: Bandinelli
authors.forename: Fulvio
authors.initials: F
authors.lastname: Lauretani
authors.forename: Anna Maria
authors.initials: AM
authors.lastname: Corsi
authors.forename: Paulo H M
authors.initials: PH
authors.lastname: Chaves
authors.forename: William B
authors.initials: WB
authors.lastname: Ershler
authors.forename: Dan L
authors.initials: DL
authors.lastname: Longo
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000097:blood* / Q000209:etiology; D015415:Biomarkers; D015897:Comorbidity; D016207:Cytokines / Q000097:blood; D004921:Erythropoietin / Q000097:blood*; D005260:Female; D005492:Folic Acid / Q000097:blood; D006306:Health Surveys; D006454:Hemoglobins / Q000032:analysis; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000150:complications; D018836:Inflammation Mediators / Q000097:blood; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins / Q000097:blood; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D011990:Receptors, Transferrin / Q000097:blood; D012494:Sampling Studies; D012795:Sialoglycoproteins / Q000097:blood; D014168:Transferrin / Q000032:analysis
chemical_list: D015415:Biomarkers; D016207:Cytokines; D006454:Hemoglobins; C507763:IL1RN protein, human; D018836:Inflammation Mediators; D053590:Interleukin 1 Receptor Antagonist Protein; D007378:Interleukins; D011990:Receptors, Transferrin; D012795:Sialoglycoproteins; D014168:Transferrin; D004921:Erythropoietin; D005492:Folic Acid