Anemia in Hodgkin's lymphoma: the role of interleukin-6 and hepcidin.
OBJECTIVE
Cytokines play a pivotal role in Hodgkin's lymphoma (HL). Because interleukin-6 (IL-6) induces expression of hepcidin, one of the principal regulators of iron metabolism, we studied the contribution of hepcidin in anemia in HL at diagnosis.


METHODS
Plasma samples from 65 patients with HL were analyzed for hepcidin levels using a combination of weak cation exchange chromatography and time-of-flight mass spectrometry; cytokine levels were analyzed using enzyme-linked immunosorbent assays and parameters of iron metabolism and acute-phase reaction.


RESULTS
Hepcidin plasma levels were significantly higher in HL patients when compared with controls, independent of the presence of anemia (P = .001). In the subset of patients with anemia, hepcidin levels inversely correlated with hemoglobin levels (P = .01). Analyzing parameters of iron metabolism, hepcidin levels showed a positive correlation with ferritin (P < .001) and an inverse correlation to iron and iron-binding capacity. Hepcidin strongly correlated to IL-6 levels (P < .001) but not to IL-10 or thymus and activation-regulated cytokine (TARC)/chemokine (C-C motif) ligand 17 (CCL17) levels. In a multivariate regression analysis, IL-6 and fibrinogen levels were independently associated with hepcidin. Higher hepcidin levels were observed in patients with more aggressive disease characteristics: stage IV disease (P = .01), presence of B symptoms (P = .03), and International Prognostic Score > 2 (P = .005).


CONCLUSIONS
Our findings suggest that in HL, hepcidin is upregulated by IL-6. Elevated hepcidin levels result in iron restriction and signs of anemia of chronic inflammation, although hepcidin-independent mechanisms contribute to development of anemia in HL.
Hohaus
Stefan
S
Institute of Hematology, Catholic University S. Cuore, Rome, Italy. stefan.hohaus@rm.unicatt.it
Massini
Giuseppina
G
Giachelia
Manuela
M
Vannata
Barbara
B
Bozzoli
Valentina
V
Cuccaro
Annarosa
A
D'Alo'
Francesco
F
Larocca
Luigi Maria
LM
Raymakers
Reinier A P
RA
Swinkels
Dorine W
DW
Voso
Maria Teresa
MT
Leone
Giuseppe
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia / Q000097:blood* / Q000209:etiology; D023181:Antimicrobial Cationic Peptides / Q000097:blood* / Q000378:metabolism; D016022:Case-Control Studies; D054414:Chemokine CCL17 / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005293:Ferritins / Q000097:blood; D064451:Hepcidins; D006689:Hodgkin Disease / Q000097:blood* / Q000150:complications; D006801:Humans; D018836:Inflammation Mediators / Q000097:blood; D016753:Interleukin-10 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood*; D007501:Iron / Q000097:blood; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D055815:Young Adult
D023181:Antimicrobial Cationic Peptides; C106230:CCL17 protein, human; D054414:Chemokine CCL17; C578702:HAMP protein, human; D064451:Hepcidins; D018836:Inflammation Mediators; D015850:Interleukin-6; D016753:Interleukin-10; D005293:Ferritins; D007501:Iron