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Involvement of Hepcidin in the Anemia of Multiple Myeloma

Authors' Affiliations: ¹ West Los Angeles VA-University of California-Los Angeles Medical Center; ² Department of Medicine, University of California-Los Angeles, Los Angeles, California; ³ University of Illinois at Chicago and Jesse Brown VA Medical Center, Chicago, Illinois; and ⁴ University of Pittsburgh School of Medicine and Pittsburgh VA Medical Center, Pittsburgh, Pennsylvania

Requests for reprints: Sanjai Sharma, West Los Angeles VA-University of California-Los Angeles Medical Center, 11301 Wilshire Boulevard, Building 304, Room E1-115, Los Angeles, CA 90073. Phone: 310-268-3247; Fax: 310-2684508; E-mail: sasharma{at}mednet.ucla.edu.

Purpose: Hepcidin is a liver-produced peptide implicated in the anemia of inflammation. Because interleukin (IL)-6 is a potent inducer of hepcidin expression and its levels are elevated in multiple myeloma, we studied the role of hepcidin in the anemia of multiple myeloma.

Experimental Design: Urinary hepcidin and serum levels of IL-6, ferritin, C-reactive protein, tumor necrosis factor-, and IL-1β were studied in newly diagnosed myeloma patients. In vitro hepcidin induction assay was assessed by real-time PCR assay.

Results: Pretreatment urinary hepcidin levels in 44 patients with stage III multiple myeloma were 3-fold greater than normal controls. In the subset of multiple myeloma patients without renal insufficiency (n = 27), a marked inverse correlation was seen between hemoglobin at diagnosis and urinary hepcidin level (P = 0.014) strongly supporting a causal relationship between up-regulated hepcidin expression and anemia. The urinary hepcidin also significantly (P < 0.05) correlated with serum ferritin and C-reactive protein, whereas its correlation with serum IL-6 levels was of borderline significance (P = 0.06). Sera from 14 multiple myeloma patients, with known elevated urinary hepcidin, significantly induced hepcidin mRNA in the Hep3B cells, whereas normal sera had no effect. For 10 patients, the ability of anti-IL-6 and anti-IL-6 receptor antibodies to prevent the serum-induced hepcidin RNA was tested. In 6 of these patients, hepcidin induction was abrogated by the anti-IL-6 antibodies, but in the other 4 patients, the neutralizing antibodies had no effect.

Conclusions: These results indicate hepcidin is up-regulated in multiple myeloma patients by both IL-6-dependent and IL-6-independent mechanisms and may play a role in the anemia of multiple myeloma.