Serum prohepcidin levels are potential prognostic markers in patients with multiple myeloma

Haraguchi,Kouichi; Uto,Hirofumi; Ohnou,Nobuhito; Tokunaga,Masahito; Tokunaga,Mayumi; Utsunomiya,Atae; Hanada,Shuichi; Tsubouchi,Hirohito

doi:10.3892/etm.2012.663

Serum prohepcidin levels are potential prognostic markers in patients with multiple myeloma

Authors:
- Kouichi Haraguchi
- Hirofumi Uto
- Nobuhito Ohnou
- Masahito Tokunaga
- Mayumi Tokunaga
- Atae Utsunomiya
- Shuichi Hanada
- Hirohito Tsubouchi
View Affiliations

Affiliations: Digestive and Lifestyle Diseases, Department of Human and Environmental Sciences, Kagoshima University Graduate School of Medical and Dental Sciences, Kagoshima 890-8544, Japan , Department of Hematology, Imamura Bun-in Hospital, Kagoshima 890-0064, Japan, Department of Hematology, National Hospital Organization Kagoshima Medical Center, Kagoshima 892-0853, Japan
Published online on: August 13, 2012 https://doi.org/10.3892/etm.2012.663
Pages: 581-588

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Prohepcidin is the prohormone of hepcidin. Anemia is one of the main clinical features in patients with multiple myeloma (MM) and hepcidin may be associated with iron homeostasis in these patients. However, the clinical significance of prohepcidin is not fully understood. In this retrospective study, we measured serum prohepcidin levels using an immunoassay technique to study its clinical significance in 39 MM patients. Serum prohepcidin levels in patients with MM were weakly correlated with alkaline phosphatase (ALP) levels (r=0.32, P=0.048), calculated by Spearman's rank correlation, but not with other clinical data, including hemoglobin, serum iron or ferritin. In addition, patients with severe renal insufficiency [creatinine clearance (CCr) <50 ml/min] had significantly higher prohepcidin levels compared with patients with mild or no renal insufficiency (CCr ≥50 ml/min, P=0.047). In contrast, low serum prohepcidin levels less than 110 ng/ml were an independent predictor of poor overall survival [hazard ratio (HR), 5.29; 95% confidence interval (CI), 1.65-17.03] in addition to serum creatinine levels of at least 2 mg/dl (HR, 5.32; CI, 1.10‑25.64), serum calcium (HR, 3.53; CI, 1.01-12.33) and ECOG performance status grade 4 (HR, 4.15; CI, 1.32-13.09) in the multivariate analysis using Cox proportional hazards model. In the subset of 31 MM patients with CCr ≥50 ml/min, low serum prohepcidin (HR, 5.65; CI, 1.60-19.95) was an indicator of poor prognosis in multivariate analysis. These results indicate that serum prohepcidin levels may be associated with ALP and renal function but not iron homeostasis, in MM patients. In addition, lower serum prohepcidin levels are potential independent indicators of poor overall survival in MM patients regardless of renal function.

View Figures

View References

1	Vanderkerken K, Asosingh K, Croucher P and Van Camp B: Multiple myeloma biology: lessons from the 5TMM models. Immunol Rev. 194:196–206. 2003. View Article : Google Scholar : PubMed/NCBI
2	Palumbo A and Anderson K: Multiple myeloma. N Engl J Med. 364:1046–1060. 2011. View Article : Google Scholar
3	Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, Fonseca R, Rajkumar SV, Offord JR, Larson DR, et al: Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 78:21–33. 2003. View Article : Google Scholar : PubMed/NCBI
4	Krause A, Neitz S, Mägert HJ, Schulz A, Forssmann WG, Schulz-Knappe P and Adermann K: LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett. 480:147–150. 2000.
5	Nemeth E and Ganz T: Regulation of iron metabolism by hepcidin. Annu Rev Nutr. 26:323–342. 2006. View Article : Google Scholar : PubMed/NCBI
6	Valore EV and Ganz T: Posttranslational processing of hepcidin in human hepatocytes is mediated by the prohormone convertase furin. Blood Cells Mol Dis. 40:132–138. 2008. View Article : Google Scholar
7	Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T and Kaplan J: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 306:2090–2093. 2004. View Article : Google Scholar : PubMed/NCBI
8	Tomosugi N, Kawabata H, Wakatabe R, Higuchi M, Yamaya H, Umehara H and Ishikawa I: Detection of serum hepcidin in renal failure and inflammation by using ProteinChip System. Blood. 108:1381–1387. 2006. View Article : Google Scholar : PubMed/NCBI
9	Kemna E, Tjalsma H, Laarakkers C, Nemeth E, Willems H and Swinkels D: Novel urine hepcidin assay by mass spectrometry. Blood. 106:3268–3270. 2005. View Article : Google Scholar : PubMed/NCBI
10	Ganz T, Olbina G, Girelli D, Nemeth E and Westerman M: Immunoassay for human serum hepcidin. Blood. 112:4292–4297. 2008. View Article : Google Scholar : PubMed/NCBI
11	Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, Taube DH, Bloom SR, Tam FW, Chapman RS, et al: Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int. 75:976–981. 2009. View Article : Google Scholar : PubMed/NCBI
12	Schwarz P, Strnad P, von Figura G, Janetzko A, Krayenbühl P, Adler G and Kulaksiz H: A novel monoclonal antibody immunoassay for the detection of human serum hepcidin. J Gastroenterol. 46:648–656. 2011. View Article : Google Scholar : PubMed/NCBI
13	Kulaksiz H, Gehrke SG, Janetzko A, Rost D, Bruckner T, Kallinowski B and Stremmel W: Pro-hepcidin: expression and cell specific localisation in the liver and its regulation in hereditary haemochromatosis, chronic renal insufficiency, and renal anaemia. Gut. 53:735–743. 2004. View Article : Google Scholar
14	Kemna E, Pickkers P, Nemeth E, van der Hoeven H and Swinkels D: Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood. 106:1864–1866. 2005. View Article : Google Scholar : PubMed/NCBI
15	Nemeth E, Valore EV, Territo M, Schiller G, Lichtenstein A and Ganz T: Hepcidin, a putative mediator of anemia of inflammation, is a type II acute-phase protein. Blood. 101:2461–2463. 2003. View Article : Google Scholar : PubMed/NCBI
16	Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK and Ganz T: IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest. 113:1271–1276. 2004. View Article : Google Scholar : PubMed/NCBI
17	Lee P, Peng H, Gelbart T, Wang L and Beutler E: Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA. 102:1906–1910. 2005. View Article : Google Scholar : PubMed/NCBI
18	Pelliniemi TT, Irjala K, Mattila K, Pulkki K, Rajamäki A, Tienhaara A, Laakso M and Lahtinen R: Immunoreactive interleukin-6 and acute phase proteins as prognostic factors in multiple myeloma. Finnish Leukemia Group Blood. 85:765–771. 1995.PubMed/NCBI
19	Sharma S, Nemeth E, Chen YH, Goodnough J, Huston A, Roodman GD, Ganz T and Lichtenstein A: Involvement of hepcidin in the anemia of multiple myeloma. Clin Cancer Res. 14:3262–3267. 2008. View Article : Google Scholar : PubMed/NCBI
20	Lee SH, Jeong SH, Park YS, Hwang JH, Kim JW, Kim N and Lee DH: Serum prohepcidin levels in chronic hepatitis C, alcoholic liver disease, and nonalcoholic fatty liver disease. Korean J Hepatol. 16:288–294. 2010. View Article : Google Scholar : PubMed/NCBI
21	Jaroszewicz J, Rogalska M, Flisiak I and Flisiak R: Successful antiviral therapy is associated with a decrease of serum prohepcidin in chronic hepatitis C. World J Gastroenterol. 16:1747–1752. 2010. View Article : Google Scholar : PubMed/NCBI
22	Shinzato T, Abe K, Furusu A, Harada T, Shinzato K, Miyazaki M and Kohno S: Serum pro-hepcidin level and iron homeostasis in Japanese dialysis patients with erythropoietin (EPO)-resistant anemia. Med Sci Monit. 14:CR431–CR437. 2008.PubMed/NCBI
23	Durie BG and Salmon SE: A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer. 36:842–854. 1975. View Article : Google Scholar : PubMed/NCBI
24	Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, Boccadoro M, Child JA, Avet-Loiseau H, Kyle RA, et al: International staging system for multiple myeloma. J Clin Oncol. 23:3412–3420. 2005. View Article : Google Scholar : PubMed/NCBI
25	Roe MA, Spinks C, Heath AL, Harvey LJ, Foxall R, Wimperis J, Wolf C and Fairweather-Tait SJ: Serum prohepcidin concentration: no association with iron absorption in healthy men; and no relationship with iron status in men carrying HFE mutations, hereditary haemochromatosis patients undergoing phlebotomy treatment, or pregnant women. Br J Nutr. 97:544–549. 2007. View Article : Google Scholar
26	Hadley KB, Johnson LK and Hunt JR: Iron absorption by healthy women is not associated with either serum or urinary prohepcidin. Am J Clin Nutr. 84:150–155. 2006.PubMed/NCBI
27	Young MF, Glahn RP, Ariza-Nieto M, Inglis J, Olbina G, Westerman M and O’Brien KO: Serum hepcidin is significantly associated with iron absorption from food and supplemental sources in healthy young women. Am J Clin Nutr. 89:533–538. 2009.PubMed/NCBI
28	Katodritou E, Ganz T, Terpos E, Verrou E, Olbina G, Gastari V, Hadjiaggelidou C, Varthaliti M, Georgiadou S, Westerman M and Zervas K: Sequential evaluation of serum hepcidin in anemic myeloma patients: study of correlations with myeloma treatment, disease variables, and anemia response. Am J Hematol. 84:524–526. 2009. View Article : Google Scholar
29	Maes K, Nemeth E, Roodman GD, Huston A, Esteve F, Freytes C, Callander N, Katodritou E, Tussing-Humphreys L, Rivera S, et al: In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood. 116:3635–3644. 2010. View Article : Google Scholar : PubMed/NCBI
30	Pigeon C, Ilyin G, Courselaud B, Leroyer P, Turlin B, Brissot P and Loréal O: A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload. J Biol Chem. 276:7811–7819. 2001. View Article : Google Scholar
31	Oustamanolakis P, Koutroubakis IE, Messaritakis I, Malliaraki N, Sfiridaki A and Kouroumalis EA: Serum hepcidin and prohepcidin concentrations in inflammatory bowel disease. Eur J Gastroenterol Hepatol. 23:262–268. 2011. View Article : Google Scholar : PubMed/NCBI
32	Taes YE, Wuyts B, Boelaert JR, De Vriese AS and Delanghe JR: Prohepcidin accumulates in renal insufficiency. Clin Chem Lab Med. 42:387–389. 2004.PubMed/NCBI
33	Cherng NC, Asal NR, Kuebler JP, Lee ET and Solanki D: Prognostic factors in multiple myeloma. Cancer. 67:3150–3156. 1991. View Article : Google Scholar : PubMed/NCBI
34	Sakamori R, Takehara T, Tatsumi T, Shigekawa M, Hikita H, Hiramatsu N, Kanto T and Hayashi N: STAT3 signaling within hepatocytes is required for anemia of inflammation in vivo. J Gastroenterol. 45:244–248. 2010. View Article : Google Scholar : PubMed/NCBI