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Published in: Critical Care 1/2011

Open Access 01-02-2011 | Research

Inflammation-induced hepcidin-25 is associated with the development of anemia in septic patients: an observational study

Authors: Lucas T van Eijk, Joyce JC Kroot, Mirjam Tromp, Johannes G van der Hoeven, Dorine W Swinkels, Peter Pickkers

Published in: Critical Care | Issue 1/2011

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Abstract

Introduction

Anemia is a frequently encountered problem during inflammation. Hepcidin is an interleukin-6 (IL-6)-induced key modulator of inflammation-associated anemia. Human sepsis is a prototypical inflammatory syndrome, often complicated by the development of anemia. However, the association between inflammation, hepcidin release and anemia has not been demonstrated in this group of patients. Therefore, we explored the association between hepcidin and sepsis-associated anemia.

Methods

92 consecutive patients were enrolled after presentation on the emergency ward of a university hospital with sepsis, indicated by the presence of a proven or suspected infection and ≥ 2 extended systemic inflammatory response syndrome (SIRS) criteria. Blood was drawn at day 1, 2 and 3 after admission for the measurement of IL-6 and hepcidin-25. IL-6 levels were correlated with hepcidin concentrations. Hemoglobin levels and data of blood transfusions during 14 days after hospitalisation were retrieved and the rate of hemoglobin decrease was correlated to hepcidin levels.

Results

53 men and 39 women with a mean age of 53.3 ± 1.8 yrs were included. Hepcidin levels were highest at admission (median[IQR]): 17.9[10.1 to 28.4]nmol/l and decreased to normal levels in most patients within 3 days (9.5[3.4 to 17.9]nmol/l). Hepcidin levels increased with the number of extended SIRS criteria (P = 0.0005). Highest IL-6 levels were measured at admission (125.0[46.3 to 330.0]pg/ml) and log-transformed IL-6 levels significantly correlated with hepcidin levels at admission (r = 0.28, P = 0.015), day 2 (r = 0.51, P < 0.0001) and day 3 (r = 0.46, P < 0.0001). Twelve patients received one or more blood transfusions during the first 2 weeks of admission, not related to active bleeding. These patients had borderline significant higher hepcidin level at admission compared to non-transfused patients (26.9[17.2 to 53.9] vs 17.9[9.9 to 28.8]nmol/l, P = 0.052). IL-6 concentrations did not differ between both groups. Correlation analyses showed significant associations between hepcidin levels on day 2 and 3 and the rate of decrease in hemoglobin (Spearman's r ranging from -0.32, P = 0.03 to -0.37, P = 0.016, respectively).

Conclusions

These data suggest that hepcidin-25 may be an important modulator of anemia in septic patients with systemic inflammation.
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Literature
1.
go back to reference Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, Adermann K: LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000, 480: 147-150. 10.1016/S0014-5793(00)01920-7PubMedCrossRef Krause A, Neitz S, Magert HJ, Schulz A, Forssmann WG, Schulz-Knappe P, Adermann K: LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000, 480: 147-150. 10.1016/S0014-5793(00)01920-7PubMedCrossRef
2.
go back to reference Park CH, Valore EV, Waring AJ, Ganz T: Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001, 276: 7806-7810. 10.1074/jbc.M008922200PubMedCrossRef Park CH, Valore EV, Waring AJ, Ganz T: Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001, 276: 7806-7810. 10.1074/jbc.M008922200PubMedCrossRef
3.
go back to reference Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T: IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004, 113: 1271-1276.PubMedPubMedCentralCrossRef Nemeth E, Rivera S, Gabayan V, Keller C, Taudorf S, Pedersen BK, Ganz T: IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. J Clin Invest 2004, 113: 1271-1276.PubMedPubMedCentralCrossRef
4.
go back to reference Fleming RE, Sly WS: Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci USA 2001, 98: 8160-8162. 10.1073/pnas.161296298PubMedPubMedCentralCrossRef Fleming RE, Sly WS: Hepcidin: a putative iron-regulatory hormone relevant to hereditary hemochromatosis and the anemia of chronic disease. Proc Natl Acad Sci USA 2001, 98: 8160-8162. 10.1073/pnas.161296298PubMedPubMedCentralCrossRef
5.
go back to reference Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004, 306: 2090-2093. 10.1126/science.1104742PubMedCrossRef Nemeth E, Tuttle MS, Powelson J, Vaughn MB, Donovan A, Ward DM, Ganz T, Kaplan J: Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 2004, 306: 2090-2093. 10.1126/science.1104742PubMedCrossRef
6.
go back to reference Dallalio G, Law E, Means RT Jr: Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood 2006, 107: 2702-2704. 10.1182/blood-2005-07-2854PubMedPubMedCentralCrossRef Dallalio G, Law E, Means RT Jr: Hepcidin inhibits in vitro erythroid colony formation at reduced erythropoietin concentrations. Blood 2006, 107: 2702-2704. 10.1182/blood-2005-07-2854PubMedPubMedCentralCrossRef
7.
go back to reference Cherian S, Forbes DA, Cook AG, Sanfilippo FM, Kemna EH, Swinkels DW, Burgner DP: An insight into the relationships between hepcidin, anemia, infections and inflammatory cytokines in pediatric refugees: a cross-sectional study. PLoS ONE 2008, 3: e4030. 10.1371/journal.pone.0004030PubMedPubMedCentralCrossRef Cherian S, Forbes DA, Cook AG, Sanfilippo FM, Kemna EH, Swinkels DW, Burgner DP: An insight into the relationships between hepcidin, anemia, infections and inflammatory cytokines in pediatric refugees: a cross-sectional study. PLoS ONE 2008, 3: e4030. 10.1371/journal.pone.0004030PubMedPubMedCentralCrossRef
8.
go back to reference Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, Wroblewski VJ, Wurz E, Datz C, Weiss G: Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 2009, 113: 5277-5286. 10.1182/blood-2008-12-195651PubMedCrossRef Theurl I, Aigner E, Theurl M, Nairz M, Seifert M, Schroll A, Sonnweber T, Eberwein L, Witcher DR, Murphy AT, Wroblewski VJ, Wurz E, Datz C, Weiss G: Regulation of iron homeostasis in anemia of chronic disease and iron deficiency anemia: diagnostic and therapeutic implications. Blood 2009, 113: 5277-5286. 10.1182/blood-2008-12-195651PubMedCrossRef
9.
go back to reference Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, Taube DH, Bloom SR, Tam FW, Chapman RS, Maxwell PH, Choi P: Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int 2009, 75: 976-981. 10.1038/ki.2009.21PubMedCrossRef Ashby DR, Gale DP, Busbridge M, Murphy KG, Duncan ND, Cairns TD, Taube DH, Bloom SR, Tam FW, Chapman RS, Maxwell PH, Choi P: Plasma hepcidin levels are elevated but responsive to erythropoietin therapy in renal disease. Kidney Int 2009, 75: 976-981. 10.1038/ki.2009.21PubMedCrossRef
10.
go back to reference Ukarma L, Johannes H, Beyer U, Zaug M, Osterwalder B, Scherhag A: Hepcidin as a predictor of response to epoetin therapy in anemic cancer patients. Clin Chem 2009, 55: 1354-1360. 10.1373/clinchem.2008.121285PubMedCrossRef Ukarma L, Johannes H, Beyer U, Zaug M, Osterwalder B, Scherhag A: Hepcidin as a predictor of response to epoetin therapy in anemic cancer patients. Clin Chem 2009, 55: 1354-1360. 10.1373/clinchem.2008.121285PubMedCrossRef
11.
go back to reference Kemna E, Pickkers P, Nemeth E, van der HH, Swinkels D: Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 2005, 106: 1864-1866. 10.1182/blood-2005-03-1159PubMedCrossRef Kemna E, Pickkers P, Nemeth E, van der HH, Swinkels D: Time-course analysis of hepcidin, serum iron, and plasma cytokine levels in humans injected with LPS. Blood 2005, 106: 1864-1866. 10.1182/blood-2005-03-1159PubMedCrossRef
12.
go back to reference Dombrovskiy VY, Martin AA, Sunderram J, Paz HL: Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 2007, 35: 1244-1250. 10.1097/01.CCM.0000261890.41311.E9PubMedCrossRef Dombrovskiy VY, Martin AA, Sunderram J, Paz HL: Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med 2007, 35: 1244-1250. 10.1097/01.CCM.0000261890.41311.E9PubMedCrossRef
13.
go back to reference Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003, 31: 1250-1256. 10.1097/01.CCM.0000050454.01978.3BPubMedCrossRef Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G: 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Crit Care Med 2003, 31: 1250-1256. 10.1097/01.CCM.0000050454.01978.3BPubMedCrossRef
14.
go back to reference Nguyen HB, Rivers EP, Abrahamian FM, Moran GJ, Abraham E, Trzeciak S, Huang DT, Osborn T, Stevens D, Talan DA: Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med 2006, 48: 28-54.PubMed Nguyen HB, Rivers EP, Abrahamian FM, Moran GJ, Abraham E, Trzeciak S, Huang DT, Osborn T, Stevens D, Talan DA: Severe sepsis and septic shock: review of the literature and emergency department management guidelines. Ann Emerg Med 2006, 48: 28-54.PubMed
15.
go back to reference Kroot JJ, Hendriks JC, Laarakkers CM, Klaver SM, Kemna EH, Tjalsma H, Swinkels DW: (Pre)analytical imprecision, between-subject variability, and daily variations in serum and urine hepcidin: implications for clinical studies. Anal Biochem 2009, 389: 124-129. 10.1016/j.ab.2009.03.039PubMedCrossRef Kroot JJ, Hendriks JC, Laarakkers CM, Klaver SM, Kemna EH, Tjalsma H, Swinkels DW: (Pre)analytical imprecision, between-subject variability, and daily variations in serum and urine hepcidin: implications for clinical studies. Anal Biochem 2009, 389: 124-129. 10.1016/j.ab.2009.03.039PubMedCrossRef
16.
go back to reference Swinkels DW, Girelli D, Laarakkers C, Kroot J, Campostrini N, Kemna EH, Tjalsma H: Advances in quantitative hepcidin measurements by time-of-flight mass spectrometry. PLoS ONE 2008, 3: e2706. 10.1371/journal.pone.0002706PubMedPubMedCentralCrossRef Swinkels DW, Girelli D, Laarakkers C, Kroot J, Campostrini N, Kemna EH, Tjalsma H: Advances in quantitative hepcidin measurements by time-of-flight mass spectrometry. PLoS ONE 2008, 3: e2706. 10.1371/journal.pone.0002706PubMedPubMedCentralCrossRef
17.
go back to reference Lee P, Peng H, Gelbart T, Wang L, Beutler E: Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA 2005, 102: 1906-1910. 10.1073/pnas.0409808102PubMedPubMedCentralCrossRef Lee P, Peng H, Gelbart T, Wang L, Beutler E: Regulation of hepcidin transcription by interleukin-1 and interleukin-6. Proc Natl Acad Sci USA 2005, 102: 1906-1910. 10.1073/pnas.0409808102PubMedPubMedCentralCrossRef
18.
go back to reference Jelkmann W: Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 1998, 18: 555-559. 10.1089/jir.1998.18.555PubMedCrossRef Jelkmann W: Proinflammatory cytokines lowering erythropoietin production. J Interferon Cytokine Res 1998, 18: 555-559. 10.1089/jir.1998.18.555PubMedCrossRef
19.
go back to reference Rogiers P, Zhang H, Leeman M, Nagler J, Neels H, Melot C, Vincent JL: Erythropoietin response is blunted in critically ill patients. Intensive Care Med 1997, 23: 159-162. 10.1007/s001340050310PubMedCrossRef Rogiers P, Zhang H, Leeman M, Nagler J, Neels H, Melot C, Vincent JL: Erythropoietin response is blunted in critically ill patients. Intensive Care Med 1997, 23: 159-162. 10.1007/s001340050310PubMedCrossRef
20.
go back to reference Kempe DS, Akel A, Lang PA, Hermle T, Biswas R, Muresanu J, Friedrich B, Dreischer P, Wolz C, Schumacher U, Peschel A, Götz F, Döring G, Wieder T, Gulbins E, Lang F: Suicidal erythrocyte death in sepsis. J Mol Med 2007, 85: 273-281. 10.1007/s00109-006-0123-8PubMedCrossRef Kempe DS, Akel A, Lang PA, Hermle T, Biswas R, Muresanu J, Friedrich B, Dreischer P, Wolz C, Schumacher U, Peschel A, Götz F, Döring G, Wieder T, Gulbins E, Lang F: Suicidal erythrocyte death in sepsis. J Mol Med 2007, 85: 273-281. 10.1007/s00109-006-0123-8PubMedCrossRef
21.
go back to reference Zhang DL, Hughes RM, Ollivierre-Wilson H, Ghosh MC, Rouault TA: A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab 2009, 9: 461-473. 10.1016/j.cmet.2009.03.006PubMedPubMedCentralCrossRef Zhang DL, Hughes RM, Ollivierre-Wilson H, Ghosh MC, Rouault TA: A ferroportin transcript that lacks an iron-responsive element enables duodenal and erythroid precursor cells to evade translational repression. Cell Metab 2009, 9: 461-473. 10.1016/j.cmet.2009.03.006PubMedPubMedCentralCrossRef
Metadata
Title
Inflammation-induced hepcidin-25 is associated with the development of anemia in septic patients: an observational study
Authors
Lucas T van Eijk
Joyce JC Kroot
Mirjam Tromp
Johannes G van der Hoeven
Dorine W Swinkels
Peter Pickkers
Publication date
01-02-2011
Publisher
BioMed Central
Published in
Critical Care / Issue 1/2011
Electronic ISSN: 1364-8535
DOI
https://doi.org/10.1186/cc9408

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