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Journal of Crohn's and Colitis (2014) xx, xxx–xxx

CROHNS-01011; No of Pages 6

Serum hepcidin concentrations correlatewith ferritin in patients with inflammatorybowel disease☆

Ingo Mecklenburg a,1, Diana Reznik a,1, Elizaveta Fasler-Kana,b,Jürgen Drewea, Christoph Beglinger a,Petr Hruza,⁎, On behalf of the Swiss IBD Cohort Study Group

a Department of Gastroenterology and Hepatology, University Hospital Basel, Basel, Switzerlandb University of Applied Sciences Northwestern Switzerland (FHNW), Institute of Chemistry and Bioanalytics,Muttenz, Switzerland

Received 7 March 2014; received in revised form 7 April 2014; accepted 21 April 2014

Abbreviations: UC, Ulcerative colitCohort Study; ACD, Anemia of chronicWitts activity Index; ELISA, Enzyme-lin☆ Financial disclosure: The authors h⁎ Corresponding author at: Departm

Switzerland. Tel.: +41 61 328 66 09; faE-mail address: petr.hruz@usb.ch (

1 Both authors contributed equally to

http://dx.doi.org/10.1016/j.crohns.201873-9946/© 2014 European Crohn's an

Please cite this article as: Mecklenbudisease, J Crohns Colitis (2014), http:

KEYWORDSHepcidin;Ulcerative colitis;Crohn's disease;Inflammatorybowel disease;Anemia

Abstract

Background and aims: Anemia is a frequent complication of inflammatory bowel disease (IBD).Hepcidin, a key mediator in this anemia, is up-regulated by high iron levels and inflammation,and serum levels are elevated in IBD. However, the extent of inflammatory activity and irondeficiency for the regulation of hepcidin is not known. This study aimed to evaluate serumhepcidin levels in anemic and non-anemic IBD patients, with iron or non-iron deficiency, andactive or inactive disease.

Methods: This retrospective, observational study analyzed serum hepcidin levels from 247patients with IBD (130 Crohn's patients and 117 with ulcerative colitis) recruited at SwissInflammatory Bowel Disease Cohort Study centers. Patients were divided into 5 different groupsusing criteria of active and inactive diseases (C-reactive protein, and CDAI/MTWAI = diseaseactivity-index), anemia (hemoglobin) and iron deficiency (ferritin) and compared to healthycontrols with no signs of anemia and normal ferritin levels. Hepcidin was measured usingenzyme-linked immunosorbent assay.Results: Independent of inflammatory activity, all patients with decreased ferritin (b30 μg/L)had significantly lower hepcidin levels when compared to patients and healthy controls having

is; CD, Crohn's disease; IBD, Inflammatory bowel disease; SIBDCS, Swiss Inflammatory Bowel Diseasedisease; CRP, C-reactive protein; CDAI, Crohn's disease activity index; MTWAI, Modified Truelove andked immunosorbent assay.ave no financial relationships relevant to this article to disclose.ent of Gastroenterology and Hepatology, University Hospital Basel, Petersgraben 4, 4031 Basel,x: +41 61 265 53 52.P. Hruz).this work.

14.04.008d Colitis Organisation. Published by Elsevier B.V. All rights reserved.

rg I, et al, Serum hepcidin concentrations correlate with ferritin in patients with inflammatory bowel//dx.doi.org/10.1016/j.crohns.2014.04.008

2 I. Mecklenburg et al.

Please cite this article as: Mecklenbudisease, J Crohns Colitis (2014), http:

normal ferritin (N30 μg/L). A significant correlation between serum ferritin levels and serumhepcidin was found (Spearman's Rho = 0.491; p b 0.001). A backward multi-linear stepwiseregression analysis showed that only ferritin, and none of the inflammatory markers or age andsex correlated significantly (p = 0.005) with hepcidin.Conclusion: This retrospective analysis suggests that iron deficiency is the key trigger forhepcidin regulation in IBD patients with anemia.© 2014 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

rg I, et al, Serum hepcidin conc//dx.doi.org/10.1016/j.crohns

1. Introduction

Inflammatory bowel disease (IBD) defined as chronic inflam-matory and frequently relapsing disease of the gastrointesti-nal tract, implies two major disorders, Crohn's disease (CD)and ulcerative colitis (UC). CD is characterized by a discon-tinuous, transmural inflammation that can occur anywhere inthe gastrointestinal tract, whereas UC shows a more superfi-cial, continuous colonic inflammation that affects only themucosal and submucosal layers.1 Both diseases are idiopathic,but the chronic inflammatory condition of the gut is related toa combination of genetic and environmental factors thatimpact on normal host–microbe interactions.2 The prevalenceof CD in Europe varies from 1.52 to 213 cases per 100,000persons, whereas the prevalence of UC is slightly higher andvaries from 2.42 to 294 cases per 100,000 persons.3

Recent studies have demonstrated that anemia representsthe most common systemic complication of IBD patients.4,5 Inan analysis of the Swiss IBD Cohort Study, anemia was found in21.2% of all IBD patients, with a higher rate in patients fromtertiary referral centers (28.8%) when compared to generalpractice patients (12.9%).6 The cause of anemia in chronicinflammatory diseases is multifactorial. Most often anemia inIBD results in iron deficiency anemia (IDA), caused by reducediron uptake from enterocytes and obvious chronic blood lossdue tomucosal inflammation. Other causes that can aggravateanemia in IBD patients include vitamin B12 deficiency, folatedeficiency and drug-induced anemia. On the other hand, inIBD patients, anemia of chronic diseases (ACD) can also occur,which is mediated via inflammatory mechanisms with theconsequence of decreased iron levels in the circulation andlimited iron availability for erythroid cells. In this latter causeof anemia, pro-inflammatory cytokines induce the formationof hepcidin, a key regulator of iron homeostasis. Hepcidin is asmall antimicrobial peptide produced in the liver andtranscriptionally up-regulated by high iron levels as well asinflammation.7 Hepcidin reduces the amount of circulatingiron by binding to ferroportin, a divalent iron transporter,located on the cell surfaces of hepatocytes, macrophages andthe basolateral membranes of enterocytes.8,9 Ferroportinblocks cellular iron (Fe2+) export from macrophages andinhibits the transfer of absorbed iron from the basolateralmembranes of enterocytes into the circulation. The reducedcirculating iron results in a limited availability for erythroidprogenitors and impaired erythropoiesis.

Various studies in patients having IBD and anemia exposeda relationship between hepcidin and Crohn's disease andulcerative colitis.10–13 Hepcidin is upregulated by inflamma-tion through IL6-mediated STAT3 signaling.14,15 It triggers ananti-inflammatory response in macrophages and, through itsantimicrobial activity, hepcidin may be involved in the

en.201

control of microbial growth. These characteristics makehepcidin an interesting target of IBD research as thesesuggest a dual role in host defense and iron homeostasis.10

Hepcidin is significantly elevated in patients with CD andUC.13 However, the exact contribution of inflammatoryactivity (hepcidin's function as an acute phase protein) andiron deficiency (hepcidin's function as gatekeeper of ironhomeostasis) in the regulation of hepcidin in patients withIBD is not known.

With this observational study, we aimed to assess serumhepcidin levels in IBD patients with active and inactive IBDsand to correlate these levels with C-reactive protein (CRP),ferritin and hemoglobin.

2. Methods

2.1. Study patients

In this observational study, we evaluated serum hepcidinlevels from 247 patients with IBD (130 patients with CD and117 with UC), recruited at the centers participating in theSwiss Inflammatory Bowel Disease Cohort Study (SIBDCS)—anational prospective clinical cohort that started in 2006. A fulldescription of the cohort profile has been published previous-ly.16 Patients were recruited through their gastroenterologistsin private practices, regional hospitals and tertiary centers.Inclusion criteria were diagnoses of CD or UC established atleast 4 months before inclusion and confirmed by radiological,endoscopic or surgical assessment, or after at least onerecurrence of the disease. CD case ascertainment was madebased on Lennard-Jones criteria.17 Patients were excluded ifthey suffered from another form of colitis, were not regularlyfollowed up for CD or UC, had no permanent residency inSwitzerland, or if they did not sign the informed consent form.Patients with UC and CD included in this analysis were dividedinto 5 different groups, based on criteria for active andinactive diseases, presence or absence of anemia, and irondeficiency. Allocation into groups with active or inactivedisease was based on measurement of C-reactive protein(CRP N 5 mg/L) and the clinical disease activity indices, CDAI(Crohn's disease activity index) for CD and MTWAI (ModifiedTruelove and Witts activity index) for UC. In addition, anemia(serum hemoglobin level: men Hb b 140 g/L; for womenHb b 120 g/L) and iron deficiency (serum ferritin b 30 μg/L)were used for further group stratification. A group of 21healthy subjects with no laboratory or clinical signs of acute orchronic inflammation was used as the control group. Thesesubjects had no laboratory signs of anemia and had normal ironstatus parameters. The study was approved by the localethical committee.

trations correlate with ferritin in patients with inflammatory bowel4.04.008

3Hepcidin in IBD

2.2. Determination of serum hepcidin levels

Hepcidin was measured with enzyme-linked immunosorbentassay (ELISA) using Cusabio Human Hepcidin ELISA kit (CusabioBiotech, Wuhan, China, catalog number: CSB-E13062h) ac-cording to the manufacturer's instructions.

2.3. Statistical analysis

Demographic data are presented as median and range.Hepcidin values were compared among the patient groups bygeneral linear model analysis. Pair-wise comparison be-tween the groups used Scheffe's multi-comparison test toaccount for the multiplicity of testing. Local linear regres-sion analysis of ferritin values b380 μg/L was performed bynon-parametric robust regression analysis (Matlab software,version R2013, Mathworks Inc., Natick, MA, USA). Thepredictive value of different demographic and laboratoryparameters (e.g., age, sex, albumin, CRP, ferritin, hemo-globin, leucocyte count, thrombocyte counts) for the serumconcentration of hepcidin was analyzed by backwardmulti-linear stepwise regression. If predictors were notnormally distributed as indicated by Kolmogorov-Smirnovtest, regression analysis was performed on logarithmicallytransformed data. For statistical analysis, IBM SPSS statis-tics, version 21 was used. A p-value b0.05 was consideredstatistically significant.

3. Results

Analysis of serum hepcidin levels in patients with chronicinflammatory bowel disease (CD and UC) was performed andcompared to healthy controls. The demographic data ofpatients with CD and UC are presented in two tables. InTable 1, data from CD are shown. As defined, patients withactive disease (groups 1, 2 and 3) had signs of inflammationwith elevated inflammatory parameters CRP, leucocytes and

Table 1 Group stratification and laboratory parameters of patie

Active disease (CDAI N 150, CRP N 5)

Hemoglobin (g/L) Anemia(Hb b 120♀,140♂)

No anemia(Hb ≥ 120♀,140♂)

Ferritin (μg/L) Ferritin b 30 Ferritin ≥ 30Group size (n=) 8 27Age 28 (20–46) 36 (21–62)Male:female 1:7 12:15Parameter median(range)CDAI 180 (155–251) 217 (152–378)Leucocytes (×109/L) 7.9 (4.2–13.3) 9.0 (4.8–15.4)CRP (mg/L) 18.0 (7–58) 12.1 (5.6–193)Albumin (g/L) 29 (26–34) 38 (24–45)Hemoglobin (g/L) f 100 (90–120) 129 (123–139)Hemoglobin (g/L) m 136 (136–136) 147 (140–158)Ferritin (μg/L) 16 (4–29) 86 (31–259)Hepcidin (ng/mL) 97.1 (0–2125) 388.7 (9.8–1219)

Group 1 2

Please cite this article as: Mecklenburg I, et al, Serum hepcidin concentdisease, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.201

CDAI when compared to patients in disease remission (groups 4and 5). Lower albumin levels were observed in the activedisease groups. In Table 2, data are presented for patientswith UC. Similarly to CD patients, UC patients with activedisease (groups 6, 7 and 8) had signs of inflammation as shownfor the inflammatory parameters CRP, leucocytes and thedisease activity score MTWAI when compared to UC patients indisease remission (groups 9 and 10). Furthermore, loweralbumin levels were observed in the active disease groups. Forboth diseases (CD and UC) as defined, Hb levels were normal inpatients in the non-anemic groups and were decreased in thegroups with anemia, respectively. As a measure of the ironstorage, ferritin levels were considered as normal whenN30 μg/L and decreased when b30 μg/L.

Because of small group sizes, hepcidin serum levels of CDand UC patients were combined for the statistical analysis(Fig. 1). This analysis demonstrated that, for non-anemic(groups 2 and 7) or anemic (groups 3 and 8) patients withactive disease and a ferritin level N30 μg/L, hepcidin levelscomparable to non-anemic patients with inactive disease(groups 5 and 10) and healthy controls were seen. Incontrast, anemic patients with active disease (groups 1 and6) and patients in remission (groups 4 and 9) with a ferritinb30 μg/L showed significantly decreased hepcidin levelswhen compared to patients and healthy controls with anormal ferritin value N30 μg/L.

A significant correlation between serum ferritin levelsand serum hepcidin was found (Spearman's Rho = 0.491;p b 0.001, Fig. 2). The optimal fit calculated for ferritinvalues was ≤380 μg/L. These data suggest that, in theregulation of hepcidin, ferritin levels may be more impor-tant than the inflammatory parameters.

Therefore, the predictive values of different demograph-ic and laboratory parameters (e.g., age, albumin, CRP,ferritin, hemoglobin, leucocyte count) for the concentrationof serum hepcidin were analyzed by backward multi-linearstepwise regression and showed that only ferritin—and noneof the inflammatory markers—was significantly (p = 0.005)

nts with Crohn's disease.

Inactive disease (CDAI ≤ 150, CRP ≤ 5)

Anemia(Hb b 120♀,140♂)

Anemia(Hb b 120♀,140♂)

No anemia(Hb ≥ 120♀,140♂)

Ferritin ≥ 30 Ferritin b 30 Ferritin ≥ 3025 15 5535 (20–73) 35 (17–46) 36 (19–72)15:10 12:3 30:25

210 (158–279) 64 (9–143) 57 (0–126)8.3 (5.1–15.3) 5.9 (4.0–7.6) 7.1 (2.6–12.4)30.1 (6–260) 3.0 (0.3–5.0) 2.3 (0.3–5.0)31 (17–45) 40 (31–46) 40.5 (29–48)108 (82–118) 117 (109–118) 139 (122–153)128 (94–139) 133 (105–137) 151 (142–168)130 (30–1111) 18 (6–26) 103 (30–636)557.7 (2.7–1822) 93.1 (0–742) 457.6 (8.8–1822)3 4 5

rations correlate with ferritin in patients with inflammatory bowel4.04.008

Table 2 Group stratification and laboratory parameters of patients with ulcerative colitis.

Active disease (MTWAI ≥ 5, CRP N 5) Inactive disease (MTWAI ≤ 5, CRP ≤ 5)

Hemoglobin (g/L) Anemia(Hb b 120♀,140♂)

No anemia(Hb ≥ 120♀,140♂)

Anemia(Hb b 120♀,140♂)

Anemia(Hb b 120♀,140♂)

No anemia(Hb ≥ 120♀,140♂)

Ferritin (μg/L) Ferritin b 30 Ferritin ≥ 30 Ferritin ≥ 30 Ferritin b 30 Ferritin ≥ 30Group size (n=) 15 18 27 12 45Age 42 (20–62) 40 (20–75) 35 (19–65) 35 (18–47) 45 (20–82)Male:female 9:6 10:8 19:8 8:4 19:26Parameter median(range)MTWAI 8 (6–15) 9 (6–15) 11 (6–16) 3 (0–5) 1 (0–5)Leucocytes (×109/L) 7.9 (4.1–19.0) 9.1 (5.8–15.6) 7.1 (2.1–16.0) 6.4 (5.0–11.1) 6.4 (3.5–13.7)CRP (mg/L) 17.0 (7–100) 9.2 (6–54) 35 (6–222) 3.0 (0.5–5.0) 3.0 (0.3–5.0)Albumin (g/L) 33 (21–42) 39.5 (30–47) 31 (17–44) 42 (32–48) 44 (29–49)Hemoglobin (g/L) f 111 (103–119) 129 (122–142) 105 (85–115) 113 (111–118) 133 (122–147)Hemoglobin (g/L) m 113 (83–139) 147 (140–163) 121 (70–140) 128 (105–137) 152 (141–175)Ferritin (μg/L) 15 (4–29) 98.5 (43–590) 122 (36–1210) 13 (4–18) 97 (31–1400)Hepcidin (ng/mL) 16.3 (0–1914) 577.2 (7.9–2157) 698.2 (0–2251) 54.9 (0–1479) 464.1 (0–1512)

Group 6 7 8 9 10

4 I. Mecklenburg et al.

correlated with hepcidin. The results of the regressionanalysis are given in Tables 3a and 3b.

4. Discussion

Our results show that hepcidin serum levels are significantlydecreased in anemic IBD patients with depleted iron storage,as evidenced by decreased levels of ferritin independent oftheir disease activity status. Anemic as well as non-anemicIBD patients with active disease and non-anemic patients inremission, but all with normal ferritin, presented withsimilar hepcidin levels and had levels comparable to healthy

Figure 1 Correlation of hepcidin and ferritin levels in patientswith ulcerative colitis (n = 117) and Crohn's disease (n = 130).The analysis was performed for ferritin values ≤380 μg/L bynon-parametric robust regression analysis. The non-parametricSpearman's Rho correlation coefficient (ρ) was calculated. Theellipse represents the 95% confidence interval.

Please cite this article as: Mecklenburg I, et al, Serum hepcidin concendisease, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.201

subjects. A multi-linear regression analysis showed that onlyferritin and none of the inflammatory markers was signifi-cantly (p = 0.005) correlated with hepcidin. These resultssuggest that primarily the iron storage level, and not theinflammatory activity, contributes to hepcidin regulation inour cohort of IBD patients.

Several other studies have recently addressed levels ofhepcidin and the precursor protein, prohepcidin, in patientswith IBD. Oustamanolakis found significantly increased levelsof hepcidin and significantly decreased levels of prohepcidin

Figure 2 Distribution of serum hepcidin levels in patients withIBD (ulcerative colitis, n = 117 and Crohn's disease, n = 130) andhealthy controls (n = 21) is shown. The allocation of patients tothe respective groups is described in the Methods section.Patient characteristics and laboratory parameters are shown inTables 1 and 2. Boxes indicate the interquartile range withmedian value. Bars show the 5th and 95th percentiles and datapoints representing the 1st and 99th percentile are shown as astar. In addition, all individual values are shown.

trations correlate with ferritin in patients with inflammatory bowel4.04.008

Table 3a Regression coefficients.

Unstandardizedcoefficients

Standardizedcoefficients

t p-Value 95% Confidence intervals for B

Model B Standard error Beta Lower bound Upper Bound

(Constant) 1.106 0.465 2.378 0.024 0.156 2.056Log ferritin a 0.694 0.230 0.482 3.016 0.005 0.224 1.165a Data were not normally distributed and logarithmically transformed.

5Hepcidin in IBD

in unselected CD and UC patients.13 Some 42% of this group ofIBD patients had anemia. In a multivariate analysis in patientswith UC, hepcidin significantly correlated only with ferritinand disease activity, but not with anemia. Prohepcidin did notcorrelate with any of the examined parameters. In contrast,when compared to healthy controls, decreased serum levels ofhepcidin were observed in IBD patients, independent ofwhether or not these patients were iron-deficient.10 Further-more, prohepcidin levels did not differ significantly whencompared to control subjects, and suggested that serumprohepcidin level may not be a satisfactory diagnostic orprognostic measure in anemia of chronic inflammatorydisease.12

Current data from the literature point out the considerabledifficulty in interpreting serum hepcidin and prohepcidinlevels in IBD patients. Furthermore, in our analysis, weobserved a high variability of hepcidin levels within theindividual groups that may indicate complex pathophysiolog-ical mechanisms involved in hepcidin regulation.

Indeed, hepcidin is associated with a variety of chronicinflammatory conditions. Inflammation due to infection,autoimmune disease or cancer stimulates the synthesis ofpro-inflammatory cytokines and especially interleukin-6 (IL-6)which has been shown to induce hepcidin production.18–20 ThisIL-6-induced hepcidin up-regulation is mediated via STAT3.15

Patients with inflammation characterized by high C-reactiveprotein levels (N10 mg/L) and patients withmultiplemyeloma(known to secrete excess IL-6) all have inappropriatelyelevated hepcidin levels.8 After injection of bacterial lipo-polysaccharide into healthy humans, one observes an acuteinflammation with marked IL-6 production that is correlatedwith increased hepcidin production.18 For IBD patients, onlystudies with few patients have been performed. In 17 CDpatients with ACD, a strong positive correlation betweenserum IL-6 and hepcidin levels was demonstrated.11 In thesame study, similar to our findings, a strong correlation

Table 3b Excluded variables.

Model predictors Beta t p-Value

Log thrombocyte count a −0.209 −1.248 0.222Leucocyte count −0.117 −0.722 0.476Logs hemoglobin a 0.070 0.405 0.688Gender −0.156 −0.969 0.341Log age a 0.097 0.592 0.558Albumin 0.198 1.249 0.222Log CRP a 0.018 0.109 0.914a Data were not normally distributed and logarithmically

transformed.

Please cite this article as: Mecklenburg I, et al, Serum hepcidin concentdisease, J Crohns Colitis (2014), http://dx.doi.org/10.1016/j.crohns.201

between serum ferritin and hepcidin levels was observed.However, in our analysis, we could not demonstrate anycorrelation with inflammatory disease markers. This may berelated to the fact that IBD patients with an establisheddiagnosis of CD or UC for at least 4 months are included in ourSwiss IBD cohort, and patients with a severe flare-up may beunderrepresented in our evaluation.

An interesting study was performed in 19 pediatricpatients with Crohn's disease. After an overnight fast,serum iron, hemoglobin levels, serum markers of inflamma-tion and urine hepcidin were analyzed before and after oraladministration of ferrous sulfate (1 mg/kg). Patients withactive disease had significantly elevated CRP, IL-6 and urinehepcidin when compared to patients with inactive disease.In addition, impaired intestinal iron absorption correlatedwith disease activity and markers of inflammation, andindicated that the inflammatory effects have functionalconsequences.21 Blocking endogenous hepcidin productioncould therefore be an effective treatment for anemia ofchronic disease.22

In conclusion, our analysis confirmed a modest correla-tion between serum hepcidin and ferritin levels as a measureof iron storage in patients with IBD. For our IBD patients, wedid not find any correlation between serum hepcidin levelsand inflammatory parameters.

Conflict of interest

The authors have no conflicts of interest to disclose.

Acknowledgments

We would like to thank Ulrich Baumgartner and ViktoriaGillich for technical assistance. The Swiss National ScienceFoundation (33CSC0_134274) provided a research grant tosupport this study, but did not have an active role in thedesign, collection, analysis and interpretation of data, nor inthe writing of the manuscript or in the decision to submit themanuscript for publication.

PH and IM conceptualized and designed the clinicalquestion, drafted the initial manuscript; DR evaluated thepatient data, and drafted the initial manuscript; CB concep-tualized, and critically reviewed the manuscript; EF per-formed laboratory analysis, and critically reviewed themanuscript; JD conceptualized, critically reviewed the man-uscript and performed the statistical calculation. All authorsread and approved the final manuscript as submitted.

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