Limitations of Serum Ferritin in Diagnosing Iron ......ReviewArticle Limitations of Serum Ferritin in Diagnosing Iron Deficiency in Inflammatory Conditions AxelDignass ,1,2 KarimaFarrag,2,3

Review ArticleLimitations of Serum Ferritin in Diagnosing Iron Deficiency inInflammatory Conditions

Axel Dignass 12 Karima Farrag23 and Juumlrgen Stein 23

1Department of Medicine 1 Agaplesion Markus Hospital Goethe University 60431 Frankfurt am Main Germany2Interdisciplinary Crohn Colitis Center Rhein-Main 60594 Frankfurt am Main Germany3Department of Gastroenterology and Clinical Nutrition DGD Clinics Sachsenhausen 60594 Frankfurt am Main Germany

Correspondence should be addressed to Axel Dignass axeldignassfdkinfo

Received 3 November 2017 Revised 9 January 2018 Accepted 6 February 2018 Published 18 March 2018

Academic Editor Jose Tellez-Zenteno

Copyright copy 2018 Axel Dignass et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Patients with inflammatory conditions such as inflammatory bowel disease (IBD) chronic heart failure (CHF) and chronic kidneydisease (CKD) have high rates of iron deficiency with adverse clinical consequences Under normal circumstances serum ferritinlevels are a sensitivemarker for iron status but ferritin is an acute-phase reactant that becomes elevated in response to inflammationcomplicating the diagnosis Proinflammatory cytokines also trigger an increase in hepcidin which restricts uptake of dietary ironand promotes sequestration of iron by ferritin within storage sites Patients with inflammatory conditions may thus have restrictedavailability of iron for erythropoiesis and other cell functions due to increased hepcidin expression despite normal or high levels ofserum ferritin The standard threshold for iron deficiency (lt30 120583gL) therefore does not apply and transferrin saturation (TSAT)a marker of iron availability should also be assessed A serum ferritin threshold of lt100 120583gL or TSAT lt 20 can be considereddiagnostic for iron deficiency in CHF CKD and IBD If serum ferritin is 100ndash300 120583gL TSAT lt 20 is required to confirm irondeficiency Routine surveillance of serum ferritin and TSAT in these at-risk groups is advisable so that iron deficiency can bedetected and managed

1 Iron Deficiency in Inflammatory Diseases

Iron deficiency is amajor global health problem representingone of the leading nonfatal disease conditions worldwide[1] and is frequently seen in everyday clinical practice [2]Timely detection and treatment are important because ofthe critical role played by iron in the function of all organsystems Despite its prevalence however iron deficiency isoften overlooked especially in patients with inflammatoryconditions partly due to the heterogeneity of definitionsprovided in clinical practice guidelines [3] Iron deficiencycan be defined as ldquoa health-related condition in which ironavailability is insufficient to meet the bodyrsquos needs and whichcan be present with or without anaemiardquo [4]

Conventionally the most well-recognized risk groups foriron deficiency are the poorly nourished those with highiron demands such as pregnant women or adolescents andindividuals with chronic blood loss for instance from heavyuterine or gastrointestinal bleeding [5] In addition growing

attention is now being paid to the iron status of patientswith inflammatory conditions which predispose them toiron deficiency [4 6] The most frequent of these are chronicheart failure (CHF) chronic kidney disease (CKD) andinflammatory bowel disease (IBD)

Estimates of iron deficiency in these groups have variedwidely between studies due to differing definitions anddiverse patient selection criteria Overall however approx-imately 50 of patients with CHF 24ndash85 of patientswith CKD and 45 of patients with IBD are iron-deficient(Table 1)

The causes of iron deficiency in these conditions aremultiple and vary between individuals [2 4 5] (Table 1)Patients with chronic illnesses may have a poor appetite andinadequate dietary iron intake This can be exacerbated byimpaired iron absorption from the intestinal lumen caused bymedications such as proton pump inhibitors [7] histamine-2 receptor antagonists [7] and calcium-based phosphatebinders [8] while antiplatelet therapy can increase the risk of

HindawiInternational Journal of Chronic DiseasesVolume 2018 Article ID 9394060 11 pageshttpsdoiorg10115520189394060

2 International Journal of Chronic Diseases

Table 1 Causes prevalence and clinical consequences of iron deficiency in inflammatory conditions

Disease Key causes of iron deficiency[2 4 5] Estimated prevalence Potential clinical

consequences [4]

Chronic heart failure

Inflammatory stateLoss of appetitepoor

nutritionReduced iron uptake from GI

tract due to edema orcommon concomitant

medications (eg histamine-2receptor antagonists

calcium-based phosphatebinders antiplatelet therapiesand proton pump inhibitors)

sim50 (range 37ndash63)[11ndash14]a

Fatigue and reducedexercise capacitywork capacity and

quality of lifeAssociated with

increasedhospitalization and

mortality

Chronic kidneydisease

Inflammatory stateReduced hepcidin excretion

by the kidneysBlood loss from dialysis

sessionsChronic intestinal bleeding(eg platelet dysfunction)Frequent phlebotomy

Acute expansion of erythroidmass under ESA therapy

Poor appetite

24ndash85 (highestincidence with moresevere CKD) [15ndash17]b

Iron-deficiencyanemia associated

with fatigueincreased mortalityand progression toend-stage renal

disease

Inflammatory boweldisease

Inflammatory stateChronic blood loss from the

GI tractPoor appetite

Reduced uptake of iron fromthe GI tract

Bowel resection

sim45 (range 43ndash55)[18ndash20]c

Fatigue exhaustionreduced exercise

capacity and qualityof life

CKD chronic kidney disease ESA erythropoietin-stimulating agent GI gastrointestinal aIron deficiency defined as serum ferritinlt 100120583gL or 100ndash300120583gL[11ndash13] (or lt800120583gL [14]) with transferrin saturation (TSAT) lt 20 bIron deficiency defined as serum ferritin lt 100120583gL or TSAT lt 20 cIron deficiencydefined as serum ferritin lt 30120583gL or TSAT lt 16 [18 19] or lt20 [20] or as serum ferritin lt 100120583gL if C-reactive protein (CRP) gt 5mgL [20] or gt10mgL[18]

gross gastrointestinal blood loss [9] Blood loss from frequentblood sampling from gastrointestinal bleeding in IBD orduring dialysis in CKD patients can also contribute Inaddition to these patient-specific etiologies CHF CKD andIBD share the common effect of an ongoing inflammatorystimulus In these chronic conditions high hepcidin levelscan restrict the uptake of dietary iron and over time lead toiron deficiency with reduced availability of iron for essentialcellular functions [10] (see ldquoTheEffect of Inflammation on IronHomeostasisrdquo below)

All too often investigation and treatment of iron defi-ciency are only triggered by the onset of (iron deficiency)anemia at which point iron deficiency has become severeenough to exhaust iron stores and restrict erythropoiesisHowever iron has multiple biochemical and physiologicalfunctions other than erythropoiesis [21] and iron deficiencyexerts various adverse effects that may arise either before orafter the onset of anemia As well as being critical for ery-thropoiesis iron is essential for the function of key enzymesin the mitochondrial electron transport system [22] whichmay explain the fatigue that can develop in nonanemic iron-deficient individuals Iron deficiency has also been associatedwith poor immune function [23] There is a clear need for

systematic diagnosis and correction of iron deficiency ininflammatory conditions

In normal circumstances iron status can usually beassessed adequately by measuring serum levels of ferritinIn the presence of proinflammatory stimuli however thediagnosis of iron deficiency is more complex Understandingthe nature of serum ferritin and particularly how levelsof serum ferritin are influenced by inflammation is key tosuccessful diagnosis in this context

2 Ferritin The Ubiquitous IronStorage Protein

Intracellular ferritin is a complex made up of two typesof subunit termed H (heavy chain) and L (light chain)[24] Twenty-four subunits combine to form a shell-likemolecule that incorporates a cavity that can store up to4500 iron atoms [25 26] The H chains of ferritin haveferroxidase activity and convert Fe(II) to Fe(III) as the ironis internalized within the ferritin complex [27] Fe(III) issequestered within the mineral core of ferritin in the formof ferric oxyhydroxide phosphate [25] Concentration ofhigh amounts of iron in this unreactive form within ferritin

International Journal of Chronic Diseases 3

reduces the concentration of reactive intracellular Fe(II)lowering the potential for generation of oxidant species TheL-subunit promotes formation of the iron core within theferritin shell [24] The ratio of H-subunits and L-subunitsvaries between organs with L-subunits predominating in theliver and spleen while H-subunits predominate in the heartand kidney [28] Production of ferritin is controlled by theiron regulatory proteins 1 and 2 (IRP1 and IRP2) whichrespond to a reduction in cytosolic iron by binding to 51015840-iron responsive elements in ferritin mRNAs to inhibit itstranslation [29 30]

Small quantities of ferritin are also present in the serumdue to secretion from macrophages or following cell deathand lysis [31] In contrast to intracellular ferritin serumferritin is iron-poor and consists almost exclusively of L-subunits [32] with the addition of glycosylated subunits (G-subunits) which are similar to the L-chain [33]

Under normal conditions levels of serum ferritin showa close correlation with iron stores in liver biopsy samples[34] the ldquogold standardrdquo for measuring the amount ofiron in the body However serum ferritin levels can beprofoundly affected by the presence of inflammation sinceserum ferritin is an acute-phase protein The acute-phaseresponse is a major physiological defense reaction wherebythe body aims to restore physiological homeostasis in theface of inflammation [35] Serum levels of positive acute-phase proteins including ferritin C-reactive protein (CRP)and alpha-1-acid glycoprotein (AGP) rise dramatically aspart of the inflammatory response mediated by increasedexpression of cytokines such as IL-6 [35ndash37]

Increased levels of serum ferritin as part of the acute-phase response mean that serum ferritin levels no longer cor-relate with iron availability in the presence of inflammation

Assessment of patientsrsquo iron status becomes more com-plex under these conditions and requires wider awareness ofiron homeostatic mechanisms

3 Ferritin as a Component of the IronRegulatory System in Healthy Individuals

The uptake transport and storage of iron are closely reg-ulated in the body with ferritin playing an important roleDietary iron in the form of inorganic Fe(III) is absorbed fromthe intestinal lumen across the brush border of duodenalenterocytes via active uptake mechanisms that reduce Fe(III)to Fe(II) This uptake of iron from the lumen occurs viathe divalent metal transporter-1 (DMT1) which is expressedon the apical membrane of the duodenal enterocytes and isclosely associated with the membrane ferrireductase DCYT-B that is responsible for the reduction of Fe(III) [5] Oncewithin the enterocyte Fe(II) is then exported across thebasolateral membrane by the Fe(II) transporter ferroportin[29] After export it is reoxidized from Fe(II) to Fe(III) bythemembrane-bound ferroxidase hephaestin and possibly byintestinal ceruloplasmin [38] Fe(III) is then released into thecirculation where it binds to the iron transport glycoproteintransferrin Transferrin has two high-affinity binding sitesfor Fe(III) which maintain the iron in a redox-inert state[39] Iron is delivered by transferrin to cells by binding to

transferrin receptor 1 which is expressed on the cell surfaceas a response to low intracellular iron levels Circulating iron-laden transferrin binds to transferrin receptor 1 triggeringendocytosis and uptake of the iron cargo Once internalizedthe iron may be transported to mitochondria for the syn-thesis of heme or of iron-sulfur clusters which are essentialcofactors of various enzymes or are used to synthesize otheriron-containing enzymes that are important for fundamentalcellular functions such as DNA synthesis or repair [39]

If not required immediately the iron is instead safelystored within the cell in the form of ferritin [27] The mainintracellular storage compartment where most ferritin islocated is the cytosol In response to the cellrsquos need ferritinis targeted towards lysosomes for degradation by a specificcargo molecule (NCOA4) via a process called ferritinophagy[40] The iron is then in the so-called labile iron pool a formof readily available cytosolic iron and can be used for cellularfunctions

The bodyrsquos stores of ferritin are predominantly foundin hepatocytes and in the macrophages of the reticuloen-dothelial systemMacrophages phagocytose aged or damagederythrocytes recycling the iron contained in heme usingheme oxygenase 1 to release the iron [29] (Figure 1) Thisrecycling accounts for approximately 90 of the bodyrsquos dailyiron needs with onlysim10beingmet by intestinal absorption[29] Iron is released from these storage sites as Fe(II) via fer-roportin in the cell membraneThe export process is coupledto reoxidation of Fe(II) to Fe(III) by the ferroxidase enzymeceruloplasmin and is followed by loading of Fe(III) ontotransferrin for systemic distribution to other sites [26] Trans-ferrin saturation (TSAT) is a marker for the amount of ironavailable for erythropoiesis or other cellular requirements

Systemic iron homeostasis is usually maintained in theface of fluctuating dietary iron intake and varying levelsof demand by regulatory mechanisms coordinated by thehepatic hormone hepcidin Hepcidin binds to and leads tointernalization and degradation of the iron exporter ferro-portin This reduces the mobilization of iron into the circu-lation from enterocytes and from iron stores in hepatocytesand macrophages (Figure 2(a)) [41] In healthy individualsincreasing levels of transferrin-bound iron and elevated ironstores stimulate hepcidin upregulationwhich suppresses ironexport and thus lowers circulating levels of iron [29 41]Conversely hepcidin production is inhibited in the presenceof declining levels of iron in the circulation and in tissues orin response to other stimuli such as hypoxia and intensifiederythropoiesis after blood loss [29 41] In this situationreduced levels of hepcidin stimulate increased iron acqui-sition and release by the enterocytes in the duodenum andefflux of ferritin-bound iron from storage sites to normalizeiron availability and meet increased erythroid needs

4 The Effect of Inflammation onIron Homeostasis

Patients with inflammatory conditions may have diminishediron stores a situation described as ldquoabsolute iron deficiencyrdquoAs in patients without inflammation this can arise due to lowdietary iron intake poor iron absorption andor blood loss


Red bloodcell Heme

Fe(II)

Fe(II)

Ferritin

Ferritinophagy

Fe(III)Transferrin

Fe(III)

Ferroportin

Lysosome

Hemeoxygenase

Excessiron

Hemeoxygenase

Figure 1 Normal iron homeostasis in the reticuloendothelial macrophage Macrophages phagocytose aged or damaged red blood cells usingheme oxygenase 1 to release iron from heme a recycling process that accounts for approximately 90 of the bodyrsquos daily iron needs Iron israpidly released to circulating transferrin or when present in excess stored in ferritin When required ferritin is degraded in the lysosomesvia a process called ferritinophagy and the iron is released Iron(II) is exported from the macrophage via ferroportin in the cell membrane ina process coupled to reoxidation from iron(II) to iron(III) by membrane-bound ceruloplasmin Iron(III) is then loaded onto transferrin fortransport in the plasma

Liver

Hepcidin

Spleen

Duodenum

Hepcidininhibits ironexport fromhepatocytes Hepcidin

inhibits ironexport from

splenicmacrophages

Hepcidininhibits ironexport from

duodenalenterocytes

Erythroblastsin bonemarrow Red blood

cells

Transferrin-bound

serum iron

(a)

LiverIL-6

Inflammation

Hepcidin

Spleen

Duodenum

Macrophage

Transferrin-bound

serum iron

Reduced ironefflux from

splenicmacrophages

Reduced ironefflux fromduodenal

enterocytesReduced ironefflux fromhepatocytes


cells

(b)

Figure 2The role of hepcidin in systemic ironhomeostasis (a) In healthy individuals hepcidin production increases in response to increasinglevels of transferrin-bound serum iron and iron stores Hepcidin internalizes and degrades the iron transporter ferroportin restricting theexport of iron from enterocytes and from iron stores in hepatocytes and macrophages to restore normal iron levels (b) In inflammatoryconditions hepcidin production increases in response to inflammatory cytokines such as IL-6 disrupting the usual homeostaticmechanismsFerroportin is internalized and degraded reducing transmembrane export of iron and the availability of iron to bind to transferrin isrestricted

(Table 1) In some cases however there may be adequate ironstores with normal levels of serum ferritin but insufficientiron is delivered by transferrin to meet cellsrsquo demand asituation termed ldquofunctional iron deficiencyrdquo [42]

Functional iron deficiency (or iron-restricted erythro-poiesis) in inflammatory conditions is caused by elevatedhepcidin levels triggered by inflammatory cytokines such asIL-6 [41] The consequent internalization and degradation of

ferroportin lowers the amount of iron available for binding totransferrin Accordingly TSAT is reduced (Figure 2(b))

The increase in hepcidin levels in the presence of inflam-mation can be profound Normal serum hepcidin valuesare gender-specific with one large sample reporting medianlevels of 114 ngmL in premenopausal women 237 ngmLin postmenopausal women and 218 ngmL in men [44]Although ELISA shows considerable variation [45] making


Table 2 Proposed serum ferritin and TSAT thresholds for the diagnosis of iron deficiency in patients with or without inflammatoryconditions

Population Thresholds

No inflammatory condition [43] Serum ferritin lt 30120583gL (NB false negatives arecommon)

Inflammatory conditions [4 5]Serum ferritin lt 100 120583gL or TSAT lt 20

If serum ferritin is 100ndash300 120583gL a TSAT test isrequired to confirm iron deficiency

TSAT transferrin saturation

comparisons difficult studies in patients with inflammatoryconditions have indicated far higher levels of hepcidin meanvalues up to 98 ngmL have been reported in patients withmild CHF [46] 270 ngmL in CKD stages 2ndash4 [47] and577 ngmL in active IBD [48] There is evidence that levelsof hepcidin correlate with the inflammatory marker CRP[44 49] but the relation between hepcidin levels and theseverity of inflammatory diseases is complex with factorssuch as levels of stored iron and anemia playing a role

Other mechanisms can also affect iron homeostasis inthe presence of inflammation [50] These include downreg-ulation of transferrin expression by hepatocytes in responseto increased levels of circulating IL-6 and other proinflam-matory cytokines [51] and suppression of ferroportin mRNA[52 53]

5 Serum Ferritin and TSAT asComplementary Markers of Iron Statusin Inflammatory Conditions

Since serum ferritin level rises as part of the acute-phaseresponse measurement of serum ferritin alone cannotexclude iron deficiency in patients with CHF CKD or IBDAdditional testing is required usually by the assessment ofTSAT

Both serum ferritin and TSAT tests are readily availableand inexpensive There are certain limitations to both typesof tests however Serum ferritin levels in normal individualshave been reported to vary by 15 inmen and 27 in womenon a day-to-day basis [54] with variations of up to 62when measured over a longer term [55] Additionally serumferritin assays differ in terms of the antigens used and havetechnical variations for example in calibration proceduresand in the choice of reference standards [56] leading tosignificant analytical variability One large-scale comparisonin the USA found that interassay differences could be as highas 54 [55] Accordingly where serum ferritin levels aremea-sured in different laboratories (eg before and after hospitaldischarge) a change in serum ferritin may not necessarilyreflect a change in iron status For TSAT there is also substan-tial biological variability (up to 38 [57]) Serum iron levelsused to calculate TSAT show diurnal fluctuation [58] and areinfluenced by oral iron supplements and the amount of ironin the diet [59] Serum iron should generally be measured inthe morning on an empty stomach to minimize variation Aswell as physiological alterations there is a degree of interassayvariability for serum iron measurements which are the basis

for calculation of the TSAT level One study of 10 ferritinassays and five TSAT assays which analyzed samples from 114patients on hemodialysis found 63variation in the reportedlevels of serum ferritin but only 10 variation for TSAT [56]

One practical caveat to note is that laboratory reportsusually include a reference range of ldquonormalrdquo serum ferritinlevels These ranges can vary and the ldquonormalrdquo range isboth assay-dependent and laboratory-dependent Howeverthe ldquonormalrdquo ranges are all based on healthy patients withoutelevated inflammatory cytokine levels and should not beapplied to patients with inflammatory conditions

6 Diagnostic Thresholds for Serum Ferritinand TSAT in Inflammatory Conditions

In the general population WHO defines low serum ferritinas lt15 120583gL in adults and lt12120583gL in children [43] A levelof 30 120583gL has been identified as the most sensitive (92)and specific (98) cutoff level to indicate iron deficiencycorrelatingwith the absence of iron stores in the bonemarrowregardless of the presence or absence of anemia [60] Expertguidelines in inflammatory conditions usually specify bothserum ferritin and TSAT thresholds for the diagnosis of irondeficiency [3 61ndash63] but cutoff values are not consistent [3]

A simplified diagnostic approach in patients with CHFCKD or IBD recommends that iron deficiency be diagnosedbased on the following cutoff values serum ferritinlt 100120583gLor TSAT lt 20 and if serum ferritin is between 100 and300 120583gL a TSAT test is required to confirm iron deficiency[4] (Table 2) Hemoglobin levels may support the diagnosisof iron deficiency but do not need to be below normal toconfirm the diagnosis [3] This diagnostic approach has beenused widely in recent large-scale prevalence studies of irondeficiency [11ndash13]

Where doubt about a patientrsquos iron status persists despitemeasurement of both serum ferritin and TSAT other testsmay be required to definitively exclude iron deficiency

7 Other Diagnostic Tests for Iron Deficiency

Where inflammation is present and serum ferritin with TSATtesting is inconclusive other tests may be necessary (Table 3)

71 Hematological Markers The percentage of hypochromicerythrocytes ( HYPO) and the content of reticulocytehemoglobin (CHr or RetHb) are the most frequently usedhematological indices of iron status


Table 3 Laboratory tests for iron deficiency [4 32 50 64]

Absolute iron deficiencyFunctional irondeficiency ininflammation

Both absolute irondeficiency andfunctional irondeficiency

Serum ferritin darr uarrDepends on the degree

of iron deficiencyTSAT darr darr darr

Hepcidin darr uarrDepends on degree of

iron deficiencyCHr darr darr darr

HYPO uarr uarr uarr

sTfR uarr darr darr or normalsTfRlog ferritin uarr darr uarr

CRP Normal uarr uarr

CHr content of reticulocyte hemoglobin CRP C-reactive proteinHYPO percentage of hypochromic erythrocytes sTfR soluble transferrin receptor TSATtransferrin saturation

Iron-deficient erythropoiesis increases the proportion of HYPO generally defined based on a mean corpuscularhemoglobin concentration (MCHC) lt 280 gL [32] Anincreased level of HYPO is regarded as a sensitive and earlyindicator of iron deficiency [32] A cutoff of 6 for HYPOhas been proposed in guidelines for the management of CKDas being diagnostic for functional iron deficiency when com-bined with low TSAT [65 66] Measurements of HYPOare sensitive to temperature since erythroid expansion with areduction inMCHC occurs when samples are stored at roomtemperature or above so the analysis should be performedwithin four hours if the sample is not refrigerated [32] Thishas hampered more extensive use of HYPO as a diagnostictest [67]

CHr content provides a ldquoreal-timerdquo indication of thefunctional state of bone marrow with a value lt 28 pgproposed as the cutoff point for diagnosis of iron-deficienterythropoiesis [68] One study of 36 patients on chronichemodialysis showed CHr to have 100 sensitivity and 73specificity for iron-deficient erythropoiesis [69] and othertrials have confirmed the predictive value of CHr in thissetting [70 71] Decreased CHr is a convenient marker thatis available via standard cell count measurements withoutadditional costs Preservation of samples during storage anddelivery to the laboratory is again an issue however creatinglogistic challenges [67]

72 Soluble Transferrin Receptor (sTfR) and the sTfR-FerritinIndex Soluble transferrin receptor (sTfR) is a truncated formof transferrin receptor 1 (TfR) When TfR is not stabilized byiron-laden transferrin it is cleaved by a membrane proteasein erythroid cells releasing sTfR Levels of sTfR increase inthe presence of iron deficiency and are reduced in patientswith iron overload [5 32] The ratio of sTfR (levels of whichare high when iron stores are low but normal or low in thepresence of inflammation) to log ferritin (levels of whichare low when iron stores are low but normal or high ininflammatory condition) has been suggested to be a usefultest and is known as the ldquosTfRlog ferritin indexrdquo [5 72]

sTfR is a marker for the activitysize of the erythrocyteprecursors in the bone marrow and is not directly influencedby inflammation [73] However production of inflamma-tory cytokines can inhibit erythropoiesis both directly andindirectly by suppressing erythropoietin synthesis and ery-thropoiesis [74] an effect that reduces levels of sTfR sTfRconcentrations can therefore remain normal despite depletediron stores [75] and become less reliable as the degree ofinflammation increases Levels of sTfR are also affected byage and ethnicity and by altitude complicating interpretation[74 76] Since sTfR is a marker of erythropoietic activitylevels increase after administration of ESAs [77] Variouscommercial immunoassays have been developed for theassessment of sTfR but practical issues such as variationsin assay types and lack of standardization mean that neithersTfR nor the sTfR-ferritin index are widely used [5 32 74]They tend to be applied when automated red cell parameterssuch as CHr or HYPO are not available [68]

73 C-Reactive Protein Assessing the severity of inflamma-tion based on the level of high sensitivity CRP (hsCRP)could theoretically be helpful in order to understand theextent to which serum ferritin levels have risen as part ofthe acute-phase response Recently the effect of adjustingferritin-based diagnostic criteria for iron deficiency accord-ing to levels of CRP or AGP was examined using data fromthe international Biomarkers Reflecting Inflammation andNutritional Determinants of Anemia (BRINDA) project [78]Researchers found that the observed rate of iron deficiencyshowed a clear inverse relation to CRP levels In women ofreproductive age the incidence of iron deficiency (based ona serum ferritin threshold of 15120583gL) was 61 and 290respectively in the subgroups with the highest and lowestdeciles of CRP Similar inverse associationswere seen forAGPlevels and in preschool children [78] The authors proposedthat corrections should be applied for CRP or AGP levelsduring iron deficiency surveillance programs [78]

However there is currently no consensus on when toinclude CRP in the diagnostic work-up for iron deficiency


or what thresholds should be applied CRP is not includedin guidelines for the evaluation of iron status in inflam-matory conditions [3] In IBD however measurement ofCRP (with a threshold of 5mgL) or use of stool markerssuch as calprotectin or lactoferrin has been recommendedto confirm whether the disease is active or in remission withtransabdominal ultrasound or endoscopy if required [4]Thisallows serum ferritin results to be interpreted accordinglysince levels are raised in active IBD [63]

8 Assessing High Serum Ferritin inInflammatory Conditions

The body has no active excretion mechanism for iron and isthus vulnerable to a positive iron balance and eventually riskof iron overload if the homeostatic systems become disruptedor are bypassed Excess body iron can be toxic saturatingthe iron-binding capacity of transferrin and resulting in non-transferrin-bound iron [79] which can be taken up in anuncontrolled manner with the risk of organ damage in theendocrine system heart and liver [79]

WHO guidelines state that in the absence of inflamma-tion serum ferritingt 200120583gL inmen orgt150120583gL inwomenconfers a risk of iron overload in the general population [43]In inflammatory conditions where serum ferritin levels areraised as part of the acute-phase response however thesethresholds do not apply and TSAT should be measured toavoid a misdiagnosis of iron overload

Striking increases in serum ferritin levels can also occurin the event of acute inflammatory or infectious events Onecase control study of 47 patients found the mean serumferritin level to be 1000 120583gL in patients with acute kidneyfailure compared to 90 120583gL in patients with CKD [80] Thesame study reported very high serum ferritin levels (mean505 120583gL) in a control group of 10 patients with normal renalfunction who had an acute infection High serum ferritinlevels in patients with a chronic inflammatory condition whoexperience an acute episode or who develop an infectionshould thus be interpreted particularly cautiously

Other causes of iron overload include multiple bloodtransfusions for example in long-term treatment of trans-fusion-dependent anemias such as thalassemia and myelo-dysplastic syndromes where hepcidin-regulated homeostaticmechanisms are bypassed Certain genetic conditions canalso lead to iron overload The most frequent of these ishereditary hemochromatosis in which control of iron uptakefrom the gut is defective due to abnormally low levels ofhepcidin [81]

9 Special Situations Affecting SerumFerritin Levels

Certain demographic and physical characteristics alter ironhomeostasis and affect serum ferritin levels Some of these(particularly obesity and old age) are frequent in patientswith inflammatory conditions such as CHF Obese patientsare known to have an increased risk for iron deficiency [82]Patients with high body mass index have increased levels ofhepcidin [83] likely due to adiposity-related inflammation

[84] resulting in restricted dietary iron absorption [85]and reduced TSAT levels [82] As in other inflammatoryconditions serum ferritin levels are higher than in nonobeseindividuals [86] Older patients are also prone to absoluteiron deficiency due to factors such as an iron-poor diet andmedications that inhibit dietary iron absorption [87] Low-grade inflammation [88] is often present in older people[88ndash90] with the potential for functional iron deficiencyInadequate iron for erythropoiesis as determined by bonemarrow aspirates is frequently found even in elderly patientswith serum ferritin levels up to 75120583gL [91]

Concomitant diseases can also complicate the interpre-tation of serum ferritin concentrations Ferritin levels areelevated in the serum of many patients with cancer partic-ularly in the presence of more aggressive disease [92] due tochronic inflammatory effects as indicated by upregulation ofIL-6 CRP and hepcidin [93ndash95] Patients with liver diseaseexhibit complex iron homeostasis disturbances [96] thatbecome more pronounced with greater severity of disease[97] Reduced expression of ferroportin and the consequentinhibition of iron export from hepatocytes [98] can lead toiron deposits in the liver [99] stimulating increased hepcidinproduction [97 100 101] Hepatitis promotes an increasein serum ferritin in response to the inflammatory stimulus[99] such that functional iron deficiency can develop Innonalcoholic liver disease for example approximately one-third of patients have elevated serum ferritin levels [99 102]Careful interpretation of serum ferritin levels in the obeseand elderly and in patients with liver disease is required andTSATmeasurement should be performed before ruling out adiagnosis of iron deficiency

10 Conclusions

Iron deficiency often remains undiagnosed and untreatedin the context of inflammatory conditions [103] It maynot be suspected because the typical symptoms such asfatigue can be similar to those of the underlying diseaseEven in the absence of anemia however iron deficiency cannegatively affect patientsrsquo quality of life and expert guidelinesin CHF CKD and IBD recognize that iron deficiency shouldbe detected and managed [61ndash63 104] Routine laboratorytesting is advisable with reassessment every 3 to 12months orin the event of disease progression [4] Measurement of bothserum ferritin and TSAT offers a straightforward means toidentify the presence of iron deficiency in these at-risk groups[4] A diagnosis of iron deficiency can be made in theseconditions regardless of whether anemia is present if serumferritin islt100 120583gL or TSAT islt20 using TSAT to confirmiron deficiency if serum ferritin is between 100 and 300 120583gL[4 5] This approach improves diagnostic sensitivity andallows prompt initiation of treatment Iron replenishmentcan be achieved despite the presence of inflammation by useof intravenous iron therapies as per expert guidelines [61ndash63 104 105] The intravenous route bypasses the hepcidin-induced blockade of oral iron uptake and release and avoidsthe problem of intolerance to oral iron [6 106] Clinical trialshave shown intravenous iron to achieve iron repletion morerapidly and efficiently than oral iron including studies in


patients with inflammatory conditions [107ndash111] Intravenousiron should be avoided in case of potential infections

With effective therapy available surveillance of serumferritin and TSAT levels in these at-risk groups is prudentso that iron deficiency can be treated before progression tosymptomatic anemia or other complications At the sametime iron overload should be avoided and markers to befollowed need to be established

Conflicts of Interest

Axel Dignass has received consultancy fees from AbbottMSD Ferring UCB Otsuka RocheGenentech TakedaPharmacosmos Holystone Biotech and Falk FoundationDr Dignass has also received grants from Institut furGemeinwohl and Stiftung Leben mit Krebs as well as pay-ment for lectures including service on speakersrsquo bureaufrom Falk Foundation Ferring MSD Abbott Otsuka ViforStiftung Leben mit Krebs Kompetenznetz CED Takedaand Pharmacosmos Additionally Dr Dignass has receivedpayment for manuscript preparation from Falk Foundationand payment for development of education presentationsfrom Abbott Pharmacosmos Falk Foundation and FerringKarima Farrag has no conflicts of interest to declare JurgenStein has received consultancy fees from AbbVie FreseniusKabi Immundiagnostik MSD Pharmacosmos Takeda GIDynamics and Vifor Dr Stein has also received payment forlectures from AbbVie Falk Foundation Ferring Immundi-agnostik MSD Pharmacosmos Takeda Thermo Fischer GIDynamics and Vifor Additionally Dr Stein has receivedpayment for manuscript preparation from AbbVie FalkFoundation and MSD

Acknowledgments

The authors would like to thank Clara Camaschella SanRaffaele Institute in Milan for her critical review of themanuscript Editorial support was provided by a medicalwriter (C Dunstall) funded by Vifor Pharma GlattbruggSwitzerland

References

[1] GBD 2016Disease and Injury Incidence and Prevalence Collab-orators ldquoGlobal regional and national incidence prevalenceand years lived with disability for 328 diseases and injuries for195 countries 1990-2016 a systematic analysis for the GlobalBurden of disease Study 2016rdquo The Lancet vol 390 no 10100pp 1211ndash1226 2017

[2] C Camaschella ldquoIron-deficiency anemiardquo The New EnglandJournal of Medicine vol 372 no 19 pp 1832ndash1843 2015

[3] L Peyrin-Biroulet NWilliet and P Cacoub ldquoGuidelines on thediagnosis and treatment of iron deficiency across indications Asystematic reviewrdquo American Journal of Clinical Nutrition vol102 no 6 pp 1585ndash1594 2015

[4] M D Cappellini J Comin-Colet A de Francisco et al ldquoIrondeficiency across chronic inflammatory conditions Interna-tional expert opinion on definition diagnosis and manage-mentrdquoAmerican Journal ofHematology vol 92 no 10 pp 1068ndash1078 2017

[5] C Camaschella ldquoNew insights into iron deficiency and irondeficiency anemiardquo Blood Reviews vol 31 no 4 pp 225ndash2332017

[6] L De Franceschi A Iolascon A Taher and M D CappellinildquoClinical management of iron deficiency anemia in adultsSystemic review on advances in diagnosis and treatmentrdquoEuropean Journal of Internal Medicine vol 42 pp 16ndash23 2017

[7] J R Lam J L Schneider C P Quesenberry and D A CorleyldquoProton Pump Inhibitor and Histamine-2 Receptor AntagonistUse and Iron Deficiencyrdquo Gastroenterology vol 152 no 4 pp821ndash829 2017

[8] T McDonagh and I C Macdougall ldquoIron therapy for the treat-ment of iron deficiency in chronic heart failure Intravenous ororalrdquo European Journal of Heart Failure vol 17 no 3 pp 248ndash262 2015

[9] K Barada H Abdul-Baki I I El Hajj J G Hashash andP H Green ldquoGastrointestinal bleeding in the setting ofanticoagulation and antiplatelet therapyrdquo Journal of ClinicalGastroenterology vol 43 no 1 pp 5ndash12 2009

[10] M Wessling-Resnick ldquoIron homeostasis and the inflammatoryresponserdquoAnnual Review of Nutrition vol 30 pp 105ndash122 2010

[11] E A Jankowska P Rozentryt A Witkowska et al ldquoIrondeficiency An ominous sign in patients with systolic chronicheart failurerdquo European Heart Journal vol 31 no 15 pp 1872ndash1880 2010

[12] I T Klip J Comin-Colet A A Voors et al ldquoIron deficiencyin chronic heart failure An international pooled analysisrdquoAmerican Heart Journal vol 165 no 4 pp 575ndashe3 2013

[13] C Enjuanes I T Klip J Bruguera et al ldquoIron deficiency andhealth-related quality of life in chronic heart failure Resultsfrom a multicenter European studyrdquo International Journal ofCardiology vol 174 no 2 pp 268ndash275 2014

[14] J Comın-Colet C Enjuanes GGonzalez et al ldquoIron deficiencyis a key determinant of health-related quality of life in patientswith chronic heart failure regardless of anaemia statusrdquo Euro-pean Journal of Heart Failure vol 15 no 10 pp 1164ndash1172 2013

[15] C-Y Hsu C E McCulloch and G C Curhan ldquoIron status andhemoglobin level in chronic renal insufficiencyrdquo Journal of theAmerican Society of Nephrology vol 13 no 11 pp 2783ndash27862002

[16] S Fishbane S Pollack H I Feldman and M M Joffe ldquoIronindices in chronic kidney disease in the National Health andNutritional Examination Survey 1988-2004rdquo Clinical Journal ofthe American Society of Nephrology vol 4 no 1 pp 57ndash61 2009

[17] WMcClellan S L AronoffW K Bolton et al ldquoThe prevalenceof anemia in patients with chronic kidney diseaserdquo CurrentMedical Research andOpinion vol 20 no 9 pp 1501ndash1510 2004

[18] J R Goodhand N Kamperidis A Rao et al ldquoPrevalence andmanagement of anemia in children adolescents and adultswithinflammatory bowel diseaserdquo Inflammatory Bowel Diseases vol18 no 3 pp 513ndash519 2012

[19] C Herrera-Deguise F Casellas V Robles E Navarro and NBorruel ldquoIron deficiency in the absence of anemia impairsthe perception of health-related quality of life of patients withinflammatory bowel diseaserdquo Inflammatory Bowel Diseases vol22 no 6 pp 1450ndash1455 2016

[20] A Lupu M Diculescu R Diaconescu et al ldquoPrevalenceof anemia and iron deficiency in Romanian patients withinflammatory bowel disease a prospective multicenter studyrdquoJournal of Gastrointestinal and Liver Diseases vol 24 no 1 pp5ndash20 2015


[21] K M Musallam and A T Taher ldquoIron deficiency beyonderythropoiesis should we be concernedrdquo Current MedicalResearch and Opinion vol 34 no 1 pp 81ndash93 2018

[22] M Stugiewicz M Tkaczyszyn M Kasztura W BanasiakP Ponikowski and E A Jankowska ldquoThe influence of irondeficiency on the functioning of skeletal muscles experimentalevidence and clinical implicationsrdquo European Journal of HeartFailure vol 18 no 7 pp 762ndash773 2016

[23] J L Beard ldquoIron biology in immune function musclemetabolism and neuronal functioningrdquo Journal of Nutritionvol 131 no 2 pp 568Sndash580S 2001

[24] N D Chasteen and P M Harrison ldquoMineralization in ferritinAn efficientmeans of iron storagerdquo Journal of Structural Biologyvol 126 no 3 pp 182ndash194 1999

[25] F M Torti and S V Torti ldquoRegulation of ferritin genes andproteinrdquo Blood vol 99 no 10 pp 3505ndash3516 2002

[26] J Wang and K Pantopoulos ldquoRegulation of cellular ironmetabolismrdquo Biochemical Journal vol 434 no 3 pp 365ndash3812011

[27] D M Lawson A Treffry P J Artymiuk et al ldquoIdentification ofthe ferroxidase centre in ferritinrdquo FEBS Letters vol 254 no 1-2pp 207ndash210 1989

[28] G D Stoner M B Shimkin M C Troxell T L Thompsonand L S Terry ldquoStructural and immunological relationships ofisoferritins in normal andmalignant cellsrdquoCancer Research vol36 no 5 pp 735ndash739 1976

[29] MWHentzeMUMuckenthaler BGaly andCCamaschellaldquoTwo to tango regulation ofmammalian ironmetabolismrdquoCellvol 142 no 1 pp 24ndash38 2010

[30] L C Kuhn ldquoIron regulatory proteins and their role in control-ling iron metabolismrdquo Metallomics vol 7 no 2 pp 232ndash2432015

[31] L A Cohen L Gutierrez A Weiss et al ldquoSerum ferritin isderived primarily from macrophages through a nonclassicalsecretory pathwayrdquo Blood vol 116 no 9 pp 1574ndash1584 2010

[32] N M Archer and C Brugnara ldquoDiagnosis of iron-deficientstatesrdquo Critical Reviews in Clinical Laboratory Sciences vol 52no 5 pp 256ndash272 2015

[33] P Santambrogio A Cozzi S Levi and P Arosio ldquoHumanserum ferritinG-peptide is recognized by anti-L ferritin subunitantibodies and concanavalin-Ardquo British Journal of Haematol-ogy vol 65 no 2 pp 235ndash237 1987

[34] L Costa Matos P Batista N Monteiro et al ldquoIron storesassessment in alcoholic liver diseaserdquo Scandinavian Journal ofGastroenterology vol 48 no 6 pp 712ndash718 2013

[35] K L Streetz T Wustefeld C Klein M P Manns andC Trautwein ldquoMediators of inflammation and acute phaseresponse in the liverrdquo Cellular and Molecular Biology vol 47no 4 pp 661ndash673 2001

[36] A F Suffredini G Fantuzzi R Badolato J J Oppenheim andN P OrsquoGrady ldquoNew insights into the biology of the acute phaseresponserdquo Journal of Clinical Immunology vol 19 no 4 pp 203ndash214 1999

[37] R A Feelders G Vreugdenhil A M Eggermont P A Kuiper-Kramer H G van Eijk and A J Swaak ldquoRegulation of ironmetabolism in the acute-phase response interferon gamma andtumour necrosis factor alpha induce hypoferraemia ferritinproduction and a decrease in circulating transferrin receptorsin cancer patientsrdquo European Journal of Clinical Investigationvol 28 no 27 pp 520ndash527 1998

[38] S Cherukuri R Potla J Sarkar S Nurko Z L Harris andP L Fox ldquoUnexpected role of ceruloplasmin in intestinal ironabsorptionrdquo Cell Metabolism vol 2 no 5 pp 309ndash319 2005

[39] B T PaulDHManz FMTorti and SV Torti ldquoMitochondriaand Iron current questionsrdquo Expert Review of Hematology vol10 no 1 pp 65ndash79 2017

[40] J D Mancias X Wang S P Gygi J W Harper and A CKimmelman ldquoQuantitative proteomics identifies NCOA4 asthe cargo receptor mediating ferritinophagyrdquo Nature vol 508no 7498 pp 105ndash109 2014

[41] TGanz ldquoSystemic iron homeostasisrdquoPhysiological Reviews vol93 no 4 pp 1721ndash1741 2013

[42] L T Goodnough ldquoIron deficiency syndromes and iron-restricted erythropoiesis (CME)rdquo Transfusion vol 52 no 7 pp1584ndash1592 2012

[43] WHO Serum Ferritin Concentrations forThe Assessment of IronStatus and Iron Deficiency in Populations Vitamin and Min-eral Nutrition Information System World Health OrganizationGeneva 2011

[44] T E Galesloot S H Vermeulen A J Geurts-Moespot et alldquoSerum hepcidin Reference ranges and biochemical correlatesin the general populationrdquo Blood vol 117 no 25 pp e218ndashe2252011

[45] I C Macdougall J Malyszko R C Hider and S S BansalldquoCurrent status of the measurement of blood hepcidin levels inchronic kidney diseaserdquoClinical Journal of the American Societyof Nephrology vol 5 no 9 pp 1681ndash1689 2010

[46] E A Jankowska J Malyszko H Ardehali et al ldquoIron status inpatients with chronic heart failurerdquoEuropeanHeart Journal vol34 no 11 pp 827ndash834 2013

[47] J Zaritsky B Young H-J Wang et al ldquoHepcidinmdasha potentialnovel biomarker for iron status in chronic kidney diseaserdquoClinical Journal of the American Society of Nephrology vol 4no 6 pp 1051ndash1056 2009

[48] I Mecklenburg D Reznik E Fasler-Kan J Drewe CBeglinger and P Hruz ldquoSerum hepcidin concentrations corre-late with ferritin in patients with inflammatory bowel diseaserdquoJournal of Crohnrsquos and Colitis vol 8 no 11 pp 1392ndash1397 2014

[49] P Oustamanolakis I E Koutroubakis I Messaritakis NMalliaraki A Sfiridaki and E A Kouroumalis ldquoSerum hep-cidin and prohepcidin concentrations in inflammatory boweldiseaserdquo European Journal of Gastroenterology amp Hepatologyvol 23 no 3 pp 262ndash268 2011

[50] M Nairz I Theurl D Wolf and G Weiss ldquoIron defi-ciency or anemia of inflammation Differential diagnosis andmechanisms of anemia of inflammationrdquo Wiener MedizinischeWochenschrift vol 166 no 13-14 pp 411ndash423 2016

[51] R Coffey and T Ganz ldquoIron homeostasis An anthropocentricperspectiverdquoThe Journal of Biological Chemistry vol 292 no 31pp 12727ndash12734 2017

[52] I De Domenico T Y Zhang C L Koening et al ldquoHepcidinmediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in micerdquoThe Journal of Clini-cal Investigation vol 120 no 7 pp 2395ndash2405 2010

[53] N Harada M Kanayama A Maruyama et al ldquoNrf2 reg-ulates ferroportin 1-mediated iron efflux and counteractslipopolysaccharide-induced ferroportin 1 mRNA suppressionin macrophagesrdquo Archives of Biochemistry and Biophysics vol508 no 1 pp 101ndash109 2011

[54] M J Borel S M Smith J Derr and J L Beard ldquoDay-to-dayvariation in iron-status indices in healthy men and womenrdquo


American Journal of Clinical Nutrition vol 54 no 4 pp 729ndash735 1991

[55] B A Ford D W Coyne C S Eby and M G Scott ldquoVariabilityof ferritin measurements in chronic kidney disease implica-tions for iron managementrdquo Kidney International vol 75 no1 pp 104ndash110 2009

[56] D Kamei K Tsuchiya H Miura K Nitta and T Akiba ldquoInter-method variability of ferritin and transferrin saturation mea-surement methods in patients on hemodialysisrdquo TherapeuticApheresis and Dialysis vol 21 no 1 pp 43ndash51 2017

[57] D B Van Wyck H Alcorn Jr and R Gupta ldquoAnalytical andbiological variation in measures of anemia and iron statusin patients treated with maintenance hemodialysisrdquo AmericanJournal of Kidney Diseases vol 56 no 3 pp 540ndash546 2010

[58] J C Dale M F Burritt and A R Zinsmeister ldquoDiurnalvariation of serum iron iron-binding capacity transferrinsaturation and ferritin levelsrdquo American Journal of ClinicalPathology vol 117 no 5 pp 802ndash808 2002

[59] M Hoppe L Hulthen and L Hallberg ldquoSerum iron concentra-tion as a tool tomeasure relative iron absorption from elementaliron powders in manrdquo Scandinavian Journal of Clinical ampLaboratory Investigation vol 63 no 7-8 pp 489ndash496 2003

[60] L Gotloib D Silverberg R Fudin and A Shostak ldquoIrondeficiency is a common cause of anemia in chronic kidneydisease and can often be corrected with intravenous ironrdquoJournal of Nephrology vol 19 no 2 pp 161ndash167 2006

[61] F Locatelli P Barany A Covic et al ldquoKidney Disease Improv-ing Global Outcomes guidelines on anaemia management inchronic kidney disease a European Renal Best Practice positionstatementrdquo Nephrology Dialysis Transplantation vol 28 no 6pp 1346ndash1359 2013

[62] T B Drueke and P S Parfrey ldquoSummary of the KDIGOguideline on anemia and comment Reading between the(guide)line(s)rdquoKidney International vol 82 no 9 pp 952ndash9602012

[63] A U Dignass C Gasche D Bettenworth et al ldquoEuropeanconsensus on the diagnosis and management of iron deficiencyand anaemia in inflammatory bowel diseasesrdquo Journal of Crohnrsquosand Colitis vol 9 no 3 pp 211ndash222 2015

[64] J Stein F Hartmann and A U Dignass ldquoDiagnosis andmanagement of iron deficiency anemia in patients with IBDrdquoNature Reviews Gastroenterology ampHepatology vol 7 no 11 pp599ndash610 2010

[65] D W Thomas R F Hinchliffe C Briggs I C Macdougall TLittlewood and I Cavill ldquoGuideline for the laboratory diagno-sis of functional iron deficiencyrdquoBritish Journal ofHaematologyvol 161 no 5 pp 639ndash648 2013

[66] National Institute for Health and Care Excellence (NICE)ldquoNICE guideline NG8 Chronic kidney disease managinganaemiardquo Primary Health Care 2015

[67] A E Gaweda ldquoMarkers of iron status in chronic kidneydiseaserdquo Hemodialysis International vol 21 pp S21ndashS27 2017

[68] M Munoz A G Acheson M Auerbach et al ldquoInternationalconsensus statement on the peri-operative management ofanaemia and iron deficiencyrdquoAnaesthesia vol 72 no 7 pp 233ndash247 2017

[69] P Cullen J Soffker M Hopfl et al ldquoHypochromic red cells andreticulocyte haemglobin content as markers of iron-deficienterythropoiesis in patients undergoing chronic haemodialysisrdquoNephrology Dialysis Transplantation vol 14 no 3 pp 659ndash6651999

[70] S Fishbane C Galgano R C Langley Jr W Canfield and J KMaesaka ldquoReticulocyte hemoglobin content in the evaluationof iron status of hemodialysis patientsrdquo Kidney Internationalvol 52 no 1 pp 217ndash222 1997

[71] N Mittman R Sreedhara R Mushnick et al ldquoReticulocytehemoglobin content predicts functional iron deficiency inhemodialysis patients receiving rHuEPOrdquo American Journal ofKidney Diseases vol 30 no 6 pp 912ndash922 1997

[72] GWeiss and L T Goodnough ldquoAnemia of chronic diseaserdquoTheNew England Journal of Medicine vol 352 no 10 pp 1011ndash10232005

[73] I Theurl E Aigner M Theurl et al ldquoRegulation of ironhomeostasis in anemia of chronic disease and iron deficiencyanemia diagnostic and therapeutic implicationsrdquo Blood vol113 no 21 pp 5277ndash5286 2009

[74] C A Northrop-Clewes ldquoInterpreting indicators of iron statusduring an acute phase response - Lessons from malaria andhuman immunodeficiency virusrdquo Annals of Clinical Biochem-istry vol 45 no 1 pp 18ndash32 2008

[75] Y Beguin ldquoSoluble transferrin receptor for the evaluation oferythropoiesis and iron statusrdquo Clinica Chimica Acta vol 329no 1-2 pp 9ndash22 2003

[76] K Punnonen K Irjala and A Rajamaki ldquoSerum transferrinreceptor and its ratio to serum ferritin in the diagnosis of irondeficiencyrdquo Blood vol 89 no 3 pp 1052ndash1057 1997

[77] B S Skikne ldquoSerum transferrin receptorrdquo American Journal ofHematology vol 83 no 11 pp 872ndash875 2008

[78] S M Namaste F Rohner and J Huang ldquoAdjusting ferritin con-centrations for inflammation Biomarkers Reflecting Inflam-mation and Nutritional Determinants of Anemia (BRINDA)projectrdquo American Journal of Clinical Nutrition vol 106 Suppl1 pp 359Sndash371S 2017

[79] N C Andrews ldquoDisorders of iron metabolismrdquo The NewEngland Journal of Medicine vol 341 no 26 pp 1986ndash19951999

[80] K Mavromatidis C Fytil P Kynigopoulou T Fragia and KSombolos ldquoSerum ferritin levels are increased in patients withacute renal failurerdquo Clinical Nephrology vol 49 no 5 pp 296ndash298 1998

[81] R J Salgia and K Brown ldquoDiagnosis and management ofhereditary hemochromatosisrdquo Clinics in Liver Disease vol 19no 1 pp 187ndash198 2015

[82] L Zhao X Zhang Y Shen X Fang Y Wang and F WangldquoObesity and iron deficiency a quantitative meta-analysisrdquoObesity Reviews vol 16 no 12 pp 1081ndash1093 2015

[83] JMMoreno-NavarreteMMoreno J Puig et al ldquoHepatic ironcontent is independently associated with serum hepcidin levelsin subjects with obesityrdquo Clinical Nutrition vol 36 no 5 pp1434ndash1439 2017

[84] A C Cepeda-Lopez J Allende-Labastida A Melse-Boonstraet al ldquoThe effects of fat loss after bariatric surgery on inflam-mation serum hepcidin and iron absorption A prospective6-mo iron stable isotope studyrdquo American Journal of ClinicalNutrition vol 104 no 4 pp 1030ndash1038 2016

[85] A C Cepeda-Lopez A Melse-Boonstra M B Zimmermannand I Herter-Aeberli ldquoIn overweight and obese women dietaryiron absorption is reduced and the enhancement of ironabsorption by ascorbic acid is one-half that in normal-weightwomenrdquo American Journal of Clinical Nutrition vol 102 no 6pp 1389ndash1397 2015


[86] J M Moreno-Navarrete G Blasco G Xifra et al ldquoObesityis associated with gene expression and imaging markers ofiron accumulation in skeletal musclerdquo The Journal of ClinicalEndocrinologyampMetabolism vol 101 no 3 pp 1282ndash1289 2016

[87] S J Fairweather-Tait A AWawer R Gillings A Jennings andP K Myint ldquoIron status in the elderlyrdquo Mechanisms of Ageingand Development vol 136-137 pp 22ndash28 2014

[88] L Ferrucci A Corsi F Lauretani et al ldquoThe origins of age-related proinflammatory staterdquo Blood vol 105 no 6 pp 2294ndash2299 2005

[89] R A Daynes B A Araneo W B Ershler C Maloney G-ZLi and S-Y Ryu ldquoAltered regulation of IL-6 production withnormal aging possible linkage to the age-associated declinein dehydroepiandrosterone and its sulfated derivativerdquo TheJournal of Immunology vol 150 no 12 pp 5219ndash5230 1993

[90] P Sebastiani B Thyagarajan F Sun et al ldquoAge and sexdistributions of age-related biomarker values in healthy olderadults from the long life family studyrdquo Journal of the AmericanGeriatrics Society vol 64 no 11 pp e189ndashe194 2016

[91] T L Holyoake D J Stott P J McKay A Hendry J B MacDon-ald and N P Lucie ldquoUse of plasma ferritin concentration todiagnose iron deficiency in elderly patientsrdquo Journal of ClinicalPathology vol 46 no 9 pp 857ndash860 1993

[92] A A Alkhateeb and J R Connor ldquoThe significance of ferritinin cancer Anti-oxidation inflammation and tumorigenesisrdquoBiochimica et Biophysica Acta (BBA) - Reviews on Cancer vol1836 no 2 pp 245ndash254 2013

[93] M Victor H Evgeniy T Gergana et al ldquoSerum hepcidin levelsin multiple myelomardquo Clinical Laboratory vol 63 no 7 pp1273ndash1277 2017

[94] S Mei H Wang R Fu et al ldquoHepcidin and GDF15 in anemiaof multiple myelomardquo International Journal of Hematology vol100 no 3 pp 266ndash273 2014

[95] M C Tisi V Bozzoli M Giachelia et al ldquoAnemia in diffuselarge B-cell non-Hodgkin lymphomaThe role of interleukin-6hepcidin and erythropoietinrdquo Leukemia amp Lymphoma vol 55no 2 pp 270ndash275 2014

[96] S Milic I Mikolasevic L Orlic et al ldquoThe role of iron and ironoverload in chronic liver diseaserdquoMedical Science Monitor vol22 pp 2144ndash2151 2016

[97] K V Kowdley P Belt L A Wilson et al ldquoSerum ferritin isan independent predictor of histologic severity and advancedfibrosis in patients with nonalcoholic fatty liver diseaserdquo Hepa-tology vol 55 no 1 pp 77ndash85 2012

[98] E Aigner I Theurl M Theurl et al ldquoPathways underlyingiron accumulation in human nonalcoholic fatty liver diseaserdquoAmerican Journal of Clinical Nutrition vol 87 no 5 pp 374ndash378 2008

[99] C Datz E Muller and E Aigner ldquoIron overload and non-alcoholic fatty liver diseaserdquo Minerva Endocrinologica vol 42no 2 pp 173ndash183 2017

[100] C-H Guo P-C Chen and W-S Ko ldquoStatus of essential traceminerals and oxidative stress in viral hepatitis C patients withnonalcoholic fatty liver diseaserdquo International Journal ofMedicalSciences vol 10 no 6 pp 730ndash737 2013

[101] B J Kim B S Kim and J H Kang ldquoThe association betweenserum ferritin level microalbuminuria and non-alcoholic fattyliver disease in non-diabetic non-hypertensive menrdquo Clinicaland Experimental Hypertension vol 36 no 6 pp 380ndash3852014

[102] J Stein S Connor G Virgin D E H Ong and L PereyraldquoAnemia and iron deficiency in gastrointestinal and liver con-ditionsrdquo World Journal of Gastroenterology vol 22 no 35 pp7908ndash7925 2016

[103] M Auerbach and J W Adamson ldquoHow we diagnose and treatiron deficiency anemiardquo American Journal of Hematology vol91 no 1 pp 31ndash38 2016

[104] J J V McMurray S Adamopoulos S D Anker et al ldquoESCguidelines for the diagnosis and treatment of acute and chronicheart failure 2012 the task force for the diagnosis and treatmentof acute and chronic heart failure 2012 of the european societyof cardiology Developed in collaboration with the heart FailureAssociation (HFA) of the ESCrdquo European Heart Journal vol 14no 8 pp 803ndash869 2012

[105] A Qaseem L L Humphrey N Fitterman M Starkey and PShekelle ldquoTreatment of anemia in patients with heart diseaseA clinical practice guideline from the American College ofPhysiciansrdquoAnnals of InternalMedicine vol 159 no 11 pp 770ndash779 2013

[106] J Stein A Aksan K Farrag A Dignass and H H RadekeldquoManagement of inflammatory bowel disease-related anemiaand iron deficiency with specific reference to the role ofintravenous iron in current practicerdquo Expert Opinion on Phar-macotherapy vol 18 no 16 pp 1721ndash1737 2017

[107] G D Lewis R Malhotra A F Hernandez et al ldquoEffect of oraliron repletion on exercise capacityrdquo Journal of the AmericanMedical Association vol 317 no 9 pp 1958-1566 2017

[108] W Reinisch M Staun R K Tandon et al ldquoA randomizedopen-label non-inferiority study of intravenous iron isomal-toside 1000 (Monofer) compared with oral iron for treatmentof anemia in IBD (PROCEED)rdquo American Journal of Gastroen-terology vol 108 no 12 pp 1877ndash1888 2013

[109] B Froessler C Cocchiaro K Saadat-Gilani N Hodyl andG Dekker ldquoIntravenous iron sucrose versus oral iron ferroussulfate for antenatal and postpartum iron deficiency anemia arandomized trialrdquo The Journal of Maternal-Fetal and NeonatalMedicine vol 26 no 7 pp 654ndash659 2013

[110] P K Kochhar A Kaundal and P Ghosh ldquoIntravenous ironsucrose versus oral iron in treatment of iron deficiency anemiain pregnancy A randomized clinical trialrdquo Journal of Obstetricsand Gynaecology Research vol 39 no 2 pp 504ndash510 2013

[111] W Y Qunibi CMartinezM Smith J Benjamin AMangioneand S D Roger ldquoA randomized controlled trial comparingintravenous ferric carboxymaltose with oral iron for treatmentof iron deficiency anaemia of non-dialysis- dependent chronickidney disease patientsrdquo Nephrology Dialysis Transplantation vol 26 no 5 pp 1599ndash1607 2011

Stem Cells International

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BioMed Research International

OncologyJournal of



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Hindawi Publishing Corporation httpwwwhindawicom Volume 2013Hindawiwwwhindawicom

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Evidence-Based Complementary andAlternative Medicine

Volume 2018Hindawiwwwhindawicom

Submit your manuscripts atwwwhindawicom


Table 1 Causes prevalence and clinical consequences of iron deficiency in inflammatory conditions

Disease Key causes of iron deficiency[2 4 5] Estimated prevalence Potential clinical

consequences [4]

Chronic heart failure

Inflammatory stateLoss of appetitepoor

nutritionReduced iron uptake from GI

tract due to edema orcommon concomitant

medications (eg histamine-2receptor antagonists

calcium-based phosphatebinders antiplatelet therapiesand proton pump inhibitors)

sim50 (range 37ndash63)[11ndash14]a

Fatigue and reducedexercise capacitywork capacity and

quality of lifeAssociated with

increasedhospitalization and

mortality

Chronic kidneydisease

Inflammatory stateReduced hepcidin excretion

by the kidneysBlood loss from dialysis

sessionsChronic intestinal bleeding(eg platelet dysfunction)Frequent phlebotomy

Acute expansion of erythroidmass under ESA therapy

Poor appetite

24ndash85 (highestincidence with moresevere CKD) [15ndash17]b

Iron-deficiencyanemia associated

with fatigueincreased mortalityand progression toend-stage renal

disease

Inflammatory boweldisease

Inflammatory stateChronic blood loss from the

GI tractPoor appetite

Reduced uptake of iron fromthe GI tract

Bowel resection

sim45 (range 43ndash55)[18ndash20]c

Fatigue exhaustionreduced exercise

capacity and qualityof life

CKD chronic kidney disease ESA erythropoietin-stimulating agent GI gastrointestinal aIron deficiency defined as serum ferritinlt 100120583gL or 100ndash300120583gL[11ndash13] (or lt800120583gL [14]) with transferrin saturation (TSAT) lt 20 bIron deficiency defined as serum ferritin lt 100120583gL or TSAT lt 20 cIron deficiencydefined as serum ferritin lt 30120583gL or TSAT lt 16 [18 19] or lt20 [20] or as serum ferritin lt 100120583gL if C-reactive protein (CRP) gt 5mgL [20] or gt10mgL[18]

gross gastrointestinal blood loss [9] Blood loss from frequentblood sampling from gastrointestinal bleeding in IBD orduring dialysis in CKD patients can also contribute Inaddition to these patient-specific etiologies CHF CKD andIBD share the common effect of an ongoing inflammatorystimulus In these chronic conditions high hepcidin levelscan restrict the uptake of dietary iron and over time lead toiron deficiency with reduced availability of iron for essentialcellular functions [10] (see ldquoTheEffect of Inflammation on IronHomeostasisrdquo below)

All too often investigation and treatment of iron defi-ciency are only triggered by the onset of (iron deficiency)anemia at which point iron deficiency has become severeenough to exhaust iron stores and restrict erythropoiesisHowever iron has multiple biochemical and physiologicalfunctions other than erythropoiesis [21] and iron deficiencyexerts various adverse effects that may arise either before orafter the onset of anemia As well as being critical for ery-thropoiesis iron is essential for the function of key enzymesin the mitochondrial electron transport system [22] whichmay explain the fatigue that can develop in nonanemic iron-deficient individuals Iron deficiency has also been associatedwith poor immune function [23] There is a clear need for

systematic diagnosis and correction of iron deficiency ininflammatory conditions

In normal circumstances iron status can usually beassessed adequately by measuring serum levels of ferritinIn the presence of proinflammatory stimuli however thediagnosis of iron deficiency is more complex Understandingthe nature of serum ferritin and particularly how levelsof serum ferritin are influenced by inflammation is key tosuccessful diagnosis in this context

2 Ferritin The Ubiquitous IronStorage Protein

Intracellular ferritin is a complex made up of two typesof subunit termed H (heavy chain) and L (light chain)[24] Twenty-four subunits combine to form a shell-likemolecule that incorporates a cavity that can store up to4500 iron atoms [25 26] The H chains of ferritin haveferroxidase activity and convert Fe(II) to Fe(III) as the ironis internalized within the ferritin complex [27] Fe(III) issequestered within the mineral core of ferritin in the formof ferric oxyhydroxide phosphate [25] Concentration ofhigh amounts of iron in this unreactive form within ferritin
















Red bloodcell Heme

Fe(II)

Fe(II)

Ferritin

Ferritinophagy

Fe(III)Transferrin

Fe(III)

Ferroportin

Lysosome

Hemeoxygenase

Excessiron

Hemeoxygenase


Liver

Hepcidin

Spleen

Duodenum



splenicmacrophages


duodenalenterocytes


cells

Transferrin-bound

serum iron

(a)

LiverIL-6

Inflammation

Hepcidin

Spleen

Duodenum

Macrophage

Transferrin-bound

serum iron


splenicmacrophages




cells

(b)



































HYPO uarr uarr uarr





















10 Conclusions







Acknowledgments


References
























































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of


































Red bloodcell Heme

Fe(II)

Fe(II)

Ferritin

Ferritinophagy

Fe(III)Transferrin

Fe(III)

Ferroportin

Lysosome

Hemeoxygenase

Excessiron

Hemeoxygenase


Liver

Hepcidin

Spleen

Duodenum



splenicmacrophages


duodenalenterocytes


cells

Transferrin-bound

serum iron

(a)

LiverIL-6

Inflammation

Hepcidin

Spleen

Duodenum

Macrophage

Transferrin-bound

serum iron


splenicmacrophages




cells

(b)



































HYPO uarr uarr uarr





















10 Conclusions







Acknowledgments


References
























































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of




















Red bloodcell Heme

Fe(II)

Fe(II)

Ferritin

Ferritinophagy

Fe(III)Transferrin

Fe(III)

Ferroportin

Lysosome

Hemeoxygenase

Excessiron

Hemeoxygenase


Liver

Hepcidin

Spleen

Duodenum



splenicmacrophages


duodenalenterocytes


cells

Transferrin-bound

serum iron

(a)

LiverIL-6

Inflammation

Hepcidin

Spleen

Duodenum

Macrophage

Transferrin-bound

serum iron


splenicmacrophages




cells

(b)



































HYPO uarr uarr uarr





















10 Conclusions







Acknowledgments


References
























































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
















































HYPO uarr uarr uarr





















10 Conclusions







Acknowledgments


References
























































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



























HYPO uarr uarr uarr





















10 Conclusions







Acknowledgments


References
























































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






























10 Conclusions







Acknowledgments


References
























































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of
























Acknowledgments


References
























































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of






















































































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















































































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of


















































of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of























of




Disease Markers



OncologyJournal of





PPAR Research



Volume 2018


Journal of

ObesityJournal of



















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