Ischemia-modified albumin as a possible marker of oxidative stress in patients with telogen effluvium,

Anais

Brasileiros

de

Dermatologia

www.anaisdedermatologia.org.br

INVESTIGATION

Ischemia-modified

albumin

as

a

possible

marker

of

oxidative

stress

in

patients

with

telogen

effluvium

夽,夽夽

Unsal

Savci

_,

_Engin

_Senel

_,

_Aynure

_Oztekin

_,

_Mustafa

_Sungur

_,

Ozcan

Erel

_,

_Salim

_Neselioglu

a_{DepartmentofMedicalMicrobiology,ErolOlcokEducationandResearchHospital,HititUniversity,C¸orum,Turkey} b_{DepartmentofDermatology,FacultyofMedicine,HititUniversity,C¸orum,Turkey}

c_{DepartmentofUrology,ErolOlcokEducationandResearchHospital,HititUniversity,C¸orum,Turkey} d_{DepartmentofBiochemistry,AtaturkTrainingandResearchHospital,Ankara,Turkey}

Received29May2019;accepted10January2020 Availableonline6May2020

KEYWORDS

Alopecia; Inflammation; Oxidativestress

Abstract

Background: Telogeneffluviumisthemostcommonformofnon-scarringalopeciacharacterized bydiffusehairloss.Ischemia-modifiedalbuminisamarkerofoxidativestressandinflammation.

Objective: Theaimofthisstudywastocomparethelevelsofischemia-modifiedalbuminof telogeneffluviumpatientswithhealthycontrols.

Methods: Ninety-one patients diagnosed with telogen effluviumand 35 healthy volunteers wereincludedinthestudy.Serumischemia-modifiedalbuminlevelwasdeterminedbya fast-colorimetricmethod,andalbumincobaltbindingtest.Theresultswereevaluatedstatistically.

Results: Therewasnostatisticallysignificantdifferencebetweentheserumalbuminvaluesof patientandcontrolgroups (p=0.739).Serumischemia-modifiedalbuminvalueswere signifi-cantlyhigherinthepatientswithtelogeneffluviumthanhealthycontrols(p<0.001).

Studylimitations: Body massindex values of the patient and control groups could not be calculated.

Conclusions: Tothebestoftheauthors’knowledge,thisisthefirstclinicalstudytoinvestigate theroleofoxidativestress inthepathogenesisoftelogeneffluviumusingischemia-modified albuminasabiomarker.Basedontheresultsofthepresentstudy,itcanbeconsideredthat oxidative stressplaysanimportantrole inthepathogenesisoftelogeneffluvium.Thereisa

夽 _{Howtocitethisarticle:SavciU,SenelE,OztekinA,SungurM,ErelO,NeseliogluS.Ischemiamodifiedalbuminasapossiblemarkerof}

oxidativestressinpatientswithtelogeneffluvium.AnBrasDermatol.2020;95:447---51.

夽夽_{StudyconductedattheErolOlcokEducationandResearchHospital,HititUniversity,C¸orum,Turkey.}

∗_{Correspondingauthor.}

E-mail:[email protected](U.Savci).

https://doi.org/10.1016/j.abd.2020.01.005

0365-0596/©2020SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.ThisisanopenaccessarticleundertheCC

needforfurtherstudiestosupporttheresultsofthisstudy,todemonstratethepossibleeffects ofoxidativestress,andtoinvestigatetheotheroxidativestressmarkersinthepathogenesisof telogeneffluvium.

©2020SociedadeBrasileiradeDermatologia.PublishedbyElsevierEspa˜na,S.L.U.Thisisan openaccessarticleundertheCCBYlicense(http://creativecommons.org/licenses/by/4.0/).

Introduction

Telogeneffluvium(TE)isatypeofnonscarringalopecia cha-racterized by often acute and diffuse hair shedding and caused or induced by various acute and chronic diseases andphysiologicalstressfulevents.Thediseaseisoneofthe mostcommon causes of diffuse hair loss. Pathogenesis of thedisorderisquiteheterogenous.1_{Headingtonattempted}

toclassifythediseaseandsuggestedfivedifferent pathoge-nies:(1)immediateanagenrelease,(2)immediatetelogen release, (3) delayed anagen release, (4) delayed telogen release,and(5)shortenedanagen.2

Each hair follicle has three cyclic phases: anagen (growth),catagen(regressionleadingtoapoptosis),and tel-ogen(resting). Approximately 100,000 hairs arefound on thescalp, of which 10---15% are in the telogen phaseand 85---90%intheanagenphase.Onaverage,theanagenphase laststwoto sixyears,the catagenphaselasts fourtosix weeks,andtelogenphaselaststhreetofourmonthsinthe scalp.3 _{Theend oftheanagenphaseandtheonsetofthe}

catagen/telogen phaseare associated with the biological clock, which is a highly complex phenomenon that arises onamolecularbasisinthehumanbody.Variousmetabolic changesduetopregnancy,malnutrition,andvarious stress-ful conditions may affect the biological clock in the hair folliclesandabnormallymanyhairfolliclescanenterthe tel-ogenphasesimultaneously.Ifthegrowthofasignificantpart ofthehairintheanagenphasestopsearlyduetotheeffect ofanystimulation,itentersthecatagenphase,followedby telogenphase,resultingintheformationofTE.4_The

patho-genesisofTEisunclearandmanytriggeringconditionsmay play rolein the pathogenesis, such asenvironmental and metabolic factors, including hormones, toxins, cytokines, nutrients,vitamins,andenergydeficiencies.5

Oxidative stress has been shown to play a key role in thesedisordersasinmanydiseases.Presenceofoxidative stresshasbeen demonstratedin manydermatological dis-easessuchasseborrheicdermatitis, vitiligo,skin cancers, lichen planus, atopic dermatitis, acne vulgaris, psoriasis, andpemphigusvulgaris.6---12

Various biochemical markers have been detected in oxidativestressandinflammationsofar.Ischemia-modified albumin(IMA)isoneofthesemarkers.Thismarkerhasbeen usedfor thedetectionof myocardial ischemia.IMA levels havebeenreportedtoincreaseinvascularendothelialcell dysfunction and oxidative stress-related diseases. During ischemia,themetalbindingcapacityofalbumindecreases duetofreeradicaldamageattheendoftheaminoterminus (N-terminus)ofthemetal-bindingpart.13 _Thisnew,

chemi-callyalteredordegradedalbumincausedbytissueischemia iscalledIMAandisusedasasensitivebiochemicalmarker ofischemiaandoxidativestress.14

Inrecentyears,highlevelsofIMAhave beenindicated tobe associatedwithvarious diseases basedonoxidative stress.15_{InalimitednumberofstudiesinvestigatingIMA}

lev-elsindermatologicaldiseases,highlevelsofIMAhavebeen reportedinseveraldermatologicaldiseasessuchasvitiligo, psoriasis,andBehc¸et’s.16---18_{Increasedmedianandadjusted}

IMAlevelsweredetectedinalopeciaareatapatientsinthe liteature.19 _{Ina recent study,it wasnoted thatoxidative}

stress is closely associatedwith TEpathogenesis.20 _{In the}

medicalliteraturetherearenostudiesinvestigatingIMA lev-elsasoxidativestressbiomarkersinpatientswithTE.Inthe presentstudy,itwashypothesizedthatthepathogenesisof TEmightbeassociatedwithIMA.

Theaim ofthis studywastocompare IMAlevelsof TE patients with the healthy control group. To best of the authors’knowledge,therehavebeennostudies investigat-ingoxidant---antioxidantbalanceandoxidativestressinthe patientswithTEinthemedicalliterature.Thisrepresents the firstclinical studyevaluating oxidativestress and IMA levelsinthepatientswithTE.

Methods

Thisstudyincluded91patients(83females,8males)older than 18yearsadmitted tothedermatology clinic withTE diagnosisand35healthyvolunteers(31females,4males). The current study wasapprovedby the EthicsCommittee of Tokat Gaziosmanpas¸a Medicine Faculty under number 19-KAEK-002, carried outin accordance with theHelsinki Declaration. Written informedconsentwasobtained from allpatientsandhealthyvolunteers.

The diagnosis wasmade by detailedphysical examina-tion,patienthistory(morethan100hairslostperday),and positivehairpulltest.Thehairpulltestisstronglypositive in TE andis performed by grasping 40---60 scalphair with thumbandindexfingerandpullinggently.Ifmorethantwo tothreehairsareremovedwithtraction,thetestshouldbe consideredaspositive.

Othercausesofhairlosssuchastrichotillomania, alope-ciaareata,cicatricialalopecia,andandrogeneticalopecia wereruledoutinthepatientsincludedandallpatientswith an additionalhair disorderwereexcluded fromthestudy. The controlgroup comprisedvolunteers whohadno com-plaintsofhair lossandwiththesameexclusioncriteriaas theTEpatientgroup.

The exclusion criteria for patient and healthy control groupswereasfollows:presenceofsystemicdisease, car-diovascular disease, history of surgery, low calorie diet, severe weightloss,activesmoking, ironsupplementation, presenceof menstrualirregularities,pregnancy,lactation, andhairlosscausedbydruguse.Allpatientswithpossible conditionsthatwerelikelytoalterIMAlevelwereexcluded.

Table1 Demographiccharacteristicsofpatientandcontrolgroups,andserumalbuminandIMAlevels.

Parameter Control(n=35) Patients(n=91) p

Age(mean±SD,years) 32.08±11.60 31.64±12.86 p=0.867

Gender(male/female) 4/31 8/83 p=0.736

Serumalbumin(mean_±SD,g/L) 4.08_±0.11 4.08_±0.10 p=0.739

IMA(mean±SD,g/L) 0.50±0.09 0.77±0.14 p<0.001a

IMA,ischemia-modifiedalbumin;SD,standarddeviation.

a _{Statisticallysignificant.}

Venousblood sampleswere collectedafter at least8hof fastingfrom the patientand controlgroups. The samples werecentrifugedat1500gfor10minandtheserumsamples wereseparated.Separatedserumsampleswereplancedin Eppendorftubesandstoredat−80◦C.

The IMA level was measured using the albumin cobalt bindingtest,afast-colorimetricmethoddevelopedby Bar-Or et al.21 _{The method is based on the reduction of the}

abilityof humanserumalbumin tobindcobaltions(Co2+₎

depending on ischemia. As a result of the ischemic pro-cess,modified albuminwasmuchlessboundtoCo(II)and theexcess(unbound)Co2+ _{amountformed acomplexwith}

dithiothreitol, and this complex was measured at 450nm spectrophotometrically.Plasmaalbuminlevelwasmeasured intheautoanalyzerbyusingthebromocresolgreenmethod (ArchitectPlusC8000;Abbott---UnitedStates).

ThestatisticalanalysiswasperformedbyusingSPSS(SPSS v.23.0forWindows---SPSSInc.,Chicago,IL,UnitedStates; licensedforHititUniversity).Shapiro---Wilktestwasusedto checkthenormalityassumptionforthedistributionofthe quantitativevariables(serumalbumin,IMA).Foralltested variables, the normality assumption could be considered valid.Student’st-testforindependentsamplesandFisher’s exacttestwereperformedtodetectpossibledifferencesof ageandgenderbetweenthepatientandcontrolgroups.A

p-value<0.05wasconsideredstatisticallysignificant.

Results

Themeanagewas31.64±12.86yearsforthepatientgroup and 32.08±11.60 years for the controls. There was no statistically significant difference between the groups in termsofageandsex(p=0.867andp=0.736,respectively). There was no statistically significant difference between thetwogroupsinterms ofalbuminvalues(p=0.739).The meanIMAvaluewassignificantlyhigherinthepatientgroup (0.77±0.14g/L) than the control group (0.50±0.09g/L). Therewerestatisticallysignificantdifferencesbetweentwo groupsIMAvalues(p<0.001).Demographiccharacteristics, albumin,andIMAvaluesandstatisticalvaluesofthegroups areshownintable1.

Discussion

TEisadiseasecharacterizedbythinningorsheddingofthe hairinresponsetotheearlyentryofthehairintothetelogen phase.Thedisorderwasfirstdescribedin1961byKligman. DiagnosticpropertiesofTEarethinningoftheaffectedhair anddiffusehairlosswithastronglypositivehairpullteston

ascalpthatlooksnormal.AtriggeringfactorcausingTEis oftenfoundinthepatient’shistory.1

IMA was accepted asa marker of myocardial ischemia bytheFoodandDrugAdministration.As aresultof expo-suretoreactiveoxygenspeciesinthecaseofischemia,the metal(cobalt,copper, zinc)bindingcapacityofalbuminis decreased.15 _{This marker is not only specific for}

myocar-dialinjuryandischemia.IMAlevelshavebeenreportedin manydiseasessuchassepsis,cancer,diabetes,chronicliver disease,andasthma.22---25

IMAhasbeendescribedasabiomarkerofoxidativestress andextensivelyinvestigatedrecently.21 _{The susceptibility,}

specificity, capacity, and positive and negative predictive values of IMA were detected higher than other studied biomarkers.There have been no studies in the literature investigating oxidative stress in patients with TE. To the bestoftheauthors’knowledge,alimitednumberofstudies havebeenconductedevaluatingIMAlevelsindermatological diseases.

Atas¸etal.investigatedtheimportanceofoxidativestress in the pathogenesis of vitiligo by measuring the level of IMA; in their study, IMA levels were found to be signifi-cantlyhigher inthe patientgroup than the controlgroup (p<0.0001).16

Ozdemiretal.reportedthatIMAlevelswere significan-tly higher in patients withpsoriasis comparedto healthy controls.TheynotedthatIMAcouldbeproducedasan adap-tiveresponsetochronichypoxiaandoxidativestress,which is responsible for the systemic inflammation in psoriasis, andthatoxidativestresshasanimportanceinthe develop-mentofpsoriasis.17_{Inanotherstudy,Ommaetal.evaluated}

theroleofIMAasabiomarkerinBehc¸et’sdiseaseactivity. Inthisstudy,serumIMA levelsweresignificantlyhigherin Behc¸et’sdiseasethanhealthyvolunteers(p<0.001).18_Like

theresultsofpreviousdermatologicaldiseasesreportedin theliterature,thepresentstudyfoundthatserumIMA lev-elswerestatisticallyhigherinTE patientsthaninhealthy controls(p<0.001).Previousstudiesandtheresultsofthe presentstudymaysupporttherelationshipbetween oxida-tive stress and the pathogenesis of these dermatological diseases.

Itishypothesizedthatthescalpskinmaybechronically exposedtobothendogenousandenvironmentalpro-oxidant agents,leadingtotheformationofreactiveoxygenspecies fromdamagetocellularcomponentssuchasnucleicacids, proteins, and cell membrane lipids, and that this may resultindeteriorationoftheantioxidant/oxidantbalance. Inaddition,insufficientantioxidantdefenseandexcessive productionoffreeradicalsmaycontributetotheformation ofoxidativestress.26_{Itisimportanttoemphasizethatthere}

isanincreaseinIMAlevelsincasesofhypoxia,acidosis,and tissuedamagecausedbyfreeradicals.17 _{IMAlevelsmaybe}

higherinTEpatientsasincreasedoxygenradicalsaffectthe structureofalbumin.Thelimitationofthepresentstudywas thatbodymass indexvaluesofpatientandcontrolgroups couldnotbecalculated.

Conclusions

Basedontheresultsofthisstudy,oxidativestressmayplay animportantroleinthepathogenesisofTE.Thisisthefirst clinicalstudy toinvestigatetheroleof oxidative stressin thepathogenesisofTEusingIMAasabiomarker.Inaddition, thisstudymayprovidesignificantevidencethatantioxidant therapywouldbeusefulinTE.Furtherstudiesareneededto supporttheresultsofthisstudy,todemonstratethe proba-bleeffectsofoxidativestress,andtoinvestigatetheother oxidativestressmarkersinthepathogenesisofTE.

Financial

support

Authors’

contributions

UnsalSavci:Statisticalanalysis;approvalofthefinalversion of themanuscript; conception and planningof the study; drafting andediting of the manuscript; collection, analy-sis,andinterpretationofdata;intellectualparticipationin thepropaedeuticand/ortherapeuticconductofthestudied cases;criticalreviewoftheliterature.

EnginSenel:Conceptionandplanningofthestudy; col-lection,analysis,andinterpretationofdata;criticalreview oftheliterature;criticalreviewofthemanuscript.

Aynure Oztekin:Conceptionand planningof thestudy; collection,analysis, andinterpretationof data; participa-tioninthestudydesign;criticalreviewoftheliterature.

MustafaSungur:Statisticalanalysis;draftingandediting ofthemanuscript.

OzcanErel:Conceptionandplanningofthestudy; draft-ingandeditingofthemanuscript;participationinthestudy design.

SalimNeselioglu:Conceptionandplanningofthestudy; participationinthestudydesign;criticalreviewofthe lit-erature.

Conflicts

of

interest

References

1.ReboraA. Proposing asimplerclassificationof telogen efflu-vium.SkinAppendageDisord.2016;2:35---8.

2.HeadingtonJT. Telogeneffluvium.Newconceptsandreview. ArchDermatol.1993;129:356---63.

3.Grover C, Khurana A. Telogen efuvium. Indian J Dermatol VenereolLeprol.2013;79:591---603.

4.Malkud S. Telogen effluvium: a review. J Clin Diagn Res. 2015;9:1---3.

5.TrüebRM.Telogeneffluvium:isthereaneedforanew classifi-cation?SkinAppendageDisord.2016;2:39---44.

6.OzturkP,AricanO,BelgeKurutasE,KarakasT,KabakciB. Oxida-tivestress inpatientswithscalp seborrheicdermatitis.Acta DermatovenerolCroat.2013;21:80---5.

7.AkogluG,EmreS,MetinA,AkbasA,YorulmazA,IsikogluS,etal. Evaluationoftotaloxidantandantioxidantstatusinlocalized andgeneralizedvitiligo.ClinExpDermatol.2013;38:701---6.

8.SanderCS,HammF,ElsnerP,ThieleJJ.Oxidativestressin malig-nantmelanomaandnon-melanomaskincancer.BrJDermatol. 2003;148:913---22.

9.SapuntsovaSG, Lebed’ko OA, Shchetkina MV, Fleyshman MY, KozulinEA,Timoshin SS.Statusoffree-radicaloxidationand proliferationprocessesinpatientswithatopicdermatitisand lichenplanus.BullExpBiolMed.2011;150:690---2.

10.Grange PA, Weill B, Dupin N, Batteux F.Does inflammatory acneresultfromimbalanceinthekeratinocyteinnateimmune response?MicrobesInfect.2010;12:1085---90.

11.BacchettiT,CampanatiA,FerrettiG,SimonettiO,LiberatiG, OffidaniAM.Oxidativestressandpsoriasis:theeffectof anti-tumournecrosisfactor-␣inhibitortreatment.BrJDermatol. 2013;168:984---9.

12.YesilovaY,UcmakD,SelekS,Dertlio˘gluSB,SulaB,BozkusF, etal. Oxidativestressindex mayplaya key roleinpatients with pemphigus vulgaris. J Eur Acad Dermatol Venereol. 2013;27:465---7.

13.Kılıc¸S,Is¸ıkS, HizMM,C¸akırDÜ, TürkönH, CevizciS,et al. Theischemiamodifedalbuminandmeanplateletvolumelevels inpatientswithBehc¸et’sdisease. Postepy Dermatol Alergol. 2016;33:345---8.

14.ÖzcanO, ErdalH, ˙Ilhan G,DemirD,GürpınarAB,Nes¸elio˘glu S,etal.Plasmaischemia-modifiedalbuminlevelsanddynamic thiol/disulfide balancein sickle cell disease: a case---control study.TurkJHematol.2018;35:265---70.

15.Is¸ikS, Kılıc¸ S, Ö˘gretmen Z, C¸akır DÜ, Türkön H, Cevizci S, et al. The correlation between the psoriasis area severity index and ischemia-modifed albumin, mean platelet volume levels in patients with psoriasis. Postepy Dermatol Alergol. 2016;33:290---3.

16.Atas¸ H, Kocabıyık M, Gönül M, Öztürk Y, Kavutc¸u M. Use-fulness ofischemiamodifiedalbumin inpredicting oxidative stress in patients with vitiligo. Biomark Med. 2017;11: 439---49.

17.OzdemirM,KiyiciA,BaleviA,Mevlito˘gluI,PeruC.Assessment ofischaemia-modifiedalbuminlevelinpatientswithpsoriasis. ClinExpDermatol.2012;37:610---4.

18.Omma A, Sandikci SC, Colak S, Tecer D, Yucel C, Ozbalkan Z.Serumcalprotectinandischemiamodifedalbuminlevelsas markersofdiseaseactivityinBehc¸et’sdisease.Postepy Derma-tolAlergol.2018;35:609---13.

19.Incel-UysalP,AkdoganN,AlliN,OktemA,CandarT,Topcuoglu C,etal.Assessmentofmetabolicprofileandischemia-modified albuminlevelinpatientswithalopeciaareata:acase---control study.IndianJDermatol.2019;64:12---8.

20.SavciU,SahinM,SenelE,OztekinA,MusluU,SungurM,etal. Thiol/disulfidehomeostasisinpatientswithtelogeneffluvium: is oxidative stress important in the pathogenesis of telogen effluvium?TurkJDermatol.2019;13:131---4.

21.YinM,LiuX,ChenX,LiC,QinW,HanH,etal.Ischemia-modified albuminisapredictorofshort-termmortalityinpatientswith severesepsis.JCritCare.2017;37:7---12.

22.HuangQX,MaJ,WangYS.Significanceofpreoperative ischemia-modified albumin in operable and advanced gastric cancer. CancerBiomark.2018;22:477---85.

23.GulpamukB,TekinK, SonmezK, InancM,NeseliogluS, Erel O, et al. The significance ofthiol/disulfide homeostasisand ischemia-modifiedalbuminlevelstoassesstheoxidativestress

inpatientswithdifferentstagesofdiabetesmellitus.ScandJ ClinLabInvest.2018;78:136---42.

24.Chen CY, Tsai WL, Lin PJ, Shiesh SC. The value of serum ischemia-modified albumin for assessing liver function in patients with chronic liver disease. Clin Chem Lab Med. 2011;49:1817---21.

25.DogruM,AkogluH,KilinckayaMF,UlferG. Ischemia-modified albumin levels in children with asthma: a pilot study. Arch ArgentPediatr.2018;116:e522---8.

26.PrieBE,VoiculescuVM,Ionescu-BozdogOB,PetrutescuB,Iosif L,GamanLE,etal.Oxidativestressandalopeciaareata.JMed Life.2015;8:43---6.