Diagnosis and quantification of fibrosis, steatosis, and hepatic siderosis through multiparametric magnetic resonance imaging

Diagnosis and quantification of fibrosis, steatosis, and hepatic siderosis through multiparametric magnetic resonance imaging ARTICLE IN PRESS+Model Revista de Gastroenterología de México 2017;xxx(xx)[.]

´

REVIEW ARTICLE

M Stoopen-Romettia , ∗, E.R Encinas-Escobarb, C.R Ramirez-Carmonaa,

E Wolpert-Barrazac, E Kimura-Hayamaa, L.A Sosa-Lozanod, R Favilae,

Y Kimura-Fujikamid, J.A Saavedra-Abrila, A Loaeza-del Castilloc

aDepartamento de Imagen, C.T Scanner Lomas Altas, Mexico City, Mexico

bCurso Universitario de Radiología, C.T Scanner, Instituto Nacional de Cardiología Ignacio Chávez, Universidad Nacional

Autónoma de México, Mexico City, Mexico

cUnidad de Gastroenterología y Hepatología, Clínica Lomas Altas, Mexico City, Mexico

dDepartamento de Imagen, C.T Scanner de México, Mexico City, Mexico

eGeneral Electric Healthcare, Durango, Mexico

Received21December2015;accepted16June2016

KEYWORDS

Fibrosis;

Magneticresonance

elastography;

Viralhepatitis;

Steatosis;

Hepaticsteatosis;

Hepaticsiderosis

Abstract

Background: The presenceofliverfibrosis isthecommondenominatorinnumerous chronic liverdiseasesthatcanprogresstofibrosisandhepatocellularcarcinoma.Mostimportant,with respecttofrequency,areviralhepatitisandnon-alcoholicfattyliverdisease,theprevalence

ofwhichisincreasinginepidemicproportions.Liverbiopsy,albeitimperfect,continuestobe thecriterionstandard,butinmanyclinicalsituationstendstobereplacedwithnoninvasive imagingmethods

Objectives: Theaimofthepresentarticlewastodescribeourimagingdepartmentexperience withmagneticresonanceelastographyandtoanalyzeanddiscussrecentlypublishedresultsin gastroenterology,hepatology,andradiologyfromotherauthorsintheliterature,complemented withaPubMedsearchcoveringthelast10years

Results and conclusions:Magnetic resonance elastography is an efficacious, noninvasive method with results that are concordant with liver biopsy It is superior to ultrasound

夽 Pleasecitethisarticleas:Stoopen-RomettiM,Encinas-EscobarER,Ramirez-CarmonaCR,Wolpert-BarrazaE,Kimura-HayamaE, Sosa-Lozano LA, et al Diagnóstico y cuantificación de fibrosis, esteatosis y hepatosiderosis por medio de resonancia magnética multiparamétrica Revista de Gastroenterología de México 2016 http://dx.doi.org/10.1016/j.rgmx.2016.06.001

∗Correspondingauthor.DepartamentodeImagen,C.T.ScannerLomasAltas,PaseodelaReforma2608,DelegaciónMiguelHidalgo,11950 Mexico City, Mexico Phone: +52 (55) 6378 0222; fax: +52 (55) 6378 0218.

2255-534X/© 2016 Asociaci´ on Mexicana de Gastroenterolog´ıa Published by Masson Doyma M´ exico S.A This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).

RGMXEN-344; No of Pages 14

elastographybecauseitevaluatesamuchgreatervolumeofhepatictissueandshowstheoften heterogeneouslesiondistribution.Thegreatestadvantageofthemagneticresonanceprotocol describedisthefactthatitquantifiesfibrosis,fatcontent,andironcontentinthesame25min examinationspecificallydirectedforthatpurpose,resultinginafavorablecost-benefitratio forthepatientand/orinstitution

©2016Asociaci´onMexicanadeGastroenterolog´ıa.PublishedbyMassonDoymaM´exicoS.A.This

isanopenaccessarticleundertheCCBY-NC-NDlicense(http://creativecommons.org/licenses/ by-nc-nd/4.0/)

PALABRAS CLAVE

Fibrosis;

Elastografíapor

resonancia-magnética;

Hepatitisvirales;

Esteatosis;

Esteatohepatitis;

Hepatosiderosis

Diagnóstico y cuantificación de fibrosis, esteatosis y hepatosiderosis por medio

de resonancia magnética multiparamétrica Resumen

Antecedentes: Lapresenciadefibrosishepáticaeseldenominadorcomúndenumerosas enfer-medadescrónicasdelhígadoquepuedenevolucionarafibrosisyahepatocarcinoma.Lasmás importantesporsufrecuenciasonlashepatitisviralesy elhígado grasonoalcohólico, cuya prevalenciaaumentaenproporcionesepidémicas.Labiopsiahepática,auncuandoimperfecta, continúasiendoelestándardeoroquetiendeaserreemplazadoenmuchassituacionesclínicas pormétodosdeimagennoinvasivos

Objetivos: Describirlaexperienciaobtenidaennuestrodepartamentodeimagenconla téc-nicadeelastografíaporresonanciamagnética,analizarycomentarlosresultadospublicados porotrosautoresenlaliteraturarecienteengastroenterología,hepatologíayradiología, com-plementadaconunabúsquedaenPubMeddelosúltimos10a˜nos

Resultados y conclusiones: Laelastografíaporresonanciamagnéticaesunmétodonoinvasivo

yeficaz,cuyosresultadostienenconcordanciaconlabiopsiahepática,presentasuperioridad sobrelosmétodosdeelastografíaporultrasonidodebidoaqueevalúaunvolumenmuchomayor

detejidohepático ymuestraladistribucióndelaslesionesque,amenudo,esheterogénea

Lamayorventajadelprotocoloderesonanciamagnéticadescritoestribaencuantificarenla mismasesión,ademásdelafibrosis,elcontenidodegrasaydehierro,locualserealizaenuna exploracióndirigidaespecíficamenteaestefin,enuntiempode25minyauncosto-beneficio favorableparaelpacienteylainstitución

©2016Asociaci´onMexicanadeGastroenterolog´ıa.PublicadoporMassonDoymaM´exicoS.A Esteesunart´ıculoOpenAccessbajola licenciaCCBY-NC-ND(http://creativecommons.org/ licenses/by-nc-nd/4.0/)

Introduction

Liverfibrosis isthe cicatrizationresponsethatis a

conse-quence ofacuteor chronic liver damagedue toavariety

ofcauses.Itisadynamicandpotentiallyreversiblerepair

processthatisassociatedwithhepatocellularregeneration

The activation of stellar cells causes fibroblast

prolifer-ation and excessive extracellular matrix deposit Fibrous

bandsare produced, distorting the structure of the liver,

formingscarsandregenerationnodules.Consequently,liver

function is altered and there is increased hepatic

resis-tancetothebloodflow,causingchronicliverdisease(CLD),

manifested by cirrhosis and complications such as: liver

failure,portalhypertension,andhepatocellularcarcinoma

(HCC).1,2

The main causes of cirrhosis in the industrialized

countriesincludechronichepatitisCandBvirusinfections,

immoderatealcoholingestion,andnonalcoholicfattyliver

(NAFL) that can progress to nonalcoholic steatohepatitis

(NASH)andcirrhosis

The prevalence of viral infections and alcoholism as causesofCLDremainedstablebetween1998and2008.In contrast, the prevalence of NAFL as a cause of CLD has increasedfrom46.8to75.1%withinthesametimeframe.3 NAFL has become the most frequent cause of CLD in the United StatesandEurope,associatedwiththeprevalence

ofobesityandmetabolicsyndrome.Thecontinuingincrease

inNAFLprevalenceisestimatedtosubstantiallycontribute

totheincreaseinCLDandwillrepresentanepidemiologic burdeninnumerouscountries,includingMexico.4 -6 Thediagnosisoffibrosishasrecentlygainedimportance duetothefactthatitsvariouscausescanbepreventedor treated,makingit potentiallyreversibleifthecausal fac-toriseliminated.2,5Clinicalmanagementofthesepatients requires knowing the stage of fibrosis and the frequently coexistingfatandironcontents,andtheirincreaseor reduc-tionduringthecourseoftreatment

Liver biopsy, traditionally considered the ‘‘criterion standard’’ for diagnosis hasseveral limitations: itis inva-sive,costly,subjecttocomplications,andallowsonlyavery

smallportionof the organ(approximately 1/50,000 of its

volume)tobeexamined.Histologicanalysishasgreatintra

andinterobservervariability,withlowefficacyintheinitial

stagesoffibrosis(F1andF2),anditdoesnotprovide

infor-mationaboutthedistributionoffibrosisintheparenchyma,

whichcanbeheterogeneous.7 -9

Some imaging methods such as ultrasound (US),

com-puted tomography (CT), magnetic resonance (MR), and

ultrasoundelastography(USE)overcomesomeorseveralof

theselimitationsandhavebeenincreasinglyusedinrecent

years,providinganewnoninvasivediagnosticoption

A more recently acquired technique is magnetic

reso-nanceelastography(MRE),developedbyresearchersatthe

MayoClinicinRochester, NewYork,toobtain quantitative

andqualitativeinformationaboutliverfibrosis.10

This technique has continuedto be perfected and has

recently been made more attractive because during the

samesession,itcanbecombinedwithotherMRsequences

thatareuseful forquantifyingtheparenchymal infiltrates

duetofatand/oriron,whichenablesa‘‘multiparametric’’

examinationprotocoltobeestablished

The aim of this article wasto describe the technique

and clinical applications of the multiparametric liver MR

protocolusedinourdepartmentforthediagnosisand

quan-tificationoffibrosis,steatosis,andhepaticsiderosis,during

a25-minspecificexaminationthatisclinicallyand

econom-icallyviableforboththepatientandthehospitalcenter

The present review is supported by the experience

obtainedwithinthelast18monthsatourimaging

depart-mentandbyanamplereviewofarticlespublishedbetween

2006and2016injournalsofhepatology,gastroenterology,

andradiology,inEnglishandFrench,found inthePubMed

databasewiththeKeywords

fibrosis,liverfibrosis,elastography,USelastography,and

MRelastography

Fibrosis

Elasticity and stiffness

Themechanicalbehaviorofthetissuesofthehumanbody

is similar to that of viscoelastic materials Liver

elastic-ity is inversely proportional to parenchymal stiffness and

the quantity of fibrous tissue As the fibrosis increases,

parenchymalstiffnessincreasesanditselasticitydecreases

Thisphysicalphenomenoncanbemeasuredthrough

elastog-raphytechniques

General principles of elastography

The purposeofliverelastography istoobtain noninvasive

andinvivoinformationaboutthemechanicalpropertiesof

theparenchymaaftersubmittingittoatypeofstressthat

deformsit Elastographycan be performed through

ultra-sound(USE)ormagneticresonance(MRE)

ThreebasicstagesarerequiredtocarryoutMREofthe

liver:a)excitation,whichconsistsoftransmittingstressto

the organ by means of a source of movement that sends

wavelengthsthatdeformtheparenchyma;b)data

acquisi-tion,whichconsistsofregisteringthedeformationproduced

inthetissueasaconsequenceoftheappliedstress;andc)

theanalysisandquantificationofthedatathatthe equip-mentpresentsintheformofimages.11,12

Magnetic resonance elastography

ThephysicalprinciplesofMREhavebeenexplainedinmany specializedpublications andso only ageneral description will be provided herein.10,11,13 -15 They are based on the transmissionoflow-frequency longitudinal wavelengths of approximately65Hzby means ofan instrumentplaced at theribcageclosetotheliver.Thelongitudinalwavelengths thatpenetratetheorganaretransformedintotransversal wavelengths, called cutsor shears, whichare propagated

bytheliverparenchymaandcalculatedthroughtheshear modulus.Themeasurementsobtainedarequantifiedin kilo-pascals(kPa)

Equipment

Inourdepartment,MRE(alsocalledFibro-RM)isperformed with1.5Tesla(Optima450w,GeneralElectric,Milwaukee, Wisconsin,USA)RMequipment.Theresonatorhasadditional hardwarethat produces mechanical wavelengths that are sentintotheliverandaspecificsoftwareprogramfor ana-lyzingtheinformationobtained

The hardware is made up of 4 mechanical elements (Figure 1): 1) a pulse or vibration generator that acts as

an ‘‘active driver’’, which is located in the neighboring machineroom,2)aflexibletube thattransmitsthepulses

orvibrationsproducedbythedriver,conductingthemto3)

aplasticplate,10cmindiameter,thatisplacedontheskin

ofthe ribcage at the patient’s liver,called the ‘‘passive driver’’,and4)an elasticband thatattachestheplate to thebodyofthepatient

Result presentation

The information generated by the wavelengths that pass throughtheparenchymaisprocessedbyelastography soft-warethatdisplaysthedataonaworkingstationscreenin theformofimagesin4differentpresentations(Table1): Thefirst,isalow-resolutiongray-scalereferenceimage whose only function is to select the areas of the liver parenchymathat aretobe measured, notincluding inad-equatezonessuchastheportalvessels, largefissures,the gallbladder,etc.(Figure2a)

The second image corresponds to a map of the wave-lengthsincolorandmotionthatshowstheadvanceofthe wavelengthsintothelivertissue(Figure2b)

Thethirdimage,calledanelastographicmap,isacolor map of the stiffness of the liver A colorimetric scale is attachedtoeachelastographicmap(Figure2c)

Table 1 MRelastography

Presentationoftheresults a)Referenceimage b)Wavelengthmap c)Elastographicmap(colormap) d)Confidenceimage

Machine room

Examination room

Passive driver Active driver

Figure 1 Diagramofthecomponentsofthemagneticresonanceelastographyequipment.Theactivedriverthatgeneratesthe pulsesisinthemachineroom.Thepulsesaretransmittedintheformofwavelengthsthroughaplastictubethatconnectsthat devicewiththeplate.Theplateisapassivedriver,10cmindiameter,thatisplacedattheliverandittransmitsthewavelengths

totheorgan.Theplateissecuredtothebodywithanelasticband

Theelastographysoftwarecreatesafourthimagecalled

the‘‘confidencemap’’thatoutlinesthezonesoftheliver

thatcanbereliablymeasured(Figure2d)

Image analysis and liver stiffness measurement

Wavelength map. Wavelengthanalysiscanbedone

stati-callyinafixedimageorinavideoshowingthewavelength

motion It verifies that the wavelengths sent by the

pas-sivedriverpenetratedthelivertissueandwereadequately

distributed.Wavelengthsarethinandparallelinthenormal

liver(Figure3a).Asthegradeoffibrosisincreases,the

wave-lengthsbecomethickerandfaster(figures3c,3e,and3g)

Elastographic map. This color map makes it possible to

makearapidvisualevaluationofnormalityorabnormality

ofliverparenchymalstiffness.Tomakethisassessment,the

colorsoftheliverarecomparedwiththecolorimetricscale

accompanyingeachimage.Thisaffordsafirstappreciation

ofthegradeof fibrosisasabsent,incipient,moderate, or

intense(figures3b,d,f,andh)

Inourequipment,blueandpurpletonesarelocatedat

thelowerendofthescaleandcorrespondtominimum

stiff-ness.Red is atthe upperend ofthe scaleand represents

maximumstiffness, whereasyellowandorangetones

cor-respond to intermediate stiffness values The color map

providesa visual appreciationof whetherthe fibrosis dis-tributionishomogeneousorheterogeneous.16

The radiologist carries out the stiffness measurements

bymanuallyplacingtheelectroniccursorsonthereference image(takingcaretoavoidtheportalvesselsand gallblad-der)orontheelastographicmapinthezonesoftheso-called

‘‘confidencearea’’

Automatic quantification programs have recently been developedthatneednohumanintervention.Giventhatthe elastographicmapcovers the entire circumferenceof the abdomen, it also makes it possible to recognize whether thereis anincrease in spleenstiffnessin thesame image (Figure3h)

Normal liver hardness values in magnetic resonance elastography

The normal liver is softand elasticwitha mean stiffness

of2.05to2.44kPaandarangeof1.54to2.87kPa.15,16The cutoffpointfordetectingfibrosiswithMREvariesbetween 2.4and2.9kPawith98%sensitivityand99%specificityfor thevalueof2.93kPa.13,16,17

Huart et al have correlated the kPa values with the METAVIR scalefromF0toF4.13 Thisscale wasmodified by Asbachetal.,whoformulatedthetablethatweuseinour practicetoreporttheresultsofthestudy(Figure4).14

Figure 2 Magneticresonanceelastographyimages:a)referenceimage,b)wavelengthmap,c)elastographicmap,d)elastographic mapwithanoverlyinggridthatmarksthelimitsofthesafetyareaforcarryingoutthemeasurements

Figure 3 Informationanalysis.Thewavelengthmapin4patientswithdifferentgradesofstiffnessisintheupperrow.Thelower rowcorrespondstotheelastographicorcolormapofeachofthem.Figuresa,c,e,andgshowtheincreaseinthicknessandthe irregularityofthewavelengthsasthegradesoffibrosisincrease.Theelastographicmapsshowthechangesincoloroftheliverand theirrespectivestiffnessmeasurements:b)purplesfor2.1kPa=F1;d)greensandbluesfor2.6kPa=F2;f)greensandyellowsfor 4.4kPa=F3;andh)redfor9.2kPa=F4.Comparethecolorsoftheliverwiththecolorbarontheleftside

It is important to know that the kPa scale in MR is

different from the one used in US This is due to the

factthatinUS, thevaluesareprocessedwiththeYoung’s

modulus,whichevaluates thelongitudinalwavelengths on

ascalefrom2.5to75kPa.Incontrast,inMRE,thevalues

areprocessedwiththetransversemodulusofelasticity,or

shearmodulus,whichmeasuresthetransversewavelengths

thataredistributedintheparenchyma,alsoinkPa,buton

ascalefrom0to8kPa

Clinical follow-up of fibrosis utilizing magnetic

resonance elastography

DifferentstudieshaveshownthatMREcandetectliver

stiff-nessmodificationsoverthecourseoftime.Itisarepeatable

andreproduciblestudythatisnotveryoperator-dependent

andthusisauseful,noninvasivemarkerformonitoringthe

kPa

8.0

7.0

6.0

5.0

4.0

3.0

2.0

Figure 4 Diagramshowingthelow,medium,andhigh

quar-tilesoftheshearmodulusforfibrosisstagesF1-F4,compared

withvolunteers

(Reproducedwithpermission).Source:Asbachetal.14

increaseorpossibledecreaseofliverfibrosisduringclinical follow-up.15 -17

Spleen stiffness measurement

The techniques of elastography employed for measuring liverstiffness have alsobeen used toexplore thespleen, underthe hypothesisthat theincreasein splenicstiffness canberelatedtothe developmentof portalhypertension andcanbeusefulforclassifyingcirrhosis

Measuring with ultrasound. Spleenstiffnesscanbe mea-suredwith USE or MREin a manner similar tothat when measuringstiffnessoftheliver.ThefirstUSEstudieswere performed usingtransitoryelastography equipment How-ever, recent studies report onthe use of equipmentthat utilizesacousticradiation forceimpulses(ARFIs)to gener-ateshear waveimages This equipmentmakesit possible

tomeasurethespleenundergray-scaleandrealtime ultra-soundimageguidance,withoutmeasuringthesplenichilum vesselsthatcanbeprominentwhenthereisportal hyper-tension,thusobtainingamoreprecisemeasurement.18 -23

Measuring with magnetic resonance. Agrowingnumberof publicationsreportontheusefulnessofMREformeasuring thestiffnessofthespleenwithfavorableresults,compared withthoseofUSE.24 -30

ItispossibletostudythespleenduringMREoftheliver, duetothefactthattheelastographicmapcoverstheentire circumferenceoftheabdomen,whichincludesbothorgans The spleen can also be explored in the study area by placingthepulse-emittingplatedirectlyonthesplenicarea Normal stiffnessof thespleenmeasured by MREvaries from2.35to5.6kPa,withameasurementof3.6kPain nor-mal volunteers.27 Ongoing studies should provide greater knowledgeonthissubjectmatter

Advantages of magnetic resonance elastography

MRE obtains information from the vectors of the wave-lengthsthatarepropagatedin2or3dimensionsintheliver

Table 2 Tissue volume quantified by the USE and MRE

methods22

Elastography

method

Manufacturer Volume

1.Transitory

elastography

(Fibroscan®)

Echosens,FR 4cm3

2.USARFIpSWE Siemens,Philips 0.5-1.0cm3

3.USARFI2DSWE Supersonics,Toshiba,

GeneralElectric(GE)

20cm3

4.RMelastography GeneralElectric(GE),

Siemens,Philips

250cm3

parenchyma The liver tissue volume analyzed in 2D MRE

iscalculatedtobeapproximately250cm3,comparedwith

thevolumeevaluated throughultrasoundmethods, which

variesfrom0.5cm3to20cm3(Table2).Therefore,the

vol-umeoftissueanalyzedinMREismuchmorerepresentative

ofparenchymalinfiltration andreduceserrorsdue to

pos-siblefibrosis heterogeneity.2 The MREstudyis notlimited

bythepresenceofascitesorclosedintercostalspaces.RM

equipmentutilization timeand the cost of the study are

considerablyreducedwhenaspecificelastographystudyis

carriedout

Limitations of magnetic resonance elastography

Themostimportantlimitationisthepresenceofexcessive

irondepositionintheparenchymaduetohemosiderosisor

hemochromatosisthatcancoexistwithfibrosis inpatients

with CLD When there is iron overload, the wavelengths

are transmitted into the parenchyma well, but the

sig-nal emitted into the liver is too low (especially in 3T

equipment) and measurement can be imprecise

Exces-siveobesity,bileductobstruction,claustrophobia,andthe

inabilitytoholdone’sbreatharecausesthatcanlimitthe

examination

Steatosis

MRoffersvarioustechniquesfor detectingandquantifying

fatcontentintheliverparenchyma(Table3).Theyarebased

onthedifferentprecession frequencies-resonance-ofthe

hydrogenprotons(1H+)inwaterandfat.31 -33

Chemical shift imaging technique

Thesimplesttechniqueisthevisualanalysisoftheimageof

theliverobtainedin thedualechoT1-weightedsequence

Table 3 MRtechniquesforquantifyingsteatosis

Chemicalshiftimage

Magneticresonancespectroscopy

Dualortripleechoacquisition(Dixon,IDEAL)

Multi-echoacquisition(IDEAL-LQ)

Parametricimage(cartographyofthesteatosis)

Others

Figure 5 Imageoftheliverinthein-phase(leftcolumn)and out-of-phase(rightcolumn)T1sequencein3differentpatients

Inanormalpatient,thesignalissimilarinthea)in-phaseandb) out-of-phasesequences.Theimagesinthecenterarethoseofa patientwithsteatosisinwhomtheintensityoftheparenchymal signalisnormalinthe‘‘in-phase’’sequence(c)anditmarkedly decays inthe‘‘out-of-phase’’ sequence,where itacquiresa toneofblackduetothegreaterfat content(d).Thebottom rowcorrespondstoapatientwithhemochromatosis.Thesignal decaysinthe‘‘in-phase’’sequence(e),duetotheincreasein ironsaturation, comparedwiththe‘‘out-of-phase’’sequence (f)

thatmakesuppartofallMRliverprotocols.Itprovidesapair

ofgoodqualityanatomicimagesoftheliver,‘‘weightedto T1’’andin2distinctacquisitionphases:one‘‘in-phase’’(IP) andtheother ‘‘out-of-phase’’ (OP)that enablethe visual andqualitativedetectionoffat.Inthenormalpatient,the liverparenchymahasthesamesignalinboththein-phase andout-of-phaseimages(Figure5aand5b).Inpatientswith steatosis,signaldecayinthe‘‘out-of-phase’’imagesis pro-duced,makingtheimageoftheliverturndarker,thegreater the quantity of triglycerides (Figure 5c and d), enabling the fat fraction to be calculated, as described further ahead

Spectroscopy

The most precise quantitative technique today for quan-tifying fat is MR spectroscopy (1H-RM) It separates the watercurvespectrum fromthoseofthe lipidcurves, pro-vidingan exactquantification.In thespectralcurve,each metaboliteisdetectedaccordingtoitsresonancefrequency, measuredinpartspermillion(ppm).Thewaterpeakcanbe distinguishedfromvariouspeaksproducedbytriglycerides and occasionally by other metabolites (Figure 6a and b) Spectroscopy is the noninvasive reference technique for

10 ×10 5

8×10 5

6 ×10 5

4×10 5

2 ×10 5

0

6×10 5

4 ×10 5

2×10 5

0

5 4 3 2

Frequency (ppm) Frequency (ppm)

Real Real

1 0 –1 5 4 3 2 1 0 –1

Figure 6 Spectroscopyoflipids.Graphsaandbshow2mainpeaks:ontheleft,anelevatedpeakthatcorrespondstowaterand

ontheright,alowerpeakthatcorrespondstotriglycerideconcentration.Notethatthetriglyceridepeakishigherinimagebina patientwithagreaterlipidconcentration

diagnosing steatosis.32,34,35 Nevertheless, it is the most

complex, slow, and costly It requires specialized

soft-wareandthereforeisusedonlyin academicandresearch

studies

Fat quantification in chemical shift sequences

The most widely used technique is the one described

by Dixon36 that measures the chemical shift between fat

and water protons It utilizes the dual echoT1-weighted

sequence: theIP sequencecontains thesum ofthe water

andlipidprotonsandtheOPsequencecontainstheabsolute

valueofthedifferenceofwaterminuslipids(IP-OP)

The fat content is calculated with the following

equation:35

FSF = SFat

SWater+SFat = SIP−SOP

2SIP Where:FSFisthefatsignalfraction;SFatisthefatsignal;

SWateristhewatersignal;SIP=isthe‘‘in-phase’’signal,and

SOP=isthe‘‘out-of-phase’’signal

Thecurrent recommendationis tousethemorerecent techniques from the same family, suchas the multi-echo 3D proton density sequences that provide the most pre-cisefat fractioncalculation, separatingitfromwaterand withagoodhistologiccorrelation.Thesearemoreprecise, especiallywhensteatosiscoexistswithirondepositsinthe parenchymathatcanfalsifythereading

Themulti-echosequencesmakeitpossibletoeliminate theeffectofiron,providing amoreprecise corrected fat quantification.32,34,35,37

Steatosis quantification in color cartography

Liverfatquantificationcanalsobecarriedoutthrough car-tographyoracolormap.Itprovidesrapidvisualappreciation

of the existence of steatosis and the measurements are madedirectlyontheimage(Figure7a,b,andc)

Thedifferentcolorsofthemapcorrespondtothe distri-butionandintensityoftheinfiltratethatcanbediffuseor regional(‘‘geographicsteatosis’’or‘‘inpatches’’),oreven

bepresentinafocallesion,suchasoccursinlipomasand someadenomasandhepatocellularcarcinomas

Figure 7 Colormapsin3patientswithdifferentsteatosisgrades:a)patientwithnormalfatcontent:thedarkblueoftheliver correspondstothelowerpartofthecolorimetricscaleandtoaquantificationbelow6%(normal);b)inthispatientthelightblue

ishigheronthescaleandthefatcontentisincreasedtoanaverage17%;c)theimageinthethirdpatientassignedgreentothe liver,whichisindicativeofahighfatcontentandwasquantifiedat33%

Figure 8 Liveradenomawithfat.a)TheT1sequenceshows 3smallfocallesions insegments7and8oftheliver.Thecolor mapforquantifyingfatshowsthat2ofthemhavebluetonesinthecenter(b),inwhichthelipidconcentrationwas37and19%, respectively(c).ThehistologicdiagnosiswasHNF1adenoma

Cartography facilitates the analysis of fat content by

comparingthecolorsofthecolorimetricbarthatisattached

totheimage.Inourequipment,darkbluetonescorrespond

tothelowestlipidconcentration.Lightblueandgreentones

indicatelargerquantities ofinfiltrate,andyellowandred

tonesappearinthehighestconcentrations.Thecartography

imagecoverstheentirecircumferenceoftheabdomen,and

thusthesubcutaneousfatandtheperitonealandperirenal

spacesarealsohighlightedinredtones

To quantify the liver infiltrate, the radiologist utilizes

electronicdevicesthatcanchoosetheregionsinwhichthe

percentageoftheexistingfatistobecalculated.The

pres-ence of fat within a focal lesion of the liver aids in its

characterization(Figure8)

Normal values of liver fat

Fat content values below 6% are considered normal

MRcanidentifytriglycerideinfiltratesaslowas6-15%.The

fatpercentagefiguresobtainedintheparametricimageare

reproducibleintime,makingthemusefulinthediagnosis,

aswellasin thefollow-up of theprogressionof steatosis

undertreatment

In 2comparative, prospectivestudies, MR results have

beenmoreaccuratethanthoseofUSandCTstudiesforthe

diagnosisandquantificationofsteatosis.38 -40

MRalsohasspecialsequencesforstudyingtheironcontent

in theliver parenchyma and in other organs, such asthe

pancreas,spleen,andthe heart Itcan accurately detect

andquantifytheamountofirondepositedintheliver,with

reproducibility, and therefore is a useful tool for

diagno-sisandfor monitoring treatment response When thereis

alargeamount ofironaccumulationin thelivertissue,it

distortsthemagneticfieldandproducessignaldecayinthe

T1,T2,andT2*sequences

ThedualechoT1sequencecanmakearapidqualitative

appreciationoftheincreaseinthehepaticironcontentdue

tothefactthatinthissequencethedecaypresentsinthe

IPimage(Figure5eandf),incontrasttowhatoccursinthe

caseofsteatosis,asdescribedabove

The most well-known quantitative technique in our environment, and the most widely used in our depart-ment, is that of Gandon et al., from the University of Rennes, France, published on the university website: http://www.radio.univrennes1.fr/Sources/EN/Hemo.htlm Thestudycanbeperformedonvariousmagneticresonance machines, adapting the protocol to themagnitude of the available magnetic field,either at 0.5, 1.0,or 1.5T.The calculation is made ‘‘online’’ with a Java application providedbytheuniversity.41

The method is efficacious for ruling out the existence

of small parenchymal iron overloads, even when values are below 60␮mol Fe/g In contrast, the efficacy of the techniquecanbelostwhenthedepositsareveryintense, becausetheycause completeloss of theresonancesignal duetotheeffectthathepaticironproducesonthemagnetic field

Thereareother techniquesfor evaluatingparenchymal iron Among them, the so-called MRI R2 and R2* tech-nique canprovide parametricimagesthat reflecttheiron content in the liver and spleen (Figure 9) The results

of comparisons with liver biopsy have been dissimilar due to the heterogeneity of the iron deposits They are generally similar, but MR has the obvious advantages in treatmentfollow-upandpatientpreferencebecauseofits noninvasiveness.42,43

Normal and pathologic values of iron concentration

WiththetechniquedescribedbyGandonetal.,valuesof40

to100␮ml/mlrepresentaslightironoverloadinlivertissue, whereas valuesof 100 to200␮ml/ml correspond to mod-erateoverload,andthoseover300␮ml/mlindicatemajor overload,whichcansaturatethesequencesandfalsifythe readings.41The MRIR2-R2*measurestheparenchymaliron concentrationinmgofFe/g.42,43

The protocol utilized in our imagingdepartment includes thepresentationof2additionalnon-contrastenhancedMR anatomic sequencesthat areclinically useful: the above-mentioned T1-weighted sequence with IP and OP images that also serve the purpose of qualitatively evaluating

Figure 9 Hemochromatosis.a)Inthecolorimetricmap,theredscorrespondtothehigherpartofthescale,indicatinggreateriron concentrationintheliverparenchyma.b)AlsonotethereddotintheamplifiedimageofthespleenproducedbytheGamna-Gandy sideroticbodies.c)Inaddition,theanatomicimageinT1ofthispatientshoweddecayoftheparenchymalsignalofthepancreas (arrow)andthepresenceofenlargedperipancreaticlymphnodes(arrows)inrelationtothehemochromatosis(d)

fat and iron, plus an axial T2 sequence They provide

an excellent anatomic image of the liver, the organs of

the upper abdomen, and the retroperitoneum, including

thegallbladderandbileducts, thespleen,intestine,

pan-creas,pancreaticduct,kidneys,adrenalglands,aorta,and

vena cava They can detect benign or malignant focal

lesions of the liver, in which case broadening the study

to include sequences with endovenous contrast medium,

whethergadoliniumorgadoxetic acid(Primovist®),should

beevaluated

The need for precise, reproducible, noninvasive methods

that arecapable ofdetecting thedifferent stages of CLD

derivesfromvariousfacts,amongwhichthefollowingstand

out:theincreaseindiseaseprevalence(whichinthecaseof

NAFLhasbeenqualifiedasepidemic),improvedknowledge

ofthepathology,andthegreatertherapeuticopportunities

(thathavealsomadethedecisionsthattheclinicianmust

makemorecomplex).44,45

Fibrosis

Even though there are still few opportunities for curein

advancedstages of cirrhosis, withthe exception of

trans-plantation, early or intermediate stages of fibrosis are

becoming entities that are treatable through preventive

means andother possiblycurative ones that can stop the

progression or enable the regression of fibrosis, such as

the new direct antiviral agents and certain experimental drugs.46 -50

The diagnosis of fibrosis as the central factor in CLD pathogeny acquires greater significance in this context Recent AASLD-IDSA guidelines point out that the correct evaluation of fibrosis is essential for evaluating treat-mentindication, andin somecases, itsduration.51 Inthe consensus meeting on the use of different elastography techniquesheldinDenver,Colorado, inOctober2014that includedinfectologists,hepatologists,radiologists, patholo-gists,biomedicalengineers,andFDArepresentatives,itwas establishedthatthepriorityfor givingantiviral treatment

topatientswithhepatitisBandCvirusesiscurrently deter-minedbythepresenceor absenceof moderate-to-intense fibrosis(F3orhigher).22

The MRE technique developed at the Mayo Clinic in Rochesterhas enrichedourdiagnosticcapacity by provid-ingtheclinicianwithawiderangeofinformationonfibrosis thatothertechnologiescannot.Amongthemare:

a) The sample of tissue volume examined through MRE

is significantly larger than that analyzed by ultra-soundmethods:Fibroscan®=approximately4cm3;ARFI pSWI=0.5to1cm3;andARFI2DSWE=20cm3,compared withapproximately250cm3oftheMRE22(Table2) b) Akineticimageissimultaneouslyobtainedthatconfirms thepassageofwavelengthsintheamplitudeanddepth

oftheorgan

c) Thepresentation of acolor elastographicmapenables thevisual evaluation of stiffness gradeand the homo-geneous or irregular distribution of fibrosis so that

measurements directed by the image to the zone of

interestcanbemade

d) MREandUSE,whetherARFIpSWEorARFI2DSWE,provide

theanatomicimagesoftheliverandtheorgansofthe

upperabdomeninthesameprocedure,whichisnotthe

casewithtransitoryelastographythroughFibroscan®.22

e) Thepossibilityofquantifyingspleenstiffnessisanextra

advantage,andhowthismeasurementmightbea

predic-torofportalhypertensionisdiscussedfurtherahead.52

The specific fibrosis study protocol can be broadened

duringthe same MRE session with2 additional sequences

for quantifying the concentration and distribution of the

fat infiltrate, and if so desired, the measurement of the

ironcontentof theparenchyma, whichfrequently coexist

inpatientswithCLD

Unlike the USE techniques that have differing results

depending on the equipment manufacturer, making it

impossibletocomparetheir equivalence,the 3MRE

man-ufacturerscurrentlyapprovedbytheFDA(GeneralElectric,

Siemens,andPhillips)usethesameshearwavemanagement

methods,processingalgorithms,andimagedisplay,making

theirresultscomparable.22,53

Thissetofparametricdataobtainednoninvasively

qual-ifiesMRasthemethodthatprovidesthemostinformation,

comparedwiththeother diagnostic procedures,including

biologictests,USE,andevenbiopsy,withwhichithasshown

excellentconcordance.12,22,44,54

MREisalsothemethodthatguaranteesthegreatest

per-formancesuccess:inacaseseriesof141patients,Huwart

etal.obtainedsuccessfulstudieswithMREin133/141(94%),

comparedwith118/141(84%)withtransitoryelastography,

inadditiontoobtaininggreaterdiagnosticefficacy.13Similar

resultshavebeenreportedintherecentstudybyIchikawa

etal.55

TheefficacyandcorrelationofMREwithliverbiopsyhas

beenthemotivationforanincreasingnumberofstudies.The

2012meta-analysisbyWangetal.showedthattheefficacy

ofMREfordiagnosingfibrosisprovidedfiguresof0.95,0.98,

0.98,and0.99undertheAUROCcurve.56Theseauthorsalso

statedthatliverstiffnessmeasuredwithMREincreasedin

parallelwiththegradeoffibrosis:whentherewasgreater

stiffness,therewasmorefibrosis.Huwarthetal.reported

thatin 141patients in whomliverbiopsy wasperformed,

theMREareasundertheAUROCcurvewere:0.994forF≥

2;0.985forF≥3;and0.998forF=4.13

A meta-analysis carried out in 2014 by Su et al that

included989patientsin13studies,showedgreatdiagnostic

efficacyofMREforthedetection,quantification,andstaging

ofliverfibrosis.Themeansensitivityandspecificityfigures

for:F≥1,F≥2,F≥3,andF≥4were:0.87,0.92,0.87,

and0.92,respectively.57

Anothermeta-analysisconductedby Singetal.in2015

that included 697 patients, 92.1% of whom had less than

aone-yearintervalbetween MREandbiopsy, showedthat

themeanvaluesoftheareaundertheAUROCcurve(with

a95% confidence interval)for the diagnosis of anystage:

negativefibrosis (≥ stage 1), significant fibrosis (≥ stage

2),advancedfibrosis(≥stage3),andcirrhosis,were:0.84

(0.76-0.92), 0.88 (0.84-0.91), 0.93 (0.90-0.95), and 0.92

(0.90-0.94),respectively.58 Inaddition, thepercentage of

procedurefailuresinthe697patientscollectedinthesame meta-analysis was4.3%, a verylow figure comparedwith othertechniques.TheauthorsconcludedthatMREishighly efficaciousforthediagnosisofsignificantoradvanced fibro-sisandthattheresultisindependentofbodymassandCLD etiology

MRE is an efficacious tool for following the progres-sionofpatientswithCLDanditsmeasurementshavebeen proven to be reliable, repeatable, and reproducible.59 -61 ThepossibilityofMREreplacingliverbiopsyfordiagnosing fibrosishasbeenexpressedinseveralstudies,emphasizing the fact that the tissue volume analyzed in MRE is sub-stantially greater than that in liver biopsy, which is only 0.2%oftheparenchyma,andthereisnoinformationabout whetherthe distributionofthe infiltratesishomogeneous

orheterogeneous.13,16,43,44,59

Portal hypertension

Examination of the liver by MRE has also awakened the interest instudying splenic viscoelasticityand itspossible relationtothedevelopmentofportalhypertension.The cor-relationbetweentheincreaseinstiffnessofthespleenand thepressuregradientofthehepaticveins(HVPG)hasshown promisingresultsforthedetectionofsevereportal hyper-tensionandthepresenceorabsenceofesophagealvarices TheexperimentalstudiescarriedoutbyNedredaletal andYinetal.24,25withMREonanimalsfoundthattherewas

asignificantcorrelationbetweenspleenstiffnessmeasured withMRE andthe HVPG In their preliminarystudy on 38 patientswithCLD,Talwalkar etal demonstrateda signif-icant correlation between the stiffness of the spleen and thatoftheliver,withincreasedsplenicstiffnessinthemore advancedstagesofliverfibrosis(Figure3h).Amean stiff-ness≥10.5kPahasbeenconsideredamarkerofhigh-grade esophagealvarices.24,25,28

The majority of thosestudies have been basedon the measurement of stiffness of the liver and spleen Ronot

etal.recentlyutilizedathree-dimensionalMREtechnique (3DMRE),measuring3parameters:stiffness,elasticity,and viscosityofthespleen.Theyconcludedthat3DMREis use-ful for: a)noninvasively estimating theincrease in HVPG, b)detecting high-riskesophagealvarices,andc) recogniz-ing advanced portal hypertension.29 Likewise, Shin et al found a linear correlation with the endoscopic grade of esophageal varices, using the 3DMRE techniques.30 The abovementioned works constitute progress in the knowl-edge of portal hypertension and even though they do not replace endoscopy or HVPG measurement, they rep-resent an advance that can be useful in the selection of patientsthatrequiretreatment,anditshouldcontinuetobe studied.23

Steatosis

Anotherareaofrenewedinterestindiagnosisthrough para-metric imaging has been the diagnosis of steatosis This interesthasbeenbroughtaboutbytheincreaseinobesityin thegeneralpopulation,whichisthemostfrequentcauseof fatinfiltrateintheliver.Theriseinobesityhasbeen