L G A L D P L F S L D A L R L A D A L P F D P F L A R A D ......Rachelle Crescenzi, PhD Research...
Transcript of L G A L D P L F S L D A L R L A D A L P F D P F L A R A D ......Rachelle Crescenzi, PhD Research...
LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FATDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSALGIA LIPOLYMPHEDEMA PAINFUL FAT SYNDROME LIPOEDEM ADIPOALGESIA RARE ADIPOSE DISEASE LIPALGIA PAINFUL FAT DISORDER LIPÖDEM GYNOID LIPOHYPERTROPHY DOLOROSA LIPOEDEEM LIPOMATOSIS DOLOROSA OF THE LEGS LIPOEDEMA ADIPOSA
A GIVING SMARTER GUIDE
AUTHORS
LEADAUTHOR
ErikLontok,PhD
CONTRIBUTINGAUTHORS
LaTeseBriggs,PhDMauraDonlanYooRiKim,MS
EbonyMosleyEkeminiA.U.Riley,PhDMelissaStevens,MBA
LIPEDEMASCIENTIFICADVISORYGROUP
WegraciouslythankthemembersoftheLipedemaScientificAdvisoryGroupfortheirparticipationandcontributiontotheLipedemaResearchProjectandGivingSmarterGuide.Theinformativediscussionsbefore,during,andaftertheLipedemaScientificRetreatwerecriticaltoidentifyingtheunmetneedsandphilanthropicopportunitiestodevelopthelipedemaresearchspaceandultimatelybenefitlipedemapatients.SaraAl-Ghadban,PhDPostdoctoralResearchFellow,DepartmentofMedicineTREATProgramUniversityofArizonaTobiasBertsch,MD,PhDSeniorLecturer,DepartmentofHealthEducation,UniversityofFreiburgSeniorConsultant,FoeldiClinic,GermanyEchoeBouta,PhDResearchFellow,RadiationOncologyMassachusettsGeneralHospitalGlenBriceGeneticCounselor,ClinicalGeneticsSt.George’s,UniversityofLondonBruceA.Bunnell,PhDProfessor,DepartmentofPharmacologyDirector,TulaneCenterforStemCellResearchChairman,DivisionofGeneTherapy,TulaneNationalPrimateResearchCenterTulaneUniversitySchoolofMedicine
DeborahClegg,PhDProfessor,DepartmentofBiomedicalResearchCedars-SinaiDiabetesandObesityResearchInstituteRachelleCrescenzi,PhDResearchFellow,InstituteofImagingScienceVanderbiltUniversityWalterCromer,PhDAssistantResearchScientist,Immunology,VascularPhysiology,andLymphaticBiologyTexasA&MHealthScienceCenterKristianaGordon,MBBS,MRCP,CLT,MD(Res)ConsultantinDermatologyandLymphovascularMedicine,St.George’s,UniversityofLondonCarolHaft,PhDProgramDirector,DivisionofDiabetes,Endocrinology,andMetabolicDiseasesNationalInstituteofDiabetesandDigestiveandKidneyDiseases,NationalInstitutesofHealth`
NatashaHarvey,PhDHead,LymphaticDevelopmentLaboratoryCentreforCancerBiologyUniversityofSouthAustraliaAdHendrickx,BHS,PhysicalTherapistDoctoralCandidate,HanzeUniversityofAppliedSciences,GroningenHead,DepartmentofPhysicalTherapy,ExpertCentreforLymphovascularMedicineNijSmellingheHospitalKarenHerbst,PhD,MDAssociateProfessorofMedicine,DivisionofEndocrinologyDirectoroftheTREATProgramUniversityofArizonaYannKlimentidis,PhDAssistantProfessor,DepartmentofEpidemiologyandBiostatisticsUniversityofArizonaAmiraKlip,PhDSeniorScientist,CellBiologyProgram,TheHospitalforSickChildren,ProfessorofBiochemistry,PhysiologyandPaediatrics,TheUniversityofTorontoBabakMehrara,MDPhysician-scientist,PlasticandReconstructiveSurgeryMemorialSloanKetteringCancerCenterChia-LingNhan-Chang,MD,MS,FACOGAssistantClinicalProfessorofObstetricsandGynecology,DivisionofMaternalFetalMedicineDepartmentofObstetrics&GynecologyColumbiaUniversityMedicalCenterPiaOstergaard,PhDSeniorLecturerinHumanGenetics,InstituteofCardiovascularandCellSciencesSt.George’s,UniversityofLondon
TimPadera,PhDAssociateProfessor,RadiationOncology,MassachusettsGeneralHospitalandHarvardMedicalSchoolNeilPiller,PhD,FACPDirector,LymphoedemaClinicalResearchUnitProfessor,DepartmentofSurgeryFlindersMedicalCentreJosephRutkowski,PhDAssistantProfessor,MedicalPhysiologyTexasA&MCollegeofMedicinePhilippScherer,PhDProfessor,DepartmentofInternalMedicineDirector,TouchstoneDiabetesCenterTheUniversityofTexasSouthwesternMedicalCenterHamishScott,PhDHead,DepartmentofMolecularPathologyCentreforCancerBiologyUniversityofSouthAustraliaEvaSevick-Muraca,PhDProfessor,CullenChairinMolecularMedicineDirector,CenterforMolecularImagingUniversityofTexasHealthScienceCenter,HoustonCarrieShawber,PhDAssistantProfessor,ReproductiveSciencesinOB/GYN&SurgeryDepartmentofObstetrics&GynecologyColumbiaUniversityMedicalCenterMelodySwartz,PhDWilliamB.OgdenProfessor,InstituteforMolecularEngineeringUniversityofChicago
JensMarcTitze,MDAssociateProfessor,DepartmentofMedicine,MolecularPhysiologyandBiophysicsVanderbiltUniversityH.EserTolunay,PhDDeputyChief,VascularBiologyandHypertensionBranchDivisionofCardiovascularSciencesNationalHeart,Lung,andBloodInstituteNationalInstitutesofHealthHenricusGerardusJacobusVoesten,MDGeneralandEndovascularSurgeryChiefSurgeon,ExpertCentreforLymphovascularMedicineNijSmellingheHospital
PeterWangDoctoralCandidate,DepartmentofPathologyandImmunologyWashingtonUniversity,SchoolofMedicineAnnalisaZecchin,PhDPostdoctoralFellow,LaboratoryofAngiogenesisandVascularMetabolismVesaliusResearchCenter(VRC)VIB-KULeuven
LIPEDEMAFOUNDATIONREPRESENTATIVES
FelicitieDaftuar,MBAFounderandExecutiveDirectorBoardMemberandFormerPresident,FatDisordersResearchSocietyDanielleWildsteinVicePresident,OperationsShannonSeebergVicePresident,Communications
Table of Contents AUTHORS...................................................................................................................................................1
LIPEDEMASCIENTIFICADVISORYGROUP...........................................................................................1
LIPEDEMAFOUNDATIONREPRESENTATIVES.....................................................................................3
PHILANTHROPIST’SFOREWORD...........................................................................................................5
EXECUTIVESUMMARY............................................................................................................................7
OVERVIEW.................................................................................................................................................8
EpidemiologyofLipedema......................................................................................................................9
HEALTHBURDENANDQUALITYOFLIFE...........................................................................................10
DiagnosisChallenges.............................................................................................................................10
ImpactonQualityofLife.......................................................................................................................10
Pain........................................................................................................................................................11
MentalHealthandPsychosocialStress.................................................................................................12
LIPEDEMADIAGNOSIS,STAGING,ANDPROGNOSIS......................................................................13
DiagnosticCriteria.................................................................................................................................13
TypeandStageofLipedema..................................................................................................................18
PrognosisofLipedema...........................................................................................................................21
DISEASEBIOLOGY..................................................................................................................................22
AdiposeTissue.......................................................................................................................................22
LymphaticSystem..................................................................................................................................23
PainandInflammation..........................................................................................................................24
EndocrineSignaling...............................................................................................................................24
TREATMENTS..........................................................................................................................................25
CLINICALPIPELINE.................................................................................................................................27
RESEARCHCHALLENGESANDPHILANTHROPICOPPORTUNITIES................................................29
NONPROFITORGANIZATIONSINVOLVEDINLIPEDEMA................................................................32
Research-FundingFoundations.............................................................................................................32
PatientSupportandAdvocacyGroups..................................................................................................32
GLOSSARY................................................................................................................................................34
REFERENCES............................................................................................................................................38
5
PHILANTHROPIST’SFOREWORD
Iwastoldtostophavingchildrenbythefirsttherapistwhoconfirmedmysuspicionoflipedema.IwastoldtogotoGermany,getliposuctionandwait18monthsbeforecontinuingtohavechildrenbyanexpert.IwastoldbymyamazingGPthatthelumpoffatandfluidundermykneewaspostpartumdepression,eventhoughIwasn'tdepressed.Ihiredaconciergemedicinecompanytoinvestigate1)Islipedemaarealthing?2)DoIhaveit?3)WhatshouldIdoaboutit?Monthslater:Yes,Yes,Wedon'tknow.SoIdidwhatothersbeforemedid.IsearchedPubmedandGoogleScholarforresearchpapers.Ireadsomeofthem.Iputtheminaspreadsheet.IjoinedFacebookgroupsandLinkedIn-edpeopleIthoughtwouldhelp.Iwenttopatient,researcher,andtherapistconferences.Ihelpedresurrectadefunctnon-profit,theFatDisordersResearchSociety,andtheteamsetupawebsiteandhosted2patientconferences(onewith270attendees!).In2015,Inarrowedmyfocustoresearch,startedtheLipedemaFoundation(LF),andstartedfundingresearchprojects.ButIkeptcomingupshort.Howcouldadiseasethat'sseeminglyeverywherehavesolittlepublished?Suretherearesomedescriptivepapers,casereports,andstudieswithafewpatients.Thereareevenliteraturereviews.Butnopathogenesis.Nogenes.Nobloodtest.Nobiomarkers.Noreplicableimagingtest.Nadazipzero.Icouldn’tfindanswerstomyquestionsaboutlipedema.Whyarepainandswelling(whicharesubjective)recognizedcriteriaoflipedema,butthephysicalchangeinthetextureofthefatisnot?Whyarethereonly5USphysicianswillingtodiagnoselipedema,butthereare12surgeonswillingtooperate,100softherapistswillingtotreat,and2,000patientsparticipatinginFacebookgroups?Domyrelativeshaveit?Aremy3daughtersgoingtogetit?HowcoulditbethatIcarried3children,andmyabdomenlooksbetter,butmylegslookworse?Isitadisease?Acondition?Asyndrome?Idon'tfeelsick,butmybodyisdifferent.WhycanIfeelnodulesoffatinmylegs,butnoonecanimagethemwithultrasound,MRIorahighlytechnicalpieceofequipment?WhyisitthatifIcookhealthymealsandexercisetherightway,Idon'thavepain,butifIgoonvacationmylegsburnwhenIlaydownatnight?DoIreallyneedliposuctionifmyBMIisinthe20s?Willitgetworse?Willitgetbetter?Willitevergoaway?Howislipedemadifferentfromlymphedema,obesity,lipodystrophyandDercum’sdisease?Istheprevalencereally11%ofpost-adolescentwomen?Or5%?Or1%?HowwasInowoneoftheworld'sexpertsinamedicalcondition?
6
Alongcameasmallbandofheroes.Peoplewhohadseenthisbefore.PeoplewhothoughtIwasn'tcrazyforhuntingforanswers.Peoplewhoraisedthelevelofdiscoursearoundsomethingthathadbeenpredominantlypatient-leddiscussions.Peoplewhoknowtheinsandoutsofthetypicaldiseasepathfromdiagnosistotreatmenttocure.TheMilkenInstitute’sCenterforStrategicPhilanthropy(CSP)openeddoorsIcouldn't.Theyperseveredthroughsetbacksthatweretoughformetodealwith.Theyremainedobjectiveandfocused,divingdowndeepintomanyfacetsofthebiologyandthenresurfacingtoputthebigpicturetogether.CSPcouldtalktoresearchersanddoctorsontheirlevel.Theycouldassesswhichexpertiseofresearcherswereneededinordertomoveforward,andbrought20differentspecialtiesintotheconversation.TheheroesaresowellnetworkedaroundDCthattheycouldgetboththeNIDDKandNHLBIrepresentedatourfirsteverLipedemaScientificRetreat.Theyinvitedmetositattableswithotherpeoplelikeme.Theykeptmyexpectationsgroundedandatonepointtoldme:weareattheverybeginningofthecourseofthisdisease;weknownothing.Buttheyprovidedaroadmapandtoolstomoveforward,viaboththisGivingSmarterGuideandaninvaluableprivatereportidentifyingnames,tools,andprojects.Ibecamewe.Wewenttoconferencesandcalledpeoplearoundtheworld.Weworkedtogether.Wewonderedtogether.Weopinedtogether.Wehostedameetingconveningaglobalcohortofthebest-of-the-bestand,andtogetherattheScientificRetreat,wemappedoutthegapsinthefieldoflipedemaresearchsothatwecouldcollaborateandcoordinatetheresearchneededtodefinethespace.Wehavechosentostrategicallyaddresskeyresearchchallengesoflipedema.Fortheshortterm,LF'sfirstpriorityisthesciencebehindthecause(s)oflipedema.Wecannotdomeaningfulresearchintolipedematreatmentsuntilweunderstandthescientificcause(s)ofthecondition.Thereisalackofscientificconsensusonthemostbasicelementsofthisdisease,andLFhassetabouttofixthat.Wecan’tgetanywhereuntilwetacklethefundamentals.Please,readonandbecomepartofourjourney.Takenotesandjotdownideas,thencallLF.We'llbehappytotalktoyouaboutyourideastomovethisforward.Wehavealongroadaheadofusandwe'dlikeyourcompany,becauseittakesavillagetomovediseasesforward.
FelicitieDaftuarFounderandExecutiveDirectorLipedemaFoundation
7
EXECUTIVESUMMARY
Lipedemaisachronicconditionthatoccursalmostexclusivelyinwomenandmanifestsassymmetricalbuildupofpainfulfatandswellinginthelimbs,sparingthehandsandfeet.Acriticalissueisthepoorlyunderstooddiseasebiology,whichfordiagnosedpatientsresultsinlimitedtreatmentoptionsthat,atbest,amelioratethesymptomsoflipedema.Individualswhosufferfromthediseasearefurtherimpactedbytheabsenceofdiagnostictools,thelackofpublicandmedicalawarenessoflipedema,andthestigmaassociatedwithweightgain.Asaresult,thetruenumberofwomenwithlipedema,oritsepidemiology,isunknown.
Bravingthesechallengesisanactive,numerous,andengagedpatientcommunityeagertoparticipateinlipedemaresearch.Supportedbyequallydevotedcaregiversandresearchers,thelipedemafieldpresentsanimmenseopportunityforscientificandmedicaladvancements.Tocapitalizeonthispotential,theLipedemaFoundationandtheMilkenInstitute’sCenterforStrategicPhilanthropyconvenedleadingstakeholderstodiscussthecurrentstateoflipedemascienceandidentifythekeyphilanthropicresearchopportunitiestoadvancethefield.
Littleisknownabouthowandwhylipedemadevelopsinapatient.Althoughthediseaseisreportedtooccurduringpubertyandotherperiodsofhormonalchanges,whythishappensisnotunderstood.Thepainfulfatandswellinginsomepatientscanbesodebilitatingthattheirmobilityisimpaired;yetwhatdrivesthesesymptomsisunknown.Psychosocialissuesarealsoprevalentinwomenwithlipedema,contributingtohealthburdenandcomplexityofdiseasemanagement.Furthermore,manypatientsdevelopthediseasealongsideobesity;however,diet,exercise,andweightlosssurgeryhavelimitedeffectonlipedemafat.Althoughthelackofdiseasebiologyisstaggering,philanthropicinvestmentsinresearchcanleveragethedesireofpatientstoparticipateinstudiestoimprovetheirandtheentirefield’sunderstandingoflipedema.Theconvergenceofmultiplescientifictopicsaroundlipedemaindicatesthataddressingthesegapsinresearchwillalsoimprovetheunderstandingofhormone,painandedema,mentalhealth,andmetabolicbiology.
Therearenodiagnostictoolsortestsforlipedema.Diagnosisoflipedemainvolvesaclinicalassessmentanddiscussionoftheindividual’smedicalhistory,aprocessthatisdifficulttoscalewithinthecurrenthealthcaresystem.Theabsenceofdiagnostictoolstostreamlineorconfirmaclinicaldiagnosisisakeyunmetneed,whichifaddressedbyphilanthropy,hasthepotentialtodramaticallychangethetrajectoryofthedisease.Investinginresearcheffortstoadvancenovelimagingtechnologiestodiagnoselipedemaisapromisingresearchavenuethatwouldsimultaneouslybenefitindividualswhosufferfromthediseaseandhealthcareprovidersunfamiliarwiththecondition.
Thepublicandmedicalcommunityarenotawareoflipedema.Lipedemawasinitiallydescribedin1940,yetlittleknowledgeaboutthediseasehaspermeatedthegeneralpublic,withaconcomitantlackofmentionintheeducationalcurriculumofmedicaltrainees.Addressingthischallengewillrequirephilanthropiceffortstodefinethediseasefromabasic,clinical,anddiagnosticperspective.Akeyphilanthropicopportunityissupportforalipedemapatientregistrylinkedtoatissuebiorepository.Thisefforthasthepotentialtogenerateandsupporttheneededdiseaseresearch,whileengagingpatientsaspartnersinunderstandingthescienceoflipedema.
8
OVERVIEW
Firstdescribedinthe1940s,lipedemaisachronicconditionthatpresentsassymmetricalaccumulationoffatinthesubcutaneoustissuewithalmostexclusiveoccurrenceinwomen.1,2Fattissueexpandsprimarilyinthelowerlimbs,frombuttockstoankles,aswellasinthearms,withweightlossstrategiesexhibitinglimitedeffectsonlimbfat.1,3,4
Lipedemaisfurthercharacterizedbypain,tendernessuponcontact,easybruising,swelling(edema),andpsychosocialissuesthatallimpactapatient’soverallqualityoflife.Onsetoflipedemaisreportedtooccurduringpuberty.5However,itcanoccurorbeexacerbatedbyperiodsofhormonalshifts,suchaspregnancyormenopause,althoughdataastowhyarelimited.6Weightgainandobesityarealsoconsideredtoplayaroleinlipedemaonsetandexacerbationofsymptoms.7
Unmet Clinical and Research Needs
Thelackofaconsistentandscalablediagnosticprocedure,multiplenames(seebox),andlimitedawarenessofthediseaseinthemedicalfieldstymielipedemadiagnosis,culminatinginsparseepidemiologicalinformation.
Theclinicalpresentationandsymptomsoflipedemacancommonlyresultinamisdiagnosisoflymphedema,obesity,Dercum’sdisease,orchronicvenousinsufficiency,resultinginincorrecttreatment(seeDiagnosis).Thusaffectedindividualandthefieldwouldgreatlybenefitfromadiagnostictooltoserveasaninitialtestorconfirmatorytestofaclinicaldiagnosis.
Inaddition,thestaggeringlackoflipedemabasicbiologyresearchhaslimitedunderstandingofthediseaseetiology,ororiginanddriversofonset.
Consequently,patientscontendwithapoorlyunderstoodchronicconditionwiththerapeuticoptionsthat,atbest,onlyamelioratesymptoms.
Synonyms and related terms for l ipedema v Lipoedemav Lipödemv Lipoedemv Lipoedeemv Lipolymphedemav PainfulFatDisorderv Lympholipedemav Lipohypertrophyv Lipohypertrophydolorosav Lipomatosisdolorosaofthelegsv Lipalgiav Adiposalgiav Adipoalgesiav RareAdiposeDiseasev Adiposisdolorosav Dercum’sdisease
9
EPIDEMIOLOGYOFLIPEDEMA
Unfortunately,dataontheincidence(occurrence,rate,orfrequency)andprevalence(commonness)oflipedemaareunknown.Becausemanypeoplewithlipedemaaremisdiagnosedwithlymphedema,themajorityofprevalencevaluesarebasedonthepercentageofpatientsseeninlymphedemaclinics.Thefollowingarecurrentlyavailablebutlimitedlipedemaepidemiologicaldata:
• TheFöldiClinicinGermanystatedaprevalenceinwomenof11percent.However,thispercentagewasderivedbyextrapolatinganestimateofmisdiagnosedlipedemapatientsseekingmedicalattentionintheclinictothegeneralpopulation.8
• TheLymphedemaUnitofUniversityHospitalLaFe(Valencia,Spain)reportedthat18.8percentofthe843patientsseenbyitsclinicfrom2005to2011havelipedema.9
• AreviewofpatientstreatedbyalymphedemaclinicinGermanyfrom1995to1996foundthat15percenthavelipedema.10
• In2003,fourlymphedemaclinicsinGermanyreportedthat8to17percentoftheirpatientshavelipedema.4
• UsingdataaboutpeopleseenbytheregionalDermatologyDepartmentofSt.GeorgesHospital(London,UnitedKingdom),researchersestimatedthat,ataminimum,0.0014percentofwomenhavelipedema.However,theystressthatthispercentageislikelyasignificantunderestimatebecauseofproblemswithmisdiagnosisorfailurebycommunityphysicianstoreferpatients.11
Itisnotablethatmostoftheseepidemiologicaldatacomefrommisdiagnosescapturedbylymphedemaclinics.Giventhepotentialfordiseaseonsetduringperiodsofhormonalshift,thecloserelationshipwithobesity,anddisease-associatedchangesintheskin(seeDifferentialDiagnosissection),researchisneededtodeterminewhetherundiagnosedpatientscanbefoundinObstetricsandGynecological,EndocrineandObesity,andDermatologydepartments,respectively,tounderstandbetterthetruepopulationburdenoflipedema.
10
HEALTHBURDENANDQUALITYOFLIFE
Thechronicnatureoflipedemagreatlyimpactsthephysicalwell-beingandmentalhealth(psychosocialstress)ofpatients.In2012,LipoedemaUKandTheBritishLymphologySocietylaunchedasurveytoprovideobjectivedataandstatisticsonhowwomenwithlipedemawerediagnosedandtreatedbythemedicalprofession,therangeofsymptoms,theefficacyofinterventions,andtounderstandbetterthepatientexperienceoflivingwiththedisease.Thesurvey’skeyfindingsfrom250womenwithlipedemafollow.5
DIAGNOSISCHALLENGES
• Lipedemaispoorlyunderstoodbythemedicalcommunity.Only9percentofrespondentsreportedthattheirhealthprofessionaldiagnosedlipedemathefirsttimetheyreportedtheirsymptoms.Only5percentwerediagnosedbytheirgeneralpractitioner.
• 46percentofrespondentsreportedthatlipedemaonsetcoincidedwithpuberty;however,theaverageageofdiagnosiswas44yearsold.
• Themajorityofrespondentsreportedthatmedicalprofessionalsweredismissiveoftheconditionandmisdiagnosedtheirlipedemaasexcessweight/baddiet/lackofexercise.
• Themostcommonlyreportedresponsetodiagnosiswasrelief.Respondentsalsofeltangryandfrustratedthatdiagnosishadtakensolong,aswellasscaredaboutafuturewithnocureandfewoptionstoamelioratesymptoms.
IMPACTONQUALITYOFLIFE
• Lipedemaaffectsapatient’semotionalstate:87percentofrespondentsagreedthattheirlipedemahashadanegativeeffectontheirqualityoflife.
• Lipedemaalsoaffectspatients’careers:51percentreportedthatlipedemahasaffectedtheirabilitytosucceedintheirchosencareer,commonlycitingalackofmobility,discomfort,andinabilitytostand.Inaddition,39percentbelievedthattheirlipedemarestrictedtheircareerchoices.
• Whenasked“Hasyourbodyshapeleadtoanyofthefollowing?”
o 95percentreporteddifficultyinbuyingclothesandboots
o 86percentreportedlowself-esteem
o 83percentreportedavoidingbeingphotographed,orensuringthattheirbodydidnotappearintheimage
o 76percentreportedlackofenergy
o 60percentreportedrestrictedsociallife
o 60percentreportedfeelingsofhopelessness
o 55percentreportedrestrictedmobility
o 50percentreportedrestrictedsexlife
11
PAIN
Painandtendernessoflipedema-affectedareasisaconsistentlyreportedproblemandposesasignificanthealthburden.Generallyreportedaschronic,thispaincansignificantlyimpactmobilityandoverallqualityoflife.77percentofrespondentstotheLipoedemaUKsurveyexperiencelegpain.5Thefollowingresultsfromlipedemapublicationsandpatientsurveysthatfurtherdescribetheeffectofpainonpatientlives:
• InAllenandHines(1940),andanexpandeddiseasedescriptionbyWoldetal.basedon119lipedemacasereports,foundthatpainwasthedistinguishingcharacteristicfor40percentofpatients.1,3
• Acontextualbehavioralapproachassessmentofthequalityoflifeof120womenwithlipedema,whowererecruitedthroughonlineandFacebookpatientdiscussiongroups,foundthat93percentofthesewomenexperiencedlipedema-associatedpainandtenderness(sensitivitytotouch),withalmosthalfofthemratingthesymptomsasseveretoextremelysevere.12
• Amedicalchartreviewandsurveyof50lipedemapatientsseenbyanacademicmedicalcenterreportedthatnearly90percentexperienceddailypain.13
• Anapplicationofthevisualanaloguescale(VAS),whichisapsychometricresponsescaleusedinquestionnairestomeasuresubjectivecharacteristicsorattitudesthatcannotbedirectlymeasured,wasusedtoquantitativelyassesslipedema-associatedcharacteristicsin25pre-liposuctionsurgerypatients.Mostpatientsreportedpaininlipedema-affectedareas,and,sixmonthsaftersurgery,theyreportedasignificantreductioninpainfrom7.2to2.1VASpointswithaconcomitantimprovementinpsychologicalstressfrom8.7to3.6VASpoints.14
12
MENTALHEALTHANDPSYCHOSOCIALSTRESS
AsdescribedbytheLipoedemaUKsurvey,patients’qualityoflifecanbeaffectedbymorethanthesymptomsandphysicalissuesassociatedwiththedisease.5,12,15,16Patientsmustalsocontendwiththementalhealthissuesthatoftenaccompanythechallengesofmanaginglipedema.Itiscurrentlyunknownwhethermentalhealthissuesprecedeoroccurwithonsetoflipedema;however,suchstressorsaffectpatientqualityoflifeintermsof:
• Psychologicalhealth(e.g.,anxiety,depression)
• Levelandqualityofsocialrelationships,includingsupportandengagementoffriendsandotherlipedemapatients(seebox)
• Perceptionoftheenvironment(e.g.,stigma)
Toaccountforpsychosocialstress,theDutchSocietyofDermatologyandVenereologydevelopedaguidelinesdocument(DutchLipedemaGuidelines)whichincludedaholisticassessmentandcaremodelthatassessesapatient’sphysicalstateandlevelsofpsychosocialdistress.7,17Thismodelwasbasedonevidence-andexpert-basedrecommendationstoinformanddefinethecriteriaforamedicaldiagnosisoflipedema.
Importantly,theguidelinesproposeaminimumdatasetofrepeatedclinicalmeasurements,orclinimetrics,tooutlineandassessachroniccaremodelforlipedemameasuringtheimpactandsuccessofconservativetreatmentprogramsforthedisease(seeTreatmentssection).17-19Thevalueofthisclinimetrics-basedcaremodelisderivedfromitsholisticapproachtoassessingapatient’sphysicalstate,dailyandindividual-driventreatmentprogram,andlevelsoflipedema-associatedpsychosocialdistress.
TheapplicationofclinimetricstoevaluatediagnosisandtreatmentisexemplifiedbythecalculationofmeanVASvaluesbeforeandafterliposuctionsurgerytoassesschangesinpainandpsychosocialstress.14
Alongwiththeactiveandconnectedlipedemapatientcommunity,theseeffortssetthestageforaholisticandquantitativelydrivenapproachthatwillhopefullycaptureandunderstandthetruehealthburdenoflipedema.
Facebook L ipedema Pat ient Groups Highlevelsofsocialconnectednesswerefoundtocorrelatewithhighlevelsofqualityoflifeandsatisfactionoflife.Listedbelowareonlinepatientgroupsfocusedonlipedema:
v FriendsofLipedemaSistersUSA(anyonecanjoin)
v FatDisordersResearchSociety(FDRS)v LipedemaSistersUSAv LipedemaEducationv LovingLifewithStage1and2Lipedemav LipedemaStage3and4v LipedemaFitnessv LiposuctionforLipedemav LipedemaUSAEspañolv LipedemaCanadianSupportGroupv LipoedemaAustraliaSupportSocietyv LipoedemaUKv LipoedemaLadiesUKv TalkLipoedema
Somegroupsareprivateandrequestthatinterestedpeopleagreetotheirrulesbeforecontactingorjoiningthegroup.
13
LIPEDEMADIAGNOSIS,STAGING,ANDPROGNOSIS
DIAGNOSTICCRITERIA
Diagnosinglipedemainvolvesatakingthemedicalhistoryandperformingaphysicalexaminationofthepatient.7Asthefieldlacksadiagnostictest,cliniciansconsidermultiplecriteriatodeterminewhetheranindividualhaslipedema.Thefollowingsectionsdescribethesecriteria,aswellashowlipedemaisdifferentiallydiagnosedfromlymphedema,obesity,Dercum’sdisease,andchronicvenousinsufficiency.
Allen & Hines diagnostic criteria Lipedemawasfirstdescribedin1940byAllenandHines.In1949,Wold,Allen,andHinespublishedaseminalreportthatelaboratedontheclinicalpresentationandproposeddiagnosticcriteria,basedon119cases.1,3Becauselipedemaiscommonlymisdiagnosedaslymphedema(seebox),theproposeddiagnosticcriteriaweredesignedtodistinguishbetweenthetwodiseases.Stillusedtodaythecriteriainclude:
1. Almostexclusiveoccurrenceinwomen
2. Abilateralandsymmetricalaccumulationofadiposetissue(bodyfat)onthelegswithminimalinvolvementofthefeet,resultinginabraceleteffectorcuffattheankle(Figure1,A)
3. MinimalpittingedemaandnegativeStemmer’sTest(Figure1,B)
4. Painandtendernessofaffectedtissue
5. Persistenceofthetissueenlargementdespitecaloricrestrictionorstimulationoflymphaticflowthroughelevationoftheextremities
6. Increasedvascularfragility,andeasybruising
Figure1:VisualizationofLipedemaDiagnosticCriteria.(A)Front,side,andrearviewofalipedemapatient’sanklecuffs.Woldetal.notedthepresenceofprominentinnerankle,ormalleolarfatpads(rear).(B)Pittingedemaiscommoninlymphedema,whereinapplicationofpressure(left)leavesanindentationinthetissue(right).ImagescourtesyoftheFatDisordersResearchSociety(A)andWikimediaCommons(B).
Lymphedemaisabuildupofthefluidsurroundingtissues,orinterstitialfluid,inthemuscleandskinleadingtoincreasedfatdeposition.Thediseasecanbehereditary(primarylymphedema)orarisefromdamagetothelymphaticsystemfromdifferentinsultssuchascancer,surgery,radiationtherapy,trauma,orinfection(secondarylymphedema).Itcanoccurinbothmenandwomenandpresentsasunilateralorbilateralswelling—mostofteninthearmsorlegs.CommonpresentationsincludepittingedemaandpositiveStemmer’sTest;swellingthatrespondstoelevationchanges;afeelingofheaviness;restrictedrangeormotion;discomfort;recurringinfections;andhardeningandthickeningoftheskin.
B
14
Clinical characteristics of lipedema Treatmentprovidersusethefollowingcriteriatofacilitateadifferentialdiagnosisoflipedemafromotherdiseases.
Lipedemaischaracterizedbyaccumulationoffatonthelimbs,whichcanbepainfulandfeelnodular.Thisfatbuild-upnecessitatesadifferentialdiagnosisoflipedemafromobesityandDercum’sdisease.(Table1)
• Disproportionalfatdistributiononthelegs,withoutasimilarlyproportionalbuildupintheupperbody/trunkregion,isakeydistinguishingcharacteristicoflipedema.ThisfatdistributionisunlikethatforobesityorDercum’sdisease,inwhichfataccumulatesatthetrunkandthroughoutthebody4,20,21.Becausemanylipedemapatientsarealsoobese,considerabledebateexistsregardingwhetherobesitybegetslipedemaorviceversa.22
• Unlikethesmoothfeelofobesefat,reportsindicatethatlipedemafatcanpresentwithpalpablenodules–describedasfeelinglikefrozenpeasinabagorpearls–whichcanbemorenoticeablyfeltatlaterstagesofthedisease.4,6ThisnodularityissimilartothediffusetypeofDercum’sdisease.6,24
Table1:DifferentialDiagnosisbetweenObesity,Dercum’sDiseaseandLipedema4,6,20,23
Obesity Dercum’sDisease Lipedema
Areasofexcessfataccumulation
Trunk,throughoutbody Trunk,throughoutbody ArmsandLegs
Tendencytobruise Mild Mild-Moderate Moderate-Severe
Painassociatedwithfat Mild Severe Moderate-Severe
Presenceofnodularfat No Yes Yes,especiallyatlaterstages
Comorbidwithdiabetes Yes Yes No
Comorbidwithhypertension Yes Yes No
Dercum’sdisease,alsoknownasadiposisdolorosaandMorbudDercums,isararediseasethatoftenpresentswithgeneralobesityandpainfulfatinaffectedareas.21Unlikethesmoothfeelofobesityfat,Dercum’sdiseasefatcanfeelnodularwhenpalpated,andformmassesoffattissue(lipomasorangiolipomas).Dercum’sdiseaseisclassifiedbasedontheareasoffatthatexperiencepain:diffuse,widespreadpainfrominareaswithfattissue;nodular,intensepaininandaroundfattissuewithnodulesorlipomas;andmixed.6Thediseaseismorecommoninwomenthanmen,withtheaverageofonsetbetweentheagesof35-50,buthasbeenreportedtooccurearlier.22
15
• AlthoughthefatdistributionbetweenlipedemaandDercum’sdiseaseisdifferent,thehighprevalenceofobesityinbothpopulationsincreasesthechallengeofaccuratelydiagnosinglipedema.ThenodularityandpainassociatedwiththefatlipedemaandDercum’sdiseasefurtherincreasesthecomplexityofdifferentialdiagnosis.
Theageofonsetforlipedemahasbeenreportedtooccurprimarilyduringpuberty.5Furthermore,patientshavereporteddevelopmentorexacerbationoflipedemaduringtimeperiodssurroundingpregnancyormenopause.3,9,11
Swellingoredemaofaffectedregionsworsenswhilestandingupright(orthostasis)andduringhotweather.3,6Thepresenceofedemainlipedemacontributestoamisdiagnosisoflymphedema.4
Vascularchangeslikespiderveinsandtelangiectasiaarepresentinlipedema-affectedareas(Figure2).3,11Becausethesevascularmanifestationsalsooccurinpatientswithchronicvenousinsufficiency(CVI),withadvancedcasesdevelopinguni-orbilateraledemaandswellingofthelegsknownasphlebedema,CVIisadifferentialdiagnosisthatrequiresconsideration.4,25
Theskinelasticityisreducedinlipedema-affectedareas,suggestingimpairedconnectivetissuebeneaththeepidermis.6,26Insomecases,theskinalsofeelscoldtothetouchbutisnotfirmorhardenedasinlymphedema.6,27
Lipedemaisalsoconsideredtohaveaheritabilitycomponent,becausepatienthistoriesoftenrefertorelativeswithsimilarlegandbodystructure.3PedigreestudiesfromasingleacademicmedicalcentersuggesteitheranX-linkeddominantinheritance,orautosomaldominantinheritancewithsexlimitation.11However,morestudiesarerequiredtoaccuratelydeterminethegeneticarchitectureoflipedema.
Figure2:SpiderVeinsandVenousManifestationsonaWomanwithLipedema.(Top)Rightleg,(Bottomleft)rightfoot,and(Bottomright)leftcalf.ImagescourtesyoftheFatDisordersResearchSociety.
16
Table2:DifferentialDiagnosisofLipedemavsLymphedemavsObesityvsCVI6,25,28–31
Lipedema Lymphedema(PrimaryandSecondary)
Obesity Phlebedema,ChronicVenousInsufficiency
DiseasePresentation
Symmetricalfatdepositionandswellinginlegsand/orarms,butnotthefeetorhands
Fatdepositionandswellinginaffectedlimb,includinghandsorfeet
Widespreadfatdeposition,withthepotentialforswellingduetocomorbidities
Nofat,butswellinganditchyareasnearankleswithabrownishdiscolorationoflowerlegs
Sex Almostallfemale Malesandfemales Malesandfemales Malesandfemales
DiseaseOnset Duringhormonalshifts(puberty,pregnancy,menopause)andperiodsofweightgain
Primary:Congenital,duetopresenceofgeneticmutationsSecondary:Duetodamagetothelymphaticsystem
Ageindependent Duringpregnancyoronsetofcomorbiditiessuchasobesity,diabetes,orhypertension
PresenceofPain
Yes,inaffectedtissues
Discomfortandachingcanoccurovertime
Yes,chronicpainassociatedwithcomorbidities
Yes,inaffectedareas
ImpactofCaloricRestrictionandExerciseonFat
Limited None Weight-lossstrategiescanbeeffective
Notapplicable
RiskofCellulitis
No Increased Increased Increasedriskinareasaffectedbyedema.Itchyanddiscoloredareaswitheczemacanlooklikecellulitis
Heritability Potential Primarylymphedemacanbeinherited
Potential Potential
Forfurtherdifferentialdiagnosistools,see:
• DifferentialDiagnosis:ApproachtothePatientwithSwollenLegs
• FatDisordersResearchSocietyContinuingMedicalEducation
17
Hypermobility in lipedema patients Accordingtoarecentstudyof160lipedemapatientsfromasingleacademicmedicalcenter,58percentdemonstratedhypermobilityofthejoints,asdeterminedbyBeightonScore23(Figure3).Hypermobilityistheabilitytomovejointsbeyondthenormalrangeofmovement,althoughaBeightonScoreofhigherthan5isnottheonlycriterionforhypermobility,becauseothersignsandsymptomsofthesyndromearerequiredforanaccuratediagnosis.32,33
Diagnostic devices and lipedema Todate,noimagingassayisapprovedasaninitialdiagnostictoolortesttoconfirmaclinicaldiagnosisoflipedema.Althoughmultipleimagingtechniquessuchasmagneticresonanceimaging,34,35computedtomography,36lymphscintigraphy,37dual-energyX-rayabsorptiometry,38indirectlymphangiography,39andultrasound35haveallbeenappliedtoandgeneratedconsiderablelipedema-specificdata,moreresearchisneededtodeterminewhetheranindividualmodalityorcombinationofimagingtestscansuccessfullydiagnosethedisease.
Figure3:HypermobilityinWomenwithLipedema.Examplesofhypermobilityof(A)hipjoints,(B)shoulder,elbow,andwristjoints,and(C)fingerjoints.ImagescourtesyoftheFatDisordersResearchSociety.
18
TYPEANDSTAGEOFLIPEDEMA
Nearly97percentand30percentofwomenwithlipedemapresentwithfatonthelegsandarms,respectively.4,10,28Differentclassificationschemesexist,andthisreportwillutilizetheType(I-V)andStage(1-4)parametersasdescribedbySchmellerandMeier-Vollrath.4,6OtherclassificationsystemsincludethoseusedbycliniciansinAustralia,UnitedKingdomandtheNetherlands.7,11
Lipedematypedescribestheareasofthebodywithfat,whilestagesindicatethelevelofthefataccumulationandrelatedcomorbidities.Itshouldbenotedthatawidevarietyofdiseasepresentationexists,anditisnotfullyunderstoodwhethereachpatientprogressesthrougheachstage.6Thefollowingimagesareofwomenwithdifferenttypesandstagesoflipedema,andareprovidedcourtesyoftheFatDisordersResearchSociety.Unfortunately,imagesofeveryiterationofType/Stage(e.g.,TypeI/Stage3,TypeIVb,TypeV)arenotavailable.Thefullphotoessaycanbefoundhere.
LipedemaType:Areasofthebodywithfataccumulation
Type I:Pelvis,buttocks,andhips
Type II:Buttockstoknees,withformationsoffoldsoffataroundtheinnersideoftheknee
Type III:Buttockstoankles
Type IV a-c:a,Upperarm;b;Lowerarm;c,Wholearm
Type V:Kneestoankles
LipedemaStages:Diseasepresentationandlevelsoffataccumulation
Stage 1:Normalskinwithenlargedsubcutaneoustissue
Stage 2:Unevenskinwithindentationsinthefat;largermoundsoffattissue(lipomas)arepresent
Stage 3:Largeextrusionsoftissuecausingdeformations;especiallyonthethingsandaroundtheknees
Stage 4:Developmentoflipolymphedemawithlargeoverhangsoftissue Figure4:LipedemaTypeIwithFatAccumulationatthe
Pelvis,Buttocks,andHips.(Top)Stage1;(Bottom)Stage2,notethepresenceofindentationsintheskin.Whitearrowsindicateendingoflipedemafatabovetheknees.ImagescourtesyoftheFatDisordersResearchSociety.
19
Figure6:LipedemaTypeIIIwithFatAccumulationfromButtockstoAnkles.(Top)Stage1;(Middle)Stage2;(Bottom)Stage3,notethatthisimageisnotscalewiththeothersbecauseonlythelowertorsoisvisualized.ImagescourtesyoftheFatDisordersResearchSociety.
Figure5:LipedemaTypeIIwithFatAccumulationfromtheButtockstoKnees,andFormationsofFoldsofFataroundtheInnerSideoftheKnee.(Top)Stage1;(Middle)Stage2;(Bottom)Stage3.ImagescourtesyoftheFatDisordersResearchSociety.
20
Transitionoflipedematolipolymphedema(Stage4)canoccurduringstages2or3andinvolvesdevelopmentoflymphedemaclinicalcharacteristicssuchasapositiveStemmer’sTest,increasedfibrosisandstiffeningofskin,andswellingandadiposetissuebuildupatthehands,feet,trunk,andhead.
Figure7:LipedemaTypeIVArmPresentationwithFatAccumulationattheUpperandLowerArm.(A)TypeIVa,Stage3sideandrearview.(B)TypeIVc,Stage3sideviews.ImagescourtesyoftheFatDisordersResearchSociety.
B
A
Figure8:TypeIII,Stage4Lipolymphedema.(A)Frontview.(B)Rearview.Pleasenotethatfor(A)and(B)thepatientdoesnotexhibitthecharacteristicaccumulationoffatseeninmanyStage4patients.(C)Demonstrationofhypermobility.(D)TypeIVcarmpresentation.ImagescourtesyoftheFatDisordersResearchSociety.
A B C
D
21
PROGNOSISOFLIPEDEMA
Theprognosisoflipedemaisnotfullyunderstood.4,13Althoughthestageoflipedemadescribestheseverityoffataccumulation,somepatientsmayremainatonestageformanyyears,whileothersmayrapidlyprogressthroughstagesasaresultofstressfulevents(surgery)orchangesinoverallweight.28,40,41Theoccurrenceoflipedemafromlipohypertrophyortolipolymphedemaandobesityisdiscussedbelow:
• Lipohypertrophy―Thesimilarphysicalmanifestationsoflipohypertrophyandlipedemaraisethequestionofwhethertheformerisanearly-stageprecursortothelatter.Casereportsindicatethatpatientswithlipohypertrophycandeveloptolipedema;however,theexacttriggersofdiseasetransitionarenotunderstood.4,9
• Lipolymphedema―Lipedemapatientscandeveloplymphedemasuddenly,gradually,ornever.Theexactdriversofsecondarylymphedemaisnotfullyunderstood;however,developmentofthiscomorbidityresultsinstage4lipolymphedema.28Furthermore,itispoorlyunderstoodwhetherthediseaseprogressionisdrivenbyanincreaseinlocalizedfatorbuildupofedemainaffectedareasthatdrivesdegradationoflymphaticfunctionand/oranincreaseinfibrosis,andtherebyresultsinprogressiontolipolymphedema.4,42
• Obesity―Lipedemapatientsmayalsopresentwithobesity.TheFöldiClinicreportedthatthemajorityoflipedemadiagnosesoccurinobeseindividuals.22However,howdiseaseprognosischangesifobesityorlipedemaistheinitialinsultisnotknown.20
Overall,moreresearchisneededtounderstandfullyhowlipohypertrophy,lymphedema,obesity,andlipedemaaffecteachother’sprognosis.Furthermore,lipedemaisoneofseveralfatdisorders,suchasDercum’sdisease,Madelung’sdisease,andlipodystrophy,andexactlyhowthesedisordersaresimilarordifferintheirbiologyispoorlyunderstood.6Increasedresearchandawarenessofthemedicalfieldofthesharedanduniquepathwaysacrossallthelistedconditionswouldultimatelyimprovetheoutlookforallpatientsaffectedbythesediseases.
Lipohypertrophyisaconditionthatexhibitsahighlysimilarbodyshapetoearly-stagelipedema.Patientswiththisconditionpresentwithfataccumulationinthelowerlimbs,rarelyinthearms,and—criticalforadifferentialdiagnosis—donotexperiencepainorbuildupofedemaintheaffectedareas.Althoughreportsindicatethatpatientswithlipohypertrophyhavedevelopedlipedema,moreresearchisneededtodeterminewhethertheconditionservesasaveryearlystageoflipedema.4LipohypertrophyisatermismorecommonlyusedinEurope.ThetermisusedintheUnitedStates,butisunrelatedtolipedema,whereinitreferstothebuild-upoffatatsitesofinsulin-injection.
22
DISEASEBIOLOGY
Littleisknownaboutthebasicbiologyandetiologyoflipedema,withmostpublicationsfocusedonthevascularandlymphaticfindingsofsurgeonsandphysicaltherapists.Thetissuemostaffectedbylipedemaisskin,composedoftheepidermis,dermis,andhypodermis―andincludesthefatthatexpandsinpatients.Giventhedisease’spresentationofadipose,lymphatic,andinflammationissues,aswellasapotentiallinktoendocrinesignaling,itishighlypossiblethatresearchershaveonlyjustbeguntoexplorethebiologyunderlyingthedisease.43
ADIPOSETISSUE
Adipocytes(fatcells)areapartoftheendocrinesystemandarethemajorcomponentofadiposetissue(bodyfat).Thereareseveralsitesofadiposetissuestorage,ordepots,andtheycanbroadlybedividedintovisceral(locateddeepintheabdomen),subcutaneous(locateddirectlybelowtheskin),andectopic(aroundorgansliketheliver,andwithinmusclefibers)depots.44Subcutaneousdepotsarepresentthroughoutthebody,includingtheface,chest,arms,legs,abdomen,andbuttocks.Lipedemacanaffecttheseveralsubcutaneousdepotsbutpredominantlyimpactsthelegsandarms.4,13
Insubcutaneousadiposetissue,adipocytesaresurroundedbyfluidthatbathesthecells(interstitialfluid),anetworkofproteinsthatprovidestructureandstability(extracellularmatrix),aswellasothercellsimportantforadiposetissuephysiology45(Figure9).Otheradiposetissuecellsincludeadipocytestemcells(thecellsourceofadipocytes),immunecells,andtissueandbloodlymphaticcapillariescomposedofendothelialcells.46
Dependingondiseasestage,reportsindicatethatthefeeloflipedemaadiposetissuecanrangefromsmooth,granular,tonodular.1,4,6,28Furthermore,MRI,CTscans,andtissuebiopsiesindicatethat,intheearlystagesoflipedema,edema(composedofinterstitialfluid)isminimal,andthatadiposetissueexpansionislikelyduetoadiposecellenlargement(hypertrophy)and/oranincreaseinnumber(hyperplasia).42-46Researchershavehypothesizedthattheedemaassociatedwithlipedemamayinvolveimpairmentoflymphaticvesselsduetopressureexertedbyfattissue,whichsubsequentlylimitstheinwardflowofinterstitialfluid.42,43Limitedresearchhasbeenperformedtoassesswhetheradiposegrowthandsubsequentimpairmentlymphaticvesselsplaysarolecausativeroleinlipedema.
Despitethecentralroleofadipocyteexpansioninlipedema,littleisknownaboutthecharacteristicsofthesecells.Forexample,themechanismsofhyperplasiaandhypertrophyaredistinct,withtheformerdrivenbycelldivision,andthelatterbasedinthetissue’sneedforadditionalfatstorage.43,47Adipocytes,ascomponentsoftheendocrinesystem,respondtoandreleaseavarietyofmoleculesthatmayberelatedtolipedema.Theseincludethekeyplayersinhormonalresponse,levelsofinflammationandtheresultingpainandtenderness,andmetabolism.52Towhatextentthesegrowthandsignalingactivitiesareon/offorimpairedisunknownforlipedema.
Figure9:SubcutaneousAdiposeTissue.Pinkcellsareadiposecells,greenisthelymphaticvessel,andlightgreencellsarelymphaticendothelialcellsthatserveasthewallofthelymphaticcapillary.Greenarrowsindicatetheflowofinterstitialfluidintothelymphaticvessel.ImagemodifiedfromWikimediaCommons.
23
LYMPHATICSYSTEM
Thelymphaticsystemiscomposedofanetworkoflymphaticvessels,thefluidinthevesselscalledlymph,andlymphnodesthatfilterlymphasitpassesthroughthem.Thesystemalsoincludesthetonsils,adenoids,spleen,andthymus.Unlikeblood,thelymphaticsystemisnotpumpedbytheheart,butinsteadreliesonthemovementofthediaphragm,musclecontraction,skintension,andthefluidpressuresinthebloodcapillaries,lymphaticcapillariesandinterstitialspacetopropellymphfluidfromacrossbodytowardsthetrunk.53Previouslyderidedas“thebody’ssewersystem,”thelymphaticsystemisnowunderstoodtobeapartofthecirculatorysystemandavitalcomponentoftheimmunesystem.
Adiposecells,likeanycellinthebody,arefedbybloodthroughbloodcapillaries,andbloodreturnstomaincirculationbysmallveins,orvenules.45Theinterstitialfluid,fluidthatleavesthecells,bathesandsurroundstheadiposetissue,beforeflowingintolymphcapillariesandeventuallyintolymphaticvessels,therebycomprisingthemajorityoflymphfluid(Figure10).
Inlipedema,theedemaexperiencedbypatientsisprimarilycomposedofinterstitialfluidanditscomponents.4,42,54Theswellingoflipedematissuehasbeenfoundtohaveanincreaseininterstitialspace,hypothesizedtoresultfromtheincreaseinfluid.20Thusthepresenceofedemainearlystagesoflipedemaindicatesaslightimpairmentofthelymphaticsystem’sabilitytotakeupfluid.48
Previousworkhasshownthatsomelipedemapatientspresentwithleakylymphaticcapillariesandvessels,referredtoasmicroaneuryms.55,56Ascomponentsofthevascularsystem,spiderveinsandvascularchangesinlipedemapatientsalsosuggestalevelofmicroangiopathy(diseaseofthesmallbloodvessels).57Acouplingoftheseresultswouldsuggestthatlipedemamaybedrivenbyvascularissuesthatmanifestinincreasedbuildupofedema,andsubsequentlimitationsoffluidremovalfromtheinterstitialspace.8
Thecomplexbidirectionalrelationshipbetweenimpairmentofthelymphaticsystemandgrowth/enlargementofadipocytesisapotentialdriveroflipedema,aslate-stagepatientsdemonstrateboth.However,toshedlightontheinitialinsultthatcauseslipedemaonset,moreresearchisneededtodeterminewhetherlymphaticdysfunctionarisesfromanintrinsicimpairedlymphaticandvascularactivityorisasecondarymanifestationofthediseasearisingfromthepressureexertedbyexpandedadipocytesonthelymphcapillariesandvessels.
Figure10:InterstitialSpaceofAdiposeTissue.Theredandtransitiontobluetubesdepictsthetransitionofbloodfromthecapillarytovenule;theyellowcellsrepresentadiposetissue;thegreentubesrepresentthelymphaticcapillariesandvessels;andtheblackarrowsshowtheflowofinterstitialfluidintothelymphaticsystem,andsubsequentrenamingtolymphfluid.ImagemodifiedfromWikimediaCommons.
24
PAINANDINFLAMMATION
Thepainandtendernessexperiencedbylipedemapatientssuggestsanactivatedstateofinflammationwithinthesubcutaneousspace(Figure11).Withintheepidermis(dermisandadiposetissuethatcomposethesubcutaneousspace),multipleimmunecellsplayaroleinactivatingandmediatinganinflammatoryresponse.58Althoughnoresearchhasbeenperformedonwhetherdendriticcells,Tcells,orLangerhanscellsplayaroleinthesymptomsoflipedema,activatedmacrophageswerefoundinasinglestage4lipolymphedemapatient.59
Researchisneededtodeterminetheroleofanactivatedimmunesysteminlipedema,anditspotentialimpactonthepainassociatedwiththedisease.Furthermore,stressisknowntoplayaroleininflammation,andwhetherthelong-termmentalhealthissuesexperiencedbylipedemapatientscontributestoimmuneactivationiscompletelyunknown.
ENDOCRINESIGNALING
Theendocrinesystemisthecollectionofglandsthatproducehormonesthatregulateahostofbodilyfunctions.Giventhealmostexclusiveoccurrenceinwomenanddiseaseonsetduringpubertyandperiodsofhormonalshift,thereisapotentialroleforfemale-specifichormonesinlipedemaetiology6(Figure12).Aroleforsex-specifichormonesisalsosupportedbytherareoccurrenceoflipedemainmen.2
Giventhecentralroleofestrogen,itsnumeroustypes,receptors,andinvolvementinmanybiologicalprocesses,researchisneededtounderstandwhetherdiseaseonsetisaffectedbytheestrogenpathway.23,60,61Furthermore,estrogenanditstypescompriseonlyaportionofthesex-specifichormonesthatfluctuateduringperiodsofhormonalshift;thusmoreresearchisneededtounderstandtheoverallroleofhormonesinlipedema.
Figure11:ImmuneCellsintheSkinOccupyDistinctLocationsandFunctionalRoles.TheseimmunecellsincludeTcells,Langerhanscells,lowerlayerofskindendriticcells(dermalDC),innatelymphoidcells(ILC),andmacrophages.FigurecreatedbyRachelCotton,JustSkin.Deep–YourImmuneSystemattheSurfaceforPLOSBlogs.
Figure12:Sex-specificHormonesProducedbyReproductiveEndocrineOrgans.ImagecourtesyofWikimediaCommons.
25
TREATMENTS
Lipedemaisachronicdiseasewithlimitedtherapeuticoptions.Becausethecausesordriversofdiseaseonsetremainunknown,currentlyavailabletherapiesaregearedtowardamelioratingsymptomsandpreservingpatienthealth.TheDutchLipedemaGuidelinesalsodevelopedclinimetricstoassessthehealthprofilesofpatientsundergoingtherapyforlipedema.Thesemeasurementsincludecircumferenceoflipedemaaffectedareas,mobility,strength,painviatheVAS,fatigue,weight,levelsofactivity,conditionandwalkingcapacity,andqualityoflife.7,17
CONSERVATIVETHERAPY
Thegoalofconservativetherapyistoaidindiseasemanagementandaddressthesymptomsassociatedwithlipedema.7TheFatDisordersResearchSocietyprovidesvideosthatcomprehensivelydescribetreatmentoptions.Itiscriticaltonotethatalthoughthetreatmentsbelowarewhatpatientsandcaregiversemploytoaddresslipedema,limitedresearchisavailabletounderstandwhycertaintreatmentsareeffectiveorineffectiveforpatients.
Exerciseisakeycomponentofconservativetherapyandservestoreduceorstabilizeweight,strengthenmuscles,improvebloodandlymphflow,andboostmentalhealth.5,16,17,62Commonlyusedexercisesincludelow-impactworkoutssuchaswalking,lymphaticyoga,rebounding,cycling,andPilates.Aquaticexerciseinvolvessubmersioninapooltoperformlow-impactexercises.5,63
Healthyeating,suchastheRareAdiposeDiet,PaleoDiet,andAnti-inflammatoryDiet,isastrategythathasbeenusedbythepatientcommunity.Althoughtheeffectsandsuccessofspecificdietsdifferfrompatienttopatient,regularexerciseandpropernutritionwillaffectbodyfat,therebyimprovingapatient’swell-being.16,64
Psychosocialcounselingandsupportgroupsareimportantduetothementalhealthissuesassociatedwithlipedema.Patientsareencouragedtoparticipateinsupportgroups,engagetheirfriendsandfamily,andseektheaidofmentalhealthprofessionalstosupportdiseasemanagement.5,30,62
Locomotion(orthopedic)problemsandlackofpropershoewearareverycommoninpatientswithlipedemaandleglymphedema.Thisissuenegativelyimpactsupwardtransportoffluidfromthelegs,therebycontributingtothebuildupandprogressionofedema.Flatfeetshouldbeanalyzedandtreatedwithadequateshoes.Mechanicalhindranceduetoenlargedfatdepositsontheinnerandupperthighsshouldbetreatedaspossible,asthiscandirectlyimpactpatientmobilityandhealth.65,66
Compressiontherapyinvolvesgarmentsthatcanbefittedtospecificareasaffectedbylipedema.Theseincludebandagingwithgarmentswithinelasticsystems,andwrapswithVelcroattachmentstoallowforeasywearandadjustment.Thesegarmentsworkbyapplyingpressuretotheaffectedlimbstokeeplymphmovingfromthetissuesintothevesselsandareusefulforpatientswhoexperienceedemabuildup,andhavebeenreportedtoreducepain.5,16,17
Manuallymphaticdrainage(MLD),sometimescalledmanuallymphatictherapy,isaspecifictypeofmassagedesignedtomoveexcessinterstitialfluidoutofthetissuesandintothelymphaticvessels.ThegoalofMLDistoincreasetheflowoflymph,therebygeneratingasuctioneffectanddrivinglymphfromafluid-richareatoafluid-poorarea.5,16,30,67AlthoughMLDisstandardtherapyforlymphedema,itssuccessfortreatinglipedemaisconsideredunproven.17
26
Completedecongestivetherapy(CDT),alsocalledcomplexdecongestivetherapyanddecongestivelymphatictherapy,isaprogramthatcombinesmultipletreatmentapproachestoreducetheswellingandedema-relatedsymptomsoflipedema.Tailoredtotheindividual,CDTinitiallyinvolvesregularsessionswithaphysicaltherapistinvolvingMLDorintermittentpneumaticcompression,useofbandagingandcompressiongarments,andtherapeuticexercises.57Oncetheswellingisreduced,patientself-managementinvolvesapplicationtheirownbandaging,compression,andexerciseinanefforttomaintainthereductioninswelling.5,16CDTandMLDhavebeenshowntoreducecapillaryfragilityinlipedemapatients,buttowhatextentthisimpactsthediseaselong-termisnotfullyunderstood.57
Deepbreathingisbeneficialasitactivatesthediaphragmandpromoteslymphaticpumping.63
SupplementssuchasButcher’sBroomandseleniumhavebeenusedbypatientswithisolatedandanecdotalreportsofimprovementoflymphaticflowandlimbreduction.68
LIPOSUCTIONANDREDUCTIVESURGERY
Surgeryistheonlyavailabletechniquetocorrectabnormaladiposetissue.Twotypesofsurgeryhavebeenusedinlipedematreatment,liposuctionandreductivesurgery.
Liposuctionisasurgicaltreatmentthatinvolvesapplicationofgeneralorlocal(tumescentandwater-assisted)anesthesia,andsubsequentremovalofadiposetissuethroughastraw-likedevicecalledacannula.42Oneendofthecannulaisconnectedtoavacuumdevice,andtheotherendisinsertedthroughasmallincisionoftheskinandremovesfatviaaspiration.
• Tumescent l iposuction involvesintroductionoflargevolumesoftumescentsolutionintothesubcutaneousspacetotumesce(swell)thearea.Thesolutioncontainsananesthetic,whichinduceslocalnumbing;epinephrine,whichcausesconstrictionofbloodvesselstoreducebleeding;andsaline,whichcausesswellingoftheadiposetissue.Thesolutionisallowedtoinfiltratethetissue,anditshighsalinitycausestheadiposetissueandcellstoswellandseparatefromtheconnectivetissue,atwhichpointthecannulaisusedtoaspiratethefat.14,20,69,70
• Water-assisted l iposuction doesnotinvolveover-swellingoftheadiposetissue.Instead,smallamountsoftumescentsolutionandwaterareintroducedintotheadiposetissue.Oncesufficientnumbingoccurs,amodifiedcannulawithanattachedfan-shapedwaterjetisinsertedintothesubcutaneousspaceandappliedtoseparatetheadiposecellsfromthetissue,whilesimultaneouslyaspiratingthesolutionanddetachedcells.71
Althoughliposuctionhasbeenmorecommonlyusedtotreatlipedema,theDutchlipedemaguidelinesstatethat“[liposuction]isonlythetreatmentofchoiceforpatientswithasuitablehealthprofileand/orinadequateresponsetoconservativetherapy.Beforeusing[liposuction],associateddeterioratingcomponentssuchasedema,obesity,unhealthylifestyle,lackofphysicalactivity,lackofknowledgeaboutthedisease,andpsychosocialdistressshouldbeaddressed.Moreover,evenafterliposuction,womengenerallyrequireconservativetherapy,andweightnormalizationshouldremainagoal.”17
Reductivesurgery,alsocalledexcisionandresection,isamoreinvasiveprocedurethatinvolvesexcisionoflargelocalizeddepositsoflipedematoustissue,orlumps,possiblyincludingthesurroundingskin.Developmentoftheselumpscancausethekneestotwistoutward(valgusdeformity)ordrooptothesideoftheleg(ptosis)and,inseriouscases,leadtotheinabilitytowalk,therebydramaticallyimpactingthepatient’slife.
27
CLINICALPIPELINE
Clinicalresearchisabranchofbiomedicalresearchthatinvolveshumansubjects.Thegoalofclinicalresearchistounderstandbetterthehealthoutcomesofparticipantsandtoevaluatethesafetyandefficacyoftherapy,drugs,medicaldevices,ordiagnosticsintendedforuseinhumans.Thesestudiescanalsobeusedtocollectspecimensfromhumansubjectsforfurtherresearch.Therearetwokeytypesofclinicalstudies:observational,andinterventional(seebox).
Importantly,informationonpotentialsideeffectsofinterventionsaregatheredduringthestudyandweighedagainstthepotentialtherapeuticbenefitofthetreatmentunderinvestigation.
L IPEDEMACLINICALSTUDIES
AsofJanuary2017,onlyfourclinicalstudieshavebeenconductedinlipedema.ObservationalStudiesInsightIntoSubcutaneousAdiposeTissueDisorders(INSIGHT)―Thisstudyaimstounderstandtheobservablephysicalcharacteristicsofapersonthatresultsfromtheinteractionofhisorhergeneticmakeupwiththeenvironment.Thistypeofinteractioniscalledaphenotype.Morespecifically,thisstudyfocusesonunderstandingthephenotypesofindividualswithsubcutaneousadiposetissuedisorderssuchaslipedemaandDercum’sdisease.Thisstudyiscurrentlyrecruitingparticipants.ImagingLymphaticFunctioninNormalSubjectsandinPersonswithLymphaticDisorders—Thisstudyaimstounderstandthepotentialapplicabilityofnear-infraredfluorescencelymphaticimagingasadiagnosticassayoflymphaticflowinparticipantswithlymphedema,lymphaticdisorders,vasculardisorders,orlipedema.Thisstudyisenrollingparticipantsbyinvitationonly.
ObservationalStudiesInthistypeofclinicalstudy,investigatorsassessthehealthoutcomesingroupsofparticipantsaccordingtoaresearchprotocolwithoutanyspecificmedicalintervention.InterventionalStudy(orClinicalTrial)Inthistypeofclinicalstudy,participantsareassignedtoreceiveanintervention/therapysothatresearcherscanevaluatetheeffectoftheinterventiononhealth-relatedoutcomesaccordingtoaresearchprotocol.Participantsmayreceivediagnostic,therapy,ordruginterventions.
28
InterventionalStudiesPhysicalConditioninLipedemaandObesity—Becauselipedemaandobesityareoftenmisdiagnosedforeachother,theprimaryaimofthisstudyistounderstandwhetherthereisadifferenceinmusclestrengthbetweenwomenwithlipedemaandwomenwithobesity.ThisstudyhasbeencompletedandcontributeddatatotheDutchLipedemaGuidelines.17
QuadrivasTherapytoReduceLipedemaSubcutaneousAdiposeTissue—Quadrivasisanintensivemassagetherapyfordifferenttissues.Thisstudyaimstounderstandwhetherthetherapycanreducesubcutaneousadiposetissueinparticipantswithlipedema.Thisstudyisongoingbutisnotrecruitingparticipants.
29
RESEARCHCHALLENGESANDPHILANTHROPICOPPORTUNITIES
Thelittlethatisknownabouttheetiologyoflipedemaanditsholisticeffectonpatientsisbasedonisolatedclinicalcasereportsandlimitedresearchstudies.Researcheffortsarecomplicatedbyasubjectiveclinicaldiagnosisprocessthatfacesscalabilityandstandardizationissues.Discussionsbefore,during,andafterthe2016LipedemaScientificRetreatrevealedseveralresearchchallengesandphilanthropicopportunities,which,ifaddressed,willhelptodefineanddevelopthelipedemaresearchfield.
Lipedema Basic Biology and Genetics
Todefinelipedemaanddeveloptreatmentsforpatients,researchtoolssuchascelllines,mousemodels,andanunderstandingoftheaberrantcellsandphysiologicalprocessesthatdrivethediseasearerequired.Giventhemultiplediseasesthatrequiredifferentialdiagnosisfromlipedema,itislikelythatexpansionoflipedemaresearchwillcontributetotheunderstandingoflymphedema,obesity,Dercum’sdisease,lipohypertrophy,andotherfatdisorders.Furthermore,developmentofmultidisciplinaryteamsthatspanresearchfields(adipose,lymphatic,metabolic,etc.)anddisciplines(academics,clinicians,surgeons,etc.)wouldbetheidealapproachtoaddressthekeyunmetresearchneedsofthedisease.
Developmentoflocalsurgeon-researcherteams
• ResearchChallenge:Accesstofreshresearchsamplesandtheirsharing/storageatbiobanksarecomplicatedbyprocessingchallengesforresearchersandfewincentivesforliposuctionsurgeonstoparticipateinresearchefforts.
• ResearchOpportunity:Apotentialapproachistoleveragethedesireoflipedemapatientstoreceiveliposuctionsurgerybydevelopinglocalsurgeon-researcherteams,whichwillfacilitateaccesstofreshpatientsampleswhilemaintainingandexpandingabiorepository’stissuebank.
RNAsequencingoflipedemapatientsamplessuchasblood,adiposetissue,andexosomes
• ResearchChallenge:Thetranscriptional(geneexpressionlevels)differencesinthegenestranscribedintoRNA,orbetweennormalandlipedemafat,remainunknown.
• ResearchOpportunity:Inanunbiasedmanner,thisefforthasthepotentialtodeterminethegenesthataredifferentiallyexpressedbetweenlipedematissueandnon-lipedematissuefromthesamepatient,aswellasbyaffectedandunaffectedfamilymembers.
Histology,morphology,andimmunostainingoflipedematissue
• ResearchChallenge:Todate,lipedemapublicationsoffertwotothreecasereportswiththeoccasionalhematoxylinandeosinstainingofpatientbiopsiestovisualizecellularstructures.
• ResearchOpportunity:Ifperformedinaconcertedandcollaborativemanner,thisefforthasthepotentialtovisualizeaberrantcellularstructuresandprocessesoflipedematissue.
30
Molecularprofilingoflipedemaadiposestemcells
• ResearchChallenge:Itisunknownwhetheradiposestemcellsdrivetheexpansionandgrowthoflipedematissue.
• ResearchOpportunity:Thisefforthasthepotentialtodeterminethecurrentproteomic(proteinexpressionlevels),transcriptomic(geneexpressionlevels),andmetabolicstateoflipedemaadiposestemcells,andwhetherkeypathwaysarealteredinthesecells.Furthermore,theseresearcheffortscanbeappliedtootherpotentialcellsofinterestinlipedematissue,suchaslymphaticendothelialcells,differentiatedadiposecells,andskeletalmuscle.
Assessmentofcirculatingandlocalcytokineandhormonelevelsoflipedemapatients
• ResearchChallenge:Althoughstandardpanelshavebeenperformedonlipedemapatientbloodsamples,theseeffortshavebeenneithercomprehensiveintheirtestingofallknowncytokines/hormones,norindicativeofthelocallevelsofcytokines/hormonesinlipedematissue.
• ResearchOpportunity:
o Cytokine-focusedeffortsmaydeterminewhatdrivestheinflammatoryandpaincomponentoflipedema.
o Hormone-focusedeffortsmayshedlightonwhatdrivesonsetandexacerbationofthedisease.
Lipedemasymptoms-basedmousestudies
• ResearchChallenge:Intheabsenceofknowngeneticmutationsandalteredcells/signalingpathways,therelevantmousemodelsforlipedemaareunknown.
• ResearchOpportunity:Apotentialapproachistostudythesymptomsoflipedemapatientsincurrentlyavailablemousemodels.Thiseffortwouldexpandthenetworkofanimalmodelresearchers,andpotentiallytherangeofdiseasesandresearchfieldsrelatedtolipedema.
Determinethegeneticmarkersanddriversoflipedema
• ResearchChallenge:Becausethegeneticarchitectureoflipedemaiscurrentlyunknown,theheritabilitycomponentandgeneticmarkersanddriversofthediseasearepoorlyunderstood.
• ResearchOpportunity:Understandingofthegenesthatunderliedevelopmentoflipedemacouldserveasapotentialdiagnostictoolthatwouldinformbasicbiologystudies.Theseeffortswouldbenefitfrommultiple,well-phenotypedcohortstofacilitatedatacomparisonandreproducibility.
31
Lipedema Diagnosis and Epidemiology
Theepidemiologyoflipedemaisunknown,andavailablestudiesarerestrictedbysmallsamplesizesandcomparisondifficulties.Toincreaseawarenessandacceptanceoflipedemaasadisease,accuratevaluesofincidence/prevalenceareneeded.Collectionofdatatodetermineincidence/prevalencewouldincreaseclinical,research,andindustryinterestinthefield.Furthermore,toolstofacilitatepatientidentificationandengagementareessentialtoperformingepidemiologicalstudies.
Developmentoflipedema-specificdiagnostictools
• ResearchChallenge:Currentlyavailableimaginganddiagnosticassaysarenotapprovedtoserveasaprimarytesttodiagnoselipedemaorasconfirmationofaclinicaldiagnosisoflipedema.
• ResearchOpportunity:Developmentofnoveldiagnostictoolsorimprovedapplicationofcurrentlyavailabletoolstobetterdiagnoselipedemawouldbeacriticaladvancementforthefield.
o Apotentialapproachistoexplorethevalueandapplicabilityofnovelimagingtechniquessuchassodium-basedMRIornear-infraredfluorescencelymphaticimaging.
o AnotherapproachistoexpandandimprovetheuseofcurrentlyavailableimagingtechniquessuchasMRI,CT,ultrasound,anddual-energyx-rayabsorptiometryscanstodeterminewhetheracombinationofimagingtestsmightgeneratelipedema-specificparametersabletodifferentiallydiagnosethedisease.
Developmentofconsensusandscalablesolutionsforlipedemadiagnosisandepidemiology
• ResearchChallenge:Anaccurateandscalablediagnosticprocedureforlipedemaisaclearunmetneed.However,theexactprocessforaddressingthisneedremainsundefined.
• ResearchOpportunity:Apotentialapproachistoformaworkinggroupfocusedondevelopingastandard,minimalsurvey/questionnairethatwouldbeapplicableforpatientregistryintakequestions;anepidemiologicalincidenceandprevalencestudy;andgeneralpractitionersandcentersthatseepotentiallyundiagnosedindividualswithlipedema.
Developmentandlaunchofapatientregistry
• ResearchChallenge:Lipedemapatientsarehighlyinterestedinparticipatinginresearch,andtheirparticipationiscentraltoleveragingthebasicbiology,genetic,andepidemiologicalopportunities.However,convertingpatientinterestintoengagementrequiresthereturnofresultstostudyparticipants,aswellasthesharingofresultswiththebroaderlipedemaresearchfield.
• ResearchOpportunity:Apotentialapproachistodevelopawell-curatedlipedemapatientregistryconnectedtoanexistingbiorepository.Suchaneffortwouldfacilitate
o Assessmentofdiagnosisandepidemiologystudies
o Patientrecruitmentintobasicbiology,genetic,anddiagnosticresearchstudies
o Developmentofalong-termnaturalhistorystudythatcapturesdiseaseprogression,symptoms,andtreatmenthistoryoflipedemapatients;followedbydisseminationofresultstoallparticipantsandpatientnetworks
32
NONPROFITORGANIZATIONSINVOLVEDINLIPEDEMA
RESEARCH-FUNDINGFOUNDATIONS
LipedemaFoundation―Thisfoundationwasfoundedin2015withthemissionofdefining,diagnosing,anddevelopingtreatmentsforlipedema.Todate,theFoundationhascommittedmorethan$2.9milliontowardslipedemaresearch,includinggeneticstudies,supportforpostdoctoralfellows,mousemodelresearch,andlaunchoftheUniversityofArizonaTreatment,Research,Education,AdiposeTissue(TREAT)programandtissuebiorepository.
FatDisordersSociety(FDRS)―Asafundingorganizationandpatientsupportandadvocacygroup,thisU.S.-basedsocietywasfoundedin2009andisdedicatedtoimprovingthequalityoflifeforallpeopleaffectedbyadiposetissuedisordersthroughresearch,education,advocacy,andcollaboration.Thesocietyalsoholdsannualconferencesthatbringtogetherpatients,clinicians,therapists,caregivers,andresearcherstodiscusskeyissuesfacingthefield.
LymphaticEducationandResearchNetwork(LE&RN)―Foundedin1998astheLymphaticResearchFoundation,LE&RN’smissionistofightlymphaticdiseaseandlymphedemathrougheducation,research,andadvocacy.WithfinancialsupportfromtheFatDisordersResearchSociety,LE&RNfacilitatedtheawardingofthreelipedemapostdoctoralfellowshipsin2015.
PATIENTSUPPORTANDADVOCACYGROUPS
LipoedemaUK―ThisUnitedKingdom–basedcharitableorganizationwasfoundedin2012bywomenwithlipedemaandtheLymphoedemaServiceatSt.George’sHospitalinLondon.Itsfocusistoeducatedoctors,healthprofessionals,andthepublicaboutlipedemaanditssymptomstofacilitatediagnosisandearliertreatment.
TalkLipoedema―ThisUnitedKingdom–basedcharitableorganizationprovidessupporttopeoplewithlipedemaandtheirfamiliesandcaregivers.Theorganizationsupportseffortsthatwillimprovetheaccuracyoflipedemadiagnosis,developmentofindividualpatientcareplans,andpatientaccesstoservicesandself-supportmanagement.
LipoedemaLadies―ThemissionofthisUnitedKingdom–basednonprofitorganizationistosupportwomenwithlipedema,raiseawarenessaboutthediseaseaswellastreatmentandmanagementoptions,andcontributetotheoverallbodyofknowledgeandunderstandingforlipedema.
LipoedemaAustraliaSupportSociety(LASS)―ThisAustralia-basedsocietyaimstoraisediseaseawarenessthroughpatientsupportandadvocacy.Theassociationwasformedtoinvolveandeducatesufferers,aswellastofacilitatecoordinationofthedifferentmedicalareasnecessaryforongoingmanagementoflipedema.
LipoedemHilfe(LipoedemaHelp)―ThisGermany-basedorganizationwasfoundedin2011withthegoalofincreasinggeneralawarenessandrecognitionoflipedemaasachronicdisease.Theorganizationaimstoimprovepatientaccesstotreatmentsbyfosteringclosercooperationamongdoctors,healthinsurers,hospitals,authorities,andpoliticians.
33
NederlansNetwerkvoorLymfoedeem&Lipoedeem(DutchLymphedemaandLipoedemaNetwork)―Foundedin2006,thisNetherlands-basedfoundationisfocusedonhelpingindividualsaffectedbylymphedemaandlipedema.Thenetwork’sgoalsaretodevelopanindependentplatformforscientificknowledge,throughthedevelopmentofnationalandinternationalguidelines,andtoserveasaresourceforpatients,patientorganizations,andcaregivers.
StichtingNederlandseLipoedeemdag(DutchLipoedemaFoundation)―ThisNetherlands-basedfoundationhasthegoalofraisingregional,national,andinternationalawarenessofthedisease.Thefoundationconvenesanannualsymposiumforpatients,partners,physicaltherapists,andmedicalpractitionerstosharebestpracticesandrecentdevelopmentsinlipedema.
34
GLOSSARY
adenoids Alsoknownasapharyngealtonsilornasopharyngealtonsil,itisamassoflymphatictissuesituatedwherethenoseblendsintothethroat.
adipocytestemcells Thecellpopulationfromwhichmatureadipocytesarisefrom.adipocytes Alsoknownasfatcells,theyaretheprimarycomponentsofadiposetissueand
specializeinstoringenergyasfat.adiposetissue Fat;alooseconnectivetissueprimarilymadeupofadipocytes.adiposisdolorosa AlsoknownasDercum'sdiseaseorAndersdisease,itisarareconditioncharacterized
bygeneralizedobesityandfattytumorsintheadiposetissue.Thetumorsarenormallypainfulandfoundinmultiplesontheextremities.TheunderstandingofthecauseandmechanismofDercum’sdiseaseremainsunknown.
anesthetic Adruggiventoapatienttopreventpainduringsurgery.angiolipoma Abenignmassoffattissueandbloodvessels.Theyoftenappearatmultiplesitesand
occuraspainfulsubcutaneousnodules.autosomaldominantinheritancewithsexlimitation
Aninheritedgeneticconditionwhereintheonlyonecopyofthemutantgeneisneededtopresentthephenotype.Thesexlimitationcomponentindicatesthatphenotypeisonlyexpressedinonesex.Forlipedema,itmaybeanindicatorofwhythediseaseoccursalmostexclusivelyinwomen.
cellulitis Acommon,potentiallyseriousbacterialskininfection.Itappearsasaswollen,redareaofskinthatfeelshotandtender,andcanspreadrapidlytootherpartsofthebody.
chronicvenousinsufficiency
Aconditionthatoccurswhenthevenouswalland/orvalvesinthelegveinsarenotworkingeffectively,makingitdifficultforbloodtoreturntotheheartfromthelegs,therebycausingbloodto“pool”orcollectintheseveins.Thispoolingiscalledstasis.
circulatorysystem Alsocalledthecardiovascularsystemorthevascularsystem,isanorgansystemthatcirculatesblood,facilitatingthetransportationofnutrients,oxygen,carbondioxide,hormones,andbloodcellstoandfromthecells.
clinimetrics Thepracticeofassessingordescribingsymptoms,signs,andlaboratoryfindingsbymeansofscales,indices,andotherquantitativeinstruments.
computedtomography Animagingprocedurethatusesspecialx-rayequipmenttocreatedetailedpictures,orscans,ofareasinsidethebody.Itisalsocalledcomputerizedtomographyandcomputerizedaxialtomography(CAT)scans.
connectivetissue Tissuethatconnects,supports,binds,orseparatesothertissuesororgans,typicallycomposedofcollagenorotherfibers,andincludingcartilaginous,fatty,andelastictissues.
cytokines Anyofanumberofsubstances,suchasinterferon,interleukin,andgrowthfactorssecretedbycertaincellsoftheimmunesystemandhaveaneffectonothercells.
dendriticcells Antigen-presentingcells(alsoknownasaccessorycells)ofthemammalianimmunesystem.TheirmainfunctionistoprocessantigenmaterialandpresentitonthecellsurfacetotheTcellsoftheimmunesystem.Theyactasmessengersbetweentheinnateandtheadaptiveimmunesystems.
Dercum’sdisease AlsoknownasadiposisdolorosaorMorbudDercums,isarareconditioncharacterizedbygeneralizedobesityandfatmasses,orlipomasintheadiposetissue.Thelipomascanbepainfulandfoundinmultiplesontheextremities.TheunderstandingofthecauseandmechanismofDercum’sdiseaseremainsunknown.
dermis Thelayeroftissuebelowtheepidermiscontainingbloodcapillaries,nerveendings,sweatglands,hairfollicles,andotherstructures.
diabetes Adiseaseinwhichthebody’sabilitytoproduceorrespondtothehormoneinsulinisimpaired,resultinginabnormalmetabolismofcarbohydratesandelevatedlevelsofglucoseinthebloodandurine.
35
diaphragm Asheetofinternalskeletalmusclethatextendsacrossthebottomofthethoraciccavity.Thediaphragmseparatesthethoraciccavity,containingtheheartandlungs,fromtheabdominalcavity.Duringrespiration,asthediaphragmcontracts,thevolumeofthethoraciccavityincreasesandairisdrawnintothelungs.
dual-energyX-rayabsorptiometry
DXA,previouslyDEXA,isameansofmeasuringbonemineraldensity(BMD).TwoX-raybeams,withdifferentenergylevels,areaimedatthepatient'sbones.Whensofttissueabsorptionissubtractedout,theBMDcanbedeterminedfromtheabsorptionofeachbeambybone.AlthoughwidelyusedtoassessBMD,DXAhasbeenusedtomeasuresofttissuemassandadiposity.
ectopicfat Ectopicmeans"notwhereit'ssupposedtobe".Ectopicfatisnon-normalaccumulationoffatinareassuchastheabdominalregion(beerbelly),liver,muscletissueincludingtheheart,pancreas,andperhapsinlipid-richdepositsinthearteries.
eczema Alsoknownasdermatitis,eczemaisagroupofdiseasesthatresultsinskininflammation.Thesediseasesarecharacterizedbyitchiness,redskin,andarash,withtheareaofskininvolvedvaryingfromsmalltotheentirebody.
edema Themedicaltermforswelling,whichmaybecausedbytrappedfluid,inflammation,andothercauses.
endocrinesystem Thecollectionofglandsthatproducehormonesthatregulatemetabolism,growthanddevelopment,tissuefunction,sexualfunction,reproduction,sleep,andmood.
endothelialcells Thesecellsmakeuptheendothelium,whichisatypeoftissuethatlinestheinteriorsurfaceofbloodvesselsandlymphaticvessels,forminganinterfacebetweencirculatingbloodorlymphinthelumenandtherestofthevesselwall.
epidemiology Thebranchofmedicinethatdealswiththeincidence,distribution,andpossiblecontrolofdiseasesandotherfactorsrelatingtohealth.
epidermis Theouterlayerofcellsthatoverlaysthedermis.epinephrine Ahormone,neurotransmitterandmedication.Duringsurgicalproceduresitusedasa
medicationthatfacilitatesconstrictionofbloodvessels.estrogen Theprimaryfemalesexhormonewhichisresponsibleforthedevelopmentand
regulationofthefemalereproductivesystemandsecondarysexcharacteristics.etiology Thecause,setofcauses,ormannerofcausationofadiseaseorcondition.exosomes Cell-derivedvesiclesthatarepresentinmanyandperhapsalleukaryoticfluids,
includingblood,urine,andculturedmediumofcellcultures.Researchhasshownthatthesesmallvesiclesplayaroleincell-to-cellsignalingandcanserveasdiseasebiomarkers.
extracellularmatrix Acollectionofmoleculesontheoutsideofcells,andwhicharesecretedbycellstoprovidestructuralandbiochemicalsupport.
fibrosis Thethickeningandscarringofconnectivetissue,usuallyasaresultofinjury.genotype Thegeneticconstitutionofanindividual.geneticarchitecture Referstotheunderlyinggeneticbasisofatraitordisease,anddescribeswhetherthe
genotypeconnectedtothephenotypeoccursrarely,oriscommon,andwhetheritseffectishighlypenetrant,moderateorminimal.
hematoxylinandeosin Oneoftheprincipalstainsinhistologyandisthemostwidelyusedstaininmedicaldiagnosis.Thehematoxylinstainnuclei,whiletheeosinstainsproteinsinsideandoutsideofthecells.
hormones Anymemberofaclassofsignalingmoleculesproducedbyglandsinmulticellularorganisms.Theyaretransportedbythecirculatorysystemtotargetdistantorganstoregulatephysiologyandbehavior.
hypermobility Jointsthataremoreflexiblethannormalorthatmoveinexcessofanormalrangeofmotionareconsideredhypermobile.Whengeneralized,hypermobilityoccurswithsymptomssuchasmuscleorjointpainwithoutsystemicdisease,andiscalled-hypermobilitysyndromeorjointhypermobilitysyndrome.
36
hyperplasia Infatcells,thisprocessreferstoanincreaseintherateofcellularreproductionhypertension Abnormallyhighbloodpressure.hypertrophy Infatcells,thisprocessreferstoanincreaseinthesizeofcellshypodermis Theinnermostandthickestlayerofskin,whichisprimarilycomposedofadipocytes.immunesystem Anetworkofcells,tissues,andorgansthatworktogethertodefendthebodyagainst
attacksby“foreign”invaders.Theseareprimarilymicrobes—tinyorganismssuchasbacteria,parasites,andfungi,thatcancauseinfections.
incidence Theoccurrence,rate,orfrequencyofadisease.indirectlymphangiography
AnX-raybasedassayusedtovisualizeanddelineatelymphaticvessels.Theindirectaspectoftheassayreferstoadministrationofcontrastagentstoimage,or"lightup"vessels.
inflammation Acomponentofthecomplexbiologicalresponseofbodytissuestoharmfulstimuli,suchaspathogens,damagedcells,orirritants,andisaprotectiveresponseinvolvingimmunecells,bloodvessels,andmolecularmediators.Thefunctionofinflammationistoeliminatetheinitialcauseofcellinjury,clearoutnecroticcellsandtissuesdamagedfromtheoriginalinsultandtheinflammatoryprocess,andtoinitiatetissuerepair.Theclassicalsignsofinflammationareheat,pain,redness,swelling,andlossoffunction.
interstitialfluid Thefluidreleasedbycellsandthatbathesthesurroundingcellsandtissue.Langerhanscells Dentriticcellsthatarepresentintheskinandmucosa.lipedema Achronicdiseasethatoccursalmostexclusivelyinwomen.Itpresentsassymmetrical
accumulationoffatinthesubcutaneoustissueofthelimbs.Theaffectedareasarealsopainful,easytobruise,withthefattissuedemonstratinglimitedresponsetoweightlossstrategies.
lipodystrophy Aconditioncharacterizedbyabnormalofdegenerativeconditionsinadiposetissue.lipohypertrophy AtermmorecommonlyusedinEurope,itreferstothesymmetricalaccumulationof
fatinthelegsthatdonotpresentwithpain.lipolymphedema Thelatestageoflipedema,whereintheincreasedfataccumulationandstraininthe
lymphaticsystemresultsinlymphedemaaswell.lipomas Massesoffattissuethatexpandundertheskin.lymph Thefluidinsideoflymphvessels,whichiscomposedofimmunecells,proteins,and
lipids.lymphnode Anorganofthelymphaticsystempresentwidelythroughoutthebody.Theyactas
filtersforthelymphthatpassesthroughthem.lymphangiography AnX-raybasedassayusedtovisualizelymphnodesandlymphvessels.lymphaticcapillaries Asmallnetworkofthin-walledvesselsthatcollecttheinterstitialfluidandallows
themtoflowintothelymphaticsystem,becominglymph.lymphaticvessels Thelargernetworkofvesselsthatcollectlymphfluid,passesitthroughlymphnodes,
andtowardsthetrunk.lymphedema Adiseasethatpresentswithbuildupofthefluidsurroundingtissues,orinterstitial
fluid,inthemuscleandskinleadingtoincreasedfatdeposition.Thediseasecanbehereditary(primarylymphedema)orarisefromdamagetothelymphaticsystemfromdifferentinsultssuchascancer,surgery,radiationtherapy,trauma,orinfection(secondarylymphedema).
lymphscintigraphy Animagingprocedurethatallowsvisualizationoflymphnodesthroughtheuseofinjectedcontrastagents.
macrophages Alargecellfoundinstationaryforminthetissuesorasamobilewhitebloodcell,especiallyatsitesofinfection.Itischaracterizedbyitsphagocytic,orsampling,capacityofitsextracellularsurroundings.
Madelung’sdisease Alsoknownasbenignsymmetriclipomatosis,itisaconditioncharacterizedby
37
extensivefatdepositsinthehead,neck,andshouldgirdlearea.magneticresonanceimaging
Aformofmedicalimagingthatmeasurestheresponseoftheatomicnucleiofbodytissuestohigh-frequencyradiowaveswhenplacedinastrongmagneticfield,andthatproducesimagesoftheinternalorgans.
metabolicbiologyormetabolism
Thesumofallchemicalreactionsinanorganismbywhichdigestionoffoodisturnedintoandstoredasenergy.
microaneuryms Withrespecttolipedema,thisreferstotheenlargementanddilationofavesselwall.microangiopathy Avascularconditionwhereinthevesselsappearsmallerthannormal.obesity Theconditionofhavingexcessivebodyfat,withitsrelatedcomorbiditiesthat
increasetheriskofhealthproblems.phenotype Thesetofobservablecharacteristicsofanindividualresultingfromtheinteractionof
itsgenotypewiththeenvironment.phlebedema Edemaorswellingthatistheresultofvenousinsufficiency.prevalence Thecommonnessofadiseaseortraitinapopulation.prognosis Thelikelycourseofadiseaseorailment.proteomicstudies Researchthatfocusesontheamount,types,andfunctionofgeneratedproteins.spleen Anabdominalorganinvolvedintheproductionandremovalofbloodcellsinmost
vertebratesandacomponentoftheimmunesystem.spiderveins Smallred,purple,andblueveinsthattwistandturnandareeasilyvisiblethroughthe
skin,alsocalledvenulectasia.Tcells Alymphocyteproducedorprocessedbythethymusgland,andplaysanactiveinthe
immuneresponse.telangiectasia Aconditioninwhichtherearevisiblesmalllinearredbloodvessels(broken
capillaries)ontheskin,alsocalledtelangiectases.thymus AlymphoidorgansituatedintheneckofvertebratesthatproducesTcellsforthe
immunesystem.Thehumanthymusbecomesmuchsmallerattheapproachofpuberty.
tonsils Eitheroftwosmallmassesoflymphoidtissueinthethroat,oneoneachsideoftherootofthetongue.
transcriptomicstudies Researchthatfocusesontheamount,types,andfunctionofgeneratedRNAtranscripts.
ultrasound Amedicalimagingassaythatusessoundsorvibrationsatanultrasonicfrequencytogenerateandimage.
visceralfat Depotsoffattissuelocateddeepintheabdomen.X-linkeddominantinheritance
X-linkeddominantinheritance,sometimesreferredtoasX-linkeddominance,isamodeofgeneticinheritancebywhichadominantgeneiscarriedontheXchromosome.
38
REFERENCES
1. AllenE.V.&HinesE.A.Lipedemaofthelegs:Asyndromecharacterizedbyfatlegsandorthostaticedema.StaffMeetingsoftheMayoClinic.(1940).http://bit.ly/2kUBe6V
2. Chen,S.-G.,Hsu,S.-D.,Chen,T.-M.&Wang,H.-J.Painfulfatsyndromeinamalepatient.Br.J.Plast.Surg.57,282–286(2004).
3. Wold,L.E.,Hines,E.A.,Allen,E.V.Lipedemaofthelegs;asyndromecharacterizedbyfatlegsandedema.Ann.Intern.Med.34,1243–1250(1951).
4. Schmeller,W.&Meier-VollrathI.Lymphedema.DiagnosisandTherapy.3rdEdition.Chapter7.(2007).5. LipoedemaUK.BigSurveyResearchReport.(2014).http://bit.ly/2lg2rBJ.6. Herbst,K.L.Rareadiposedisorders(RADs)masqueradingasobesity.ActaPharmacol.Sin.33,155–
172(2012).7. DutchLipedemaGuidelines.(2014).http://bit.ly/2jY8Vjt.8. Földi,E.&Földi,M.Daslipödem.InE.Földi&M.Földi(2ndEd.),LehrbuchderLymphology:für
Mediziner,MasseureundPhysiotherapeutenp444-453(2005).9. Forner-Cordero,I.,Szolnoky,G.,Forner-Cordero,A.&Kemény,L.Lipedema:anoverviewofitsclinical
manifestations,diagnosis,andtreatmentofthedisproportionalfattydepositionsyndrome-systematicreview.Clin.Obes.2,86–95(2012).
10.HerpertzU.DasLipödemundseineKombinationen.Vasomed;9,301–307(1997).11.Child,A.H.etal.Lipedema:aninheritedcondition.Am.J.Med.Genet.A.152A,970–976(2010).12.Dudek,J.E.,Białaszek,W.&Ostaszewski,P.Qualityoflifeinwomenwithlipoedema:acontextual
behavioralapproach.Qual.LifeRes.Int.J.Qual.LifeAsp.Treat.CareRehabil.25,401–408(2016).13.Herbst,K.L.,Mirkovskaya,L.,Bharhagava,A.,Chava,Y.,Te,C.H.T.Lipedemafatandsignsand
symptomsofillness,increasewithadvancingstage.Arch.Med.(2015).14.Rapprich,S.,Dingler,A.&Podda,M.Liposuctionisaneffectivetreatmentforlipedema-resultsofa
studywith25patients.J.Dtsch.Dermatol.Ges.J.Ger.Soc.Dermatol.JDDG9,33–40(2011).15.Hayes,S.C.,Villatte,M.,Levin,M.&Hildebrandt,M.Open,aware,andactive:contextual
approachesasanemergingtrendinthebehavioralandcognitivetherapies.Annu.Rev.Clin.Psychol.7,141–168(2011).
16.WilliamsA.&MacEwanI.Accuratediagnosisandself-caresupportforwomenwithlipoedema.Pract.Nurs.,27(7)325-332(2016).
17.Halk,A.B.&Damstra,R.J.FirstDutchguidelinesonlipedemausingtheinternationalclassificationoffunctioning,disabilityandhealth.Phlebology(2016).doi:10.1177/0268355516639421
18.WorldHealthOrganization.TowardsaCommonLanguageforFunctioning,Disability,andHealth:ICF(2002).http://bit.ly/1fMdTwA.
19.Rundall,T.G.etal.Asgoodasitgets?ChroniccaremanagementinnineleadingUSphysicianorganisations.BMJ325,958–961(2002).
20.Buck,D.W.&Herbst,K.L.Lipedema:arelativelycommondiseasewithextremelycommonmisconceptions.Plast.Reconstr.Surg.Glob.Open4,e1043(2016).
21.Hansson,E.,Svensson,H.&Brorson,H.ReviewofDercum’sdiseaseandproposalofdiagnosticcriteria,diagnosticmethods,classificationandmanagement.OrphanetJ.RareDis.7,23(2012).
22.Bertsch,T.Lipödemundadipositas-gemeinsambetrachtet![Lipoedemaandobesity-together!].Lymphselbsthilfe,August(2016).http://bit.ly/2ljYM1G.
23.Beltran,K.&Herbst,K.L.DifferentiatinglipedemaandDercum’sdisease.Int.J.Obes.2005(2016).doi:10.1038/ijo.2016.205
24.Herbst,K.L.,Asare-Bediako,S.Adiposisdolorosaismorethanpainfulfat.TheEndocrinologist.17,326-334(2007).
25.Eberhardt,R.T.&Raffetto,J.D.Chronicvenousinsufficiency.Circulation130,333–346(2014).
39
26.Jagtman,B.A.,Kuiper,J.P.&Brakkee,A.J.[MeasurementsofskinelasticityinpatientswithlipedemaoftheMoncorps‘rusticanus’type].Phlebologie37,315–319(1984).
27.Bilancini,S.,Lucchi,M.,Tucci,S.&Eleuteri,P.Functionallymphaticalterationsinpatientssufferingfromlipedema.Angiology46,333–339(1995).
28.Fife,C.E.,Maus,E.A.&Carter,M.J.Lipedema:afrequentlymisdiagnosedandmisunderstoodfattydepositionsyndrome.Adv.SkinWoundCare23,81–92(2010).
29.Trayes,K.P.,Studdiford,J.S.,Pickle,S.&Tully,A.S.Edema:diagnosisandmanagement.Am.Fam.Physician88,102–110(2013).
30.Todd,M.Lipoedema:presentationandmanagement.Br.J.CommunityNurs.15,S10-16(2010).31.Okifuji,A.&Hare,B.D.Theassociationbetweenchronicpainandobesity.J.PainRes.8,399–408
(2015).32.Scheper,M.C.,deVries,J.E.,Verbunt,J.&Engelbert,R.H.Chronicpaininhypermobilitysyndrome
andEhlers-Danlossyndrome(hypermobilitytype):itisachallenge.J.PainRes.8,591–601(2015).33.Levy,H.P.inGeneReviews(®)(eds.Pagon,R.A.etal.)(UniversityofWashington,Seattle,1993).
PMID:2030145634.Fonder,M.A.,Loveless,J.W.&Lazarus,G.S.Lipedema,afrequentlyunrecognizedproblem.J.Am.
Acad.Dermatol.57,S1-3(2007).35.Dimakakos,P.B.etal.MRIandultrasonographicfindingsintheinvestigationoflymphedemaand
lipedema.Int.Surg.82,411–416(1997).36.Monnin-Delhom,E.D.,Gallix,B.P.,Achard,C.,Bruel,J.M.&Janbon,C.Highresolutionunenhanced
computedtomographyinpatientswithswollenlegs.Lymphology35,121–128(2002).37.Reich-Schupke,S.,Altmeyer,P.&Stücker,M.Thicklegs-notalwayslipedema.J.Dtsch.Dermatol.
Ges.J.Ger.Soc.Dermatol.JDDG11,225–233(2013).38.Dietzel,R.,Reisshauer,A.,Jahr,S.,Calafiore,D.&Armbrecht,G.Bodycompositioninlipoedemaof
thelegsusingdual-energyX-rayabsorptiometry:acase-controlstudy.Br.J.Dermatol.173,594–596(2015).
39.Partsch,H.,Stöberl,C.,Urbanek,A.&Wenzel-Hora,B.I.Clinicaluseofindirectlymphographyindifferentformsoflegedema.Lymphology21,152–160(1988).
40.Földi,M.&Idiazabal,G.Theroleofoperativemanagementofvaricoseveinsinpatientswithlymphedemaand/orlipedemaofthelegs.Lymphology33,167–171(2000).
41.Hoffmann,J.N.,Fertmann,J.P.,Baumeister,R.G.H.,Putz,R.&Frick,A.Tumescentanddryliposuctionoflowerextremities:differencesinlymphvesselinjury.Plast.Reconstr.Surg.113,718-724-726(2004).
42.Schmeller,W.Lymph/lipoedematreatmentinitsdifferentapproaches,1stJOBSTScientificSymposium.(2008).
43.Harvey,N.L.Thelinkbetweenlymphaticfunctionandadiposebiology.Ann.N.Y.Acad.Sci.1131,82–88(2008).
44.Walker,G.E.,Marzullo,P.,Ricotti,R.,Bona,G.&Prodam,F.Thepathophysiologyofabdominaladiposetissuedepotsinhealthanddisease.Horm.Mol.Biol.Clin.Investig.19,57–74(2014).
45.Rutkowski,J.M.,Davis,K.E.&Scherer,P.E.Mechanismsofobesityandrelatedpathologies:themacro-andmicrocirculationofadiposetissue.FEBSJ.276,5738–5746(2009).
46.Jeffery,E.etal.Theadiposetissuemicroenvironmentregulatesdepot-specificadipogenesisinobesity.CellMetab.24,142–150(2016).
47.Jo,J.etal.Hypertrophyand/orhyperplasia:dynamicsofadiposetissuegrowth.PLOSComput.Biol.5,e1000324(2009).
48.vanGeest,A.J.,EstenS.C.A.M.,Cambier,J-PR.A.,GielenE.G.J.,Kessels,A.,NeumannH.A.M.,vanKroonenburgh,M.J.P.G.Lymphaticdisturbancesinlipoedema.Phlebologie,32,138-142(2003).
49.Vaughan,B.F.CTofswollenlegs.Clin.Radiol.41,24–30(1990).
40
50.Werner,G.T.&Rodiek,S.O.[Valueofnuclearmagneticresonancetomographyinlegedemaofunknownorigin.Preliminaryreport].Z.Lymphol.17,2–5(1993).
51.Fair,K.P.,Knoell,K.A.,Patterson,J.W.,Rudd,R.J.&Greer,K.E.Lipedematousalopecia:aclinicopathologic,histologicandultrastructuralstudy.J.Cutan.Pathol.27,49–53(2000).
52.Stehno-Bittel,L.Intricaciesoffat.Phys.Ther.88,1265–1278(2008).53.Scallan,J.P.,Zawieja,S.D.,Castorena-Gonzalez,J.A.&Davis,M.J.Lymphaticpumping:mechanics,
mechanismsandmalfunction.J.Physiol.594,5749–5768(2016).54.Fogh-Andersen,N.,Altura,B.M.,Altura,B.T.&Siggaard-Andersen,O.Compositionofinterstitial
fluid.Clin.Chem.41,1522–1525(1995).55.Amann-Vesti,B.R.,Franzeck,U.K.&Bollinger,A.Microlymphaticaneurysmsinpatientswith
lipedema.Lymphology34,170–175(2001).56.Bollinger,A.&Amann-Vesti,B.R.Fluorescencemicrolymphography:diagnosticpotentialin
lymphedemaandbasisforthemeasurementoflymphaticpressureandflowvelocity.Lymphology40,52–62(2007).
57.Szolnoky,G.etal.Complexdecongestivephysiotherapydecreasescapillaryfragilityinlipedema.Lymphology41,161–166(2008).
58.Cotton,R.JustSkinDeep—YourImmuneSystemattheSurface|PLOS.TheStudentBlog(2015).59.Suga,H.etal.Adiposetissueremodelinginlipedema:adipocytedeathandconcurrentregeneration.
J.Cutan.Pathol.36,1293–1298(2009).60.Szél,E.,Kemény,L.,Groma,G.&Szolnoky,G.Pathophysiologicaldilemmasoflipedema.Med.
Hypotheses83,599–606(2014).61.Gavin,K.M.,Cooper,E.E.&Hickner,R.C.Estrogenreceptorproteincontentisdifferentin
abdominalthanglutealsubcutaneousadiposetissueofoverweight-to-obesepremenopausalwomen.Metabolism.62,1180–1188(2013).
62.Irwin,B.C.,Scorniaenchi,J.,Kerr,N.L.,Eisenmann,J.C.&Feltz,D.L.Aerobicexerciseispromotedwhenindividualperformanceaffectsthegroup:atestoftheKohlermotivationgaineffect.Ann.Behav.Med.Publ.Soc.Behav.Med.44,151–159(2012).
63.Fetzer,A.&Wise,C.Livingwithlipoedema:reviewingdifferentself-managementtechniques.Br.J.CommunityNurs.SupplChronic,S14,S16-19(2015).
64.Ehrlich,C.etal.LymphedemaandLipedemaNutritionGuide:foods,vitamins,minerals,andsupplements.(LymphNotes,2016).
65.Langendoen,S.I.,Habbema,L.,Nijsten,T.E.C.&Neumann,H.a.M.Lipoedema:fromclinicalpresentationtotherapy.Areviewoftheliterature.Br.J.Dermatol.161,980–986(2009).
66.Farrelly,I.Theimportanceandfunctionoffootwearinmanaginglymphoedema.Br.J.CommunityNurs.13,S10-14(2008).
67.Fetzer,A.Specialistapproachestomanaginglipoedema.Br.J.CommunityNurs.Suppl,S30-35(2016).
68.Nourollahi,A.,Mondry,T.E.,Herbst,K.L.Bucher’sbroomandseleniumImprovelipedema:aretrospectivecasestudy.Altern.Integr.Med.,2,119(2013).
69.Schmeller,W.,Hueppe,M.&Meier-Vollrath,I.Tumescentliposuctioninlipoedemayieldsgoodlong-termresults.Br.J.Dermatol.166,161–168(2012).
70.Wollina,U.,Goldman,A.&Heinig,B.MicrocannulartumescentliposuctioninadvancedlipedemaandDercum’sdisease.G.Ital.Dermatol.EVenereol.OrganoUff.Soc.Ital.Dermatol.ESifilogr.145,151–159(2010).
71.Stutz,J.J.&Krahl,D.Waterjet-assistedliposuctionforpatientswithlipoedema:histologicandimmunohistologicanalysisoftheaspiratesof30lipoedemapatients.AestheticPlast.Surg.33,153–162(2009).