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
![Page 1: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/1.jpg)
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
![Page 2: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/2.jpg)
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`
![Page 3: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/3.jpg)
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
![Page 4: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/4.jpg)
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
![Page 5: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/5.jpg)
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
![Page 6: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/6.jpg)
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?
![Page 7: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/7.jpg)
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
![Page 8: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/8.jpg)
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.
![Page 9: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/9.jpg)
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
![Page 10: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/10.jpg)
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.
![Page 11: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/11.jpg)
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
![Page 12: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/12.jpg)
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
![Page 13: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/13.jpg)
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.
![Page 14: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/14.jpg)
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
![Page 15: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/15.jpg)
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
![Page 16: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/16.jpg)
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.
![Page 17: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/17.jpg)
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
![Page 18: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/18.jpg)
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.
![Page 19: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/19.jpg)
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.
![Page 20: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/20.jpg)
19
Figure6:LipedemaTypeIIIwithFatAccumulationfromButtockstoAnkles.(Top)Stage1;(Middle)Stage2;(Bottom)Stage3,notethatthisimageisnotscalewiththeothersbecauseonlythelowertorsoisvisualized.ImagescourtesyoftheFatDisordersResearchSociety.
Figure5:LipedemaTypeIIwithFatAccumulationfromtheButtockstoKnees,andFormationsofFoldsofFataroundtheInnerSideoftheKnee.(Top)Stage1;(Middle)Stage2;(Bottom)Stage3.ImagescourtesyoftheFatDisordersResearchSociety.
![Page 21: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/21.jpg)
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
![Page 22: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/22.jpg)
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.
![Page 23: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/23.jpg)
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.
![Page 24: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/24.jpg)
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.
![Page 25: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/25.jpg)
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.
![Page 26: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/26.jpg)
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
![Page 27: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/27.jpg)
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.
![Page 28: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/28.jpg)
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.
![Page 29: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/29.jpg)
28
InterventionalStudiesPhysicalConditioninLipedemaandObesity—Becauselipedemaandobesityareoftenmisdiagnosedforeachother,theprimaryaimofthisstudyistounderstandwhetherthereisadifferenceinmusclestrengthbetweenwomenwithlipedemaandwomenwithobesity.ThisstudyhasbeencompletedandcontributeddatatotheDutchLipedemaGuidelines.17
QuadrivasTherapytoReduceLipedemaSubcutaneousAdiposeTissue—Quadrivasisanintensivemassagetherapyfordifferenttissues.Thisstudyaimstounderstandwhetherthetherapycanreducesubcutaneousadiposetissueinparticipantswithlipedema.Thisstudyisongoingbutisnotrecruitingparticipants.
![Page 30: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/30.jpg)
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.
![Page 31: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/31.jpg)
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.
![Page 32: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/32.jpg)
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
![Page 33: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/33.jpg)
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.
![Page 34: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/34.jpg)
33
NederlansNetwerkvoorLymfoedeem&Lipoedeem(DutchLymphedemaandLipoedemaNetwork)―Foundedin2006,thisNetherlands-basedfoundationisfocusedonhelpingindividualsaffectedbylymphedemaandlipedema.Thenetwork’sgoalsaretodevelopanindependentplatformforscientificknowledge,throughthedevelopmentofnationalandinternationalguidelines,andtoserveasaresourceforpatients,patientorganizations,andcaregivers.
StichtingNederlandseLipoedeemdag(DutchLipoedemaFoundation)―ThisNetherlands-basedfoundationhasthegoalofraisingregional,national,andinternationalawarenessofthedisease.Thefoundationconvenesanannualsymposiumforpatients,partners,physicaltherapists,andmedicalpractitionerstosharebestpracticesandrecentdevelopmentsinlipedema.
![Page 35: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/35.jpg)
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.
![Page 36: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/36.jpg)
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.
![Page 37: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/37.jpg)
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
![Page 38: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/38.jpg)
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.
![Page 39: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/39.jpg)
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).
![Page 40: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/40.jpg)
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).
![Page 41: 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 Fellow, Institute of Imaging Science Vanderbilt University Walter Cromer, PhD Assistant](https://reader035.vdocuments.net/reader035/viewer/2022062507/5fbecabffd1a9d756364a284/html5/thumbnails/41.jpg)
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).