治疗色素沉着Approach to the patient with hyperpigmentation disorders.docx

治疗色素沉着Approach to the patient with hyperpigmentation disorders.docx

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治疗色素沉着Approachtothepatientwithhyperpigmentationdisorders

Approachtothepatientwithhyperpigmentationdisorders

Authors

NeelamVashi,MD

RoopalKundu,MD

SectionEditor

ErikStratman,MD

DeputyEditor

RosamariaCorona,MD,DSc

Disclosures:

NeelamVashi,MDConsultant/AdvisoryBoards:

L'Oreal[Hyperpigmentation].RoopalKundu,MDNothingtodisclose.ErikStratman,MDNothingtodisclose.RosamariaCorona,MD,DScNothingtodisclose.

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamulti-levelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.

Conflictofinterestpolicy

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.

Literaturereviewcurrentthrough:

Jul2015.|Thistopiclastupdated:

Jan19,2015.

INTRODUCTION — Hyperpigmentationisthedarkeningorincreaseinthenaturalcoloroftheskinusuallyduetoanincreaseddepositionofmelanin（hypermelanosis）intheepidermisand/ordermis.Lessfrequently,itmaybecausedbythedepositioninthedermisofendogenousorexogenouspigments,suchashemosiderin,iron,orheavymetals.

Hyperpigmentationisafeatureofamultitudeofclinicalconditions,rangingfromnormalvariationsofskincolortoacquiredandinheritedsyndromes,andisoneofthemostcommonreasonsfordermatologicconsultation,particularlyinpatientswithdarkerskintypes[1-3].Althoughhyperpigmentationisnotharmful,itcancausesignificantcosmeticdisfigurementandbecomeapersistentpsychosocialburdenforthepatient,duetothelimitedefficacyoftheavailabletreatments.

Thistopicwillreviewtheapproachtothepatientwithhyperpigmentationdisorders.Melasmaisdiscussedseparately.Benignandmalignantmelanocytictumorsarediscussedseparately.

●（See"Melasma".）

●（See"Benignpigmentedskinlesionsotherthanmelanocyticnevi（moles）".）

●（See"Acquiredmelanocyticnevi（moles）".）

●（See"Skinexaminationandclinicalfeaturesofmelanoma".）

PATHOPHYSIOLOGY

Determinantsofskincolor — Thecolorofhumanskinismainlydeterminedbythetwotypesofmelanin,theblack-browneumelaninandtheyellow-redpheomelanin.Othersignificantdeterminantsarethecapillarybloodflow,chromophoressuchascaroteneorlycopene,andthecollagencontentofthedermis.

Eumelaninandpheomelaninarepresentinindividualofallskincolors,buttheirratioishighlyvariableanddeterminesthehueoftheskin[4].Differencesinthenumber,size,andaggregationofmelanosomeswithinthemelanocytesandkeratinocytes,butnotintheoverallnumberofmelanocytes,contributetoethnicdifferencesinskincolor[5,6].Darkerskintypeshaveahighercontentofmelanin,highereumelanin-to-pheomelaninratio,nonaggregatedandlargermelanosomes,andslowermelanosomedegradationwithinthekeratinocytes[7].

Melanin — Melaninisproducedbymelanocytes,specializedcellsofneuralcrestoriginthatresideinthebasallayeroftheepidermis.Thebiosynthesisofmelaninoccursinlysosome-likeorganellescalledmelanosomes,whicharetransportedtothecellperipheryandtransferredfromthedendritictipsofthemelanocytestothesurroundingkeratinocytes[8].Eachmelanocyteisassociatedwithapproximately36basalkeratinocytestoformtheso-calledepidermalmelaninunit.

MelaninsynthesisistriggeredbythehydroxylationofL-phenylalaninetoL-tyrosineordirectlyfromL-tyrosine.TyrosinasehydroxylatesL-tyrosineto3,4-L-dihydroxyphenylalanine（L-DOPA）,whichfurtherundergoesoxidationtodopaquinone.Thereafter,twomainpathwaysdiverge,leadingtoproductionofblack-browneumelaninandyellow-redpheomelanin.Melaninsynthesisisregulatedbymultiplecomplexsignalingpathways,includingmelanocyte-stimulatinghormones（MSH）/cAMPandKIT[8].

Geneticmutationsaffectingthepathwaysthatregulatethedifferentiationandmigrationofmelanocyteprecursorsintheneuralcrestortheproliferationandactivityofmaturemelanocytesmaybeinvolvedinthepathogenesisofhyperpigmentationassociatedwithinheritedsyndromes[8].

Hypermelanosis — Skinhyperpigmentationisinmostcasescausedbyincreasedbiosynthesisanddepositionofmelaninintheepidermisand/ordermis.Epidermalhypermelanosisresultsfromanexcessofmelanininthebasalandsuprabasallayersoftheskinduetoincreasedmelaninproductioneitherbyanabnormallyhighnumberofmelanocytesorbyanormalmelanocytepopulation.Theseabnormalitiesmaybeduetobothacquiredandgeneticfactors.

Thenormaldermisdoesnotcontainmelanin.Dermalhypermelanosismaydevelopthroughseveralmechanisms:

●Transferofmelaninfromtheepidermistothedermisandaccumulationwithinmelanophages（"pigmentaryincontinence"）.Thisprocessiscommonlyobservedininflammatoryskindiseasesthatinvolveadamageofthebasallayerand/orthedermoepidermaljunction.

●Productionofmelaninbyectopicdermalmelanocytes.ExamplesofdermalmelanocytosisarethenevusofOtaandnevusofIto.

●Bindingofmelanintoexogenouspigmentsdepositedinthedermis.

Otherpigments — Cutaneoushyperpigmentationcanbecausedbythedepositioninthedermisofendogenousorexogenouspigments,suchashemosiderin,iron,orheavymetals.Recurrentextravasationofredbloodcellsinthedermisleadstodepositionofhemosiderin,resultinginared-browndiscolorationoftheskin.Dermalhyperpigmentationmimickingdermalhypermelanosiscanbecausedbytopicalorsystemicexposuretoheavymetals（eg,silver,gold,mercury）.Somemetals,suchasiron,mayalsostimulatemelanogenesis,asobservedinpatientswithhemochromatosis.

PATIENTEVALUATION — Thediagnosisofhyperpigmentationdisordersmaybechallenging.Inmostcases,theinitialpatientevaluationinvolvesadetailedfamilyandpersonalmedicalhistoryandacompletephysicalexamination,whichshouldincludeacarefulsearchforadditionalcutaneousandextracutaneoussignsandsymptoms.

Questionsthatmaybeusefulfortheevaluationofpatientswithhyperpigmentationdisordersinclude[9]:

●Isthedisordercongenitaloracquired?

●Isthedisorderisolatedorpartofasyndrome?

●Isthepigmentationlocalizedordiffuse?

●Isthepigmentationwellcircumscribedorill-defined?

●Doesthepigmentationhaveapattern（eg,linear,reticular）?

●Isthepigmentationassociatedwithinflammationand/orpriorcutaneousinjury?

●Isthepigmentationstable,progressing,orregressing?

●Doesthepatienthaveconcomitantsystemicdiseases?

●Doesthepatienthaveahistoryofexposuretoanewmedication?

History — Adetailedmedicalhistoryshouldbeobtainedfromthepatienttodetermineifthehyperpigmentationisrelatedtoanunderlyingdisease.Thepossibilityofdrug-inducedpigmentationmustbekeptinmind.Patientsshouldalsobequestionedaboutoccupationalandorhobby-relatedexposuretochemicalsthatmaycausehyperpigmentation.

Investigationofthefamilyhistorymaybehelpfultodeterminewhetherthedisorderisacquiredorinherited,and,inthelattercase,whatistheprobableinheritancepattern[10].However,althoughcongenitalorinheritedhyperpigmentationdisordersareoftenpresentatbirth,historymaybemisleading,sinceparentsmaynothavenoteditformonthsorlonger.

Thecourseofthedisorderisalsoausefulparameterintheclinicaldiagnosisofhyperpigmentationdisorders.Inheritedhyperpigmentationsareoftenstable,whereasmostacquiredformsshowprogressionorregression.

Skinexamination — Inallpatientswithhyperpigmentationdisorders,acompleteskinexaminationshouldbeperformedundervisiblelightandWood'slight.Importantclinicalparametersinclude:

●Extentofthepigmentaryabnormality（localizedversusdiffuse）

●Colorhue（shadesofbrown/black,slate-gray/blue）

●Morphologyofindividuallesions

●Distribution（eg,sun-exposedareas,areaspreviouslyinvolvedbyinflammatoryprocesses）

●Pattern（eg,linear,reticular,nonfigurate）

Acarefulsearchforassociatedcutaneousandextracutaneoussignsandsymptomsmayprovideimportantcluestothediagnosis,particularlyinpatientswithhyperpigmentationdisordersassociatedwithsystemicdiseasesorgeneticsyndromes.

Wood'slightexamination — Wood'slight,alsoknownas"blacklight,"isultravioletAlightwithapeakemissionat365nm[11].Thepatientisexaminedinadarkenedroomwiththelightsourceheldat10to15cmfromtheskin.Wood'slightishelpfulindeterminingwhetherthepigmentdepositionispredominantlyepidermal,dermal,ormixed[12].

●Epidermalhypermelanosis–Undernaturallight,epidermalhypermelanosisappearslightbrowntodarkbrownincolor.Thepigmentation,aswellasthecontrastbetweeninvolvedanduninvolvedskin,isenhancedwhenviewedunderaWood'slamp.

●Dermalhypermelanosis–Undernaturallight,dermalhypermelanosishasabluishorashengrayhuewithmarginslessdefinedthanepidermalhypermelanosis.ThepigmentationisnotaccentuatedbytheWood'slight.

●Mixedhypermelanosis–Mixedhypermelanosisappearslighttodarkbrownundernaturallight,whereasWood'slightexaminationwillshowenhancementinsomeareasandnoneinothers.

Reflectanceconfocalmicroscopy — Invivoreflectanceconfocalmicroscopyisatechniquethatallowsnoninvasiveimagingoftheepidermisandpapillarydermisathistologicresolution[13].Theconfocalmicroscopeemitsanear-infraredlightfromadiodelasersourcefocusedonamicroscopicskintarget.Asthislightpenetratescellularstructureswithdifferentrefractionindexes,itisnatural