7/28/2016 Clinicalmanifestationsofadrenalinsufficiencyinadults

OfficialreprintfromUpToDate
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Clinicalmanifestationsofadrenalinsufficiencyinadults

Author SectionEditor DeputyEditor

LynnetteKNieman,MD AndrLacroix,MD KathrynAMartin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jun2016.|Thistopiclastupdated:Feb01,2013.
INTRODUCTIONThesymptomsandsignsofadrenalinsufficiencydependupontherateandextentoflossofadrenal
function,whethermineralocorticoidproductionispreserved,andthedegreeofstress.Theonsetofadrenalinsufficiencyis
oftenverygradualanditmaygoundetecteduntilanillnessorotherstressprecipitatesadrenalcrisis.

Theacuteandchronicclinicalmanifestationsofadrenalinsufficiencyinadultsarereviewedhere.Thecauses,diagnosis,
andtreatmentofthedifferentformsofadrenalinsufficiencyarereviewedseparately.(See"Causesofprimaryadrenal
insufficiency(Addison'sdisease)"and"Causesofsecondaryandtertiaryadrenalinsufficiencyinadults"and"Diagnosisof
adrenalinsufficiencyinadults"and"Treatmentofadrenalinsufficiencyinadults".)

ADRENALCRISISThesyndromeofadrenalcrisis(acuteadrenalinsufficiency)inadultsmayoccurinthefollowing
situations:

Inapreviouslyundiagnosedpatientwithprimaryadrenalinsufficiencywhohasbeensubjectedtoseriousinfection
orotheracute,majorstress.

Inapatientwithknownprimaryadrenalinsufficiencywhodoesnottakemoreglucocorticoidduringaninfectionor
othermajorillness,orhaspersistentvomitingcausedbyviralgastroenteritisorothergastrointestinaldisorders.

Afterbilateraladrenalinfarctionorbilateraladrenalhemorrhage.

Lessfrequentlyinpatientswithsecondaryortertiaryadrenalinsufficiencyduringacutestress,butissometimes
seenwithacutecortisoldeficiencyduetopituitaryinfarction.(See'Pituitaryapoplexy'below.)

Inpatientswhoareabruptlywithdrawnfromdosesofglucocorticoidthatcausesecondaryadrenalinsufficiency.
Importantly,thisincludesnotonlyoralbutinhaledmedications[1].

Thepredominantmanifestationofadrenalcrisisisshock,butthepatientsoftenhavenonspecificsymptomssuchas
anorexia,nausea,vomiting,abdominalpain,weakness,fatigue,lethargy,fever,confusionorcoma(table1).

Hypoglycemiaisararepresentingmanifestationofacuteadrenalinsufficiencyitismorecommoninsecondary
adrenalinsufficiencycausedbyisolatedcorticotropin(ACTH)deficiency[13].

Patientswithlongstandingadrenalinsufficiencywhopresentincrisismaybehyperpigmented(duetochronic
ACTHhypersecretion)andhaveweightloss,serumelectrolyteabnormalities,andothermanifestationsofchronic
adrenalinsufficiency(table2)[2].

Themajorhormonalfactorprecipitatingadrenalcrisisismineralocorticoid,notglucocorticoid,deficiency,andthemajor
clinicalproblemishypotension.Thus,adrenalcrisiscanoccurinpatientswhoarereceivingphysiologicoreven
pharmacologicdosesofsyntheticglucocorticoidiftheirmineralocorticoidrequirementsarenotmet[4,5].

Furthermore,patientswithsecondaryadrenalinsufficiency,inwhomaldosteronesecretionisusuallynormal,rarelypresent
inadrenalcrisis.Althoughitisnotprimarilyresponsible,glucocorticoiddeficiencycancontributetohypotensionby
causingdecreasedvascularresponsivenesstoangiotensinIIandnorepinephrine,decreasedsynthesisofreninsubstrate,
andincreasedprostacyclinproduction[68].

PrimaryadrenalinsufficiencyAdrenalcrisismostcommonlypresentsasshock[9].(See"Definition,classification,
etiology,andpathophysiologyofshockinadults".)Inadditiontoshock,otherfeaturesmayinclude:

Abdominaltenderness,whichmaybeelicitedondeeppalpationandisusuallygeneralized.Thecauseisunknown
inadrenalinsufficiencyassociatedwithpolyglandularautoimmunefailure,itmaybeamanifestationoftheserositis
associatedwiththisdisorder[10].

Fever,whichisusuallycausedbyinfection,andmaybeexaggeratedbyhypocortisolemia.Itshouldbeassumed
thatfeverindicatesinfectionthatmustbeidentifiedandtreated.Thecombinationofabdominalpainandfever
mayleadtotheincorrectdiagnosisofanacutesurgicalabdomenwithpotentiallycatastrophicsurgicalexploration.

Inaddition,septicshockitselfmayoccasionallycausetransientrelativeadrenalinsufficiency.Thistopicisreviewed
separately.(See"EvaluationoftheresponsetoACTHinadrenalinsufficiency",sectionon'Criticalillness'.)

Bilateraladrenalinjury,hemorrhage,andinfarctionAdrenalinsufficiencyisapotentialcomplicationofblunttrauma
caseshavebeenrecognizedintheintensivecaresettingasaresultofadmissionCTexaminations[11].Adrenalcrisis
canalsooccurasaresultofsuddenbilateraladrenalnecrosiscausedbyhemorrhage,emboli,sepsisorveryrarely,
adrenalveinthrombosisafterabackinjury[12,13].Thesepatientsdonothaveevidenceofpreexistingadrenal
insufficiency.Beforecomputedtopography(CT)becamewidelyavailable,thediagnosisofadrenalhemorrhagewas
usuallymadeatautopsy[13].(See"Causesofprimaryadrenalinsufficiency(Addison'sdisease)",sectionon

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'Hemorrhagicinfarction'.)

Thepresentingsymptomsandsigns(andthefrequencywithwhichtheyoccurredinonereport)includehypotensionor
shock(morethan90percent)abdominal,flank,back,orlowerchestpain(86percent)fever(66percent),presumablya
responsetoinflammationanorexia,nausea,orvomiting(47percent)neuropsychiatricsymptomssuchasconfusionor
disorientation(42percent)andabdominalrigidityorreboundtenderness(22percent)[12].Surprisingly,onlyabouthalfthe
patientshavehypotensionbeforeshock.Theacuteonsetdoesnotpermitenoughtimeforthepatienttobecome
hyperpigmented.

Evidenceofocculthemorrhage,suchasasuddenfallinhemoglobinandhematocrit,andprogressivehyperkalemia,
hyponatremia,andvolumecontractionareothersignsthatshouldsuggestthediagnosis.

Themajorriskfactorsforadrenalhemorrhageorinfarctionareanticoagulanttherapyorcoagulopathy,andthe
postoperativestate.Inpatientstreatedwithananticoagulant,theresultsofclottingtestsareusuallywithinthetherapeutic
rangeandspontaneousbleedingelsewhereisnotevident[12].

Becauseadrenalcrisisisdifficulttorecognizeclinically,itmustbeconsideredwheneverthesesymptomsdevelopina
patientwithoneormoreriskfactors.Withoutappropriatetherapy,shockprogressestocomaanddeath.Ifthepatient
survives,adrenalfunctionmayrarelyreturntonormalmonthslater[14].

Adrenalhemorrhageandoftendeathhasbeenassociatedwithmeningococcemia(WaterhouseFriderichsensyndrome)
[15],butPseudomonasaeruginosawasthemostcommonpathogenin51childrendyingofsepsisandbilateraladrenal
hemorrhage[16].(See"Causesofprimaryadrenalinsufficiency(Addison'sdisease)",sectionon'Hemorrhagicinfarction'.)

PituitaryapoplexyAdrenalcrisisisrareinpatientswithsecondary(pituitary)ortertiary(hypothalamic)adrenal
insufficiencybecausefunctionofthereninangiotensinaldosteronesystemisusuallynormalandhypovolemiaisrare.
Thesepatientsmayhavesymptomsandsignsofchronicadrenalinsufficiencyorofdeficientsecretionofotheranterior
pituitaryhormones.(See"Clinicalmanifestationsofhypopituitarism".)

However,adrenalcrisiscanoccurwhenthelossofpituitaryfunctionissuddenandsevere,asinpituitaryapoplexy
(pituitaryinfarction)thesymptomsinthesepatientsareduemainlytoacutecortisoldeficiency.

Patientswithpituitaryapoplexyresultingfrominfarctionofalargetumorusuallycomplainofsevereheadachetheymay
alsohaveacutevisuallossorreductioninvisualfields.However,becauseglucocorticoidshavearoleinmaintaining
peripheralvascularadrenergictone,suddenlossofcorticotropin(ACTH)secretion,particularlyinconjunctionwithother
seriousillness,canleadtohypotensionandshock[17].(See"Causesofhypopituitarism",sectionon'Pituitaryapoplexy'.)

CHRONICPRIMARYADRENALINSUFFICIENCYPatientswithchronicprimaryadrenalinsufficiencymayhave
symptomsandsignsofglucocorticoid,mineralocorticoidand,inwomen,androgendeficiency.Incontrast,patientswith
secondaryortertiaryadrenalinsufficiencyusuallyhavenormalmineralocorticoidfunction.

Thediagnosisisusuallyobviousinpatientswiththefullblownsyndromeofadrenalinsufficiency.However,itsonsetis
ofteninsidious,withthegradualdevelopmentofsymptoms,mostofwhicharenonspecific.Initsearlystage,therefore,
diagnosismaybedifficult.Theclinicalpresentationofprimaryadrenalinsufficiencyisdiscussedseparately.(See"Causes
andclinicalmanifestationsofprimaryadrenalinsufficiencyinchildren".)

CommonfeaturesThemostcommonclinicalfeaturesofchronicprimaryadrenalinsufficiencyarelistedinthetable
(table2)[2,1820].Regardlessoftheimmediatecomplaint,mostpatientswithadrenalinsufficiencyhavethefollowing:

Chronicmalaise
Lassitude
Fatiguethatisworsenedbyexertionandimprovedwithbedrest
Weaknessthatisgeneralized,notlimitedtoparticularmusclegroups
Anorexia
Weightloss

Theweightlossisprimarilyduetoanorexia,butdehydrationmaycontribute.Theamountofweightlostcanvaryfrom2to
asmuchas15kgandmaynotbecomeevidentuntiladrenalfailureisadvanced[18].

Thepatientmayalsobeverysensitivetoopioid,analgesicorsedativedrugs,ormayrecoververyslowlyfromillnessesor
operationsthatdonotprecipitateadrenalcrisis.

GastrointestinalcomplaintsGastrointestinalsymptoms,usuallynausea,occasionallyvomiting,abdominalpain,or
diarrheathatmayalternatewithconstipation,arecommonandcorrelatewiththeseverityofadrenalinsufficiency.Vomiting
andabdominalpainoftenheraldadrenalcrisis,andthefluidlossduetovomitingordiarrheamayprecipitatethecrisis.

Thecauseofgastrointestinalsymptomsinadrenalinsufficiencyisnotknown.Esophagogastroduodenoscopyand
gastrointestinalradiographyareusuallynormal[21],butgastricemptyingmaybedelayed[22].Pepticulcerdiseaseisrare
[23].Steatorrhearesponsivetoglucocorticoidreplacementhasoccasionallybeenreported[23,24].

HypotensionCardiovascularsymptomsincludeposturaldizzinessorsyncope.Inmostpatientsthebloodpressureis
low,butsomehaveonlyposturalhypotension.Thesesymptomsareprimarilyduetovolumedepletionresultingfrom
aldosteronedeficiency.Serumconcentrationsofendothelin1,avasoconstrictivepeptide,andofadrenomedullin,a
vasodilatorpeptide,arereportedtobeincreased[25,26].(See"Pathophysiologyofheartfailure:Neurohumoral
adaptations".)

Thecontributionoftheseandothervasoactiveagentstothehypotensionofprimaryadrenalinsufficiency,ifany,is
unknown.Glucocorticoidsarenecessaryforadrenalmedullaryepinephrinesynthesis,andpatientswithadrenal
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insufficiencyhavedecreasedserumepinephrineandcompensatoryincreasesinserumnorepinephrineconcentrations[27].
Thismaycauseslightlylowerbasalsystolicbloodpressureandanexaggeratedincreaseinpulserateinresponseto
uprightposture.

Bloodpressurecontrolimprovesinpatientswithpreexistinghypertension.Thus,thepresenceofhypertensionisstrong
evidenceagainstadiagnosisofadrenalinsufficiency[18,19].

ElectrolyteabnormalitiesHyponatremiaisfoundin85to90percentofpatients,reflectingbothsodiumlossand
volumedepletioncausedbymineralocorticoiddeficiencyandincreasedvasopressinsecretioncausedbycortisol
deficiency.(See"Hyponatremiaandhyperkalemiainadrenalinsufficiency".)

Saltcraving,sometimeswithmassivesaltingestion,isadistinctivefeatureinsomepatients.Tomakeitmorepalatable,
saltmaybe"chased"withlemonjuice.Increasedthirstforicedliquidsisoftenreported.

Hyperkalemiaoftenassociatedwithamildhyperchloremicacidosisoccursin60to65percentofpatientsdueto
mineralocorticoiddeficiency.

Hypercalcemiaisarareoccurrence.(See"Etiologyofhypercalcemia".)

HypoglycemiaHypoglycemiamayoccurafterprolongedfastingor,rarely,severalhoursafterahighcarbohydratemeal
[18,19].Itisrareinadultsintheabsenceofinfection,fever,oralcoholingestion.Hypoglycemiaismorecommonininfants
andchildrenwithprimaryadrenalinsufficiency,patientswithsecondaryadrenalinsufficiencycausedbyisolatedACTH
deficiency[2,3],andpatientswithtype1diabetesmellituswhodevelopadrenalinsufficiency.Inthelatterpatients,
sensitivitytoinsulinisincreasedbecauseoflossofthegluconeogeniceffectofcortisolandthehyperglycemiceffectsof
epinephrine[27,28].(See"Physiologicresponsetohypoglycemiainnormalsubjectsandpatientswithdiabetesmellitus".)

HyperpigmentationHyperpigmentation,whichisevidentinnearlyallpatientswithprimaryadrenalinsufficiency,isthe
mostcharacteristicphysicalfinding[29].Itisaconsequenceofcortisoldeficiency,andisduetoincreasedproductionof
proopiomelanocortin,aprohormonethatiscleavedintothebiologicallyactivehormonesACTH,melanocytestimulating
hormone(MSH)andothers.TheelevatedMSHresultsinincreasedmelaninsynthesis,causinghyperpigmentation.In
humans,melaninissynthesizedinepidermalmelanocyteslyingjustbelowthebasalcellsoftheepithelium.Themelanin
ispackagedinsecretorygranules,calledmelanosomes,whicharephagocytosedbythebasalcells[30].Theentire
POMCsystemispresentinkeratinocytes.Invitro,thePOMCpeptide,ACTH117,maybeamorepotentstimulatorof
melanogenesisthanMSH[31,32].However,therelativerolesofACTH117andMSHinthehyperpigmentationobserved
inpatientswithadrenalinsufficiencyhasnotbeenstudied.

Theresultingbrownhyperpigmentationisgeneralized,butismostconspicuousinareasexposedtolight(suchasthe
face,neck,andbacksofhands),areasexposedtochronicfrictionorpressure(suchastheelbows,knees,spine,
knuckles,waist[belt],midriff[girdle],andshoulders[brassierestraps])(picture1).Pigmentationisalsoprominentinthe
palmarcreases,whereitescapesbeingwornawaybyfriction,andinareasthatarenormallypigmented,suchasthe
areolae,axillae,perineum,andumbilicus[18,19].However,sincepigmentationofthepalmarcreasesmaybenormalin
darkerskinnedindividuals,comparisonwithotherfamilymembers,andthepresenceorabsenceofadditionalabnormal
pigmentationshouldbeconsideredwhenevaluatingthissign.

Otherpatternsofhyperpigmentationinclude:

Patchypigmentationontheinnersurfaceoflipsandthebuccalmucosaalongthelineofdentalocclusion(picture
2).Itmayalsooccurunderthetongue,alongthegingivalborderinpatientswithchronicperiodontaldisease,andon
thehardpalate.

Generalizedbuccal,vaginal,andanalmucosalmembranehyperpigmentationisusuallyseenonlyinpatientswhose
skinisnormallypigmented,suchasblacksandNativeAmericans.Hyperpigmentationingeneralislessnoticeable
inblacks,butgeneralizeddarkeningmaybeevident.

Existingfrecklesbecomedarker,andnumerousnewbrownorblackfrecklesmayappear.

Scarsacquiredwhenprimaryadrenalinsufficiencyispresentanduntreatedarepermanentlypigmented,those
acquiredearlierremainunpigmented,andthoseacquiredduringtreatmentdonotbecomepigmented.

Thehairandnailsmaybecomedarker,thenailsshowinglongitudinalbandsofdarkening(picture3).

Thehyperpigmentationbeginstofadewithinseveraldaysandlargelydisappearsafterafewmonthsofadequate
glucocorticoidtherapy.Recoveryisduetokeratinizationandthensloughingofthepigmentedbasallayeroftheepidermis.
Fadingofhairandnailstakeslongerbecausethepigmentedpartofthehairshaftornailgrowsoutslowly,andscarsnever
fadebecausethemelaninistrappedinfibrousconnectivetissue.

SexualdysfunctionDecreasedaxillaryandpubichairandlossoflibidoarecommoninwomen,inwhomandrogen
productionprimarilyoccursintheadrenalglands[19].Thesechangesareunusualinmen,inwhommostandrogen
productionoccursinthetestes.TheuseofexogenousDHEAinpatientswithprimaryadrenalinsufficiencyisreviewed
elsewhere.(See"Dehydroepiandrosteroneanditssulfate",sectionon'Useinadrenalinsufficiency'.)

Amenorrheadevelopsinabout25percentofwomen.Itmaybeduetotheeffectsofchronicillness,weightloss,or
autoimmunemediatedprimaryovarianfailure[19].(See"Pathogenesisandcausesofspontaneousprimaryovarian
insufficiency(prematureovarianfailure)".)

MusculoskeletalsymptomsDiffusemyalgiaandarthralgiaarefrequentsymptomsinpatientswithadrenal
insufficiency.Occasionalpatientshavepredominantlymusculoskeletalsymptomsandafewhaveflexioncontracturesof
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legs[33,34].Serumconcentrationsofmuscleenzymes,musclebiopsy,andelectromyographyareusuallynormal.The
myalgiaandarthralgiadisappearrapidlywithglucocorticoidandmineralocorticoidreplacement,butreversalofthe
contracturesmaytakemonthsandrequireorthopedicmeasures.

AuricularcartilagecalcificationCalcificationoftheauricularcartilagesmayoccurinlongstandingprimaryor
secondaryadrenalinsufficiency[21,35,36].Thisfindingoccursexclusivelyinmenitisthoughttoresultfromchronic
cortisoldeficiency,anddoesnotimprovewithglucocorticoidreplacement[35].

PsychiatricmanifestationsManypatientswithsevereorlongstandingadrenalinsufficiencyhavepsychiatric
symptoms,including[37]:

Mildtomoderateorganicbrainsyndromein5to20percent
Impairmentofmemorythatcanprogresstoconfusion,delirium,andstupor
Depressionin20to40percent,manifestedbyapathy,povertyofthought,andlackofinitiative
Psychosisin20to40percent,manifestedbysocialwithdrawal,irritability,negativism,poorjudgment,agitation,
hallucinations,paranoiddelusions,andbizarreorcatatonicposturing

Perceptualdisturbances,withincreasedsensitivitybutimpairedrecognitionandinterpretationofauditory,tactile,
gustatory,andolfactorystimuli,mayalsooccur.

Thesepsychiatricsymptomsoccurearlyinthediseaseandmaypredateothersymptoms,makingthediagnosisoftheir
causedifficult.Mostofthesesymptomsdisappearwithinafewdaysafterglucocorticoidtherapyisbegun,butthe
psychosismaypersistforseveralmonths.Improvementdoesnotcorrelatewithcorrectionofelectrolyteimbalance
except,onoccasion,inpatientswithseverehyponatremia.

VitiligoPatchy,oftenbilaterallysymmetricalareasofdepigmentedskin(vitiligo),theresultofautoimmunedestruction
ofdermalmelanocytes,occuronthetrunkorextremitiesin10to20percentofpatientswithautoimmunebutnotthose
withothercausesofadrenalinsufficiency[19,38].(See"Causesofprimaryadrenalinsufficiency(Addison'sdisease)".)

OtherOtherfindingsassociatedwithadrenalinsufficiencyincludesplenomegalyandlymphoidtissuehyperplasia,
particularlyofthetonsils.Ahighincidenceofdentalcarieswasreportedwhentuberculosiswasthemostcommoncause
ofadrenalinsufficiency[21].

Inaddition,patientswithpolyglandularautoimmunesyndrometypeIoftenhavechronicmoniliasisofthemouthandnails
thatdoesnotrespondtoglucocorticoidreplacementtherapyandrespondstoantifungaldrugtherapypoorly.

RelativeeosinophiliawasreportedtobeamarkerofadrenalinsufficiencybyGeorgeThornin1948[39].Smallsubsequent
seriessuggestthattheeosinophilcountisgreaterthan500/mm3inlessthan20percentofpatients[40].Thus,whilethe
presenceofeosinophiliamaysuggestadrenalinsufficiency,itdoesnothaveahighsensitivityandwhenfoundincidentally,
othercausessuchasallergyorinfectionshouldbeinvestigated[41].

InpatientswithAIDS,primaryadrenalinsufficiencyoccursinupto20percent[1].Fatigueisbyfarthemostcommon
presentingsymptom.Onlyaboutonethirdofthepatientshavehyperpigmentationandonehalfhavehyponatremia[1].
(See"PituitaryandadrenalglanddysfunctioninHIVinfectedpatients".)

SECONDARYORTERTIARYADRENALINSUFFICIENCYTheclinicalfeaturesofsecondaryortertiaryadrenal
insufficiencyaresimilartothoseofprimaryadrenalinsufficiency,withafewmajorexceptions.Weakness,fatigability,
myalgia,arthralgia,andpsychiatricsymptomsallcanoccurinpatientswithsecondaryadrenalinsufficiency,indicatingthat
thesesymptomsarecausedbyglucocorticoidratherthanmineralocorticoiddeficiency.(See"Clinicalmanifestationsof
hypopituitarism".)

Themajorexceptionsarethatinsecondaryortertiaryadrenalinsufficiency:

HyperpigmentationisnotpresentbecauseACTHsecretionisnotincreased.

Dehydrationisnotpresent,andhypotensionislessprominent[2,3].

Hyponatremiaandvolumeexpansionmaybepresent,causedbyaninappropriateincreaseinvasopressinsecretion
oractionduetocortisoldeficiency.Thehyponatremiacanoccurearlyinthediseaseandmaybetheinitial
manifestation.

Hyperkalemiaisnotpresent,reflectingthepresenceofaldosterone.(See"Hyponatremiaandhyperkalemiain
adrenalinsufficiency".)

Gastrointestinalsymptomsarelesscommon[2],suggestingthatelectrolytedisturbancesmaybeinvolvedintheir
etiology.

Hypoglycemiaismorecommoninsecondaryadrenalinsufficiency[2,42].Thisdifferenceisnotsimplydueto
concomitantlossofgrowthhormonesecretion,becauseitisthepresentingfeatureinoveronethirdofthepatients
withisolatedACTHdeficiency[2,3].Onepossibleexplanationisthattheabsenceofdehydrationandhypotension
permitsthepatientstotoleratetheirillnesslongerandpresentwithsymptomsofchronicglucocorticoiddeficiency,
ratherthanmineralocorticoiddeficiency.

Theremaybeclinicalmanifestationsofapituitaryorhypothalamictumor,suchassymptomsandsignsof
deficiencyofotheranteriorpituitaryhormones,headache,orvisualfielddefects.

Patientswithraregeneticsyndromesofpanhypopituitarism(forexample,Pit1orPROP1mutations),mayhave
additionalextrapituitarymanifestations.Thesearereviewedseparately.(See"Causesofhypopituitarism",section
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on'Geneticdiseases'.)

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyond
theBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,and
theyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestfor
patientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducation
piecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevel
andarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.

Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicsto
yourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsbysearchingonpatientinfoandthe
keyword(s)ofinterest.)

Basicstopics(see"Patientinformation:Addison'sdisease(TheBasics)"and"Patientinformation:Adrenalcrisis
(TheBasics)")

BeyondtheBasicstopics(see"Patientinformation:Adrenalinsufficiency(Addison'sdisease)(Beyondthe
Basics)")

SUMMARYThesymptomsandsignsofadrenalinsufficiencydependupontherateandextentoflossofadrenal
function,whethermineralocorticoidproductionispreserved,andthedegreeofstress.Althoughmanyofthesymptomsare
similarinpatientswithprimaryorsecondary/tertiaryadrenalinsufficiency,therearesomeimportantdifferences.

AcuteadrenalinsufficiencyThesyndromeofadrenalcrisis(acuteadrenalinsufficiency)inadultsmayoccurinthe
followingsituations(see'Adrenalcrisis'above):

Inapreviouslyundiagnosedpatientwithprimaryadrenalinsufficiencywhohasbeensubjectedtoseriousinfection
orotheracute,majorstress.

Inapatientwithknownprimaryadrenalinsufficiencywhodoesnottakemoreglucocorticoidduringanacute
infection(canoccurduringacuteviralinfectionssuchasinfluenza)orothermajorillness,orhaspersistentvomiting
causedbyviralgastroenteritisorothergastrointestinaldisorders.

Afterbilateraladrenalinfarctionorbilateraladrenalhemorrhage.

Rarelyinpatientswithsecondaryortertiaryadrenalinsufficiency,butissometimesseenwithacutecortisol
deficiencyduetopituitaryapoplexy,orinpatientswithdrawnabruptlyfromsuppressivedosesofcorticosteroids.
(See'Pituitaryapoplexy'above.)

Thepredominantmanifestationofadrenalcrisisisshock,butthepatientsoftenhavenonspecificsymptomssuch
asanorexia,nausea,vomiting,abdominalpain,weakness,fatigue,lethargy,fever,confusionorcoma(table1).

Chronicadrenalinsufficiency

PrimaryThemostcommonclinicalfeaturesofchronicprimaryadrenalinsufficiencyarelistedinthetable(table2).
Mostpatientspresentwithchronicmalaise,lassitude,fatigue(worsenedbyexertionandimprovedwithbedrest),
weakness,anorexia,andweightloss.Hypoglycemiaisnotcommon.

Otherclinicalmanifestationssuchasgastrointestinalsymptoms,hypotension,electrolyteabnormalities,and
hyperpigmentationarereviewedabove.(See'Chronicprimaryadrenalinsufficiency'above.)

SecondaryortertiaryManyofthesymptomsofsecondaryortertiaryadrenalinsufficiencyarethesameasthosefor
primaryadrenalinsufficiency,andarepresumablyduetoglucocorticoidratherthanmineralocorticoiddeficiency.These
includeweakness,fatigue,myalgias,andarthralgias.(See'Secondaryortertiaryadrenalinsufficiency'above.)

Themajordifferencesfromprimaryadrenalinsufficiencyarethatinsecondaryortertiaryadrenalinsufficiency:

HyperpigmentationisnotpresentbecauseACTHsecretionisnotincreased.

Dehydrationisnotpresent,andhypotensionislessprominent.

Hyponatremiaandvolumeexpansionmaybepresent,buthyperkalemiaisnot(reflectingthepresenceof
aldosterone).

Gastrointestinalsymptomsarelesscommon,suggestingthatelectrolytedisturbancesmaybeinvolvedintheir
etiology.

Hypoglycemiaismorecommoninsecondaryadrenalinsufficiency.

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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GRAPHICS

Clinicalandlaboratoryfindingssuggestingadrenalcrisis

Dehydration,hypotension,orshockoutofproportiontoseverityofcurrentillness

Nauseaandvomitingwithahistoryofweightlossandanorexia

Abdominalpain,socalled"acuteabdomen"

Unexplainedhypoglycemia

Unexplainedfever

Hyponatremia,hyperkalemia,azotemia,hypercalcemia,oreosinophilia

Hyperpigmentationorvitiligo

Otherautoimmuneendocrinedeficiencies,suchashypothyroidismorgonadalfailure

Adaptedfrom:BurkeCW.Adrenocorticalinsufficiency.ClinEndocrinolMetab198514:947.

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Clinicalmanifestationsofchronicadrenalinsufficiency

Symptom Frequency,percent
Weakness,tiredness,fatigue 100

Anorexia 100

Gastrointestinalsymptoms 92

Nausea 86

Vomiting 75

Constipation 33

Abdominalpain 31

Diarrhea 16

Saltcraving 16

Posturaldizziness 12

Muscleorjointpains 613

Sign
Weightloss 100

Hyperpigmentation 94

Hypotension(systolicBP<110mmHg) 8894

Vitiligo 1020

Auricularcalcification 5

Laboratoryabnormality
Electrolytedisturbances 92

Hyponatremia 88

Hyperkalemia 64

Hypercalcemia 6

Azotemia 55

Anemia 40

Eosinophilia 17

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HyperpigmentationinAddison'sdisease

(A)A57yearoldwomanpresentedwithsymptomsofprimaryadrenalinsufficiency
secondarytoautoimmuneAddison'sdisease.Diffuseskinhyerpigmentationhaddeveloped
duringthelastyear,asillustratedbyherfacialappearance.
(B)Thehandsdemonstrateincreasedpigmentationofthepalmarcreasesandwrists
comparedtoanormalfemalecontrol(farright).
(C)Withlongtermglucocorticoidandmineralocorticoidtherapy,herhyperpigmentation
resolved,asshownbythenormalpalmarskinpigmentationinthepatientatage83.
Ofnote,shewearsamedicalbraceletindicatingherrequirementforglucocorticoidsin
caseofsevereillness.

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BuccalhyperpigmentationduetoACTHexcess

Lipsandgumsofa32yearoldmandemonstratinghyperpigmentation
ofthebuccalmucosaalongthelineofdentalocclusion(anareaof
repeatedtrauma)andofthegums(intheareaofchronic
inflammatoryperiodontaldisease).ThehighplasmaACTH
concentrationsresponsibleforthehyperpigmentationweredueinthis
casetoprimaryadrenalinsufficiencysimilarchangescanbeseenin
patientswithACTHdependentCushing'ssyndromeorNelson's
syndrome.

ACTH:adrenocorticotropichormone.

Reprintedwithpermissionfrom:WilliamsTextbookofEndocrinology,8thed,
FosterDW,WilsonJD(Eds),WBSaunders,Philadelphia,1996.

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Hyperpigmentationofnailsinprimaryadrenal
insufficiency

Fingersofa28yearoldwhitewomanwithAddison'sdisease
(underneath)comparedtothoseofanormalwoman(top).Thereis
hyperpigmentationoftheskinandincreasedpigmentationofthe
distalhalfofthenailsthatoccurredduringtheperiodofadrenal
insufficiency.Theproximalhalfofthenailsarehypopigmented,a
reflectionofthereductioninACTHsecretionaftertheinstitutionof
glucocorticoidtherapy.

CourtesyofDavidNOrth,MD.

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ContributorDisclosures
LynnetteKNieman,MDGrant/Research/ClinicalTrialSupport:HRAPharma[Cushing'ssyndrome(Metapirone)].Andr
Lacroix,MDGrant/Research/ClinicalTrialSupport:Novartis[Pituitarytumors,Cushingssyndrome(Pasireotide,
octreotide,osilodrostat)]Cortendo[Cushing'ssyndrome(Levoketoconazole)].Speaker'sBureau:Novartis[Cushings
syndrome(Pasireotide,octreotide,osilodrostat)]EMDSerono[Cushing'ssyndrome(Lanreotide)].Consultant/Advisory
Boards:Novartis[Pituitarytumors,Cushing'ssyndrome(Pasireotide,octreotide,osilodrostat)]EMDSerono[Pituitary
tumors(Lanreotide)].KathrynAMartin,MDNothingtodisclose.

Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedby
vettingthroughamultilevelreviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.
AppropriatelyreferencedcontentisrequiredofallauthorsandmustconformtoUpToDatestandardsofevidence.

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