7/28/2016 Clinicalmanifestationsandcausesofcentraldiabetesinsipidus

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Clinicalmanifestationsandcausesofcentraldiabetesinsipidus

Author SectionEditor DeputyEditor

DanielGBichet,MD RichardHSterns,MD JohnPForman,MD,MSc

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Jun2016.|Thistopiclastupdated:Oct27,2015.
INTRODUCTIONCentraldiabetesinsipidus(CDI)ischaracterizedbydecreasedreleaseofantidiuretichormone(ADH,
alsocalledargininevasopressinorAVP),resultinginavariabledegreeofpolyuria.LackofADHcanbecausedby
disordersthatactatoneormoreofthesitesinvolvedinADHsecretion:thehypothalamicosmoreceptorsthesupraoptic
orparaventricularnucleiorthesuperiorportionofthesupraopticohypophysealtract[1].Bycontrast,damagetothetract
belowthemedianeminenceortotheposteriorpituitarygenerallycausesonlytransientpolyuria,becauseADHproducedin
thehypothalamuscanstillbesecretedintothesystemiccirculationviatheportalcapillariesinthemedianeminence[1].
(See"Hypothalamicpituitaryaxis".)

TheclinicalmanifestationsandcausesofCDIwillbereviewedhere.ThetreatmentofCDI,theclinicalmanifestationsand
causesofnephrogenicdiabetesinsipidus(DI),andthediagnosticapproachtothepolyuricpatientarediscussed
separately.(See"Treatmentofcentraldiabetesinsipidus"and"Clinicalmanifestationsandcausesofnephrogenicdiabetes
insipidus"and"Diagnosisofpolyuriaanddiabetesinsipidus".)

CLINICALMANIFESTATIONSPatientswithuntreatedcentraldiabetesinsipidus(CDI)typicallypresentwithpolyuria,
nocturia,and,duetotheinitialelevationinserumsodiumandosmolality,polydipsia.Theymayalsohaveneurologic
symptomsrelatedtotheunderlyingneurologicdisease.

TheserumsodiumconcentrationinuntreatedCDIisofteninthehighnormalrange,whichisrequiredtoprovidethe
ongoingstimulationofthirsttoreplacetheurinarywaterlosses.Moderatetoseverehypernatremiacandevelopwhenthirst
isimpairedorcannotbeexpressed.Thiscanoccurinpatientswithcentralnervoussystemlesionswhoalsohave
hypodipsiaoradipsia,ininfantsandyoungchildrenwhocannotindependentlyaccessfreewater,andinthepostoperative
periodinpatientswithunrecognizeddiabetesinsipidus(DI).(See"Etiologyandevaluationofhypernatremiainadults",
sectionon'Adipsicdiabetesinsipidus'.)

PatientswithCDImaydevelopdecreasedbonemineraldensityatthelumbarspineandfemoralneck,eveninthose
treatedwithdesmopressin(dDAVP)[2].ItisunclearhowthedeficiencyofADHresultsinboneloss,particularlysince
treatmentfailstopreventbonedisease.However,sinceADHactsuponbothV1andV2receptorsanddesmopressin
principallyuponV2receptors,onepossiblemechanismisthatactivationofV1receptorsstimulatesboneformation.

CAUSESThemostcommoncausesofcentraldiabetesinsipidus(CDI),accountingforthevastmajorityofcases,are
idiopathicdiabetesinsipidus(DI)[1,3,4],primaryorsecondarytumorsorinfiltrativediseases(suchasLangerhanscell
histiocytosis)[5],neurosurgery,andtrauma.Inareportof79childrenandyoungadults,forexample,CDIwasidiopathicin
52percentandresultedfromatumororinfiltrativediseasein38percent[4].Inanothercohortof147childrenfollowed
from2000to2013inasingleNorthAmericancenter,themostcommonsinglediagnosiswascraniopharyngioma(25.2
percent)[6].

Cranialmagneticresonanceimaging(MRI)toidentifyhyperintensitiesintheposteriorpituitaryorthickeningofthepituitary
stalkcanhelpdeterminethecauseofCDI[79].

AnyformofCDIcanbeexacerbatedorfirstbecomeapparentduringpregnancy,sincecatabolismofantidiuretichormone
(ADH,alsocalledargininevasopressinorAVP)isincreasedbyvasopressinasesreleasedfromtheplacenta[10,11].(See
"Renalandurinarytractphysiologyinnormalpregnancy".)

IdiopathicCDIApproximately30to50percentofcasesofCDIareidiopathic,beingassociatedwithdestructionofthe
hormonesecretingcellsinthehypothalamicnuclei.Ithasbeensuggestedthatanautoimmuneprocessisinvolvedin
many,ifnotmost,patients[1215].Insightintothemechanismofautoimmunityinsomeindividualswasprovidedbya
longitudinalstudyevaluatingthepresenceofcytoplasmicantibodiesdirectedagainstvasopressincells(Abpositive)in
patientswithendocrineautoimmunediseasesbutinitiallywithoutCDI[13].Amongalmost900suchpatients,9foundto
beAbpositiveand139Abnegativecontrolswereprospectivelyfollowed.Atfouryears,noneofthecontrolsdeveloped
CDI.Bycomparison,fourofthenineAbpositivepatientshadpartialCDIatstudyentryand,amongtheremainingfive
patients,threedevelopedpartialDIandonedevelopedcompleteCDI.

Thisautoimmuneprocessischaracterizedbylymphocyticinflammationofthepituitarystalkandposteriorpituitarythat
resolvesafterdestructionofthetargetneurons.MRIearlyinthecourseoftenrevealsthickeningorenlargementofthese
structures.

TheincidenceofsuchantibodiesinthosewithCDI,theirassociationwithotherautoimmunediseases,andtheir
correlationwithradiologicfeatureswasevaluatedinastudyof150patientswithCDIthatwasperformedbythesame
Italiangroup[14].Thediseasewasidiopathicin43percent,familialin4percent,granulomatousin8percent,and
secondarytocranialtrauma,tumor,orsurgeryin45percent.Antibodiestovasopressincellswerefoundinaboutonethird
ofthepatientswithidiopathicdiseaseandapproximatelyonequarterofpatientswithnonidiopathicdisease.Antibody
positivitywasindependentlyassociatedwithagelessthan30yearsatdiseaseonsetinthosewithidiopathicdisease,a
historyofautoimmunedisease,orpituitarystalkthickening.AutoimmuneCDIwashighlyprobableinyoungpatientswitha
historyofautoimmunediseaseandpituitarystalkthickening.

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OtherautoimmunemechanismsforCDIincludeimmunoglobulin(Ig)G4relatedsystemicsyndrome,whichmaybe
successfullytreatedwithglucocorticoids[16,17],andgranulomatosiswithpolyangiitis(GPA),asystemicdisease
characterizedbypauciimmune,necrotizing,smallvesselvasculitis,oftenassociatedwithpositiveantineutrophil
cytoplasmicantibodies(ANCA)[18].(See"OverviewofIgG4relateddisease"and"Clinicalmanifestationsanddiagnosis
ofgranulomatosiswithpolyangiitisandmicroscopicpolyangiitis".)

Thickeningofthepituitarystalkisanonspecificfinding,sincesomepatientswiththisfindinglaterdevelopagerminomaor
histiocytosis[19].Inchildren,progressivethickeningofthestalkasdeterminedbyserialMRIsisstronglysuggestiveofa
germinoma[4].

Anteriorpituitaryhormonedeficiency,withdecreasedreleaseofgrowthhormone,thyroidstimulatinghormone,and
adrenocorticotropichormone,alsomaybepresentordevelopinpatientswithidiopathicCDI[4,20].However,some
patientswhodevelopananteriorpituitaryendocrinopathyyearsafterthediagnosisofCDImayhaveapituitaryor
suprasellartumor,suggestingthattheinitialabnormalitywasduetoanoccultpathologicprocess.Asanexample,inone
studyof16patientsfirstdiagnosedwithidiopathicCDI,thedetectionofevolvinggonadotropindeficiencyinthree
individualsresultedinthediagnosisofpituitaryorsuprasellargerminomas20,6,and3yearsaftertheinitialpresentation
[21].Thesedata,ifconfirmed,suggestthatsuchpatientsshouldundergoregularendocrinefollowup.(See"Diagnostic
testingforhypopituitarism".)

FamilialandcongenitaldiseaseAnumberoffamilialandcongenitaldiseaseshavebeenassociatedwithCDI.These
includefamilialCDI,Wolframsyndrome,andcongenitaldiseasessuchascongenitalhypopituitarismandseptooptic
dysplasia.

FamilialCDIFamilialCDI,alsocalledfamilialneurohypophysealDIorFNDI(MIM125700),isusuallyan
autosomaldominantdiseasecausedbymutationsinthegeneencodingantidiuretichormone(ADH,alsocalledarginine
vasopressinorAVP)[22].ADHanditscorrespondingcarrier,neurophysinII,aresynthesizedasacompositeprecursorby
themagnocellularneuronsofthesupraopticandparaventricularnucleiofthehypothalamus[23].

ThemechanismbywhichasinglemutantallelecausesautosomaldominantFNDIinvolvestheinductionofmagnocellular
celldeathbytheaccumulationofmisfoldedAVPprecursorswithintheendoplasmicreticulum[24].Transfectionstudiesin
mouseneuroblastomaNeuro2Acellssuggestthatthemechanism(s)bywhichadominantmutantallelecauses
neurogenicDIisaresultoftheaccumulationofargininevasopressinfibrillaraggregateswithintheendoplasmicreticulum,
asocalledtoxicgainoffunction[25].Thisprocessismechanisticallysimilartothatseeninotherneurodegenerative
diseases,suchasHuntingtonandParkinsondiseases[26]

AlthoughthehandlingofmisfoldedAVPmutantscouldaccountforthedelayedonsetandprogressivenatureofdominant
FNDI,theprecisemechanismofmagnocellulartoxicityisstillunknown[25].Individualswithautosomaldominantdisease
progressivelydevelopAVPdeficiency,andclinicalandhormonalsignsusuallydonotdevelopuntilseveralmonthsor
yearsafterbirth[27].

ThisautosomaldominantformofCDIcontrastswithcongenitalAVPdeficiencythathasbeendescribedinthreefamilies
withautosomalrecessiveCDI.TwofamiliesbearamissensevariationaffectingtheseventhaminoacidoftheAVP
nonapeptide(p.Pro26Leu)[28,29],andfourmembersofonefamilywithtwoloopsofinbreedingbearalargedeletion
involvingthemajorityoftheAVPgeneaswellastheintergenicregionbetweentheAVPandOXTgene[30].Affected
membershaveearlypolyuriaandhypernatremia,incontrasttotheautosomaldominantdiseasementionedabove.The
existenceofthisautosomalrecessive,earlyonsetCDIisimportantbecauseitmustbeconsidered,alongwithcongenital
nephrogenicDI,inthedifferentialdiagnosisofcongenitalpolyuriaanddehydration,andtherapyforthesedisordersdiffer.

WolframsyndromeTheWolframorDIDMOAD(diabetesinsipidus,diabetesmellitus,opticatrophy,anddeafness)
syndromeischaracterizedbyCDI,diabetesmellitus,opticatrophy,anddeafness,withcognitiveandpsychiatricissues
thatmayappearlaterinlife[31]itisinheritedasanautosomalrecessivetraitwithincompletepenetrance.TheWolfram
syndromeiscausedbyatleasttwodifferentgenes:WFS1andZCD2[32].Bothencodeendoplasmicreticulumproteins
andseemtoaffectcalciumhomeostasis.Wolframin,theproductofWFS1,isexpressedinanumberoftissues,including
thepancreas[33]andbrainsupraopticparaventricularnuclei[34].DIinthisdisorderisduetolossofvasopressin
secretingneuronsinthesupraopticnucleusandimpairedprocessingofvasopressinprecursors[35].

VariationsinWFS1alsopredisposetotype2diabetesmellitus[36].WFS1negativelyregulatesakeytranscriptionfactor
involvedinendoplasmicreticulum(ER)stresssignaling,resultinginpancreaticbetacelldeathandpossiblyin
magnocellularcelldeath,whichcouldexplainthevasopressindeficiency[37].(See"Classificationofdiabetesmellitusand
geneticdiabeticsyndromes",sectionon'Wolframsyndrome'.)

CongenitalhypopituitarismCDIhasbeendescribedinpatientswithcongenitalhypopituitarismwithorwithout
ectopiaoftheposteriorpituitarylobe[3840].Thedefectsinposteriorpituitaryfunctioninthesedisordersinclude
symptomaticCDI,nocturia,reducedADHreleaseafterosmoticchallenge,andhypodipsiaorpolydipsia.Thesefindings
maybeassociatedwithisolatedgrowthhormonedeficiencyormultipleanteriorpituitaryhormonedeficiencies.

SeptoopticdysplasiaCDIcanbeseeninanumberofcongenitalcerebralmidlineabnormalities.Asanexample,
septoopticdysplasia(SOD)hasbeenassociatedwithdefectsinbothanteriorandposteriorpituitaryfunction[41,42].
SODisahighlyheterogeneousconditionwithphenotypesthatincludemidlineandforebrainabnormalitiesaswellasoptic
nerveandpituitaryhypoplasia.MostcasesofSODaresporadic,butfamilialcaseshavebeendescribedinassociation
withmutationsingenesfordevelopmentaltranscriptionfactors(suchasHESX1)thatareessentialfornormal
forebrain/pituitarydevelopment[43].AffectedpatientsmayhaveabnormalthirstaswellasadefectinADHrelease
[42,44].Asaresult,werecommendmonitoringoftheserumsodiuminthesepatientsonceperweekforonemonth,and
thenifstable,onceeverysixmonths.

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NeurosurgeryortraumaCDIcanbeinducedbyneurosurgery(usuallytranssphenoidal)ortraumatothehypothalamus
andposteriorpituitary[4549].TheincidenceofCDIinthesepatientsvarieswiththeextentofinjury,rangingfrom10to20
percentaftertranssphenoidalremovalofanadenomalimitedtothesellatoashighas60to80percentafterremovalof
verylargetumors.

AmuchlowerrateofpostoperativeCDIhasbeenreportedwithminimallyinvasiveendoscopicpituitarysurgery(2.7
percentpermanentand13.6percenttransient)[50].Aserumsodiumhigherthan145meq/Lwithinthefirstfivedays
postoperativelyhadahighpredictivevalueforpermanentDIdevelopment.Bycontrast,patientswithaserumsodiumless
than145meq/Linthefirstfivedayspostoperativelywillrarely,ifever,developpermanentDI,therebyvalidatingshort
postoperativeinpatientstayswithminimalriskofreadmissionforDImanagement.

CraniopharyngiomahasbeenassociatedwithCDIbothbeforesurgeryandparticularlyaftersurgery[47,51].Asomewhat
differentresponsehasbeendetectedaftertransfrontalsurgeryforacraniopharyngioma.Inthissetting,thepolyuria
appearstoresultinatleastsomepatientsfromthereleaseofanADHprecursorfromthehypothalamusthatcompetesfor
butdoesnotactivateADHV2receptors[49].ThesepatientsinitiallyhavehighserumimmunoreactiveADH
concentrations,buttheirADHhaslittleornobiologicalactivityandtheyhavediminishedresponsetoexogenoushormone
replacement.Thus,theybehaveasiftheyhavenephrogenicDI(NDI),althoughthepolyuriaistypicallytransient.

Severedamagetothehypothalamusortractbyneurosurgeryortraumaoftenresultsinatypicaltriphasicresponse
[1,47].Thereisaninitialpolyuricphase,beginningwithin24hoursandlasting4to5daysthisphasereflectsinhibitionof
ADHreleaseduetohypothalamicdysfunction[45].Thisisfollowed,ondays6to11,byanantidiureticphaseinwhich
storedhormoneisslowlyreleasedfromthedegeneratingposteriorpituitary.Duringthisstage,excessivewaterintakecan
leadtohyponatremiabecauseofatransientsyndromeofinappropriateADHsecretion[52].PermanentDImaythenensue
aftertheposteriorpituitarystoresaredepleted.

Mostcasesarenotpermanent[53].Asanexample,patientswithlessseverehypothalamicortractinjuryoftenhave
transientCDIthatbegins24to48hoursaftersurgeryandmaythenresolveoverthefirstweek.Furthermore,notall
patientsprogressthroughallthreephases.Somepatientsdeveloptransienthyponatremia,withorwithoutpreceding
polyuria,andthenrecover.(See"Pathophysiologyandetiologyofthesyndromeofinappropriateantidiuretichormone
secretion(SIADH)".)

Astudyof1571patientswithpituitaryadenomasofalltypeswhounderwenttranssphenoidalsurgeryatthesamecenter
providesinsightintotherelativefrequencyofthesedifferentresponses[54].Amongthesepatients,30percenthad
microadenomasand70percentmacroadenomas.Thekeyfindingswere:

31percenthadimmediatepostoperativepolyuria,17percenthadpolyuriaondaythree,and6percentondayseven.
Ofthesepatients,24percentreceivedoneormoredosesofADH.Afterthreemonths,only0.9percentwerestill
receivingADHorhadpolyuria.

3.4percentofpatientshadtransientpolyuriaandthentransienthyponatremia.

1.1percenthadthetriphasicpatternofpolyuria,hyponatremia,andthenpolyuria.

5.2percenthadonlytransienthyponatremia,eitherwithinonetothreedaysorfivetotendaysaftersurgery.

DespitetherelativelyhighfrequencyofCDIinpatientsundergoingneurosurgery,mostcasesofpolyuriainthissettingare
notduetoCDI[45].Morecommoncausesareexcretionofexcessfluidadministeredduringsurgery[55]and/oran
osmoticdiuresisinducedbymannitolorglucocorticoids(whichcausehyperglycemiaandglucosuria)giveninanattemptto
reducecerebraledema.TheseconditionscanbedifferentiatedfromCDIbymeasuringtheurineosmolalityandthe
responsetowaterrestrictionandtheadministrationofADH.(See"Diagnosisofpolyuriaanddiabetesinsipidus".)

CDIafterneurosurgeryrarelyoccursincombinationwithcerebralsaltwasting.Dependinguponthebalanceoftheensuing
waterandsolute(NaCl)diuresis,hyponatremia,normonatremia,orhypernatremiamaybepresent[56].(See
"Pathophysiologyandetiologyofthesyndromeofinappropriateantidiuretichormonesecretion(SIADH)",sectionon
'Cerebralsaltwasting'.)

CancerPrimaryorsecondary(mostoftenduetolungcancer,leukemia,orlymphoma)tumorsinthebraincaninvolve
thehypothalamicpituitaryregionandleadtoCDI[3].Insomepatientswithmetastaticdisease,polyuriaisthepresenting
symptom[3].

HypoxicencephalopathyHypoxicencephalopathyorsevereischemia(aswithcardiopulmonaryarrestorshock)can
leadtodiminishedADHrelease[1,57].Theseverityofthisdefectvaries,rangingfrommildandasymptomatictomarked
polyuria.Asanexample,overtCDIisunusualinpatientswithSheehan'ssyndrome(postpartumhypopituitarism)even
thoughADHsecretionisoftensubnormal[58].TheappearanceofDIinthesepatientsisconsistentwiththeoccasional
pathologicfindingsofscarringandatrophyinthesupraopticnucleiandposteriorpituitarygland[59].(See"Causesof
hypopituitarism".)

InfiltrativedisordersPatientswithLangerhanscellhistiocytosis(alsocalledhistiocytosisXandeosinophilic
granuloma)areatparticularlyhighriskforCDIduetohypothalamicpituitarydisease[5,60].Upto40percentofpatients
becomepolyuricwithinthefirstfouryears,particularlyifthereismultisysteminvolvementandproptosis.(See"Clinical
manifestations,pathologicfeatures,anddiagnosisofLangerhanscellhistiocytosis".)

Asimilarinfiltrativediseasecanoccurwithsarcoidosis,whichcanalsocausepolyuriaduetoNDI(inducedby
hypercalcemia)orprimarypolydipsia[61].AdditionalinfiltrativedisordersthatrarelycauseCDIincludegranulomatosis
withpolyangiitis(formerlyWegener'sgranulomatosis)[62,63]andautoimmunelymphocytichypophysitis[12,6466]the
latterdisordermayspontaneouslyimprove.(See"Causesofhypopituitarism",sectionon'Hypophysitis'.)

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PostsupraventriculartachycardiaTransientpolyuriaisoccasionallyseenaftercorrectionofasupraventricular
tachycardia[67,68].Bothawaterdiuresisandanatriuresismaybeseen,duerespectivelyduetodecreasedsecretionof
ADHandtoincreasedreleaseofatrialnatriureticpeptide.Thesehumoralchangesmaybemediatedbyincreasesinleft
atrialandsystemicpressure,therebyactivatinglocalvolumereceptors.

AnorexianervosaADHreleaseisoftensubnormalorerraticinpatientswithanorexianervosa,presumablyduetothe
cerebraldysfunction[69].Thisdefectisrelativelymildinmostcasesandpolyuria,whenpresent,isoftenduemostlytoa
primaryincreaseinthirst.

INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,"TheBasics"and"Beyond
theBasics."TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,and
theyanswerthefourorfivekeyquestionsapatientmighthaveaboutagivencondition.Thesearticlesarebestfor
patientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.BeyondtheBasicspatienteducation
piecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevel
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Basicstopics(see"Patientinformation:Diabetesinsipidus(TheBasics)")

SUMMARYANDRECOMMENDATIONS

Centraldiabetesinsipidus(CDI)ischaracterizedbydecreasedreleaseofantidiuretichormone(ADH),resultingina
variabledegreeofpolyuria.LackofADHcanbecausedbydisordersthatactatoneormoreofthesitesinvolvedin
ADHsecretion:thehypothalamicosmoreceptorsthesupraopticorparaventricularnucleiorthesuperiorportionof
thesupraopticohypophysealtract.(See'Introduction'above.)

PatientswithuntreatedCDItypicallypresentwithpolyuria,nocturia,and,duetotheinitialelevationinserumsodium
andosmolality,polydipsia.Theymayalsohaveneurologicsymptomsrelatedtotheunderlyingneurologicdisease.
(See'Clinicalmanifestations'above.)

ThecausesofCDIincludeidiopathicdisease,familialandcongenitaldisorders,neurosurgeryortrauma,primaryor
secondarycancers,hypoxicencephalopathy,infiltrativedisorders,postsupraventriculartachycardia,andanorexia
nervosa.ThevastmajorityofcasesareduetoidiopathicCDIorresultfromprimaryorsecondarytumors,or
infiltrativediseases(suchasLangerhanscellhistiocytosis).(See'Causes'above.)

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