20/04/16
ObjecHvesfortalk
PolyuriaandPolydipsiaSyndrome:
isitDiabetesInsipidus?
ProfTriciaTan
ConsultantinMetabolicMedicine&
Endocrinology
ClinicalChemistry
DefiniHonofPolyuria
•  Aurineoutputexceeding
–  3L/dayinadults
–  2L/m2bodysurfacearea/dayinchildren.
•  MustbedifferenHatedfrom
–  FrequencyofurinaHon
–  Nocturia
–  Thesearenotassociatedwithanincreaseinthe
totalurineoutput.
1.  tounderstandthepathophysiologyofDI
2.  tounderstandthedifferenHaldiagnosis
3.  tounderstandhowwecandifferenHate
betweenthedifferentcauses
4.  tounderstandtreatmentstrategies
BasicFirstLineInvesHgaHons
•  U&E,Ca,Glucose–excludediabetesmellitus!
•  UrinalysisforglucoseandS.G.
–  S.G.<1.005issuspicious
•  PairedserumandurineosmolaliHes
–  Normalserumosmo=275-295mOsm/kg
–  Urineosmorangesfrom100to1200mOsm/kg
–  Baselineserumosmoof>295withurineosmo
<200isdiagnosHcofDI
•  Bladderdiary
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Osmolality
Bladderdiary
•  ConcentraHonofosmoHcallyacHveparHclesinasoluHon
(expressedperkgsolvent)
•  Measureusingfreezingpointdepression(proporHonalto
osmolality)
Time
In
0700
0800
Out
‘Wet’
Urgencyra4ng
300ml
✔✔
A=feltnoneedtovoidbutdidsofor
otherreasons
Tea1cup
B=couldpostponevoidingaslongas
necessarywithoutfearof‘wehng’
0900
C=couldpostponevoidingforashort
Hmewithoutfearof‘wehng’
1000
1100
300ml
Water1
cup
D=couldnotpostponevoidingandhadto
rushtovoidintoilet
E=leakedbeforegehngtotoilet
…
0400
200ml
0500
0600
Osmoreceptorsvsbaroreceptors
Osmoreceptors
measure
concentraHonof
plasma
ADH=argininevasopressin(AVP)
Baroreceptors
measureblood
pressureand
volume
AVPsecreHonis
relatedto
osmolalityand
bloodvolume
↑osmo→↑AVP
↓volume→↑AVP
↓volumemodifiesAVPresponse
toosmolality
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AVPcontrolsaquaporinrecruitmentin
thecollecHngductofkidney
RelaHonshipofAVPreleasetoplasma
osmolalityandurineosmolality
Whenpolyuriaproven…
•  Excludeuncontrolleddiabetesmellitus
•  Threemajorcausesofpolyuriainthe
outpaHentsehng:
–  primarypolydipsia
–  centraldiabetesinsipidus(DI)
–  nephrogenicDI
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Primarypolydipsia
Ø Aprimaryincreaseinwaterintake.
•  Mostoqenseenin
–  middle-agedwomen
–  paHentswithpsychiatricillnesses
–  includingthosetakingaphenothiazinewhichcanlead
tothesensaHonofadrymouth
•  Primarypolydipsiacanalsobeinducedby
–  hypothalamiclesionsthatdirectlyaffectthethirst
center,e.g.sarcoidosis
–  Xerostomia(lackofsaliva)leadingtoexcessive
drinking
CranialDI
Ø DeficientsecreHonofAVPfromposterior
pituitary
•  Oqenidiopathic
–  possiblyduetoautoimmuneinjurytotheADHproducingcells
• 
• 
• 
• 
NephrogenicDI
Ø HighAVPbutkidneysinsensiHvetothis
•  Familial
–  MutaHonsinV2receptororaquaporin
• 
• 
• 
• 
• 
Litoxicity
Hypercalcaemia
Hypokalaemia
Renaldisease(e.g.CKD)
Pregnancy–placentalvasopressinase
Trauma(headinjury)
Pituitarysurgery
Hypoxicorischaemicencephalopathy
Familial:mutaHonsinpro-AVPgene
Case1
• 
• 
• 
• 
• 
40yearoldlady
BipolardisorderonLithiumcarbonate
Polyuriaandpolydipsia(upto10litresaday)
ComplainsofadrymouthalltheHme
Whatarethepossiblediagnoses?
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Case1
•  NephrogenicDI
–  DuetochronicLitreatment
–  Li-inducedhyperparathyroidismandhyperCa?
•  Primarypolydipsia
Tests
•  Baseline
–  Na145,K4.5,Canormal,glucosenormal
–  Liundetectable
•  WentontowaterdeprivaHontest
–  Duetounderlyingpsychiatricdisorder?
•  CranialDIlesslikely
WhatisawaterdeprivaHontest?
•  Firststage
–  Serialmeasurementsofserumandurineosmounder
condiHonsofwaterdeprivaHon
–  Differen4atesprimarypolydipsia(urineosmo↑)
fromDI(urineosmofailsto↑beyondalimit)
•  Secondstage
–  IfDIproven,giveDDAVP
–  Differen4atescranialDI(urineosmo↑toDDAVP)vs
nephrogenicDI(urineosmodoesnotrespond)
•  Needstobedoneundersupervisionforsafety
InterpretaHonofwaterdeprivaHon
Pre-test
Waterdeprived(8h)
GivenDDAVP
Serum
Urine
Serum
Urine
Serum
Urine
295
460
305
605
306
598
•  Pre-test
–  Serumtopendofnormal
–  Urinecan’tcomment
•  Waterdeprived
–  Serumtoohigh
–  Urineisinappropriatelylow(wouldexpect>750)
•  DDAVPgiven
–  SerumissHlltoohigh
–  UrineissHllnotconcentratedenough
Ø  NephrogenicDI
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NephrogenicDIduetoLithium
•  20-40%takingLihave↑urinevol(2-3L/d)
•  12%ofpaHentshavefrankpolyuria(>3L/d)
•  DirectinhibitoryeffectofLionaquaporin
expressionandrecruitment
•  Chroniceffect:Li-inducedintersHHalnephriHs
cancontributetoDI
•  UsuallyreversiblewithdisconHnuaHon,butcan
persistlong-term
•  InthiscasedisconHnuaHonledtosevlingofDI
TreatmentofNephrogenicDI
•  IVfluids(ifpaHentveryhypovolaemic)
–  Needtousefluidofsimilarosmotourine
otherwiseinstabilityof[Na]mayensue
•  Lowprotein/Nadiet
–  ↓amountofsolutethatneedstobeexcretedand
therefore↓urinevolumeneeded
•  ThiazidediureHcs
–  CausesmildvolumedepleHon
–  ↑resorpHonofNaandwaterinproximaltubule
TreatmentofNephrogenicDI
•  NSAIDs(e.g.indomethacin)
–  ProstaglandinsantagoniseeffectofAVP
–  ThereforeinhibiHngproducHonofPGcauses
increasedwaterreabsorpHon
•  HighdoseDDAVP
–  MostpaHentswithnon-familialnephrogenicDI
haveparHaldefectsthatmayrespondtoDDAVP
Case2
• 
• 
• 
• 
25yearoldwoman
“Alwaysdrunklotsandpassedlots”
Nootherrelevantpasthistory
Baselines
–  Na136,K3.6,CaandGlucosenormal
–  Serumosmo277,urineosmo100
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InterpretaHonofwaterdeprivaHon
Pre-test
•  Pre-test
Waterdeprived(8h)
Serum
Urine
Serum
Urine
275
100
280
850
–  Serumlowendofnormal
–  Urineisdilute
Treatmentofprimarypolydipsia
•  FluidrestricHon
•  ConsiderarHficialsalivaifproblemdrivenby
drynessofbuccalmucosa(e.g.with
xerostomia)
•  Waterdeprived
– 
– 
– 
– 
Serumrisestonormalrange
Urinerisesto>750
NotewouldexpectUrineosmotoriseto>1000inayoungperson
Chronicpolydipsiacauses‘washout’ofmedullaryconcentraHonand
thereforesomereducHoninabilitytoconcentrateurine
Ø  Primarypolydipsia
Case3
•  24y.o.man,RTAlastyear,polyuric
•  Baselines
–  Na145,K4.0,Canormal,glucosenormal
•  WentontowaterdeprivaHontest
Case3intepretaHon
Pre-test
Waterdeprived(8h)
GivenDDAVP
Serum
Urine
Serum
Urine
Serum
Urine
295
300
302
295
285
1154
•  Baseline
–  Serumtopendofnormal
–  Urinenotinterpretable
•  Waterdeprived
–  Serumclearlyhigh
–  Urineinappropriatelydilute(shouldbe>750atleastoreven>1000in
youngperson)
•  DDAVPgiven
–  Sharpriseinurineosmoseen
–  Recoveryofserumosmotonormal
Ø  CranialDI
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CranialDIduetoheadinjury
•  Acutelyaqerheadinjuryin1in5paHents
•  Seenchronicallyin1in12paHents
•  Associatedwithotherpituitaryproblemsor
canbeisolated
OthercausesofcranialDI
•  Pituitarytumours
–  Notcommoninpituitaryadenoma
–  Morecommonwithothertypesoftumours(e.g.
craniopharyngioma,metastasis)
•  Pituitarysurgery
•  InfiltraHvedisease
–  Sarcoidosis,hisHocytosisX
•  InfecHon
•  DDAVPRx:
Tablets
–  MeningiHs,encephaliHs
Nasalspray
Sublingualmelts
HowtomonitoraPaHentonDDAVP
•  DDAVPhasdifferentdosesdependingon
preparaHon,e.g.
•  Hereditary(rare)
DDAVPisavitaldrug
Pa4entsmustreceivesteadysuppliesofDDAVP
–  Tablets:100µgnocteto200µgTDS
–  Nasalspray:10-20µg(1-2sprays)OD-TDS
–  Melts:60,120,240µgOD-TDS
–  SubcutaneousinjecHon:0.5-1µgOD-BD
•  DifferentduraHonsofacHon
–  Tablets~4-6h
–  NasalSpray~8h
–  InjecHon~12h
Pa4entsareen4tledtoexemp4onfromprescrip4oncharges
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HowtomonitoraPaHentonDDAVP
•  Twokeyparametersformonitoring:
–  Bodyweight(reflectsbodywater)
–  Na+
•  Warningsigns:
–  Tiredness
–  Confusion
–  Ataxia
–  NauseaandvomiHng
–  Headaches
–  Acutechangeof>2kgfrombaselinebodyweight
•  CHECKU&EURGENTLY
SomecommonquesHons
•  BlockageofnasalpassagesinpaHentsusingspray
(e.g.URTI)
–  ConsiderRxtablets
•  Pregnancy
–  Mayrequireincreaseddose:placentalvasopressinase
breaksdownAVP/DDAVP
•  Travelling
–  PaHentsmayrequirealeverforairportsecurityto
carrymedicaHonthroughscreening
–  PaHentsshouldtakedosesaccordingtolocalHme
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