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European Journal of 10.1530/EJE-16-0493 (<135 with myxedema may exhibit reduced sodium levels moderate toseverehypothyroidism andmainlypatients ) ( or tertiary or thyrotropin-releasing (TRH) (secondary reduced secretionofthyroid-stimulatinghormone(TSH) axisresultingin disorders ofthehypothalamic–pituitary hypothyroidism), but occasionally may be caused by associated withunderlyingthyroiddisease(primary Decreased thyroidhormonelevelsareusually Introduction levels shouldbeevaluatedforothercausesandsuperimposedfactorsofhyponatremiatreatedaccordingly. Conclusions hyponatremic encephalopathyshouldbeurgentlytreatedaccordingtocurrentguidelines. usually adequateforthemanagementofmildhyponatremiainpatientswithhypothyroidism.Patientspossible be consideredinpatientswithmild/moderatehypothyroidism.Treatment ofhypothyroidismandfluidrestrictionare Other possiblecausesandsuperimposedfactorsofhyponatremia(e.g.drugs,,adrenalinsufficiency) should hypothyroidism-induced hyponatremiaisratherrareandprobablyoccursonlyinseverehypothyroidismmyxedema. are mainlyattributedtothehypothyroidism-induceddecreaseincardiacoutput.However, recentdatasuggestthatthe hypothyroidism isthedecreasedcapacityoffreewaterexcretionduetoelevatedantidiuretichormonelevels,which reduced serumsodiumlevels.Themainmechanismforthedevelopmentofhyponatremiainpatientswithchronic , thusthyroid-stimulatinghormonedeterminationismandatoryduringtheevaluationofpatientswith data regardingitsimplicationsandtreatmentinpatientswithhypothyroidism.Hypothyroidismisoneofthecauses of Summary sodium levels(<135 Background Abstract Department ofInternalMedicine,SchoolUniversityIoannina,Greece G Liamis, TD Filippatos,A Liontos mechanisms, implicationsandtreatment Hypothyroidism-associated hyponatremia: MANAGEMENT OFENDOCRINEDISEASE DOI: 10.1530/EJE-16-0493 www.eje-online.orgwww.eje-online.org Review

mlL ( mmol/L) : Theaimofthisshortreviewisthepresentationmechanismshyponatremiaandavailable : Severehypothyroidismmaybethecauseofhyponatremia.Allhypothyroidpatientswithlowserumsodium : Patientswithmoderatetoseverehypothyroidismandmainlypatientsmyxedemamayexhibitreduced

3 ,

mmol/L). 4 ). Thus,hypothyroidismis oneof © 2017EuropeanSocietyof Endocrinology © 2016EuropeanSociety ofEndocrinology G Liamisandothers 1 , and 2 ). Patientswith M S Elisaf Printed inGreatBritain hypothyroidism. regarding its implications and treatment in patients with the mechanismsofhyponatremia andtheavailabledata hormone (ADH)secretion(SIADH) ( diagnosis ofthesyndromeinappropriateantidiuretic of hypothyroidismisonetheprerequisitesfor serum sodiumlevels( duringtheevaluationofpatients withreduced mandatory the causesofhyponatremia,andTSHdetermination is hyponatremia Hypothyroidism and Published byBioscientifica Ltd. The aimofthisshortreview isthepresentationof 5 , Downloaded fromBioscientifica.com at10/02/202111:54:41AM 6 , 7 ). Furthermore, the exclusion (2017) Endocrinology European Journal of [email protected] Email to TDFilippatos should beaddressed Correspondence 176 6 176 : , 1 176

7 , :1 8 , R15–R20 ).

R15

–R20 via freeaccess European Journal of Endocrinology www.eje-online.org associated with and (which are very potent potent associated withnauseaandanxiety(whicharevery fluid intake.Additionally, radioiodineadministrationis instructed to follow low-iodinedietand receive increased In thesettingofradioiodinetreatment,patientsare been mainlyattributedtothehypothyroidism-induced elevated ADH levels ( is thedecreasedcapacityoffreewaterexcretiondueto hyponatremia inpatientswithchronichypothyroidism associated hyponatremia( factors combinedmaycontributetohypothyroidism- stimuli ofantidiuretichormonesecretion)andthese rate; SIADH,syndromeofinappropriate antidiuretichormonesecretion. with boldlettersandtheraremechanisms areshownwithdashedlines.ADH,antidiuretichormone; GFR,glomerularfiltration Implicating mechanismsofhyponatremia inpatientswithchronichypothyroidism.Themost importantmechanismsareshown Figure 1 the mostimportantmechanismofhyponatremia( to the diluting segmentsis by diminishingwaterdelivery rate (GFR)thatcandirectlydecreasefreewaterexcretion of acutehypothyroidism,decreasedglomerularfiltration hormonetreatmentiswithheld.Inthissetting undergo preparationforradioiodinetherapy, duringwhich andfollicular)who differentiated thyroidcancer(papillary Acute hypothyroidism is usually seen in patientswith patients withhypothyroidism Possible mechanismsofhyponatremia in Review The main mechanism for the development of Fig. 1 ). The increase in ADH levels has 10 ). G Liamisandothers 9 , 10 ). ).

patients with chronic hypothyroidism ( possible mechanismofhyponatremiainatleastsome acquaporin-2 expressioninthecollectingtubules( mediated through the upregulation of ADH-induced that theimpairedwaterexcretioninhypothyroidismis reduced water excretion ( suppress maximallythesecretionofADH,whichresultsin hypothyroid patientsistheresultofinabilityto ( sinus baroreceptorsandinducesthereleaseofADH decrease incardiacoutput,whichstimulatesthecarotid exhibit increasedurinesodiumconcentrationthatpoints levels ( ADH-mediated waterretentionandreducedsodium decreased effective arterial blood volume leading to mucopolyccharides thatresultsinfluidretentionand with myxedemaistheaccumulationofinterstitial contributing factortoincreasedADHlevelsinpatients with hypothyroidism.Inthesepatients,theimpairment role inthedevelopmentof hyponatremia in patients output ( to thediagnosisofSIADHandnotreducedcardiac hyponatremia Hypothyroidism and 11 , However, reducedcardiacoutputisnotthesole 12 16 , 18 , 13 17 ). Impairedrenalfunctionseemstoplaya , ). Additionally, somehypothyroidpatients 14 ). Thus,hyponatremiainmostof Downloaded fromBioscientifica.com at10/02/202111:54:41AM 3 , 15 ). Indeed, it has been shown 176 :1 i. 1 Fig. ). Another 15 R16 ). via freeaccess

European Journal of Endocrinology Emergency MedicineDepartment reportedanincreased analysis ofdatafrom9012 patientsadmittedtoan ( concentration inthesetting ofacutehypothyroidism female genderareassociated withlowerserumsodium or are receiving . Additionally, increased age and developing hyponatremiasuchasimpairedrenalfunction monitored, unlesspatientshave‘riskfactors’for serum sodiumconcentrationmaynotneedtobe This prospectivestudyalsoshowedthatinthissetting, hyponatremia ( onlyin18patients(8.5%) andmoderate was observed ( 139.5 preisolation: between pre-andpost-isolationsodiumlevels(mean± thyroid cancerpatients,asmalldifferencewasobserved Similarly, in a prospective analysis of 212 consecutive none ofthepatientsdevelopedseverehyponatremia( hyponatremia inonly3.9%of128patients,whereas differentiated thyroid cancerwasassociatedwithmild thyroid hormonetherapywithdrawalinpatientswith showed thatacutehypothyroidisminthesettingof and hyponatremiaisratherweek.Aretrospectivestudy Generally, theassociationbetweenhypothyroidism hyponatremia andhypothyroidism? How real istheassociationbetween may coexist. In certainpatients,morethanoneofthesemechanisms of chronichypothyroidism-associatedhyponatremia. 1 Figure abnormalities associatedwithvolumelosses( may beinfrequentlyrelatedwithmultipleelectrolyte especially the Na expression ofactivetransportpumpsintherenaltubules, was proposed that thyroid hormone is essential for the hypovolemia andmultipleelectrolyteabnormalities.It sodium 134 as apossiblemechanismofmildhyponatremia(serum Finally, a case report proposed -losing nephropathy well asindiuretic(thiazides)-treatedindividuals( especially inelderlypatients(>65 diet isassociatedwiththeoccurrenceofhyponatremia development ofhyponatremia( with lowsoluteintakethatmaycontributetothe 19 subsequently reducedcapacityforwaterexcretion( tothedilutingsegmentsofkidneyand water delivery in kidneyfunction(reducedGFR)resultsdecreased 10 10 Review , ). Regardingchronic hypothyroidism, a retrospective ). Additionally, mildhyponatremia( 20 ). Moreover, a low- diet is usually associated describesthemainpathogeneticmechanisms

mmol/L) inahypothyroidpatientwith ≥ + 120 -K

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., otslto: 137.8 postisolation: 2.3, -ATPase pumps, and hypothyroidism

mEq/L) onlyin4(1.9%)patients. 21 G Liamisandothers ). Generally, low-iodine

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(T levels; however, the most active free sodium concentrationdidnotcorrelatewithserumTSH relevant (138vs139 although statisticallysignificant,wasrathernonclinically in serumsodiumconcentration between thesegroups, levels (14%vs9%, TSH levelscomparedwithpatientshavingnormal prevalence ofhyponatremiainpatientshavinghigh mediated by othercomorbidities, including hypovolemia, hyponatremia andhypothyroidism mayatleastbe tubulopathies, SIADH)should besearched ( concentration (e.g.malnutrition, volumedepletion, hyponatremia, other causes of decreased serum sodium Thus, inthecasesofcongenitalhypothyroidismand between hypothyroidism and hyponatremia ( congenital hypothyroidismdidnotshowanassociation 0.14 correlated withadecreaseinserumsodiumbyonly ( sodium levelswasshowninaretrospectiveanalysis between newlydiagnosedhypothyroidismanddecreased P hypothyroid andeuthyroidindividuals(19.7%vs20.7%, the prevalenceofhyponatremiawasalsosimilarin in euthyroidgroupwas137.4 sodium levelsinhypothyroidgroupwas137.8 concentration in hypothyroid patients (mean serum no clinicallysignificantalterationsinserumsodium Intensive CareUnit of aUniversityHospitalalsoshowed analysis fromtheEmergencyDepartmentorMedical <135 hypothyroid patients with serumsodium concentration difference wasshownintheproportionofeuthyroidand hypothyroid patients( difference inserumsodiumlevelsbetweeneuthyroidand a studyincluding33 between hypothyroidismand hyponatremia. For example, levels evenincasesofunexplainedhyponatremia( that hypothyroidismwasnotamajorcauseoflowsodium was evidentonlyintwocases( hyponatremia ( in patientswithhyponatremia.Inaseriesof sodium levels( electrolyte abnormalities,includingdecreasedserum thyroid dysfunctionexhibitedclinicallyrelevant It shouldbementionedthatonlypatientswithsevere hyponatremia Hypothyroidism and n

=

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) correlatedsignificantlywithserumsodiumlevels. S ( NS)

999), in which every increaseinTSH by10 999), inwhichevery Additionally, theincidenceofhypothyroidismislow It hasbeensuggested that the association between Other studieshavequestionedthedirectcorrelation

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mEq/L (11.4%vs12.8%)( 28 ). Moreover, noclinicallyrelevantassociation 4 ). Furthermore,studiesininfantswith 24 n

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mEq/L), hypothyroidism mEq/L), ). Otherauthorsreported ). Anotherretrospective 176 www.eje-online.org 28 :1 ). Additionally, 17 ).

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mIU/L 26 R17 ). 29 via freeaccess ). European Journal of Endocrinology www.eje-online.org <50 gated. Ineuvolemichypothyroid patientswithTSH and othercausesofhyponatremia shouldbeinvesti should be considered as a possible superimposed factor TSH levels<50 of thelowserum sodium inhypothyroid patients with hypothyroidism shouldnotbeconsideredthesolecause frequently salt-losingnephropathy( adrenalinsufficiency orless suggest coexistentprimary euvolemic; thus,thepresenceofhypovolemiamay ( vital importanceintheevaluationofhyponatremia The assessmentoftheextracellularvolumestatusis of Clinical implications hypothyroidism( of secondary of glucocorticoiddeficiencyshouldbesuspectedincases hyponatremia ( usually accompaniedbyadrenalinsufficiencyresultingin the polyglandularautoimmunesyndrometypeIIis iodine diet( patients withhighriskofhyponatremiawhoareinlow- cases ( contribute tothedevelopmentofhyponatremiainthese solute intake,aswelltheunderlyingneoplasia,may ( is stoppedbeforetheadministrationofradioactiveiodine severe symptomatichyponatremiaifthyroxinetreatment be thecauseoflowthyroidhormones. ( therapy inpreparationforradioiodinescan/treatment cancer patients4 between ageandTSHlevelshasbeenshowninthyroid 50 severe hypothyroidism can exist with TSH levels below ( >50 only inpatientswithseverehypothyroidism(TSHlevels be includedinthedifferentialdiagnosisofhyponatremia Indeed, it has been suggested that hypothyroidism should moderate hypothyroidism andhyponatremia ( should becarefullyexcludedinpatientswithmild/ causes ofdecreasedsodiumlevels(includingdrugs) retention andhyponatremia( which mayinduceincreasedADHsecretion,water nausea, infectionsordrugsaffectingwaterhomeostasis, 35 34 33 7 ). Hypothyroidism-inducedhyponatremiaisusually Review

mIU/L. Indeed,asignificantnegativecorrelation , ). Additionally, hypothyroidismcan severesecondary ). However, cliniciansshouldhaveinmindthat

mIU/mL, ifnootherobvious causeofhyponatremia mIU/L) or with symptoms or signs of As aforementioneddataclearlysuggests, Finally, inpatientswith hypothyroidism observed Patients withmetastaticthyroidcancermayexhibit 36 21 , 37 ). Thus,serumsodiummonitoringiscrucialin ). However, low-iodinedietassociatedwithlow 22

mIU/L ( ). 38

weeks afterthewithdrawalofthyroxine ). Similarly, thesimultaneouspresence 33 ). Inthissetting,hypothyroidism 5 17 , G Liamisandothers 39 , ). 30 6 ). , 31 ). Thus,other 7 , 32 ). ­

( hyponatremia throughseveralunderlyingmechanisms coexists withdiabetesmellitus,whichisassociated (e.g. )( and hyponatremiamayhaveacommonunderlyingcause hyponatremia ( antidepressants), which are all well-established causes of systemillnessordrugs(e.g. central nervous or induced byanunderlyinginfection,respiratory myxedematous ,sincemyxedemacrisisisoften is adiagnosticchallengeforclinicians,evenincasesof isessential( tumor (particularlypulmonary) and repeatedmonitoringforthepresenceofanoccult the elderly, shouldbesuspected.Inthesecases,careful especiallyin SIADH, whichisnotinfrequentlyobserved hormone replacement,thepossibilityofidiopathic and normonatremiahasnotbeenachievedafterthyroid can beidentifiedafterathoroughdiagnosticworkup in patientswithserumsodium concentration<120 be attemptedwithwaterrestriction andnormalsalineonly has beenproposedthattreatment ofhyponatremiashould contribute tothepatient’s neurologicalsymptoms ( to determinewhetherthe lowserumsodiumlevels case, urgenttreatmentofhyponatremiamaybeindicated is oftenextremely difficult tobedistinguished. Inthis picture ofmyxedemaandhyponatremicencephalopathy mental status. It should be emphasized that the neurological severe hypothyroidismusuallyaccompaniedbyaltered inpatients whohave hyponatremia ismainlyobserved enough tocorrectserumsodiumlevels.Moresevere replacement andmoderatefluidrestrictionaregenerally hypothyroidism isusuallymild;thus,thyroidhormone In most cases, hyponatremia associated with hypothyroidic patients Treatment ofhyponatremia in superimposed factorsshouldbemeticulouslyinvestigated. hypothyroidism andthepresenceofcommoncausesor of multifactorialoriginmaybeseeninpatientswith autoimmune origin)( and hypergammaglobulinemia(inhypothyroidismof are (especiallyifdiabetesmellituscoexists) pseudohyponatremia inpatientswithhypothyroidism sodium levels are due to an artifact. Potential causes of is toexcludethepossibilitythatdecreasedserum step intheapproachofanypatientwithhyponatremia for thedegreeofhyperglycemia( imperative tocorrecttheserumsodiumconcentration hyponatremia Hypothyroidism and 41 , The attributionofhyponatremia to hypothyroidism 42 ). Additionally, inhyperglycemicstates,itis 32 , 40 32 ). Itisalsopossiblethatmyxedema ). Hypothyroidismalsofrequently 44 Downloaded fromBioscientifica.com at10/02/202111:54:41AM ). Consequently, hyponatremia 43 ). Anotherimportant 176 :1 7 ).

mEq/L, 45 R18 ). It via freeaccess European Journal of Endocrinology References the public,commercialornot-for-profit sector. This researchdidnotreceiveanyspecificgrantfromfundingagency in Funding AstraZeneca, Novartis,Vianex,Teva andMSD. companies, includingBristol-MyersSquibb,Pfizer, Lilly, Abbott,Amgen, talks andattendedconferencessponsoredbyvariouspharmaceutical Solvay, Glaxo,Novartis,PfizerandFournier. Theauthorshavegiven participated inclinicaltrialswithAstraZeneca,Merck,Sanofi-Synthelabo, Merck, Pfizer, Solvay, Abbott,Boehringer IngelheimandFournier, andhas consulting feesandresearchfundingfromAstraZeneca,ScheringPlough, supported itfinancially. ProfessorMElisafhasreceivedspeakerhonoraria, This reviewwaswrittenindependently;nocompanyorinstitution Declaration ofinterest infections, adrenalinsufficiency)shouldbeconsidered. and superimposedfactorsofhyponatremia(e.g.drugs, Even inmyxedemacoma,however, otherpossiblecauses rare andprobablyoccursonlyinseverehypothyroidism. The hypothyroidism-inducedhyponatremiaisrather Conclusions induced hypovolemichyponatremia( should berestrictedonlyinrarecasesofhypothyroidism- at may be given ( 10-min intervals uptotwoadditionalinfusions administered. Ifnecessary NaCl (2 with severesymptomatichyponatremia,100 ( levels canbeobserved no significant changeorevenadecreaseinserumsodium with suspicioushyponatremicencephalopathybecause normal should not be administered in patients hyponatremia ofanycause( should notbedeviatedfromtheprinciplesoftreating relative studies,webelievethattherapyofthisentity hypothyroidism-related hyponatremiaandthelackof demyelination syndrome)( hyponatremia withitsdevastatingconsequences(osmotic be usedcautiouslytoavoidinadvertentcorrectionof (hypertonic saline solution plus furosemide) should restriction is usually adequate. More aggressive treatment while inpatientswithhigherserumsodiumlevels,water 2 1

Review practice guidelinesforhypothyroidism inadults:cosponsoredby Pessah-Pollack R, Singer PA, Woeber KA &Abbott RD. Clinical 595–615. America Endocrinology andMetabolismClinics ofNorth Garber JR, Cobin RH,Gharib H,Hennessey JV, Klein I,Mechanick JI, Devdhar M, Ousman YH&Burman KD. Hypothyroidism. However, takingintoaccounttherarityof

mL/kg bodyweight)shouldbeimmediately (doi:10.1016/j.ecl.2007.04.008) 49 , 46 50 ). ). Onthecontrary, incases 45 G Liamisandothers , 47 45 50 , ). Normal saline , 48 51 ). Specifically, 2007 ).

mL of3% 36

10 21 20 19 18 17 16 15 14 13 12 11 hyponatremia Hypothyroidism and 9 8 6 5 4 3 7

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