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European Journal of -18-0609 Oxford, UK, 9 Norway, London, Ontario,Canada, 1 Bulent O Yildiz Maria Luisa Brandi Aliya A Khan Consensus adults: aCanadianandInternational Standards ofcareforhypoparathyroidismin due toloworinappropriately normalserumlevelsof characterized by hypocalcemiaandhyperphosphatemia Hypoparathyroidism isan uncommon disorderthatis Introduction and patienteducationisessentialtoachievingoptimalcontrol ofserumcalcium. serum calciumandcontrolthesymptomsofhypocalcemia. Frequentlaboratorymonitoringofthebiochemicalprofile Main conclusions: manuscript addressesacuteandchronicmanagementof hypoparathyroidisminadults. vitamin Danalogsrequiredandmaybeofvalueinlowering long-termcomplicationsofhypoparathyroidism.This controlling thesymptomsofhypocalcemia.PTHreplacementisvalueinloweringdosescalciumandactive withcalciumsupplementsandactivevitaminDanalogsiseffectiveinimprovingserumaswell morbidity andpoorqualityoflife.Treatmentrequiresclosemonitoringaswellpatienteducation.Conventional of thehypoparathyroidisminindividualswithnonsurgicaldisease.Hypoparathyroidismisassociatedsignificant nonsurgical causesaccountingfortheremaining25%ofcases.Acarefulreviewisrequiredtodetermineetiology inappropriately normalserumparathyroidhormonelevel(PTH).Themajorityofcasesarepost-surgical(75%)with Results: by theCanadianSocietyofEndocrinologyandMetabolism. Development andEvaluation(GRADE)approach.Thesestandardsofcareforhypoparathyroidismhavebeenendorsed and editorials.ThequalityofevidencewasevaluatedbasedontheGradingRecommendationsAssessment, and pregnancy’.OnlyEnglishlanguagepapersinvolvinghumanswereincluded.Weexcludedletters,reviews 2018 usingkeywords‘hypoparathyroidism,diagnosis,treatment,,PTH,calcidiol,, a literaturereview.WesearchedPubMed,MEDLINE,EMBASEandCochranedatabasesfromJanuary2000toMarch Methods: Purpose: Abstract Minnesota, USA University HospitalofGeneva,Switzerland, McMaster University,Hamilton,Ontario,Canada, https://doi.org/ https://eje.bioscientifica.com Statement Consensus 6 Hypoparathyroidismisararediseasecharacterizedbyhypocalcemia,hyperphosphatemiaandlowor University ofFlorence,Italy, Toprovidepracticerecommendationsforthediagnosisandmanagementofhypoparathyroidisminadults. Keyquestionspertainingtothediagnosisandmanagementofhypoparathyroidismwereaddressedfollowing 10.1530/EJE 1 , Christian AKoch 12 12 Hacettepe UniversitySchoolofMedicine,Ankara,Turkey,and Hypoparathyroidismrequirescarefulevaluationandpharmacologic interventioninordertoimprove and -18-0609 6 4 Université deSherbrooke,Quebec,Canada, , Claudio Marcocci Bart Clarke 3 A Khanandothers 2 , Stan Van Uum 13 7 Published by Bioscientifica Ltd. University ofPisa,Italy, 2 Technische UniversitatDresden,Germany, 7 10 , Lars Rejnmark University ofToronto,Canada, Printed inGreat Britain © 2019Theauthors 3 , Jean Patrice Baillargeon 8 , Rene Rizzoli 8 Aarhus University,C,Denmark, during which parathyroid glands are inadvertently injured, during whichparathyroid glands areinadvertentlyinjured, hypoparathyroidism isneck , (75%ofthecases) (PTH). Themostcommoncauseof hypoparathyroidism Diagnosis andmanagementof 13 5 Oslo UniversityHospital,Oslo, Mayo Clinic,Rochester, 9 11 , M Zakarea Shrayyef University of 4 , Jens Bollerslev 3 Western University, Attribution 4.0International License. This workislicensed under a Downloaded fromBioscientifica.com at10/01/202103:09:16PM (2019) Endocrinology European Journalof [email protected] Email to A A Khan should be addressed Correspondence 5 10

, , Rajesh Thakker 180 180 :3 , P1–P23 Creative Commons

P1 –P22 11 via freeaccess , European Journal of Endocrinology https://eje.bioscientifica.com • • • • • • • • • • • Table 1 calcidiol, calcitriol,hydrochlorothiazideandpregnancy’. ‘hypoparathyroidism, diagnosis,treatment,calcium,PTH, 2000toMarch databases fromJanuary 2018usingkeywords We searched PubMed,MEDLINE,EMBASEandCochrane Methodology available today. judgment andreflectthelimitedclinicaltrialevidence well as other patient factors. They do not preclude clinical adjustments forcomorbidities,individualpreferencesas applied inthecontextofclinicalcarewithappropriate today. Thesepracticerecommendationsaretobe consensus regarding the appropriate standard ofcare These recommendations reflect current evidence and addressed followinganextensivereviewoftheliterature. diagnosis andmanagementofhypoparathyroidismwere as generalendocrinologists. Key questions addressing the a workinggroupcomprisingofparathyroidexpertsaswell University, Western UniversityandtheMayoClinicformed clinical practice.CanadianEndocrineUpdate,McMaster limiteddatacurrentlyavailabletoguide with very hypoparathyroidism duringpregnancyischallenging controlled onconventionaltherapymanagementof with chronic hypoparathyroidism who cannotbewell Europe asanadjunctivetreatmentforadultpatients (rhPTH(1–84)) isnowapprovedintheUnitedStatesand Replacement therapywithrecombinanthumanPTH provide aphysiologicreplacementforthelackofPTH. ofhypoparathyroidism,butfailsto . This therapeutic approach addresses the consists oftheusecalciumsupplements,andactive as hypoparathyroidismhoweverPTHlevelsareelevated. resistance syndromes have the same biochemical profile remaining 25%ofthecasesarelistedin of nonsurgicalhypoparathyroidismwhichcomprisethe removed ordeprivedoftheirbloodsupply. Thecauses • • • • • • • • • • • Consensus Statement Idiopathic Maternal PTH resistancestates Transient (burninjuries,acute illness) Functional (magnesiumdeficiency orexcess) Mineral deposition(copperor iron) Radiation destruction Metastatic Infiltrative Genetic variants Autoimmune Conventional therapy ofhypoparathyroidism Causes ofnonsurgicalhypoparathyroidism. A Khanandothers al 1 Table . PTH Flow diagram. Figure 1 Parathyroid Summit: A Focus on Hypoparathyroidism.’ Parathyroid Summit:AFocusonHypoparathyroidism.’ in March 2018inasymposium sessionentitled‘2018 presented attheEndocrineSocietyannualmeeting literature reviewandpracticerecommendationswere of thisstandardspaper. Thekeyquestions,resultsofthe recent data. Allco-authors contributed to the development included ifthefindings have not been supersededbymore B C).Landmarkpaperspublishedearlierthen2000werealso ( Development andEvaluation(GRADE)approach( based ontheGradingofRecommendationsAssessment, series. Evaluationofthequalityevidencewasperformed questions beingaddressed,weincludedcasereportsand reviews andeditorials.Asevidenceislimitedforcertain language papersinvolvinghumans.We excludedletters, ( to PubMedsearch forarticlespublishedaheadofprint increase search sensitivity. Thesearch strategywasadapted MeSH termswereutilizedinvariouscombinationsto treatment. tables andtoolstosimplify, enhanceandstandardize based oncurrentevidenceandconsensus.We provide incorporated intothecurrentmanuscript. The sessionincludedtimeforattendeefeedback,whichwas hypoparathyroidism Diagnosis andmanagementof Table 2 Figure 1 This concise document outlines acceptable care today ). Papers were identified by content experts (A K and ). Paperswereidentifiedbycontentexperts(AKand ). Of the 482 citations, we included only English ). Ofthe482citations,weincludedonlyEnglish Downloaded fromBioscientifica.com at10/01/202103:09:16PM 180 :3 P2 via freeaccess 1 ) European Journal of Endocrinology results forconfirmationof hypocalcemia).IfthePTHis should not be delayed and does not require two test at leasttwooccasions(emergent careforhypocalcemia level oralowionizedcalcium levelsandlowPTHon confirm alowalbumin-corrected totalserumcalcium testingshould Laboratory wheezing andlaryngospasm. irritability, confusion,,bradyarrythmias, hands orfeet,musclecramping,twitching,depression, systems andincludenumbnesstinglinginface, neurologic, behavioral/psychiatricandcardiovascular of hypocalcemia,andmayinvolveneuromuscular, hypoparathyroidism principallyreflecttheeffects surgical hypoparathyroidism.Classicsymptoms of inappropriately normalPTHisdiagnosticofpermanent with orwithoutsymptomsinthepresenceofalow or metabolites andfollow-up( supplementation with calcium and active vitamin D permanent hypoparathyroidismandrequiresappropriate a low PTH calcium prior) ( and permanent hypoparathyroidism (surgery hypoparathyroidism (surgery will determinewhetherthisisacuteand/ortransient hypocalcemia, aswellthedurationof of thesurgicalproceduretodevelopment orothernecksurgeries,thetemporalproximity laryngeal ofthyroid,parathyroid, In patientswithhistory (a) Howischronichypoparathyroidismdiagnosed? organ damage hypoparathyroidism andevaluatingtarget 1. Confirmingadiagnosisof Observational study Randomized trial Study design Table 2 Consensus Statement Hypocalcemia forsixormoremonthsaftersurgery, 2 , Quality assessmentcriteria( < 3 mlL or 2.0 mmol/L , < 4 15 , 5 pg/mL is associated with a high risk of , 6 , 7 Very low Low Moderate High Quality ofevidence ). Alowserumalbumin-adjusted < 8 8 , < mg/dL inthepresenceof 9 6 months prior)orchronic ). A Khanandothers 1 ). ( ( Publication bias ( ( Imprecision ( ( Indirectness ( ( Inconsistency ( ( Risk ofbias Lower if − − − − − − − − − − 2) Verylikely 1) Likely 2) Veryserious 1) Serious 2) Veryserious 1) Serious 2) Veryserious 1) Serious 2) Veryserious 1) Serious > 6 months 6 months (+1) Wouldsuggestaspuriouseffectwhenresultsshowno (+1) Wouldreduceademonstratedeffector All plausibleconfounding (+1) Evidenceofagradient Dose response (+2) Verylarge (+1) Large Large effect Higher if and diagnosticofhypoparathyroidism( impaired parathyroid response to thehypocalcemic insult presence ofhypocalcemia,thiswouldalsobeindicative in thenormalreferencerangeandisnotelevated 21-hydroxylase correlate withthedevelopment of adrenal are presentin and positiveantibodiesto type1interferons,which probable inthepresenceof atleastonemajorsyndrome clinical features( may betheonlyendocrinopathypresent( 80% ofAPS1patientshavehypoparathyroidism,andthis hypoparathyroidism and adrenal insufficiency. More than major clinical features: chronic mucocutaneous candidiasis, resulting in organ failure. APS1 is characterized by three and infiltrationoftheinvolvedorganswithlymphocytes fetal liver( the lymphnodes,thymus,pancreas,adrenalcortexand autoimmune regulatorgene( syndrome1 (APS1). APS1 is caused by mutations in the in isolationoraspartoftheautoimmunepolyendocrine cause ofnonsurgical hypoparathyroidism. It may occur Autoimmune hypoparathyroidismisthemostcommon 1. Autoimmunehypoparathyroidism Nonsurgical causesofhypoparathyroidism the molecularbasisfordisorder( component ( complex syndromesinwhichhypoparathyroidismisa with assessingotherclinicalfeaturesthatarepartof isessentialalong patients, obtainingthefamilyhistory hypoparathyroidism Diagnosis andmanagementof Patients mayhaveinadditionmorethan20minor APS1 isassociatedwithcirculating autoantibodies 10 4 , , 11 > 5 95% ofpatients( ). Genetictestingisavailabletodiagnose ). 3 , 5 ) ( Table 4 Downloaded fromBioscientifica.com at10/01/202103:09:16PM AIRE ). ThediagnosisofAPS1is https://eje.bioscientifica.com ), whichisexpressedin 12 Table 3 180 ). Autoantibodiesto 3 :3 ). Innonsurgical 12 ). , 13 ). P3 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Type 2(autosomal Type 1orSanjad–Sakati Kenny–Caffey syndrome DiGeorge syndrome Hypoparathyroidism, Isolated Autoimmune Autoimmune mediated Hypoparathyroidism of X-linked recessive Autosomal dominant Autosomal recessive Isolated ADH type1withBartter’s Autosomal dominant Disorder Table 3 Consensus Statement dominant) syndrome anomalies (HDR) deafness, renal type 1(APS1) polyendocrine syndrome autoimmune etiology hypoparathyroidism syndrome type5 (ADH) type1and2 hypoparathyroidism recessive) syndrome (autosomal Genetic causesofhypoparathyroidism–keyclinicalfindingsandlabtests.

Gracile bonedysplasia,shortstaturewith Short stature,growthretardation,small Cardiac defects(presentin~80%including Sensorineural deafness,renalanatomic May showonlyhypoparathyroidism Other autoimmunediseasesandfeatures Presentation dominatedbybiochemical Hypocalcemia, hypomagnesemia, Typically asymptomaticormild types oftesting consideration ofspecificgeneticorother Clinical orlaboratoryfeaturesprompting abnormalities, andhypoparathyroidism closure ofanteriorfontanelle, eye stenosis oftubularbones,delayed cortical thickeningandmedullary hypoparathyroidism eyes, dysmorphicfacies, delayed fontanelleclosure,abnormal medullary stenosisofthelongbones, hands andfeet,corticalthickening ophthalmic anomalies,hearingloss behavioral andpsychiatricproblems, laryngeal abnormalities,cleftpalate, hypoparathyroidism, pharyngealand or aplasia,Tcelllymphopenia), (recurrent infections,thymichypoplasia arteriosus), immunodeficiency Fallot, interruptedaorticarch,truncus ventriculoseptal defect,tetralogyof autosomal dominantinheritance abnormalities andrenaldysfunction, adrenal insufficiencyandhypogonadism such asmucocutaneouscandidiasis, hypoparathyroidism and clinicalfeaturesof seen dependingontheseverity and saltwaterdepletionmaybe hypokalemia, alkalosis,hypercalciuria, hypercalciuria (ADHtypes1and2) hypocalcemia withorwithout A Khanandothers hypoparathyroidism Diagnosis andmanagementof Usually dueto SOX3 locus(in PTH orGCM2 PTH orGCM2 CASR Gain offunction Molecular defect FAM111A TBCE Variety ofdefects GATA3 AIRE mutationsorof homozygous males) 11 (type2) (type 1)orGalpha mutation inCASR 22q11.2 chromosome microdeletions in and deletions unknown etiology mutations inAIRE

Downloaded fromBioscientifica.com at10/01/202103:09:16PM Presence of21-hydroxylase AIRE sequencing PTH, GCM2,sequencing CASR sequencing CASR orGNA11sequencing establish diagnosis Genetic andothertestingto FAM111A sequencing TBCE sequencing Two otherdiagnostic Fluorescence insitu GATA3 sequencing,hearing AIRE sequencing Testing forotherhormonal depending onpresentation is done In somecase,TBXsequencing amplification andSNP)array. ligation-dependent probe including PCR-basedmultiplex greater frequencythanFISH approaches areusedwith commonly done traditional testmost hybridization (FISH)isthe testing, renalimaging insufficiency) adrenal andgonadal insufficiency states(e.g., insufficiency of autoimmuneadrenal antibodies supportsdiagnosis 180 :3

(Continued) P4 via freeaccess European Journal of Endocrinology receptor results inenhancedurinecalcium losses to hypoparathyroidism( and secretionatnormalionized calciumlevelsleading parathyroid glandscausing suppression ofPTHsynthesis calcium. Themutatedreceptor isexpressedinthe the sensitivityofCASRtoextracellularionized calcium-sensing receptor( b. Autosomaldominanthypocalcemia(ADH). hypoparathyroidism duetoparathyroidglandagenesis( in isolatedhypoparathyroidismwithearlyonset of a. Glialcellsmissing(GCM2)genemutationresults A. Isolatedhypoparathyroidism Table 3 Genetic causesofhypoparathyroidismispresentedin 2. Geneticvariants autoimmune hypoparathyroidism( the CASR have been identified in individuals with ( can suppressPTHsecretionleadingtohypoparathyroidism DNA studiesofthe respectively Amoleculardiagnosiscanbeconfirmedwith of adrenalinsufficiencyandhypoparathyroidism antibodies canbeofvalueinpredictingthedevelopment development ofhypoparathyroidismandmeasuringthese insufficiency andantibodiestoNALP5correlatewiththe encephalomyopathy, lacticacidosis,andstroke-likesyndrome;MTPDS,mitochondrialtrifunctionalproteindeficiency. AIRE, autoimmuneregulatorofendocrinefunction;CASR,calcium-sensingreceptor;GNA11;Gproteinalphasubunit11;MELAS,mitochondrial MTPDS MELAS Kearns Sayresyndrome Hypoparathyroidism Disorder Table 3 15 Consensus Statement mitochondrial disorders associated with ). Antibodiesagainsttheextracellulardomainof Type 1iscausedbyanactivatingmutationinthe Activating antibodiestothecalcium-sensingreceptor . Continued. AIRE gene( 17 Disordered fattyacidoxidationassociated Encephalomyopathy, lacticacidosis,and Ophthalmoplegia, retinalpigmentaryand types oftesting consideration ofspecificgeneticorother Clinical orlaboratoryfeaturesprompting ). Inthekidney, themutated CASR liver with neuropathy,retinopathyandfatty and cognitivedysfunction early-onset strokesymptoms,migraine, ophthalmoplegia, diabetes,hearingloss, stroke-like episodesalongwithexternal ataxia proximal andbulbarweakness,possibly cardiac conductionabnormalities, 14 A Khanandothers ) genewhichincreases ). 16 ). 17 ). • • • • • • • • • • • • • • • • • Minor features • • • Major features Table 4 calcium excretionisnotaffectedintype2ADH( guanine nucleotide-binding protein alpha 11 ( nephrocalcinosis andnephrolithiasis. with relativehypercalciuria andanincreasedriskof secretion ofPTH( 11p15 havebeenassociatedwithdefectivesynthesisand c. PTHgenemutations: of PTHevenatlowserumcalciumlevels( key mediatorofCASRsignalingresultinginsuppresion gene encodingthealphasubunitofGproteinG11–a hypoparathyroidism Diagnosis andmanagementof • • • • • • • • • • • • • • • • • • • • Polyarthritis Pure red-cellaplasia Retinitis Thyroiditis Celiac disease Functional asplenia T1DM Pancreatitis Nephritis Pneumonitis Periodic feverwithrash Photophobia Enteropathy withchronicdiarrheaorconstipation Enamel hypoplasia Primary ovarianfailure Autoimmune hepatitis Keratitis Adrenal insufficiency Hypoparathyroidism Mucocutaneous candidiasis Rare mutationsinthe Type 2iscausedbyanactivatingmutationinthe Mutations in Mutations inthe mtDNA large-scale Mutations inthe Molecular defect genome mitochondrial tRNA Leugene mitochondrial deletion genome mitochondrial Features ofAPS1. 21 ). Downloaded fromBioscientifica.com at10/01/202103:09:16PM Specialized clinicalassessments Mitochondrial DNAsequencing establish diagnosis Genetic andothertestingto PTH endocrinologic andothers) ophthalmologic, neurologic, manifestations (cardiac, depending onthe https://eje.bioscientifica.com genelocatedonlocus 180 :3 18 , 19 20 ). Urine GNA11 ). P5 via freeaccess ) European Journal of Endocrinology https://eje.bioscientifica.com parathyroid glandshasbeen reportedtobeacauseof Wilson’s diseasewithcopper depositioninthe 6. Mineraldeposition been associatedwithhypoparathyroidism( Rarely highdosesofionizingradiationexposurehave 5. Radiationdestruction leukemia, skin,lung,sarcomas andlymphomas( hypoparathyroidism. Themostcommontumorsarebreast, rarely cause tumors very Infiltrating secondary 4. Metastaticcancer Riedel’s thyroiditis)hasbeenreported( granulomatous infiltration(e.g.sarcoidosis, amyloidosis, to Destruction of theparathyroid glands secondary 3. Infiltrativecauses mental retardationandfacialdimorphism( congenital hypoparathyroidism,severegrowthimpairment, syndromes type1and2.Theclinicalfeaturesinclude syndromes namelytheSanjad–SakatiandKenneyCaffey recessive hypoparathyroidismwhichencompassesthetwo syndrome. HRD syndrome is a rare form of autosomal c. Hypoparathyroidism–retardation–dysmorphism(HRD) disease ( the presenceofhypocalcemia,hearinglossandrenal and oticvesicledevelopment.Thepresentationincludes GATA 3, a proteincritical for normal parathyroid, kidney resulting inhaploinsufficiencyofthetranscriptionfactor 3 genelocalizedtochromosomalregion10p14–15 with mutations or deletions in the GATA-binding protein dysplasia syndrome(HDRsyndrome). b. Hypoparathyroidism,sensorineuraldeafnessandrenal learning disabilities( congenital heartdefects,facialanomalies,speechand aplastic orhyoplasticthymuswithimmunedeficits, aplasia or hypoplasia causing neonatal hypocalcemia, developmental delay, palatalanomalies,parathyroid 22q.21–q11.23 chromosome. The clinical features include amicrodeletionwithin 5000 livebirths,70–80%carry a. DiGeorgesyndromeisarareconditionaffecting1/4000– B. Hypoparathyroidismwithadditionalfeatures( Consensus Statement This isarareautosomaldominantdisorderassociated 25 , 26 ). 22 , 23 , 24 ). A Khanandothers 30 , 27 31 36 , , 28 , Table 3 32 37 , 35 29 , , 33 ). 38 ). , ) ). 34 ). • • • • • • • • • • • • Causes oflowmagnesium Table 5 both calciumandmagnesiuminthekidneys. the kidneys results in decreased paracellular transport of contribute tohypocalcemia.ActivationoftheCASRin high serummagnesiumlevelscandecreasePTHand cellular cAMP with inhibition of PTH release ( Mg and secretion( Mg and absorbedinthebowelapassiveparacellular ( requirefurtherevaluationandcorrection impair parathyroid function. Abnormalities in serum Both hypomagnesemiaandhypermagnesemiacan deficiency orexcess) 8. Functionalhypoparathyroidism(magnesium with transienthypoparathyroidism( Severe burninjuriesandacuteillnesscanbeassociated 7. Transienthypoparathyroidism with thalassemia( repeated transfusionsandcandevelopinindividuals hypoparathyroidism. Ironoverloadcanalsooccurwith is causedbyironoverloadandcancause hypoparathyroidism ( 6 (TRPM6)channelsinthebowelandkidney( via the transient receptor potential melastatin subtype manner ( hypoparathyroidism Diagnosis andmanagementof Tables 5 • • • • • • • • • • • • EGF-receptor inhibitors(cetuximab) cyclosporine A) Immunosuppressants (calcineurin inhibitors-tacrolimus, Anticancer drugs(cisplatin,carboplatin) pentamidine, rapamycin) Antimycotics (foscarnet,amphotericinB,aminoglycosides, Antibiotics Proton pumpinhibitor Thiazides, furosemide Drugs nephrocalcinosis (FHHNC) Familial hypomagnesemiawithhypercalciuriaand CASR Autosomal dominanthypocalcemia(activatingmutationin (TRPM6 mutation) Familial hypomagnesemiawithsecondaryhypocalcemia bowel syndrome,severevomitting,diarrhea,steatorrhea) Decreased intestinalabsorption(,short Decreased intake +2 +2 stimulatesphospholipaseCandA2 and inhibits canactivatetheCASRandlowerPTHsynthesis gene) and Causes oflowmagnesium. 47 , 48 6 ). Magnesiumisreabsorbedinthekidney ). Transcellular absorptionofMg 49 42 , , 50 43 39 ). ActivationoftheCASRby Downloaded fromBioscientifica.com at10/01/202103:09:16PM , , 44 40 ). , 41 ). Hemochromatosis 45 180 , :3 46 ). 51 +2 ). Thus, occurs P6 48 via freeaccess ). ). European Journal of Endocrinology system ( with muscleweaknessand affectsthecentralnervous acidosis, stroke-likeepisodes (MELAS)syndromepresents conduction blocksaswellataxia. ptosis, retinitispigmentosa,cardiomyopathy, cardiac Kearns–Sayer syndromeischaracterizedbyopthalmoplegia with hypoparathyroidism 9. Mitochondrialdisordersassociated FEMg renal causeofmagnesiumlossislikelytobepresentif consistent with renal magnesium wasting ( > Cr/0.7 losses fromintestinal(FEMg magnesium enables differentiation of renal magnesium can behelpful.Measuringthefractionalexcretionof magnesium of hypomagnesemiaassessingurinary the redbloodcellmagnesium( of magnesiumstorescanbeobtainedbymeasuring evaluated andnormalized.Amoreaccurateassessment plays akeyroleincalciumhomeostasisandshouldbe Mg of adenylatecyclaseanddecreasesinintracellular in hypomagnesemiaasintracellularMg Galphasubunitactivity( increasing inhibitory hypomagnesemia blocksPTHsynthesisandsecretionby hypocalcemia(HSH)( with secondary the kidneyandbowelresultinhypomagnesemia affect active transcellular Mg ( with hypercalciuria andnephrocalcinosis(FHHNC) and magnesiumcausingfamilialhypomagnesemia impair paracellularrenalreabsorptionofbothcalcium number ofpatients( hypocalcemia aswellhypomagnesemiainasignificant • • • • Table 6 52 • • • • 4% inthepresenceofhypomagnesemia,thiswouldbe Consensus Statement Tocolytic therapyforeclampsia Excess intake(cathartics,laxatives,parenteralMg Familial hypocalciurichypercalcemia Chronic kidneydisease +2 , Mitochondrial myopathy, encephalopathy, lactic A resistancetoPTHattheskeletallevelisalsoseen Loss-of-function mutations in TRPM6 channels Mutations intheclaudinproteins(claudin16and19) Activating mutationsoftheCASRresultinADHwith 53 leadtoaresistancePTH( < × , 2% ( lsa Mg plasma 59 54 Causes ofhighserummagnesium. , ). 60 58 ). ). × 52 rn creatinine urine ). +2 transportation in both A Khanandothers 47 = ). Inthepresence urine Mg × 57

100%). IfFEMg 55 +2 ). Magnesium isacofactor , 58 56 ). An extra 57 +2 ). Severe × ) plasma ).

is noresistancetootherhormones. low calcium,highphosphate andhighPTH.Usuallythere The biochemicalprofiledemonstratesPTHresistancewith the kidney( proximal renaltubules.ThePTHresistanceisconfined to Gproteininthe absence ofalphasubunitstimulatory acting element ofGNAS1 resulting in reduction or complete This conditionisassociatedwithamutationinthecis- PHP 1b(GNAS1mutationorSTXgenemutation) high PTH. profile demonstrates low calcium, high phosphate and gonadotropins, TSHandGHRH( coupled hormones may be present including developmental delay. ResistancetootherG-protein- fifth metacarpalsandmetatarsals(brachydactyly) face, subcutaneouscalcification,shortenedfourthand mental retardation, frontal bossing, short neck,round which includeshortstature,obesity, dentalhypoplasia, constellation ofdevelopmentalandskeletaldefects, osteodystrophy(AHO)–whichreferstoa hereditary The clinicalfeaturesofPHPtype1aincludeAlbright PHP type1a(GNAS1mutationonmaternallyinheritedallele) ( PTH ( signal transductiontoproduceanend-organresponse upon bindingofPTHtoitsreceptorleadingfailure the inabilityofGproteintoactivateadenylatecyclase coupled tothePTHreceptor. Thesemutationsresultin Gprotein(Gsa) the alphasubunitofstimulatory function mutationsinthe elevated. PHP type1isassociatedwithmaternallossof calcium andhighphosphate;however, PTHlevelsare the same as seen in hypoparathyroidism with low serum target organresistancetoPTH.Thebiochemicalprofileis (PHP)ischaracterizedby PTH resistancesyndromes function andhypocalcemia( hyperparathyroidism maydevelopsuppressedparathyroid Infants exposed 10. Maternalhyperparathyroidism the mutationismaternallyorpaternallytransmitted( hypoparathyroidism Diagnosis andmanagementof Table 3 64 ). ). The manifestations of PHPdependonwhether 68 , 69 ). There are no clinical features of AHO. in utero Downloaded fromBioscientifica.com at10/01/202103:09:16PM GNAS1 61 to maternal primary tomaternalprimary , https://eje.bioscientifica.com 62 66 gene,whichencodes , , 63 67 180 ). ). Thebiochemical :3 P7 65 via freeaccess ) European Journal of Endocrinology https://eje.bioscientifica.com nephrocalcinosis, nephrolithiasis andrenalinsufficiency. hypoparathyroidism on treatment, and mayleadto Hypercalciuria iscommonlyseeninchronic hypoparathyroidism? (b) Howdoweevaluatetargetorgandamage in molecular diagnosistobemade. for appropriategeneticcounseling.DNAstudiesenable a consanguineous parentsareferraltogeneticistisadvised in nonsurgical cases. Inyoung individuals or enables identificationofthecausehypoparathyroidism confirmed ontwoseparateoccasions.Furtherevaluation for albumin)andloworinappropriatelynormalPTH presence of low serum calcium (ionized or adjusted The diagnosisofhypoparathyroidismismadeinthe Key points: condition canbeconfirmedasidiopathicinetiology. evaluation,the following acarefulclinicalandlaboratory If thecauseofhypoparathyroidismisnotidentified Idiopathic phosphate andPTH. profileincludesnormalcalcium, well asAHO.Laboratory formation intheskin,musclesandconnectivetissuesas ( GNAS1 A paternally inherited inactivatingmutation in the Progressive osseousheteroplasia phosphate andPTH. normal ( if thematernalalleleisnormal,biochemicalprofile GNAS1 isalwayssilencedduetogeneticimprintingand the renaltubularresistancetoPTH.Thepaternalalleleof inactivating GNAS1mutation.AHOispresentwithout topaternallytransmitted This conditionissecondary Pseudo-PHP (GNASmutationonpaternallyinheritedalleles) ability tostimulateadenylatecyclaseisintact( the PTHreceptor. Gsaisnormalinquantityandactivity, to PTHandotherhormones. Clinical featuresofAHOarepresentaswellresistance PHP1c (GNASmutationonmaternallyinheritedallele) 72 Consensus Statement ). The clinical features include extensive ectopic bone Quality ofevidence: The GNAS1mutationaffectscouplingofGproteinsto generesultsinprogressiveosseousheteroplasia 71 ). Laboratory profileincludesnormalcalcium, ). Laboratory low. A Khanandothers 70 ). of nephrocalcinosisornephrolithiasis.Brainimaging calcium excretion,andarenalultrasoundforthepresence by evaluating renal function (eGFR), a 24-h urinefor The riskforandextentofrenalcomplicationsareassessed Key points: is unclear. the roleofbrainimagingtomonitorthesecomplications electroencephalogram. Intheabsenceofthesesymptoms, calcification, whichareevaluatedbybrainimagingandan movement disordersorseizuresmayindicatebrain 73 suspected, a slit lamp examination is performed ( complications (posteriorsubcapsularcataracts)are nephrocalcinosis ornephrolithiasis( with ultrasound is recommended with identification of and creatinineassessment( assessment for hypercalciuria with a 24-h urine calcium of renalfunction(eGFRandserumcreatinine) as well Renal complicationsareassessedbyregularmonitoring and phosphate may require closer monitoring (every and phosphatemayrequire closermonitoring(every the routine annual eye examination. The serum calcium MRI (SW-MRI) andthepresenceofcataracts aspartof can beevaluatedwithbrain CT orsusceptibility-weighted serum calciumcontroland(e)basalgangliacalcification energy orfatiguebrainfogandmaybeamarkerofpoor hypoparathyroidism arenonspecificandincludelow overall functionisalsoofvalueasmanysymptoms of hypoparathyroidism. Asking the patient regarding their monthsbasedonthestabilityof 6 be evaluatedevery symptoms ofhypocalcemiaandhypercalcemia should abnormal urinalysisoradeclineineGFR;(d)signsand is persistenthypercalciuria, ofrenalstones, ahistory calcification by imaging, such as ultrasound, if there and 25-hydroxyvitaminDlevels(annually);(c)renal by 24-hurinecollectionorrandomcollection) calciumexcretion,creatinineandsodium(either urinary months;(b) 3–6 urea nitrogenandcreatinineevery albumin (orionizedcalcium),phosphorus,magnesium, (a) serumchemistries including calciumcorrected for Current consensus supports regular monitoring of assessment beperformed? (c) Howfrequentlyshouldbiochemicalandclinical symptoms orconcerns. of cataractsandcanbecompletedinthepresence examination enablesassessmentforthedevelopment movement disordersorseizures.Opthalmoscopic is advised in the presence of cognitive impairment, hypoparathyroidism Diagnosis andmanagementof , Quality ofevidence: 74 ). Thedevelopmentofneurocognitivedecline, Downloaded fromBioscientifica.com at10/01/202103:09:16PM low. 5 , 73 , 74 , 180 75 76 :3 ). Renalimaging , 77 ). Ifocular P8 via freeaccess 5 , European Journal of Endocrinology in patientswithnonsurgical hypoparathyroidism from Denmark,therisk of cataractswasincreased in caseseries( 50% ofpatientswithchronic hypoparathyroidism developing renalinsufficiencywas6.0( in patientswithnonsurgicalhypoparathyroidismfor ( surgical hypoparathyroidism was4.8 and 3.1,respectively stones andrenalinsufficiencyinpatientswithpost- in Denmark,thehazardratio(HR)fordevelopingkidney hypoparathyroidism ( series of90patientswithchronicpost-surgical These datahavebeenrecentlyconfirmedinanother 2- to17-foldgreaterinthosewithhypoparathyroidism. the ratesofchronickidneydiseasestage3orhigherwere with age-appropriatehistoricalcontrolsfromNHANES, present in31%ofthepatientpopulation.Compared imaging in54patientsshowedrenalcalcificationwas measurement withhypercalciuria ( analysis in53patientsshowedthat38%hadaleastone calciuman average of 86% of the time, the 24-h urinary a calcium range of 7.5–9.5 ( hypoparathyroidism withameanfollow-upof7.4 years rate ofcomplicationsin120patientswithpermanent commonly seen.Alargecohortstudydeterminedthe that long-termcomplicationsofhypoparathyroidismare the brain( calcification ofthebasalgangliaandotherregions renal stones,nephrocalcinosisaswellcataractsand Long-term complicationsincluderenalimpairment, (a) Arelong-termcomplicationsarealproblem? avoiding complicationsoftreatment 2. Managementofhypoparathyroidism– D thelabprofileshouldberepeatedin1–2 weeks. Following changesinthedoseofcalciumoractivevitamin D andannuallyfor 24-h urinecalcium and creatinine. adjusted), phosphate,magnesium,25-hydroxyvitamin monthsforcalcium(ionizedoralbumin- 6 least every Serum andurinebiochemistriesshouldbeevaluatedat Key points: or activevitaminDifsymptomsarepresent. 1–2 weeks) ifchangesaremadeinthedoseofcalcium 78 75 Consensus Statement ). InanotherDanishcase–controlstudy, theHR ). Whileserumcalciumlevelsweremaintainedwithin havebeenreportedinapproximately In alargecase–controlstudyfromnationalregistry Quality ofevidence: 5 ). Severalretrospectivestudieshaveshown 80 , 81 6 ). ). Inthecase–controlstudies low. mg/dL (1.9–2.4 A Khanandothers > gdy. Renal 300 mg/day). 79 ). mmol/L) for excellent phosphatebinders.Thecalcium-phosphate increased andshouldbegivenwithmealsastheyare phosphate levelsarehigh,calciumsupplementscanbe however requirefurtherprospectiveevaluation.Ifserum complications whenelevated( to contributeextraskeletalcalcificationsandother less than 55 should bemaintainedinthenormalreferencerange(i.e. also beendescribedinsomecases( unclear; symptomsofParkinsonismanddystoniahave clinical significanceofbasalgangliacalcificationsis product arethoughttobeacontributingfactor. The serum phosphatelevelsoranelevatedcalcium-phosphate ( ganglia, candevelopinpatientswithhypoparathyroidism hypoparathyroidism ( (HR 4.32)( with 1–3 followed by a continuous infusion of intravenous calcium 50 (corresponding to 90–180 chloride. Abolusof1–2 intravenously asitislessirritatingtotheveinsthancalcium Calcium gluconateisthepreferredsalttobeadministered management inhospitalwithintravenouscalcium. and clinicalsymptoms,acutehypocalcemiamayrequire Depending ontherateofonset,biochemicalseverity (b) Howshouldacutehypocalcemiabemanaged? serum phosphorusandthecalcium-phosphateproduct. may bereducedbyloweringurinecalciumexcretion, and extraskeletalcalcificationarecommonlyseen In hypoparathyroidism, long-term renalcomplications Key points: losses. A low-saltdietisalsohelpfulasitlowersrenalcalcium may beimplementedasneededonanindividualbasis. phosphate diet(lowintakeofmeat,eggs,colaanddairy) modificationwithalow phosphorus absorption.Dietary increases intestinalcalciumabsorptionaswell the activevitaminDcanalsobereassessedas1,25(OH)2 presence ofextraskeletalcalcification( urine calcium, which may be of value in predicting the other measuresincludingserumphosphateandthe24-h and thisrequiresfurtherprospectiveevaluationaswell product maynotcorrelatewithbasalgangliacalcification hypoparathyroidism Diagnosis andmanagementof 75 mL of5%dextrosemaybe administeredover20 , Serum phosphate and the calcium-phosphate product Intracranial calcifications,inparticularthebasal Quality ofevidence: 82 ). Theexactcauseisnotknown,however, elevated mg/kg/h of elemental calcium administered as 79 mg ), butnotinpatientswithpost-surgical 2 /dL 2 (4.4 mmol 78 Downloaded fromBioscientifica.com at10/01/202103:09:16PM ). g of10%calciumgluconate mg ofelementalcalcium) in very low.very 2 https://eje.bioscientifica.com L 73 2 82 )) as they are thought , 180 ). 83 , 85 :3 84 ). Thedoseof ). Thisdoes P9 min via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Hypomagnesemia mustbecorrected. well as oral calcium supplements and active vitamin D. boluses followedbyacontinuous calciuminfusionas Acute severehypocalcemiaistreatedwithIVcalcium Key recommendation: range (75 25hydroxyvitamin Dlevelsareinthenormalreference or D3cholecalciferol)isofvaluetoensurethatthe calcification. ParentvitaminD(D2orergocalciferol to thelong-termcomplicationsofrenalandextraskeletal hypercalciuria and hypercalcemia which may contribute as calcitriol ( days) andisnotaspotent time tooffsetofaction(5–7 in doses of 0.5–4 48–72 life ofcalcitriolis5–8 Occasionally higherdosesmaybenecessary. Thehalf- titrated upward to a dose of 2.0 be initiatedwithdosesof0.25 absorption ofbothcalciumandphosphate.Calcitriolcan to correctthehypocalcemiaandenhanceintestinal as calcitriol.ActivevitaminDmetabolites are necessary hypoparathyroidism haveadeficiencyofbothPTHaswell D (calcitriol)( PTH stimulatestheformationof1,25dihydroxyvitamin hydroxylation of25hydroxyvitaminDinthekidneyas 96 in themanagementofacutehypocalcemia( reports) regardingthepossibleuseofrhPTH( supplementation. with Ca with magnesiumdeficiencyisresistanttotreatment resistance toPTH( cyclase anddecreasesinintracellularionizedMg ( induced boneresorptionisimpairedinhypomagnesemia in aresistancetotheeffectsofPTHtissues.PTH- G alphasubunits( the CaSRwithanincreaseinactivityofinhibitory parathyroid involvesintracellularsignalingpathwaysof and secretion( magnesium leadstofurthersuppressionofPTHsynthesis vitamin D levels should be normalized ( 86 supplements andactivevitaminDarealsoinitiated( continuous cardiac monitoring is advised. Oral calcium .Duringthebolusandinfusion 88 Consensus Statement ). Hypoparathyroidismisassociatedwithimpaired ). Hypomagnesemia should becorrected( , Quality ofevidence: littledata(largelyfromcase There arevery 89

h. Alfacalcidiol(1alpha(OH)D3)canalsobeused , 2+ 90

nmol/L orhigher)( orvitaminD,butrapidlyrespondstoMg ). IntracellularMg 98 , 87 99

µg once daily; however, it has a longer ). Thisparadoxicalinhibitionofthe 97 91 ). Close titration is required to avoid 57 ). Therefore,individualswith

, h andthedosecanbeincreasedin ). Hypomagnesemiaalsoresults 92 , 93 low (standardpractice). 100 2+

µg twicedailyandgradually ). Hypocalcemiacombined isacofactorofadenylate ). A Khanandothers

µg BID if necessary ( µg BID if necessary 2 , 3 ). Low serum 2+ 83 94 leadto ) and 1 , – 84 83 95 2 2+ ). ) , ,

or indapamideastolerated.Inthepresenceofrenal and consider hydrocholorothiazide, chlorthalidone calciumlosseswithalow-saltdiet Reduce urinary Key recommendation: as discussedbelow( rhPTH(1–84) replacementtherapymayalsobeconsidered calcium, whichmaycontributetohypercalciuria. Finally, evenly throughoutthedaycanavoidpeaksofserum must beexercised. Distributingcalciumsupplements exacerbate thehypokalemia;therefore,extremecaution 1 (ADH1)andADH2,thiazidediureticsmayfurther a low-salt diet ( calciumlossesespeciallywhencombinedwith urinary Thiazide diureticsmayalsobeeffectiveinlowering calciuminchronichypoparathyroidism. urinary serum calciumisthemosteffectivemethodtolower Reducing the filtered renal load of calcium by decreasing calcium? (c) What are practical strategies to lower urinary absorption ( in turnenhancesintestinal calciumandphosphate Cyp27b1 withincreasedproduction ofcalcitriol,which excretion aswellbone resorption. PTHrPstimulates and enhancesrenalcalciumreabsorptionphosphate PTHrP, whichisreleasedintothematernalcirculation increase in PTHrP levels by term ( 3rd tothe13thweekofgestationreachingathree-fold mothers. PTH-relatedprotein(PTHrP)beginstoriseinthe calcium levelremainsunchangedinnormoparathyroid ionized calcium, as well as the albumin-corrected total resulting inalowtotalserumcalcium( and withhemodilution,theserumalbumindecreases skeleton isaccretedduringthe3rdtrimester( phosphorus andmagnesiumpresentinthefull-termfetal skeleton ( order tomeetthegrowingneedsofdevelopingfetal and thecalcium-regulatinghormonesduringpregnancy? (a) Whatarethephysiologicchangesinserumcalcium pregnancy andlactation 3. Managementofhypoparathyroidismin complications rhPTH(1–84)mayalsobeconsidered. the uterus( source of the PTHrP is the placenta and breasts, as well as hypoparathyroidism Diagnosis andmanagementof The lactating breast produces significant levels of In pregnancy, theintravascularvolumeexpands During pregnancy, calciumrequirementsincreasein Quality ofevidence: 102 110 113 , 103 , , 111 114 101 ). Approximately80%ofthecalcium, 74 , , ). For individualswith ADH type 112 115 ). Downloaded fromBioscientifica.com at10/01/202103:09:16PM ). ). low. 106 180 , 107 :3 , 104 108 102 , , 105 109 ). ). The ). The P10 via freeaccess European Journal of Endocrinology been published( doses ofcalciumandcalcitriol duringpregnancyhavealso reports ofhypoparathyroid womenrequiringhigher calcium andcalcitriolduring pregnancy. However, case calcitriol andPTHrPmay lower therequirementsfor calciumexcretionasthephysiologic risesin urinary careful monitoringofserumcalcium,phosphateand may benormalorincreased( serum calcitonin( of estradiol,estroneandestriolmayresultinincreases in as wellthebreastandplacenta( ( protect thematernalskeletonfromdemineralization 125 or undetectableasnotedwiththeintactPTHassays( D ( calciumandvitamin are impactedbychangesindietary by term( levels inthefirsttrimesterandreachesmidnormal in hypoparathyroidpregnantwomen( parent andactivevitaminDsupplementationisrequired 126 and intestinalcalciumabsorptionnormalizes( levels fall into the pre-pregnant range during lactation calcitriol andtransfertothefetus( stable during pregnancy despiteincreasedconversion to in comparisontoPTH( during pregnancy. PTHrPisaweakstimulatorofCyp27b1 estradiol andprolactinmaystimulaterenalCyp27b1 that stimulaterenalCyp27b1arestillnotclear. PTHrP, levels duringpregnancy( ( 35-fold higherinmaternalkidneysthantheplacenta placenta andthefetus.RenalexpressionofCyp27b1is some contributionfromothertissuesincludingthe kidneys arethemainsource ofthecalcitriolwithpossibly intestinal calcium absorption and suppresses PTH. The in thefirsttrimester( enable themothertoachieveapositivecalciumbalance in enhanced intestinal calciumandphosphate and and boundcalcitriolrisesbytwo-tothree-foldresulting by approximately20–40%duringpregnancyandthefree calcitriol ( studies haveconfirmedariseinbothfreeandbound studies ( inlongitudinal two- tothree-foldbytermasobserved 121 102 Consensus Statement 102 , , In pregnancy, thehypoparathyroidmother requires Calcitonin increasesduringpregnancyandmay PTH is suppressed to low normal or below normal Calcitriol risesinthefirsttrimesterandincreases ). Anephricwomenondialysishavelowcalcitriol ). Thesource ofcalcitoninincludesthethyroidC-cells 133 127 , 133 , 106 106 , 134 106 128 ). During lactation, PTH levels are suppressed , , , 108 , , 135 116 116 129 140 , 102 117 , , , 136 118 ). Furtherprospectiveevaluationof , 117 ). Duringlactation,calcitoninlevels 141 102 , 125 ). ). Vitamin D-bindingproteins rise , 123 , ). Theriseincalcitriolincreases 118 142 , 126 122 ). The25(OH)Dlevelsare 105 , , , 143 ). However, thefactors 119 131 A Khanandothers , 137 118 ). Closemonitoringis , , 102 132 , , 120 130 138 126 , ). ThePTHlevels ). Longitudinal 124 ). ). Higherlevels , 139 ). Calcitriol ). 120 , 102 125 , , during pregnancy? (b) Whatarethetreatmenttargetsforserumcalcium patients. supplementation duringlactationinhypoparathyroid lower thedoserequirementsforcalcitriolandcalcium enhance renalcalciumreabsorption.Theseeffectsmay levels arehighandincreaseboneresorption increase. However, insomepatients,doserequirementsmay vitamin Dinhypoparathyroidmothersmaydecrease. calcitriol, thedoserequirementsforcalciumandactive to fetal demands; however, due to rises in PTHrP and Calcium requirementsincreaseduringpregnancydue Key finding: is maintainedinthenormalreferencerange. required duringpregnancytoensurethatserumcalcium risk ofmaternalandfetalcomplications? (c) How should management be modified to reduce the D and24-hurinecalciumin thenormalreferencerange. weeks. Maintain the 25-hydroxyvitamin calcium in 1–2 calcium orcalcitriolarerecommended,repeattheserum 3 weeks.during pregnancy every If changes in thedose of phosphorus, eGFRandmagnesiumshouldbemonitored in mid-to-lownormalreferencerange.Serumcalcium, Serum calcium(correctedorionized)shouldbemaintained Key recommendation: supplements orcalcitrioldosearebeingmade. pregnancy ormorefrequentlyifchangesinthecalcium during 3 weeks range andthisshouldbeevaluatedevery albumin bemaintainedinthelowtomidnormalreference increase theriskofpretermlabor( irritability increaseswith hypocalcemia, and this may to avoidhypocalcemiaandhypercalcemia. Uterine It isimportanttocloselymonitorpatientsinorder suppressed andtheneonatemaydevelophypocalcemia. hypercalcemic thefetal parathyroid tissuemaybecome demineralization. Incontrast,ifthemotheris hyperparathyroidism inthefetuswithfetalskeletal this canresultinthedevelopmentofsecondary supplementation andisnothypocalcemicas mother isreceivingadequatecalciumandcalcitriol it isimportanttoensurethatthehypoparathyroid As calciumrequirementsincreaseduringpregnancy hypoparathyroidism Diagnosis andmanagementof Quality ofevidence: During lactation calcitriol levels normalize. PTHrP Quality ofevidence: It isrecommendedthatthetotalcalciumcorrectedfor Downloaded fromBioscientifica.com at10/01/202103:09:16PM low. very low.very https://eje.bioscientifica.com 144 180 ). :3 P11 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Hypercalcemia Hypocalcemia Table 7 weeksand 4 continue tomonitorserumcalciumevery birth andmonitorserumcalcium.Duringlactation pediatrician toassesstheneonateimmediatelyfollowing to-mid normalalbumin-correctedcalcium.Advisethe the doseofcalciumandactivevitaminDtargetinglow- Discontinue thiazidediureticsduringpregnancy, adjust Key recommendation: outcomes. and thepediatriciantoensureoptimalmaternalfetal the treatingendocrinologistaswellobstetrician assistance asneeded.Caremustbeco-ordinatedbetween calcium iftheyarenotwellandseekurgentmedical ( informed ofthesymptomshypo-andhypercalcemia Bothpregnantandlactatingwomenshouldbe 4 weeks. 125 25-hydroxyvitamin Dlevelshouldbenormalized(75– adjusted orionized)phosphorusandmagnesium.The forserumcalcium(albumin- 2–3 weeks pregnancy every albumin-adjusted calcium with close monitoring during calcitriol canbeadjustedbasedontheserumionizedor at birthwithnormalserumcalcium( PTH(1–34) hasbeenreportedandtheneonatewasnormal C drug. A case of one patient treated with risk category evaluated inpregnancy. ItisclassifiedasanFDApregnancy Bdrug( category pregnancy asitisclassifiedanFDArisk lactation ( half ofpregnancyanddecreasesubstantiallyduring duringthesecond that therequirementsforcalcitriolvary ten pregnancieswithhypoparathyroidismdemonstrated syndrome ( distress include smallforgestationalageandrespiratory in thenormalreference range. Neonatalcomplications calcitriol supplementationtomaintaintheserumcalcium Ensure thatthemotherisreceivingadequatecalciumand may increase risk of preterm labor or miscarriage ( Uterine irritabilityincreaseswithhypocalcemiaand avoid complicationsofhypoparathyroidisminpregnancy. to for albumin,phosphateandmagnesiumisnecessary Close monitoringofcirculating levelsofcalciumcorrected Table 7 Consensus Statement

mlL (30–50 nmol/L During lactation, monitoring can continue every During lactation,monitoringcancontinueevery Hydrochlorothiazide should be avoided during A recentretrospectiveauditofanAustraliandatabase ) andadvisedtoimmediatelychecktheirserum Symptoms ofhypocalcemiaand hypercalcemia. 148 140 , , 149 145

). gm) ( ng/mL) 150 , 146 ). PTHhasnotbeenadequately Polydipsia, polyuria,nausea,anorexia, vomiting,constipation,weakness,,confusion Numbness, tinglinginface,hands andfeet,musclespasm,,depression,confusion,seizures, , 147 bradyarrhythmia, wheezing,, congestiveheartfailure 152 , 148 ). A Khanandothers ). 151 ). Thedoseofthe 144 ). active vitaminDmetabolitesandinclude Limitations of conventional therapy with calcium, chronic hypoparathyroidismhasfailed? (a) Whichcriteriaconfirmthatconventionaltherapyfor agencies. regulatory approved asanadjuncttoconventionaltherapyby Replacement therapy with rhPTH( be treatedwithrhPTH( which patientswithchronichypoparathyroidismshould A numberofkeyquestionsarisewhenconsidering to proceed? hypoparathyroidism –whenandhow 4. rhPTH(1–84)replacementtherapyin targeting mid-to-lownormalserumcalcium. adjust thedoseofcalciumandcalcitriolsupplements of apoorqualitylife. of complicationshypoparathyroidismorthepresence presence ofpoorcontrolserumcalcium,the Failure ofconventionaltherapyisconfirmedinthe Key recommendation: of supplementalcalcium. pills requireddailyaswellgastrointestinalsideeffects often poorandiscontributedtobythelargenumber of and 6) failure to maintain long-term well-being and QOL. calcium withinthereferencerangeforweightandgender within the reference range, (5) inability to keep urinary dL to keepthecalcium-phosphorusproductbelow55 serum phosphatewithinthereferencerange,(3)inability without symptomsofhypocalcemia,(2)failuretokeep serum calciuminthelowerhalfofreferencerange as meetingcertaincriteria( conventional treatmentofchronichypoparathyroidism well asnephrolithiasis( which includerenalinsufficiency, nephrocalcinosisas to thelong-termcomplicationsofhypoparathyroidism calciumexcretioniselevatedandcontributes urinary and to improve quality of life. In the absence of PTH, an inabilitytoalleviatethesymptomsofhypocalcemia hypoparathyroidism Diagnosis andmanagementof 2 (4.4 Quality ofevidence: In addition,compliancewithconventionaltherapyis

mmol 2

L 2 ), (4)failuretokeepserummagnesium 153 Downloaded fromBioscientifica.com at10/01/202103:09:16PM 1 ). Guidelinesdefinefailureof very low.very 73 – 84 , ) replacementtherapy. 74 ): (1)inabilitytokeep 180 1 :3 – 84 ) has been P12

mg via freeaccess 2 / European Journal of Endocrinology 165 reduced inpatientswithhypoparathyroidism ( however, thisrequiresfurtherevaluation ( positive skeletaleffectsonbone strengthandfracturerisk; ( hypoparathyroidism treatedwithconventionaltherapy has beenreportedinpatientswithidiopathic detected at1 yearpersists( value at year2 ( degree ofmineralizationwhichreturnstothebaseline isassociatedwithadecreaseinthe treatment after1 year hypoparathyroid bonecomparedtonormal.rhPTH(1–84) bone matrixmineralization is markedly increased in about halfofthebiopsyspecimens( Intratrabecular tunnelinghasbeendemonstratedin trabecular widthandanincreasein number. studieshaveshownreductionsin histomorphometry progressive declineatthedistal1/3radius( spine andtoalesserextentatthehip,whilethereis than pretreatmentvalues.BMDincreasesatthelumbar andsubsequentlydeclinetolevelsthatarehigher 1 year are improved.Boneturnovermarkersincreasewithin turnover status, increased density (BMD)) excretion ( calcium study suggestsaprogressivedecreaseinurinary excretion aremodest;however, along-termopen-label calcium active vitaminDanalogs.Theeffectsonurinary replacement therapyenableswithdrawalofcalciumand vitamin Dmetabolites( range, whilereducingthedailydosesofcalciumandactive serum calciumandphosphatelevelsintheappropriate while loweringserumphosphate( calcitriol requireddailyandincreasedserumcalcium 20 to calcitriol( normal range,withasignificantdifferenceincomparison marked declineinmeanurinecalciumwellwithinthe intravenous administrationusingapumpresultedin no difference compared to calcitriol ( maintained meanurinecalciuminthenormalrange,with Subcutaneous twicedailyinjectionsofPTH(1–34) hypoparathyroidism withthePTH(1–34)molecule. PTH replacement therapy wasinitially evaluated in considered inpatientswithchronichypoparathyroidism? (b) When should rhPTH( 81 Consensus Statement µg BIDledtoreductionsinthedoseofcalciumand ). ReplacementtherapywithrhPTH(1–84)mayhave , Several studies have shownthatquality of lifeis Recently, anincreasedrateofvertebral fractures Replacement therapywithPTH(1–84)maintains Quality ofevidence: 166 ). Short-termplacebo-controlled studieshave 161 156 162 ) ( ). Morerecently, PTH(1–34)indosesof al 8 Table ). Conversely, the greater heterogeneity 159 ). Skeletalabnormalities(low 1 162 – low-moderate. , 84 160 ). ) replacement therapy be A Khanandothers ). InsomepatientsPTH 157 , 154 158 161 , Table 9 ) ( 155 ). Cancellous Table 8 161 ), whereas 163 ). ). Bone , ). 164 , 1. replacement beconsideredinthefollowingcircumstances; calcium excretion,ithasbeenproposedthatPTH as wellinsomestudiesdemonstratedreductionsurinary active vitaminDanalogsandalsolowerserumphosphate demonstrated tolowertherequirementsforcalciumand humans despiteuseinmorethanamillionpeople( increased rateofosteosarcoma in hasnotbeenobserved rats treatedwithhighdosesofPTH(1–34);however, an warning because of an increased risk of osteosarcoma in The FDAhasapprovedrhPTH(1–84)witha‘blackbox’ long-term benefits of rhPTH(1–84) replacement therapy. events aremildandtransient. parameters oftheSF-36scale( a long-termopen-labelstudyhasshownbenefitinall shown eithernoeffectormodestimprovement,whereas immediate measuresofserum calciuminrealtime. monitoring ideallywithacalcimeter whichcanprovide with widefluctuationsin serumcalciumrequireclose hypocalcemia may leadtohypercalcemia and individuals and may result in hospitalization. Overcorrection of particularly followingexercise orwithintercurrent illness occur incertainindividualswithhypoparathyroidism with therapy. Wide fluctuations in serum calcium may not demonstratedreversalofmuscleweaknessandfatigue require furtherstudyascurrentlycontrolledstudieshave however, effects ofPTHreplacementonqualitylife PTH replacement therapy may improve quality of life; are noncompliantwithtakingseveralpillseachday. doses oforalcalciumsupplementsaswellthosewho who have malabsorption or are intolerant of large calcium excretion. administration withagoaltoconsistentlyreduceurine Further prospectivedatawillenablerefinementof PTH andfrequencyofadministrationthismolecule. including thefilteredcalciumloadaswelldoseof There aremanyfactorscontributingtourinecalcium 4. 3. 2. hypoparathyroidism Diagnosis andmanagementof inadequate controlofserumcalcium, product thatexceeds55 and/orcalcium-phosphate min), risk orreducedcreatinineclearanceeGFR( hypercalciuria, renal stones, nephrocalcinosis, stone calcium or control serumcalciumorsymptomsthatexceed2.5 oral calciumorvitaminDmedicationsrequiredto As PTHtherapyinhypoparathyroidismhasbeen No dataarecurrentlyavailableonthepotential PTH replacementtherapyiswelltoleratedandadverse PTH replacement may also be of value in individuals > 1.5 μ g calcitriolperday, Downloaded fromBioscientifica.com at10/01/202103:09:16PM mg 163 2 https://eje.bioscientifica.com dL ). 2 (4.4 mmol 180 :3 2 L 2 < ) ( 60 mL/ 74 167 P13 ). via freeaccess ). g European Journal of Endocrinology https://eje.bioscientifica.com

Table 8 PTH replacement therapy – evidence table. Consensus Statement

Population Study description Effects Quality Age No. of Duration Effect on urinary of Study range participants of study Design Intervention Comparator Effect on phosphate Effect on calcium calcium evidence (154) (18–70) 27 3 years Randomized, parallel PTH(1–34) (n = 14) Oral calcitriol and No significant difference No significant difference PTH(1–34) normalized Moderate group, open-label calcium between intervention between intervention urinary calcium to high trial supplementation and control group and control group excretion whereas (n = 13) (mean (s.e.) phosphorus (mean (s.e.) calcium elevated levels were levels were 4.6(0.08) levels were 1.92(0.02) reported in the control and 4.5(0.05) mg/dL and 2.0(0.01) mmol/L group (mean (s.e.) respectively) respectively) 5.8(0.27) vs 8.2(0.51) mmol/24 h, respectively) A Khanandothers (155) (5–14) 12 3 years Randomized, parallel PTH(1–34) (n = 7) Oral calcitriol, calcium No significant difference No significant difference No significant difference Moderate group, open-label and between intervention between intervention between intervention to high trial supplementation and control group and control group and control group (P = (n = 5) (P = 0.13) and (mean (s.d.) calcium 0.73) phosphate levels levels were 1.96(0.04) remained above the and 1.99(0.05) mmol/L normal range respectively) throughout the 3 years. However a significant downward trend in phosphate levels was seen over time in the PTH 1–34 group (P 0.01)

< hypoparathyroidism Diagnosis andmanagementof (156) (7–20) 12 26 weeks Randomized, (PTH) 1–34 injection (PTH) 1–34 delivered by Pump delivery of PTH1–34 Pump delivery of PTH1–34 No significant difference Moderate (13 weeks crossover trial and cholecalciferol an insulin pump and had higher phosphate produced near between pump to high each arm) cholecalciferol levels (P < 0.01) normalization of serum delivery of PTH1–34 calcium (P < 0.02) and injection (P = 0.3). However, pump delivery normalized the urinary calcium (159) (31–78) 62 24 weeks Double-blind, PTH(1–84) adjunct to Placebo and vitamin D PTH1–84 decreased PTH1–84 increased PTH1–84 increased High placebo- vitamin D analogs analogs and calcium phosphate levels ionized calcium levels urinary calcium controlled, and calcium supplementation (P < 0.05) (P < 0.01) excretion (P < 0.01) randomized trial supplementation (n = 30)

Downloaded fromBioscientifica.com at10/01/202103:09:16PM (n = 32) (160) (18–85) 134 24 weeks Double-blind, PTH(1–84) adjunct to Placebo and vitamin D PTH1–84 decreased PTH1–84 increased No significant difference High placebo- vitamin D analogs analogs and calcium phosphate levels albumin-corrected in the change of controlled, and calcium supplementation (P = 0.0025) serum calcium urinary calcium levels randomized trial supplementation (n = 44) concentrations at the between intervention (n = 90) beginning of treatment and control group (P =

then remained 0.57) 180 relatively stable :3 (161) (26–72) 33 6 years Open-label trial PTH(1–84) n/a No significant change in No significant change in PTH1–84 significantly Low phosphate levels at calcium levels at the decreased urinary 6 years. However, a end of study period calcium levels at decrease in phosphate (P = 0.53) 6 years (P = 0.007) levels was observed at

years 4 and 5 (P = 0.01) P14 via freeaccess European Journal of Endocrinology Consensus Statement Table 9 GRADE evidence profile of RCT for rhPTH(1–84) therapy.

Certainty assessment No. of studies Study design Risk of bias Inconsistency Indirectness Imprecision Other considerations Impact Certainty Importance Urinary calcium levels 2 RT Not serious Not serious Not serious Very seriousa None No significant differences between ⊕⊕◯◯ low Critical mean urinary calcium excretion in intervention and control group Phosphate levels 2 RT Not serious Not serious Not serious Very seriousa None Serum phosphate levels decreased ⊕⊕◯◯ low Critical significantly in the intervention group relative to the control

group A Khanandothers Calcium levels 2 RT Not serious Not serious Not serious Very seriousa None Albumin-corrected total calcium ⊕⊕◯◯ low Critical levels were stabilized while elevated ionized calcium levels were observed

Question: Effects of RhPTH1–84 compared to conventional therapy on serum phosphate, urinary calcium and serum calcium for adult hypoparathyroidism. Adapted from Sikjaer et al. (159), Mannstadt et al. (160). RT, randomised trials; a few number of participants. malabsorption ispresent. are present or quality of life is poor or gastrointestinal or activevitaminDarerequired,renalcomplications serum calciumispoorlycontrolled,highdosesof rhPTH(1–84) replacementtherapymaybeconsideredifthe Key recommendation: country. authoritiesofeach dependingontheregulatory may vary The approvedindicationsforPTHreplacementtherapy expected tobereleasedforgeneraluseinthenearfuture. of glucometers.Calcimetershavebeendevelopedandare the enhancedcarepossiblefordiabeteswithadvent to revolutionize care for hypoparathyroidism similar to current serumcalcium.Suchclosemonitoringisexpected symptoms and allow closer titration of therapy based on enable assessmentofserumcalciumwiththeonset Having suchdeviceseasilyavailabletopatientswill over severalweeksas abrupt cessation has been associated of rhPTH(1–84)requiresgradual reductionsinthedose comply withtherapyfor any reason.Discontinuation dose adjustment, or patients are unable to tolerate or treatment goalscannotbe achieved despiteappropriate rhPTH(1–84) replacement therapy may be stopped if This is left to the judgment of the treating . should iteverbestopped? (d) IfrhPTH(1–84)replacementtherapyisinitiated, is graduallyincreased. also begraduallyreducedasthedoseofrhPTH(1–84) and the doses of serum calcium and active vitamin D can titrated upwardsordownwardsbasedonthelabprofile and phosphate.ThedoseofrhPTH(1–84)canbegradually 50 rhPTH( Key recommendation: reduce calciumsupplementsto500 goals, aimingtodiscontinuetheactivevitaminDand reduced to 25 day, and then 100 several weeks,thedosemaybeincreasedto75 D metabolites ( concomitant 50%decreaseinthedoseofactivevitamin 50 The FDAapprovedstartingrhPTH( should therapybetitrated? (c) OncerhPTH(1–84)replacementtherapyisstarted,how hypoparathyroidism Diagnosis andmanagementof

µg daily dose with close monitoring of serum calcium µg bysubcutaneousinjectiononceeachdaywitha Quality ofevidence: Quality ofevidence: 1 –84) replacementtherapycanbeinitiatedata

µg each day, as required to meet treatment 83

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µg each P15 via freeaccess European Journal of Endocrinology https://eje.bioscientifica.com Collaboration, NIHR Oxford Grant –BRC funding, Wellcome Trustclinical Investigator Award,NIHRSeniorInvestigator, NIHR TranslationalResearch income from: Medical Research Council programme grant, Wellcome Trust Fees: Novo Nordisk, Amgen, Merck; BY:Nothing to disclose;RT:Research Support: Z S: Grants/Research Eli Lilly, Valeant, Novo Nordisk Speakers Bureau/Honoraria/Consulting M Theramex; and Effryx Sandoz, Health, Shire, AlexionandKyowaKirin;RR:AdvisoryboardorspeakerforRadius Consultancy: fee: Shire,Alexion, Eli Lilly,Amgen,TakedaPharmaceuticals; for Abiogen-Pharma and SHIRE, Research grant from SHIRE; L R:Speakers Farmaceutici, Kyowa Kirin, Servier, Shirel; C M: Consultant and speaker Kyowa Kirin, MSD, NPS, Servier,Shire,SPA; Consultant: Alexion, Bruno and/or speaker:Abiogen, Alexion, Amgen, Bruno Farmaceutici, EliLilly, MLB:Received B: Nodisclosures; J honoraria fromAmgen, Bruno Farmaceutici, Kyowa Kirin; Academic grants todeclare; interest J-PB: of conflict Pfizer; No Fees: Consulting Sanofi, Acerus Ipsen, Abbott, Novartis, pharmaceuticals, Bureau/Honoraria: Speakers Sanofi, Novartis, support: Grants/Research interests: not-for-profit and for-profit with Relationships (Book, Journals),ElsevierPublisher,RoyaltyHonorarium(Journal);SV U: Honoraria Royalty Publisher, Springer (AI), Insufficiency Adrenal Chronic Post-Authorisation Observational Study (Registry) of Patients With Consultant, Shire Pharmaceuticals, Principal Investigator, A European A K:Researchfunds Advisory Board from Shire;CK:NovartisPharma, Declaration ofinterest complications ofhypoparathyroidism. vitamin Drequiredandmaylowerthelong-term demonstrated to lower the doses of calcium and active active vitaminD.PTHreplacementtherapyhasbeen as hypocalcemia for optimal maternal and fetal outcomes. reference rangewithavoidanceofhypercalcemia aswell the mothermaintainsaserumcalciuminlownormal risk oflong-termcomplications. control ofserumcalciumandpotentiallyloweringthe and patienteducationisessentialtoachievingoptimal monitoringofthebiochemicalprofile Frequent laboratory in ordertopreventsignificantmorbidityandmortality. careful evaluationandtimelypharmacologicintervention Hypoparathyroidism isararecondition,whichrequires Conclusion unable totolerateorcomplywiththerapyforanyreason. despite appropriatedoseadjustmentorifthepatientis Stop therapyifthetreatmentgoalscannotbeachieved Key recommendation: be restartedoradjusted,asappropriate. dose treatmentwithactivevitaminDmetabolitesshould bone syndrome( remodeling favoringformationleadingtothehungry with hypocalcemia,whichmayreflectincreasedbone Consensus Statement Conventional therapyconsistsofcalciumand Pregnancy requiresclosemonitoringtoensurethat Quality ofevidence: 168 ). WhiledecreasingtherhPTH(1–84) low-moderate. A Khanandothers

References search. Research Methodology, McMaster Universityforcompletingtheliterature The authorsgreatlyappreciatedthesupportofHajarAbu Alrob Health Acknowledgment review –2018. University and Western University for the completion of the literature Funding was received from Canadian Endocrine Update, McMaster Funding board memberforAmgen,Inc.,DatamonitoringGSK. C: B Ipsen; and Research grant support and consultant for Shire, Inc., Data monitoring AstraZeneca Lilly, Novartis, from fees Honoraria/lecture consultancy and Panel, Stratified Astra-Zeneca of Chairman NPS Pharmaceuticals(USA), Marshall SmithSyndromeResearchFund. grant, KidneyGrant, ResearchUK(KRUK)projectgrant,Novartis training fellowships, EU ITN Marie Curie grant, Glaxo-SmithKline research

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