Copyright© AE&M all rights reserved. 106 PTH levels, which in adults occurs mainly after notfully compensated,hypocalcemiaoccurs(1). or are homeostasis. When these homeostatic mechanisms fail andbonetissuestomaintainmineral parathyroid, intestinal, (CaSRs)actinginrenal, sensor receptors (PTH), activevitaminD(1,25(OH) hormone mechanisms involvingtheparathyroid S INTRODUCTION São Paulo, SP, Brasil Federal deSãoPaulo (Unifesp), Cabeça ePescoço, Universidade Otorrinolaringologia eCirurgia de 8 (FMUSP), SãoPaulo, SP, Brasil da Universidade deSãoPaulo Pescoço, Faculdade deMedicina Disciplina deCirurgia deCabeçae 7 Paulo, USP, Ribeirão Preto, SP, Brasil Ribeirão Preto, Universidade deSão Interna, Faculdade deMedicina 6 (UCB), Brasília,DF, Brasil Universidade CatólicadeBrasília 5 de Janeiro, RJ, Brasil Rio deJaneiro (UFRJ),Rio Universidade Federal do Disciplina deEndocrinologia, 4 (UPE), Recife, PE,Brasil Universidade dePernambuco Faculdade deMedicina, Magalhães, AgamenonHospital 3 (SEMPR, UFPR),Curitiba,PR,Brasil da Universidade Federal doParaná deClínicas Hospital Metabologia, 2 (Unifesp), SãoPaulo, SP, Brasil Universidade Federal deSãoPaulo Disciplina deEndocrinologia, 1 guideline DOI: 10.20945/2359-3997000000015 Accepted onNov/14/2017 Received onJune/13//2017 [email protected] 05012-010 –SãoPaulo, SP, Brasil 250,ap.307 Mesquita, Rua MinistroGastão Sergio SetsuoMaeda Correspondence to: São Paulo, SP de SãoPaulo (HCFMUSP), de MedicinadaUniversidade dasClínicasdaFaculdadeHospital Celular eMolecular(LIM-25), Laboratório deEndocrinologia 9 Divisão deEndocrinologiae de Departamento deCirurgia,Departamento deMedicina Departamento Disciplina deEndocrinologia, deClínicaMédica, Departamento Disciplina deEndocrinologia, deEndocrinologiae Serviço deMedicina, Departamento Inappropriately low (insufficient) circulating circulating low(insufficient) Inappropriately narrow physiological range by complex controlling physiological range by complex controlling narrow calciumconcentrationismaintainedwithina erum , Brasil

Diagnosis andtreatment of Hypoparathyroidism; ;;PTH;guideline;diagnosis;treatment Keywords in Brazil. hypoparathyroidism ispresentedtoserveasabasisforthediagnosisandtreatmentofthiscondition strength andstudytype. fromeachevidence derived article was classifiedintorecommendationlevels accordingtoscientific Relevant wereretrievedfromthedatabasesMEDLINE/PubMed, papers LILACS, andSciELO, andthe the Guidelines Program of the of EndocrinologyandMetabolism)was invited toprepareadocumentfollowingtherulessetby Metabolism of the the mostrecentscientificevidence. Objective: ABSTRACT Ferraz-de-SouzaBruno Fábio LuizdeMenezesMontenegro Francisco José Albuquerque dePaula LuciaFleiussdeFariasMaria Victória ZeghbiCochenski Borba Sergio SetsuoMaeda andMetabolismof statement from theBrazilian Society hypoparathyroidism: aposition Arch EndocrinolMetab. 2018;62(1):106-24 2 To presentanupdateonthediagnosis andtreatmentofhypoparathyroidism basedon D), andcalcium Sociedade Brasileira de Endocrinologia e Metabologia e Endocrinologia de Brasileira Sociedade 1 Conclusion: 9 , Carolina Aguiar Moreira , Lazaretti-Castro Marise Associação Médica Brasileira Médica Associação hypercalciuria andother complications (3). hypercalciuria balancingcalciumlevelswhileavoiding is effectively . Amajortherapeutic challengeinhypocalcemia epidemiology, genetics,associatedskeletaldisease, and its regarding understanding ofhypoparathyroidism (2). themissinghormone replacing supplementation ischallengingasitdoesnotinvolve PTH levelscomprisingvitaminDanalogsandcalcium oflow treatment standard hypocalcemia. Current , is the most common cause of Materials andmethods: 4 , João Lindolfo CunhaBorges Over the past ten years, we have gained a greater Over thepasttenyears,we havegainedagreater An updateontherecentscientificliteratureaddressing 2 , Francisco Bandeira 7 , Oliveira Rodrigo Santos 6 , Felipe Augusto Brasileiro Vanderlei 1 2

, (AMB; Brazilian Medical Association). The Department ofBoneandMineral

3 Arch Metab. Endocrinol 2018;62/1 ,

(SBEM; Brazilian Society 5 , 8

, 7 ,

Arch Metab. Endocrinol 2018;62/1 inurinary byPTH-mediateddecreases then restored calciumlevelsare Serum and secretion. production pools and stimulating PTH preexisting from release by CaSRsinthep recognized ionizedcalciumare inserum Decreases 1.  ETIOLOGY andevidence as: levels ofrecommendation the (4,5).Inthisdocument,wereport to eacharticle levelorevidence strength attribute arecommendation consider thebestavailableevidenceforeachquestionto evaluatethestudydesignand These recommendations forEvidence-BasedMedicine. Centre by theOxford tothelevelofevidence,asrecommended according publications, and categorized each publication relevant MEDLINE/PubMed andSciELO/LILACSfor questions fordiscussion.We thedatabases searched we elaborated clinical of hypoparathyroidism, area relevant publications inthe role and with asignificant Federal MedicalCouncil).Afterselecting collaborators Association) and Associação MédicaBrasileira ofthe this documentfollowedtheGuidelinesProgram Themodelappliedto Practical GuidelinesProgram. We elaboratedthisguidelinemotivatedbySBEM’s MATERIALS ANDMETHODS endocrinologists andcliniciansinBrazil. asaguidelinefor questionsandserve to answerroutine Theobjectiveofthisdocumentis hypoparathyroidism. of the diagnosis and treatment regarding literature evidenceavailableinthescientific on thecurrent based for the development of recommendations Brazilian Society of Endocrinology and Metabolism) Brasileira de Endocrinologia e Metabologia Department hypocalcemia? What arethecausesanddifferentialdiagnosesof D: C:  B: A: bythe ofefforts This documentisaresult consistent results. experimental or observational studieswithless experimental orobservational consistent results. experimental or observational studieswith experimental orobservational case reports (uncontrolled studies). (uncontrolled case reports models. on guidelines,physiologicalstudies,oranimal opinion islackingcriticalevaluationorbased of BoneMetabolismthe Conselho FederaldeMedicina arathyroid glands, elicitingPTH arathyroid (AMB;BrazilianMedical Sociedade (SBEM; (CFM; corrected = Calcium measured +[(4.0- =Calciummeasured Calcium corrected inalbuminbelow4.0g/dLorbytheformula: decrease 0.8 mg/dLtothetotalcalciumlevelforeach1.0g/dL the totalcalciumvalues,whichisachievedbyadding of investigation ofhypocalcemia,alongwithcorrection duringthe albuminisalwaysrecommended serum of no clinical significance. Thus, measurement calcium fractionand,therefore, the ionized on effect total calcium levels, it has no cause of low serum Table 1(6-9). as listed in associated with hypoparathyroidism, directly separately),andthosenot (addressed or resistance be dividedintothoseassociatedwithPTHdeficiency tubules.Thus,thecausesofhypocalcemiamay renal 1,25(OH) with increased intestinal calciumabsorption,thelaterinassociation and inboneresorption andincreases calcium excretion, concomitant vitamin Ddeficiency(16). associated withtheseverityofbonediseaseand directly in skeletal mineralization. Hypocalcemiais increase to hypocalcemiaandhypophosphatemia duetoarapid leading , ofsevere surgical cure (15). hyperparathyroidism secondary disease inassociationwithlow1,25(OH) kidney is commonlyfoundinpatientswithchronic in bonebutalsoextraskeletaltissues.Hypocalcemia avidly to calcium leading to calcium deposition, mostly (7). in calciumdepositiontheretroperitoneum resulting in thepancreas, insoluble calcium saltspresent fattyacidsthatavidlychelatethe lipase generatesfree status (6-14). D thevitamin plasmahalf-lifeanddoesnotreflect short active metaboliteofthisvitamin[1,25(OH) inthebody,metabolite stored The isrecommended. D[25(OH)D],themainvitamin 25-hydroxyvitamin ofplasma Measurement hyperparathyroidism. be associatedwithhypocalcemiaandleadtosecondary PTHlevels(6-9). normal inappropriately inallpatientswithhypocalcemia andlowor considered kidney. ofhypomagnesemiashouldbe Theoccurrence inboneand toPTHeffects resistance and increases albumin) x0.8](6-9). Although hypoalbuminemiaisthemostcommon The hungry bone syndrome may occur after bone syndrome The hungry In acutehyperphosphatemia,phosphatebinds theactionofpancreatic In acutepancreatitis, calciumand/orvitaminDdeficiencycould Severe PTHsecretion hypomagnesemiadecreases Severe Diagnosis andtreatment ofhypoparathyroidism 2 D (calcitriol)synthesisinthe 2 D levelsand 2 D] hasa 107

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 108 Table 1. (19). of thesubjectbyLiamisandcols.isrecommended on calcium,vitaminD,andbonemetabolism.A havealsobeenassociatedwitha negativeimpact drugs intheintestinalaction ofvitaminD.Antiviral effects alsohavedetrimental glucocorticoids hypercalciuria; induce andglucocorticoids absorption. Loopdiuretics withcalcium ofgastricacid,interfering production pumpinhibitorsandH Proton ofvitaminD,limitingbonemineralization. breakdown low calciumlevels.Someanticonvulsantsacceleratethe concomitant useshouldbeevaluatedinpatientswith diversemechanisms,andtheir by actingthrough statessuchasPaget’sdiseaseofbone. bone turnover agentsismostcommonlyseeninhigh of antiresorptive mainly invitaminDdeficientpatients.Thissideeffect may lead to clinical hypocalcemia, osteoporosis, treat agents used to denosumab (18), potent antiresorptive Diagnosis andtreatment ofhypoparathyroidism Acute pancreatitis drugs , chemotherapeutic pump inhibitors, loop carbamazepine), proton (phenytoin, phenobarbital, foscarnet), antiepileptics chelators (EDTA, citrate, (cinacalcet), calcium denosumab), calcimimetics (bisphosphonates, Antiresorptives Drugs: bonesyndrome Hungry < 30mL/min/1.73m (CKD) andGFR Chronic kidneydisease (acute) Vitamin Ddeficiency Calcium deficiency Hypomagnesemia Hypoalbuminemia Several other drugs mayaggravatehypocalcemia Several other drugs In travenous bisphosphonates (17) and subcutaneous Causes ofhypocalcemiaotherthanhypoparathyroidismandpseudohypoparathyroidism

2 Total calcium Low Low Low Low Low Low Low Low Low 2 blockers reduce the blockersreduce Ionic calcium Variable Normal Low Low Low Low Low Low Low review review Variable Variable Variable Variable Normal High High High High PTH hypocalcemia Symptoms of term “hypoparathyroidism” is commonly reserved to iscommonlyreserved “hypoparathyroidism” term Thus, the is known as . periph from resulting (Tableand phosphorus 2).Hypoparathyroidism impacting the homeostasis of calcium directly PTHaction, PTHand/orimpaired in secreting glands aninabilityoftheparathyroid arises from a functional point of view,From hypoparathyroidism 2. What investigation ofhypocalcemia by albumin levelduring the always be corrected Thus,totalcalciumconcentration should normal. hypocalcemia, buttheionizedcalciumfractionis albumin concentrations may inaccurately indicate boundtoalbumin.Low of thetotalcalciumcirculates Highlights SBEM: Moderate/ Variable Variable Variable Variable Variable Variable Variable Absent severe are thecausesofhypoparathyroidism? Rickets/osteomalacia Rickets/osteomalacia Hyperparathyroidism Hyperparathyroidism increased resorption (decreased density) Dependent onthe Dependent onthe manifestations (eventual low turnover) etiology etiology Bone None None None In normal conditions, about 50% conditions,about50% Innormal eral resistance to PTH action eral resistance Arch Metab. Endocrinol 2018;62/1 Surgical cureofhyperparathyroidism Phosphate-containing enemas, renal Liver cirrhosis, nephroticsyndrome, Osteoporosis, orsecondary primary Diuretics, chronicdiarrhea, small transfusion, epilepsy, pepticulcer, Alcohol abuse, gallbladderstones Decreased sunexposure, obesity, pancreatic diseases, steatorrhea, failure, intensetissuebreakdown (A) Severe malnutrition, Roux-en-Y (rhabdomyolysis ortumorlysis) dark skin, RYGB, aging, severe (primary or secondary toCKD) orsecondary (primary Severe hypertension, diabetes malnutrition, celiacdisease, hyperparathyroidism, blood bowel bypassorresection burn, malnutrition, sepsis Associated diseases gastric bypass(RYGB) . mellitus, andothers antiepileptic drugs neoplasias, etc. Arch Metab. Endocrinol 2018;62/1 Genes associatedwithhypoparathyroidism areshowninsquarebrackets. Compiledfrom (23,31,32). Table 2. will bediscussedseparatelyinSection4. hypoparathyroidism Relevant aspects of surgical-related (25-27). oftheparathyroids removal or inadvertent arteries ligationoftheinferiorthyroid oftruncal result cancerormaybeaccidentalasa ofcervical treatment surgical mayoccurduetoanaggressive parathyroids of thedisease form to 75% of the cases of the acquired corresponding causeofhypoparathyroidism, is themostfrequent region Surgical manipulationoftheanteriorcervical 2.1.1. Postsurgical hypoparathyroidism genetic orautoimmunecause(23). activationofCaSRsduetoa homeostasis orabnormal ofmagnesium todisorders secondary of PTHsecretion deregulation from may also result Hypoparathyroidism listedinTable ofPTHare and/or theproduction 2. thedevelopmentofparathyroids diseases affecting radioiodine , andgenetic Riedel’sthyroiditis by neoplastic infiltration or heavy metals, irradiation, destruction suchasparathyroid hypoparathyroidism, causesof (1,2,21-23).Rare hypoparathyroidism etiologyof thesecondmostfrequent is considered oftheparathyroids destruction hypoparathyroidism of Causes 2.1. PTH producing unable ofproperly glandsare describe asituationinwhichtheparathyroid peripheral resistancetoPTHaction Functional hypoparathyroidismdueto deficiency Hypoparathyroidism duetoPTH The main cause of hypoparathyroidism is the surgical The main cause of hypoparathyroidism Causes ofhypoparathyroidism (A) (2,22-24). The destruction ofthe (2,22-24).Thedestruction Pseudohypoparathyroidism Regulation changeinPTHsecretion development and/orPTHproduction Genetic diseasesaffectingparathyroid Parathyroid destruction (A) (A) . (1-3,20). autoimmune polyglandular syndrome type 1 is a rare type 1isarare autoimmune polyglandularsyndrome develop nonsurgical hypoparathyroidism inindividuals who autoimmune hypoparathyroidism autoimmune manifestations helps the identification of ofother (2,28). Inclinicalpractice,thepresence studies antibodies isgenerallylimitedtoresearch ofthese (between 25to40%),andthemeasurement isvariable suspected autoimmunehypoparathyroidism and anti-CaSRantibodypositivityinindividualswith of antiparathyroid poorly characterized. The prevalence oftheseantibodiesisstill but thepathogenicrole and anti-CaSR antibodies, to antiparathyroid related hasbeen Isolated autoimmunehypoparathyroidism type 1 (APECED) (2,22). polyglandular syndrome oftheautoimmune isolated endocrinopathyoraspart in adults hypoparathyroidism thesecondmostcommoncauseof considered is to the parathyroids Autoimmune aggression 2.1.2. Autoimmunehypoparathyroidism hypoparathyroidism (2,21). participates in (2,21).Magnesium participates hypoparathyroidism Changes inmagnesemiamayleadtofunctional  2.2. may alsooccur severalother autoimmunemanifestations insufficiency; and adrenal candidiasis, hypoparathyroidism, AIRE diseasecausedbymutations inthe autosomal recessive PRKAR1A Genetic defectsinPTHpost-receptorsignaling [ Chronic hypomagnesemiaandhypermagnesemia Activating anti-CASRantibodies Autosomal dominanthypocalcemiatype1 [ Mitochondrial diseases TBCE CHARGE, Kenny-Caffey, Sanjad-Sakati, HDR, etc Genetic syndromesassociatedwithhypoparathyroidism(e.g. DiGeorge, Isolated hypoparathyroidism[ Riedel’s thyroiditis (Wilson’s diseaseandhemochromatosis) Parathyroid infiltrationbyneoplastic, granulomatous, orstoragediseases Autoimmune: isolatedorassociated withpolyglandulardisease[ radiotherapyorradioiodinetherapy Cervical surgery Following cervical secretion secretion Hypoparathyroidism due to deregulation of PTH PTH of deregulation to due Hypoparathyroidism gene, characterized mainly by mucocutaneous , FAM111A , PDE4D , CHD7 ] (C) Diagnosis andtreatment ofhypoparathyroidism , (29). SEMA3E PTH , ] GCM2 (A) , SOX3 CASR andmayoccurasan ] GNAS . ) [ ] andtype2[ TBX1 , STX16 , NEBL , (D) GNAS11 , NESP55 GATA3 AIRE . The ] , ] , 109

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 110 beyond thescope ofthisarticle. are and managementofpseudohypoparathyroidism pseudohypoparathyroidism tissues (for example, PRKAR1A) defects inothermediators of PTHsignalingintarget (for example,modification in inthekidneys.Othermoleculardefects particularly withPTHsignalinginperipheraltarget tissues, interfere defects in the pseudohypoparathyroidism, tothereceptor of thehormone the binding the stimulation arising from propagating and conditions actsbycouplingto the PTHreceptor coded bythe Gprotein, of thealphasubunitstimulatory inactivatingmutations are pseudohypoparathyroidism Themaingenetic defects causing production. PTH and hyperphosphatemia)stimulatesincreased (hypocalcemia resistance hormonal from resulting and the biochemical disorder isnormal, the parathyroids of PTH by theproduction pseudohypoparathyroidism, function renal levels inpatientswithnormal of elevated PTH hyperphosphatemia in the presence testsbyhypocalcemiaand is characterizedinlaboratory PTHsignalingand by geneticdefectsinpostreceptor Thisconditioniscaused pseudohypoparathyroidism. is known as in functional hypoparathyroidism to PTH action resulting Peripheral resistance pseudohypoparathyroidism of Causes 2.2.2 (28). hypoparathyroidism causeof thisisarare ofthishormone; the secretion bymimickingcalciumandinhibiting CaSR receptor byanti-CaSR antibodies activating the deregulated hypoparathyroidism upon evaluationofhypocalcemia,toexcludefunctional magnesiumlevelsmustbedetermined serum Therefore, CLDN19 in thehomeostasisofmagnesium( geneticdefectsoffactorsinvolved (22). Rare secretion PTH magnesium mayactivateCaSRsandsuppress alsoleadstohypocalcemiasince insufficiency) renal administration or (due to the excessive parenteral PTH levels.Ontheotherhand,acutehypermagnesemia low orovertly normal hypocalcemia withinappropriately cause pump inhibitors and diuretics) use of proton diabetes mellitus, and chronic poorly controlled alcoholism, diarrhea, magnesium depletion(chronic the aden andactionthrough ofPTHsecretion both processes Diagnosis andtreatment ofhypoparathyroidism ylcyclase system. Thus, conditions of chronic ylcyclase system.Thus,conditionsofchronic ) may also cause hypoparathyroidism (22). ) may also cause hypoparathyroidism GNAS (A) gene,whichinphysiological . PTH secretion mayalsobe . PTHsecretion (A) GNAS (23).Thediagnosis (A) TRMP6 may also cause methylation)or (30).Thus,in GNAS , CLND16 (A) gene . In , during thyroid surgery (35).Transient postsurgical surgery during thyroid orinjured incidentallyremoved had theirparathyroids (B) of0.25per1,000individuals estimated prevalence withan disorder isarare Hypoparathyroidism 3. Whatistheprevalence ofhypoparathyroidism? EPIDEMIOLOGY 52) (Table 3). aligned withthosedescribedabove(25,47- studies are ofBrazilian theresults isscarce, in this regard literature hyperplasia especiallyinparathyroid reoperations, parathyroid and (level VI) lymphnodedissectionsand in thyroid even higher with central compartment these rates are (Tableand hemithyroidectomy) 3).Ontheotherhand, (subtotalthyroidectomy thyroid with partial when compared ratesofhypoparathyroidism increased isassociatedwith withtotalthyroidectomy treatment injury, parathyroid isduetodirect hypoparathyroidism 0.4%to 13% (24,37-44).Sincepostsurgical from ranges while that of definitive hypoparathyroidism 3%to52%, varieswidelyfrom hypoparathyroidism oftransient among othercauses.Thus,theprevalence strategies incalciumandvitaminDsupplementation, ofindividualseries,anddifferent inreports of interest follow-up,conflicts lack ofcleardefinitions,inappropriate due to underestimated, is probably hypoparathyroidism surgical event the thansixmonthsfrom definitive whenlastingmore after surgery, isconsidered hypoparathyroidism thansixmonths more occurring ofrecoveries reports rarely,more be definitive subsequent spontaneousrecovery. However, itmay, afteracutemanipulation,with impairment parathyroid is common, due to functional hypoparathyroidism hypoparathyroidism maybeclinicallychallenging. hypoparathyroidism idiopathic autoimmunefrom although differentiating to identifythecauseofhypocalcemia is fundamentalsince,inmostcases,itnotdifficult evaluationofthesepatients Clinical andlaboratory other causesofhypocalcemiamustbeconsidered. destruction, of conditionsleadingtoparathyroid Highlights SBEM: The actual prevalence of postsurgical The actualprevalence (33,34). Most patients with hypoparathyroidism (33,34). Most patients with hypoparathyroidism (B) (D) (45,46). Although the Brazilian (2,3,20,36). In patients without a history Inpatientswithoutahistory (C) Arch Metab. Endocrinol 2018;62/1 (22). Despite literature (22). Despite literature (A) , Arch Metab. Endocrinol 2018;62/1 to thevascularpedicle,inadvertent injury thermal), tissuetrauma (mechanicalor may beduetodirect surgery glands during thyroid to the parathyroid Injury 4.  SURGICAL ASPECTS Table 3. 52 51 50 49 48 47 46 45 44 43 42 41 40 39 38 37 35 33 27 Reference of the procedures of theprocedures surgeries, alongwiththeextent thyroid/parathyroid of uponrecommendation should beconsidered surgery. Theriskofpostsurgical hypoparathyroidism after hypoparathyroidism ofpermanent the prevalence Highlights SBEM: hypoparathyroidism? Is itpossibletopreventpostsurgical Epidemiology ofpost-surgicalhypoparathyroidism Lorente-Poch andcols., 2015 Ywata de Carvalho andcols.,Ywata deCarvalho Montenegro andcols., 2012 Youngwirth andcols., 2010 Underbjerg andcols., 2013 Vanderlei andcols., 2012 Puzziello andcols., 2014 Dedivitis andcols., 2010 Molinari andcols., 2015 Accetta andcols., 2011 Powers andcols., 2013 Nawrot andcols., 2014 Snyder andcols., 2013 Järhult andcols., 2012 Rosato andcols., 2004 Pelizzo andcols., 2014 Ritter andcols., 2015 Wei andcols., 2014 Ito andcols., 2014 Author, year (C) 2015 There are noconsistentdataon are There . Denmark Country Sweden Poland Japan China Spain Brazil Brazil Brazil Brazil Brazil Brazil USA USA USA USA Italy Italy Italy 2.3% ofpatientswithoutcentralneckdissection (6/156) – parathyroid glands preserved inplace (6/156) –parathyroidglandspreserved 11.8% ofpatientswithcentralneckdissection 0.9% (3/321)–autotransplantation3.8% 1.8% (forothertypesofhyperthyroidism) Prevalence ofhypoparathyroidism 22/100,000 (generalpopulation) 6% ofthetotalthyroidectomies 0% (forotherbenigndiseases) 1.0% (forGraves’disease) 0/66 –nocase ligation of the inferior thyroid artery branchesshould artery ligation ofthe inferiorthyroid , butsomeaspects maybehighlighted: during ofhandlingtheparathyroids in terms (43,56,57). removed techniques incasetheglands are autotransplantation and commandofparathyroid meticuloussurgical technique, the parathyroids, of knowledge of theanatomyandembryology the surgeons abroad from (44,55). Thisrequires hypoparathyroidism factorinpreventing important theirlocation)(53,54). from the parathyroids couldalsoremove whichuponresection compartment, ofmetastasesinthecentral (for example,presence oftheglandsforoncologicreasons intentional removal duringsurgery, oftheparathyroids removal oreven 0.74% 1.9% 0.9% 3.3% 1.7% 5.0% 0.3% 2.5% 6.6% 8.5% 4.6% 28% 8% There is no standard andwidelyusedtechnique isno standard There inplaceisthemost Maintaining intactparathyroids Diagnosis andtreatment ofhypoparathyroidism 154 completionthyroidectomiesafteraprevious 477 thyroidectomieswith(n=321)andwithout 15,000 thyroidectomieswitha5-yearfollow-up 91 , 6patientshadbiochemical MEN-1/all withparathyroidautotransplantation hypoparathyroidism, only2requiredcalcitriolin 780 totalthyroidectomiesfordifferentreasons (n =106)andwithoutcentralneckdissection Two differentgroups: totalthyroidectomywith 265 thyroidectomiesinpatientswithGraves’ 83 patientswithhyperparathyroidismdueto 233 patientsafterasecondthyroidsurgery (n =156)parathyroidautotransplantation 657 thyroidectomies, 1-yearfollow-up 28.8% hadtransienthypocalcemia hypoparathyroidism after1month 120,000 surgeriesinoneyear 12% ofpatientshadtransient Data from1988to2012 1,054 thyroidectomies 2,631 thyroidectomies 3,411 thyroidectomies 401 thyroidectomies 40 thyroidectomies 66 thyroidectomies thyroidectomy the longterm Comments (n =478) disease 111

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 112 serial blood sample collection recommending protocols thyroidectomy. initiallyfocusedon were Theseefforts patients athigherriskofdeveloping hypocalcemiaafter theidentificationof toward havebeendirected Efforts 5.  total thyroidectomy after theratesofhypoparathyroidism unable toreduce they havebeen the identificationofparathyroids, (65).Inspiteofthesetechniques improving green association withmethyleneblue(64)orindocyanine withnear-infraredparathyroid imaging(61-63)orin ofthe and detectionofthenaturalautofluorescence (59,60) ofcarbonintothethyroid of nanoparticles glands duringthyroidectomy, suchastheinjection methodstoidentifytheparathyroid of auxiliary (44,58). hasbeenquestionedbyseveralauthors procedure ofthis (43,56,57), althoughtheactualeffectiveness muscle usually inthehomolateralsternocleidomastoid 2 mm (approximately parathyroid fragments of the removed Inthiscase,autotransplantationofsmall resected. thatmayhavebeeninadvertently ofparathyroids search in afterremoval intact andinplace;inspectthethyroid identifying and maintaining the superior parathyroids by risk),start atgreater are the inferiorparathyroids (where lymphnodedissectionisrequired compartment without causing tissueor vascular trauma; when central gentlymovingawaytheparathyroids be performed, capsuleshould dissectionofthethyroid avoided; careful themmustbe orwithinmillimetersfrom parathyroids cauterization of the to avoid vascular lesions; direct capsule asclosepossibletothethyroid be performed Diagnosis andtreatment ofhypoparathyroidism hypoparathyroidism hypoparathyroidism theratesofpermanent inreducing effective proven has intraoperative identificationoftheparathyroids Toof hypoparathyroidism. date,notechnologyfor autotransplantation techniquesmayminimizetherisk surgical technique,andcommandof parathyroid knowledge ofanatomyandembryology, meticulous Extensive hypoparathyroidism. in preventing factor in place is the most important parathyroids Highlights SBEM: after thyroidectomy? Is itpossibletopredicttheriskofhypocalcemia There have been recent attemptsatthedevelopment havebeenrecent There 3 ) is recommended, followedbytheirimplantation ) isrecommended, (B) (B) Themaintenanceofintact (66). . (B)

value, and ideal protocol have not been definedyet, value, and ideal protocol (75).Althoughthetimeperiod,PTH after surgery PTHvaluemeasured is unlikelywithanormal hypocalcemia Severe accuracy withsuch measurements. (72,76,84). Noneofthesestudieshasguaranteed100% (49,70,71,78,79,81) tillthefirstpostoperativeday theendofsurgery Samples canbecollectedfrom of hypocalcemia. with the occurrence to correlate has also shown single postoperative measurement ofhypocalcemia with theoccurrence hasbeenassociated and 1houraftersurgery before levels. ThedecayofPTHlevelsinsamplescollected PTHcutoff collected bloodsamples,anddifferent criteria forthediagnosisofhypocalcemia,number with variationsinthetimeofbloodcollection, PTHlevels(49,73,80,82), ofserum for measurement (49,70-8 recently, ofPTHlevels alsoincludemeasurement ofcalciumlevels(67-69)and,more for measurement are characteristicofthismetabolic disorder.are as carpopedalspasms,, andmusclecontraction symptomssuch excitability;therefore, neuromuscular (86,87). Hypocalcemia is as phosphokinase(CPK) of theenzymecreatine levels muscle painaccompanied or notbyincreased weakness,and in thefaceordistalextremities, calciummanifestsacutelywithparesthesias low serum how fastthemanifestationsemerge the durationandintensityofhypocalcemiaon (2,3,22). Theseverityofthesymptomsdependson skeletalmuscle,andkidneys system,heart, nervous in various organs and tissues, roles including the central and symptoms,consideringthatcalciumhasdistinct 6.  CLINICAL MANIFESTATIONS wholaterdevelophypoparathyroidism. thyroidectomy the postoperativemanagementofpatientsundergoing appeartobeusefulin perioperative PTHmeasurements to theexperienceofeachinstitution However, mustbeestablishedaccording theprotocol hypocalcemia inpatientsundergoing thyroidectomy. the risk of PTH values may be useful in predicting Highlights SBEM: manifestations ofhypocalcemia? What aretheacuteandchronicclinical Hypocalcemia maybeassociatedwithseveralsigns 5). The literature describes several protocols describes several protocols 5). The literature Theuseof perioperative Arch Metab. Endocrinol 2018;62/1 sociated with increased sociated with increased (B) (D) (B) . . Classically, (49,83). A (C) (B) Arch Metab. Endocrinol 2018;62/1 complications (100-102). will bediscussedinthesession dedicatedtochronic calcification manifestations suchascataract andcerebral hypocalcemia in chronic symptoms may be milder hypocalcemia, neuromuscular keratinocytes (97-99). of anddifferentiation theproliferation regulating specifically,role oftheintracellularcalciumin isthe for theassociationbetweenhypocalcemiaandpsoriasis, (psoriasis of von Zumbusch) andacutegeneralizedpustularpsoriasis piodermitis including to acutehypocalcemiahavebeenreported, levels ofcalcium afternormalization dysfunction reversing withsystolic ofdilatedcardiomyopathy been reports arrest fibrillation andcardiac toventricular whichmayprogress the QTinterval, of changessuchasprolongation electrocardiographic hypocalcemia triggers excitation and contraction, severe calcium levels ofserum withnormalization reversible situations are All these intracranial pressure. or not with increased stridor, characterizing dyspnea followedby laryngeal hypocalcemiacanpotentiallyleadtosudden severe hypoparathyroidism of whichmaybetheinitialpresentation , lead tospontaneoustetanyortriggergeneralized individuals signal maybealsopositiveinupto10%ofthenormal anteriortotheear(89).This overitstrajectory nerve bythetappingoffacial facial musclestriggered thelipsorother contraction ofthemusclesaround The Chvostek’ssignischaracterizedbyanipsilateral individuals inupto4%ofthenormal be present specificofhypocalcemia,itmayalso this signisvery (88).Although minutes causinganocclusivepressure forabout3 to 20mmHgabovethesystolicpressure ofthesphygmomanometerisinflated10 when thecuff the thumb (“obstetrician’s hand” or carpopedal spasm) extension of the interphalangeal joints, and adduction of with flexionofthewristandmetacarpophalangealjoint, muscles contractionoftheforearm first isaninvoluntary Trousseau’sexcitability are and Chvostek’s signs. The of hy In contrasttothemanife manifestationssecondary Some dermatological in myocardial Since calciumplaysafundamentalrole cases,excessivemusclecontraction may In severe On physicalexamination,thecharacteristicsigns pocalcemia reflecting a status of neuromuscular astatusofneuromuscular pocalcemia reflecting (C) (95,96). (D)

(C) (91), or result inpapilledemaassociated (91), orresult . (92,93). (C) (90). Inaddition,acuteand (D) (2,3,22). Some chronic (2,3,22).Somechronic (C) (C) (97-99). The reason (97-99). The reason stations inacute (94). There have (94).There (B) . defects, have also been reported defects, havealsobeenreported dentalhypoplasia,andenameltoothroot eruption, especially duringchildhood,suchasdelayedteeth hair (105). Dental abnormalities, brittle nails, anddry skin,weakand andrough suchasdry may bepresent, calcification cerebral inpatientswithhypocalcemia and have beenreported and psychoticepisodes anxiety, rarely, and,more depression, hallucinations with psychiatricmanifestations,suchasmoodchanges, are noteworthy.are Althoughionized calciumisthe (1-3,9,21). calcium 25(OH)D, inadditionto24-hour urinary and magnesium,creatinine, PTH, phosphorus, foralbumin, oftotalcalciumcorrected measurement assessment ofChvostek’sandTrousseau’s signs(1-3). and ofsignspriorsurgery insearch region cervical inspectionofthe examination mustincludeacareful manifestations (2,20). The physical or syndromic disease, suchasconcomitant autoimmune conditions and factorsthatmightsuggesttheetiologyof irradiation, orcervical ofsurgery manifestations, history ofsuggestiveclinical take intoaccountthepresence havenotbeendefined yet. hypoparathyroidism the definitecalciumandPTHvaluesfordiagnosisof ofhypocalcemia presence lowPTH levelsinthe demonstrating inappropriately tests itsdiagnosisisbasedonlaboratory grounds, clinical on issuspected Although hypoparathyroidism 7. Howishypoparathyroidismdiagnosed? DIAGNOSIS may beincludedintheclinicalmanifestations.On ,seizures, papilledema,andlaryngospasm hypocalcemia, and muscleweakness.Incasesofsevere cramps,pain, , of acutehypocalcemiaare Highlights SBEM: hypocalcemia maybeasymptomatic and Chvostek’ssignssuggesthypocalcemia.Chronic ofTrousseau’sphysical examination,thepresence Other symptomsincludingtinnitusanddizziness Hypocalcemia oflongdurationhasbeenassociated Some laboratory features of hypoparathyroidism ofhypoparathyroidism features Some laboratory evaluationmustincludeserum The laboratory should The diagnosisofhypoparathyroidism Diagnosis andtreatment ofhypoparathyroidism The most frequent symptoms Themostfrequent (C) (C) (103). (A) (104). Nonspecificsigns (C) (1-3,9,21). Ofnote, (106). (C) . (A) 113

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 114 nephrolithiasis/nephrocalcinosis prevent duringmanagementofthisconditionto important molecular CaSR analysis is hypocalcemia through (111).Thediagnosisofautosomaldominant regard IFN ofanti- in clinicalpractice,althoughthedetermination forthispurpose autoantibody hasbeenstandardized ischallenging. So far,hypoparathyroidism no withcalciumandvitaminD treatment than 4mg/kg/day),duetotheabsenceofPTHduring calciumgreater (urinary ofhypercalciuria the occurrence tomonitor calcium. Duringfollow-up,itisimportant thenutritionalintakeof calciumreflects hour urinary usefulduringfollow-up. levels are and25(OH)D creatinine ofserum The determination outfunctionalhypoparathyroidism. torule is important ofmagnesium levels Measurement range ordecreased. theymaybewithinthenormal bonesyndrome, hungry ofconcomitant butinthepresence usuallyincreased, are collection andstorage(108). withblood care certain requires PTH measurement (20). diagnosticofhypoparathyroidism 20 ng/mLare ofhypocalcemia,valuesbelow In thepresence hypocalcemia the rapid development,thesymptomsmayprecede usuallybelow7.5mg/dL levels are the range,butinhypoparathyroidism, the normal ofcalciumlevelsbelow is establishedinthepresence below 4.0g/dL(6-9).Thediagnosisofhypocalcemia inalbuminlevel 0.8 mg/dLforeach1.0g/dLdecrease foralbumin,whichiscalculatedbyadding corrected oftotalcalcium isthedetermination measurement toionizedcalcium alternative practice, themostreliable notalwaysfollowed.Inclinical both ofwhichare care, s requires physiologically active calcium fraction, its measurement Diagnosis andtreatment ofhypoparathyroidism addition to24-hour calciuria D,in and25-hydroxyvitamin magnesium, creatinine foralbumin,PTH,phosphorus, calcium corrected evaluationmust includetotalserum laboratory ofhypocalcemia levels inthepresence lowPTH testsindicatinginappropriately laboratory butitsdiagnosisisbasedon on clinicalgrounds, Highlights SBEM: The etiologicdia function,the24- renal ofanormal In thepresence hypoparathyroidism in chronic Levels ofphosphorus loworundetectable. The valuesofintactPTHare ω and anti-NALP5 has proven tobeusefulinthis andanti-NALP5hasproven tandardized blood collection and pre-analytical bloodcollectionandpre-analytical tandardized (C) (107). Hypoparathyroidism is suspected issuspected Hypoparathyroidism gnosis ofnonsurgical (A) . (A) (C) (A) . The patient’s . Thepatient’s (B) (109,110). (109,110). . Incasesof (111).

Acute manifestations threatening the patients’ Acute manifestationsthreatening hypocalcemia acute of Treatment 8.1 symptoms of rate of development ofhypocalcemia and presence strategiesmaybeused,dependingonthe different (112).Two of calciumlevelsmustbecorrected range. Persistenthypomagnesemiaafternormalization maintain thetotalcalciumclosetolowernormal isto thegoaloftreatment sideeffects, long-term To thediseaseoritstreatment. from resulting avoid complications chronic symptoms, andpreventing hypocalcemia andhyperphosphatemia,reducing Treatment is aimed at correcting of hypoparathyroidism 8.  TREATMENT patient ismildly symptomaticorasymptomatic. if the but intravenouscalciuminfusion isnotrequired patients with slowly developing hypocalcemia (chronic), hypocalcemia in Calcium concentrations must also be corrected chronic of Treatment 8.2 (A) especiallyinpatientsondigitalis also bemonitored, rhythmshould titration oftheinfusiondose;heart for concentrations mustbeperiodicallymonitored calcium levelsbecomesestablished oral medications on of the long-term until the effect body weight/hourdilutedin5%GSmayberequired infusion ofelementalcalcium0.5to2.0mg/kg a continuous normocalcemia, Toincreased. preserve concentrationsare phosphorus especially whenserum mayleadtocalcificationoflocalsofttissues, Overflow reaction inthevenouspath(). inflammatory andcauseasevere may triggercardiac infusion over10to20minutes slowly via intravenous solution (GS) and administered to 100mLof0.9%salinesolution(SS)or5%glycosylated solution. Onetotwoampoulesshouldbedilutedin50 90mgofelementalcalcium per10mLof approximately among usis10%calciumgluconate,whichcontains (1-3,7,20,21,107,112,113). Themostusedsalt withintravenouscalcium urgent treatment require failure, orcongestiveheart the QTinterval, of prolongation bradycardia, seizures, , or laryngospasm lives suchastetanicseizures, conventional treatmentbedefined? be treated?How How shouldpatientswithhypoparathyroidism (1-3,7,20,21,107,112,113). (A) . shouldtherapeuticfailure with Arch Metab. Endocrinol 2018;62/1 (B) (B) . Rapidinfusion . Serum calcium . Serum (A)

Arch Metab. Endocrinol 2018;62/1 calcium forabsorptionbythe intestinalcells to offer of hypocalcemiaandhastwoobjectives: treatment tocalcitriolalone. compared calciumwhen incontrolling with calcitrioliseffective the useofvitaminDsupplementation dosesassociated to intoxication secondary both incasesofhypocalcemiaaswellhypercalcemia of calcium levels, half-life enablesfastercorrection fortheuse ofcalcitriol,whoseshorter is apreference prolonged usually very andare mayoccurinthelongterm hypercalcemia intoxication manifesting with high, situations of severe very half-life is2to3weeks.Sincethesedosesare ten days), and their biological longer (approximately calcium levels take of these agents in increasing effects The the pastwhenaccesstocalcitriolwasrestricted. andhaveoftenbeenused in hypoparathyroidism treat mayalsobeusedto orcholecalciferol) ( (1-3,7,20,21,107,112,113). High doses of individuals, insomecasesexceeding2.0 tocalciumlevelsandvariesamong titrated according initiation.Thedoseofcalcitriol shouldbe treatment 1to3daysafter in calciumlevelsmaybeobserved 4 to6hoursafteradministration,andelevations calcitriolpeak isachieved two dailydoses.Serum 0.5to1.0 range from 12hours,anditsinitialdoses every be administered long biologicalhalf-life(4to6hours),calcitriolmay with calcitriolorhighdosesofvitaminD PTH deficiency, calciumlevelscanonlybenormalized thebone ofcalciumfrom release the and promote doses, they stimulate bone resorption inexcessive in theintestine,butwhenadministered theiractionontheabsorptionofcalcium mainly from arise drugs of these hypercalcemic (114). The effects mayalsobeused orergocalciferol) ( with oralcalcitriolispreferable half-life, treatment andduetoashorter this reason of 1,25(OH) theproduction hyperphosphatemia (11).Therefore, cells, usuallystimulatedbyPTHandinhibited by theenzyme1 metabolite (1,25(OH) (A) calcitriol, associated with oral calcium salts active form, hasbeenachievedwiththeuse ofvitaminDorits term The useoforalcalciumsalts isessentialinthe The conversionof25(OH)Dintoitsactive Maintenance ofcalciumconcentrationsinthelong (1-3,7,20,21,107,112,113). 2 D is reduced in hypoparathyroidism. For inhypoparathyroidism. D isreduced α -hydroxylase in renal tubular inrenal -hydroxylase 2 (A) D or calcitriol) iscatalyzed µ (B) g/day dividedintoatleast (114). Due to that, there (114).Duetothat,there . There is no evidence that . There (B) (A) , although vitamin D , althoughvitaminD (115). In severe (115).Insevere µ (C) g/day . With a . With (B) (B )

but most of patients can be well controlled withdaily but mostofpatientscanbewellcontrolled aslittle1gtomuch as9g(21), patients, from among elementalcalciumvariesgreatly of required use haslimitedscientificevidence.Thedailyamount such aslactogluconateandcitratemalate,buttheir maybeused, (113). Othercalciumformulations calcium pergramofsalt(21%)andahighercost despitealowerconcentrationofelemental preferred pump inhibitors),orgastrectomy, calciumcitrateis In casesofachlorhydria,lowacidity(useproton the salt and beabsorbed. acidity to dissociatefrom and a lower cost. However, gastric the calcium requires amount ofelementalcalciumpergramsalt(40%) carbonate andcitrate.Calciumhasalarger phosphatemia(1-3). reducing inthefood,indirectly present containing phosphorus ofvitaminD,andtosequesterradicals under theeffect such diuretics such diuretics useof toprolonged avoiding hypokalemiasecondary potassium, association withamiloride may helpspare in one or two doses a day and the 50 mg administered variesbetween25 to The doseofhydrochlorothiazide has variable efficacy.be used, although this approach may andhydrochlorothiazide including chlorthalidone thiazidediuretics treatment, hypoparathyroidism (24,116,117). To during hypercalciuria correct insufficiency andrenal nephrocalcinosis, to complications such as nephrolithiasis, long term may occur and lead in the hypercalciuria reabsorption, ofPTHtoinducetubularcalcium theeffect Without filtrateincreases. supply ofcalciumtotheglomerular duringvitamin Dadministration,the increased are When calcium levels in tubular calcium reabsorption. isanincrease PTHeffect substitutive. Animportant is not ofPTH,sothistreatment theeffects fully replace (B) this function calcium carbonate, which also performs necessary,may berarely in addition totheuseof not beencouraged content,should calcium buthaveahighphosphorus rich in which are products, intake of dairy increased calcium phosphate salts in the diet.Forthisreason, tolimittheamountofphosphates and recommended to theabsenceofphosphaturicPTHaction,itis day over meals timesa 1to3g,dividedin three doses rangingfrom The most commonly used calcium salts are The mostcommonlyusedcalciumsaltsare The useofintestinalphosphatechelatingagents (1-3). Unfortunately, vitamin D derivatives do not (B) (A) (1-3,7,20,21,107,112,113). Diagnosis andtreatment ofhypoparathyroidism (D) (1-3,7,20,21,107,112,113). Due . (A) 115

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 116 emergency inthecaseof indicating theirdiagnosisandtreatment, m hypoparathyroidism may bepotentiallylethal,patientswithchronic phases (125). stillinexperimental are cells, butstudiesinthisregard parathyroid use ofallograftsmacroencapsulated perspectivespointouttothe (124). Furthermore, (FDA and EMA) and will be discussed in Section 9 agencies byAmericanandEuropean been approved andtheuseofPTH (1-84)has hypoparathyroidism, of tested withsomesuccessinthetreatment be discussedinSection10. will and lactation in patients with hypoparathyroidism during pregnancy (2,118-123). Themetabolic control cancer duetolaryngeal seen inwidesurgical resections intheingestion ofmedicationsbymouth,as difficulties (suchaspost-bariatricsurgeries) and iatrogenic disease, ormalabsorptionduetoothercauses) boweldisease,celiac (inflammatory as well as conditions associated with spontaneous amongothers), cholestyramine, andglucocorticoids, absorption ofnutrientsorothermedications(orlistat, the urgent hospitalizations,medicationsaffecting infections, calcium levels,includinggastrointestinal of control orevenhinderaproper adjusted treatment many timesaday depends on the patient ingesting several pills treatment and vitaminDhassomechallenges.Thesuccessofthe mayalsobeused. formulations dose variesbetween1to2vialsaday, butmanipulated 130 mgofelementalmagnesiumineachvialandthe availablemagnesiumpidolatehas Commercially activating CaSR mutation (1-3,113). from resulting inhypoparathyroidism particularly salts isrequired, but insomecases,supplementationwithmagnesium in parallel to thoseof calcium, magnesium levelscorrect of hypocalcemia. Usually,especially in the occurrence to thoseofcalcium,anditslevelmaydecrease, Diagnosis andtreatment ofhypoparathyroidism maintain the patient asymptomatic, with total calcium maintain thepatient asymptomatic,withtotal calcium chronic complications chronic symptoms, and preventing phosphatemia, reducing hypocalcemiaandhyper aims atcorrecting roidism Highlights SBEM: Considering thatahypocalcemiaemergency The useofPTHanditsderivativeshasbeen Some clinicalsituationsmaydestabilizeawell- Treatment withcalciumsalts ofhypoparathyroidism Mag nesium has metabolic pathways very similar nesium hasmetabolicpathwaysvery (D) . (B) (1-3,113). Treatment ofhypoparathy ust carry an identification card anidentificationcard ust carry (B) . The treatment goal is to goalisto . Thetreatment - -

Winer and cols. followed up adults treated withPTH andcols.followedupadultstreated Winer with theuseofPTHanalogssince1996,when hasbeensomeaccumulated experience (1-3). There urinary calcium were observed observed calciumwere urinary in consistent,andnodifferences more levels were calcium andadults(5-70years). Serum one inchildren withtheconventional thistypeoftreatment compared (1-34,126-128) andstudieswiththedurationof3years done with replacement of the missing hormone ofthemissing hormone done withreplacement is not deficiency inwhich theconventional treatment persistsasthelastclassichormone Hypoparathyroidism  9. 100 withupto of theadultpatients(18-85 years)treated trial)hasshownthat53% phase 3,placebo-controlled be discontinued some cases,calciumandvitamin Dsupplementscould asymptomatic, especiallywiththedoseof100 havebeendescribed,mostly episodes ofhypercalcemia since calcium must be monitored and vitamin D. Serum 100 (1-84) mustbetitratedbetween25,50,75,and application. StudieshaveshownthatthedoseofPTH has alongerhalf-life,whichallowsforsingledaily standpoint,thismolecule apharmacokinetic From ofhypoparathyroidism. PTH (1-84)forthetreatment agencies fortheuseinhypoparathyroidism. by regulatory months, andhasnotbeenapproved inadultsandfor18 to 24 ofosteoporosis treatment forthe highlight that PTH (1-34) is onlyapproved calcium in urinary calciumandreduction ofserum physiological control showedamore (1-34) twicedailyinadultsandchildren, with subcutaneous PTH infusion pump, compared with acontinuous with PTH(1-34)administered active vitaminDandcalciumsalts hypocalcemiainvolvestheuseof ofchronic treatment anintravenousinfusionofcalcium.The and requires situationsleadingtoimminentlifethreat controlling kg/day. Treatment ofacutehypocalcemiaisaimedat range(below300mg/day) orbelow4mg/ normal calciumshouldbemaintainedwithinthe urinary range and24-hour levels closetothehighnormal range, phosphorus levels closetothelowernormal the treatment of hypoparathyroidism? of treatment the What evidence supports the use of PTH analogs in in analogs PTH of use the supports evidence What The REPLACEstudy(adouble-blind, randomized, theuseof 2015,theFDAapproved In January µ µ g, thus enabling a reduction inthedosesofcalcium g, thusenablingareduction g of PTH (1-84) were able to decrease by50% able todecrease g ofPTH(1-84) were (B) (B) (133-135). (131,132). It is important to (131,132).Itisimportant Arch Metab. Endocrinol 2018;62/1 (B) (B) (129,130).Studies . µ g. In (D)

Arch Metab. Endocrinol 2018;62/1 (PTHrP) produced protein action ofthe PTH-related Incontrast,the normal. for albuminremains corrected calcium isinhibited,but serum PTHsecretion maternal and sensitivity, amongotherfactors.Atthis phase, calcitriol synthesis by increased during pregnancy Calciumabsorptionisfacilitated hypoparathyroidism. themanagementofmaternal and lactationaffect fetus (138,139). womanandthe D and PTH deficiencies inpregnant intheconsequencesofvitamin differences prominent mineral metabolism.First,wemustcallattentionto and tissues(includingbone),challengeadaptationsin building blocksforthedevelopmentoffetalorgans andthedemandfor with anendocrinemachinery) oftheplacenta(which isequipped such asthepresence pregnancy, transientfactors bycardinal determined during The uniquephysiologicalenvironment 10.  (113,137). hasbeenapproved thedrug use intheUSA,where their aspotentialindicatorsofbenefit from considered in mostpatients.However, somesituationshavebeen suspended calcium andvitaminDhasnotbeenentirely andthesupplementationwith no studiesinchildren, sofar,complications hasnotbeenproven are there the emergence ofchronic in preventing their efficacy in Brazilyet(untilNovember2017).Additionally, expensive,andhavenotbeenapproved very injection, are by theseagentsmustbeadministered considered: butseverallimitingaspectsmustbe is promising, radial bonemineraldensity(BMD)in33% in calcium, but a decrease and maintenance of serum calcium inurinary wasareduction dose titration.There and cols.with33patientsfollowedupforsixyears A studywithlongerdurationwaspublishedbyRubin with2%intheplacebogroup compared their dosesofcalciumandvitaminDafter24weeks term term complicationsinthelong chronic in preventing far, isnoevidenceshowingtheireffectiveness there inspecificcases. As hypoparathyroidism to treat Highlights SBEM: Physiological adaptations during pregnancy Physiological adaptationsduringpregnancy hypoparathyroidism The useofPTHanalogstotreat during pregnancy andlactation? How shouldhypoparathyroidismbemanaged (D) . PTHanaloguesmaybeused (B) (A) (124). (136).

secondary hyperparathyroidism with devastating effects withdevastatingeffects hyperparathyroidism secondary leadstofetal hypoparathyroidism with poorlycontrolled women bone development. Hypocalcemia in pregnant labor),andimpairingfetal andpremature stillbirth, (spontaneousabortion, survival the maternal/neonatal an advisablealternative. foralbuminis oftotalcalciumcorrected determination (140).Inthiscontext, the leading to inaccurateresults protocols, rigid but often neglected pre-analytical sensitive andrequires ionizedcalciumisvery to measure 2-3 weeks. However, the technique every be measured parameterandshould control calcium isthepreferred totalcalcium.Duetothat,ionized and circulating albumin levels of hemodilution on serum is the effect duringpregnancy management ofhypoparathyroidism the skeletonduringlactation(138,139). glandtendstomobilizecalciumfrom by themammary third gestationaltrimester third to2,0003,200mginthe beginning ofpregnancy 800to1,500mgatthe elemental calciumvariesfrom oral calcitriol toavoidhypocalcemia. Incasereports, of therequirement in thelasttrimesterincreases demand ofcalciumforskeletalmineralization increased of calciumandcalcitriolinclinicalpractice.Indeed,the However, the doses is usually no need to reduce there a potentialneedforloweringthemedicationdose. 1,25(OH) (placental) of source ofan alternate The occurrence dosesofD pharmacological α necessary whilemedication tapering usually becomes resorption, bone and increased ofPTHrPbythe breast production calciumlevelsmustbecloselyverified duetothe serum range.Duringlactation, maintained inthelowernormal calciumlevelsmustbe total calcium.Circulating levelsofalbumin-corrected assess symptomsandserum to necessary evaluationsare therapies (2).Frequent studiescomparing optional randomized controlled without andmostlybasedoncasereports is scarce andlactation duringpregnancy hypoparathyroidism (C) hyperphosphatemia is an additional worsening factor Inthiscase,concomitant maternal and fractures. asbonedemineralization on fetalbone,expressed - calcidiol) are preferable, butwhenunavailable, preferable, calcidiol) are Hypoparathyroidism is a risky condition affecting isariskyconditionaffecting Hypoparathyroidism considerationinthe Another important Activated vitaminDanalogs(calcitriolor1 aboutthemanagementof The literature (138,139). (C) 2 D and PTHrP during pregnancy indicate D andPTHrP during pregnancy (141). Diagnosis andtreatment ofhypoparathyroidism (C) 2 (142,143). orD 3 maybeused. 117

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 118 associatedwith calcium levels were higher serum Mitchell andcols.inpatients withhypoparathyroidism, Inastudy by andnephrocalcinosis. nephrolithiasis to andpredisposing product calcium-phosphorus intensifying thehyperphosphatemia andincreased theintestinalabsorptionofphosphorus, to increasing in addition vitamin D (calcitriol) leads to hypercalciuria, Treatment withlarge amountsofcalciumandactive metabolism calcium andphosphorus of and hyperphosphatemiaduetolostregulation manifestations Renal 11.1 rare. condition are complications of this disease, data on the long-term aneglected remained many years hypoparathyroidism severity comorbidities of varying and theimplementedtherapyincludeclinical ofthedisease associatedwiththeprogression are 11.  COMPLICATIONS (138,139). metabolism inthissingularperiodofawoman’slife byKovacsandcols.aboutmineral insightful articles andskeletalabnormalities. hyperparathyroidism hypocalcemiamayleadtofetalsecondary maternal hypocalcemia mustbeassessed.Ontheotherhand, neonatal fetal PTH secretion, suppresses which in turn inhypercalcemia, results overtreatment When maternal duringpregnancy. hypoparathyroidism of maternal pregnancy. themedicationdoseusedbefore resumes Afterweaning,thewomanusually avoid hypercalcemia. to lactation, thedosehastobeindividuallyreduced of calcitriolisbetween0.25-3µg.Atthebeginning Diagnosis andtreatment ofhypoparathyroidism which mustbeindividualized fordoseadjustment, control frequent andmore care special andlactationrequires ism duringpregnancy Highlights SBEM: Renal complications arise from chronic hypocalcemia chronic Renal complicationsarisefrom complications of hypoparathyroidism The chronic the toreview The authorsencouragethereaders Pediatricians mustbeadvisedaboutthemanagement During pregnancy, dose thedailyrecommended monitored? hypoparathyroidism? Howshouldtheybe What arethechroniccomplicationsof Treatment ofhypoparathyroid (C) (D) . (22). Since for (D) (144). - recommended every six months. The 24-hour urinary sixmonths.The24-hoururinary every recommended are creatinine calciumandserum ofurinary measurement impairment, renal canprevent measures prophylactic (117). disorder withthis affected inchildren atbirth present already (34,27)andare the etiologyofhypoparathyroidism (24). Renal manifestations occur independently from 3.3 mg/kg/day) higher (around complications were withrenal thelevelsingroup most ofthecohort, rangein withinthenormal calciumwere of urinary was 25%; although the levels with hypoparathyroidism complicationsinpatients ofrenal cols., theprevalence hypercalcemia oftime withrelative disease duration,andproportion in 52%ofthepatientsandwasassociatedwithage, in 31% of thepatients.Renalfunctionwasdecreased observed were while lithiasisandnephrocalcinosis of38%, calciumvalues,prevalence higher urinary recommended, despite the lack of studies confirming despitethe lackofstudiesconfirming recommended, are Annual clinicalmonitoring and metaboliccontrol withthegeneralpopulation compared riskandearlieronset of cataractwhen fold increased haveafour-with nonsurgical hypoparathyroidism manifestations Ocular 11.3 hasbeenrecommended. routine andnoestablished should beindividuallymonitored, general population withthe compared nonsurgical hypoparathyroidism inpatientswith frequent more were and disease,stroke, ischemicheart was notincreased, inthesecohorts Although thegeneralmortality complications. ofcardiovascular the occurrence haveaddressed and postsurgical hypoparathyroidism in patientswithnonsurgical hypoparathyroidism manifestations Cardiovascular 11.2 evaluations includeperiodic imaging consensus recommendations andAmerican manifestations,bothEuropean of renal However,the literature. basedonthehighprevalence in notsupported tractare of thekidneyandurinary 4 mg/kg/d (20,110). Periodic imaging evaluations for gender (below 300 mg/day) (21,109) or below range calcium shouldbemaintainedwithinthenormal Although it is unclear in the literature whether Although itisunclearintheliterature Epidemiological studieshave shownthatpatients cohorts Two studieswithhistoricalandcontrolled (D) (A) (2,20). (116).InastudybyLopesand (A) (34). These complications Arch Metab. Endocrinol 2018;62/1 (A) (145). Arch Metab. Endocrinol 2018;62/1 rate, whichindicatesadeep a lowerbone resorption and boneformation, number andspacing,decreased and width,withthemaintenance ofthetrabecular trabecular volume showsincreased Histomorphometry evidence ofchanges in bone strength porosity, cortical volume anddecreased without andtrabecular cortical tomography showsincreased in BMD.Peripheral quantitative computed increase boneandaconsequent in bothtrabecularandcortical manifestations Musculoskeletal 11.5 studies between showdiscrepancies with PTH replacement these manifestations isunabletoprevent ofhypoparathyroidism treatment and atendencytodepression higher risk of hospitalization due to psychiatric diseases isa there (147). Innonsurgical hypoparathyroidism, associatedwithafeelingofpoor health and are inpostsurgical hypoparathyroidism twice asfrequent life quality of associatedwithdecreased or anxietyare and/ concentration), anddepression fog” anddifficult cognitive symptoms (“brain myalgia, and ), , muscle strength, (muscle spasms,decreased hypoparathyroidism 32%to 65% ofthepatientswith of lifeaffects quality thatdecreased studiesreport undervalued, associated withamultifactorialetiology. Although and is complication of hypoparathyroidism chronic investigation ofallpatientswithepilepsy duringtheetiological calciumisrecommended of serum hospitalization riskof andassociatedwithagreater is frequent ofseizures theoccurrence of thehypoparathyroidism, hypocalcemia associatedwiththedurationof to 74%andare 12% from inprevalence calcificationsvary Cerebral qualityoflife(146). anddecreased depression, seizures, threshold, calcifications, decreased systemandincludecerebral thecentralnervous affect manifestations Neuropsychiatric 11.4 hypoparathyroidism assessment in patients with an advantage of routine The absence of PTH leads to decreased remodeling remodeling The absence of PTHleadsto decreased qualityoflifeisacommonandimportant Decreased complicationsofhypoparathyroidism Chronic (D) (B) (22). Depression and affective disorders are are disorders andaffective (22). Depression (148,149). (A) (A) (103). Regardless oftheetiology (103).Regardless (34,145). Therefore, determination determination (34,145).Therefore, (D) (A) (B) (34,103).Physicalcomplaints (2). (18), and results obtained (18),andresults (A) (145).Traditional (D) (A) . (150). (A)

to increase with the durationof the disease (155). to increase notingthattheBMDtends with hypoparathyroidism, follow-up of patients little value during long-term (DXA)has using dual-energy X-rayabsorptiometry by otherauthors(154).Monitoringofbonemass hypoparathyroidism inwomenwithpostsurgical morphometric fractures hasshownincreased fractures assessment ofvertebral studywithradiological (34,145). Apioneerprospective populations described ascomparabletothatincontrol ingeneral,has been (34,145). The riskoffractures, innonsurgical hypoparathyroidism the forearm of riskoffracture andincreased hypoparathyroidism inpostsurgical humerus oftheproximal of fracture ofthesuperiorlimbs,showingalowerrisk fractures results concerning studies haveshownconflicting (A) rateinhypoparathyroidism inboneturnover reduction important factor in preventing hypoparathyroidism. factorin preventing important in placeisthe most maintenance ofintactparathyroids asurgical pointofview, isplanned.From procedures the andtheextentofthese recommended, surgeries are and parathyroid when thyroid always be considered should the riskofpostsurgical hypoparathyroidism and,therefore, oftheparathyroids the surgical resection is The mostcommonetiologyofhypoparathyroidism for its ideal management. potential recommendations thisconditionrestricts ofdataregarding scarcity isaneglecteddisease,andthe Hypoparathyroidism CONCLUSIONS inpatientsat risk. the spineisrecommended periodicradiologic monitoringof hypoparathyroidism, inpatientswith fractures morphometric vertebral of findingsof ahigherprevalence the recent With individualized and shouldbe of suchcomplicationsisrecommended risk cardiovascular creased andin fractures, changes inqualityoflife,vertebral manifestations, calcifications, cognitiveandaffective ,cerebral insufficiency), lithiasis, andrenal nephro nephrocalcinosis, festations (hypercalciuria, mani andincluderenal the diseaseanditstreatment, of associatedwiththeprogression are parathyroidism Highlights SBEM: (151,152). Retrospective epidemiological (151,152).Retrospective (D) Diagnosis andtreatment ofhypoparathyroidism . Chronic complicationsofhypo Chronic (B) (153), a finding confirmed (153),afindingconfirmed (A) . Periodicmonitoring (A) 119 - - - -

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 120 3. 2. 1. REFERENCES and Mantecorp-Farmasa. Sanofi, Aché,Shire, speaker and consulting fees from received has andAché.M.Lazaretti-Castro Shire and consultingfeesfrom speaker hasreceived B.Ferraz-de-Souza nothing todisclosure. F.disclosure. R.O.S.has L.M.hasnothingtodisclosure. F.A. dePaulahasnothingtodisclosure. A.B.V. hasnothingto F. Aché andShire. consultingfeesfrom Borges hasreceived J. L. F. Sanofi.J.L.C. consultingfeesfrom deFarias hasreceived M. and Shire. Sanofi, Mantecorp-Farmasa, consulting fees from Sanofi,andShire. Mantecorp-Farmasa, received F. Bandeirahas V.tant forShire. consultingfeesfrom Z.C.Borbahasreceived isaconsul C.A.Moreira andShire. 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