Copyright© AE&M all rights reserved. 566 development of IASisunknown.Thispaper describes The mechanismbywhich these radicalsleadtothe (4,6). including captopril, methimazole, and tiopronin radicals (5), withsulfhydryl exposed todrugs were contributes tohypoglycemia (4). causes hypoglycemia. Dissociation ofantibodiesalso insulin binding capacityisexceeded,andunboundfree Eventually,stimulation ofinsulinsecretion. antibody- ininitial hyperglycemia andfurther resulting proinsulin, bindtoinsulinand anddrugs byviruses triggered and anti-insulinantibodies.Anti-insulinantibodies insulin, hypoglycemia, highlevelsof immunoreactive (2,3). Itischaracterizedbyspontaneouspostprandial countrieshavebeendescribed few casesinwestern and in Japanese and Koreans, have been reported described in1970byHirataandcols.(1).Mostcases I INTRODUCTION [email protected] [email protected] 60430-370 –Fortaleza, CE,Brasil Rua CoronelNunesdeMelo,1000 Ana Rosa PintoQuidute Correspondence to: do Ceará(UFC),Fortaleza, CE,Brasil Farmacologia, Universidade Federal deFisiologiae Departamento (NPDM), Faculdade deMedicina, Desenvolvimento deMedicamentos 4 (Unifor), Fortaleza, CE,Brasil Universidade deFortaleza 3 (UFC), Fortaleza, CE,Brasil Universidade Federal doCear Medicina, Faculdade deMedicina, de (NPDM), Departamento Desenvolvimento deMedicamentos 2 Ceará (UFC),Fortaleza, CE,Brasil Medicina, Universidade Federal do Walter Cantídio–Faculdade de UniversitDiabetes, Hospital 1 case report DOI: 10.20945/2359-3997000000078 on Aug/2/2018Accepted Received onFeb/27/2018 NúcleodePesquisa e Faculdade deMedicina, NúcleodePesquisa e Servi In a Japanese cohort of197patientswithIAS,43% In aJapanesecohort disease, is a rare hypoglycemic disorder first hypoglycemicdisorder disease, isarare (IAS), or Hirata’s nsulin autoimmune syndrome ço deEndocrinologiae ário á

Insulin autoimmune syndrome in invasive surgicalprocedures. clinical suspicionofIAS canavoid unnecessarycostsassociatedwithimagingexaminationsand/or Patients withsuspectedIAS mustbescreenedforautoimmunity-related drugsforinsulin.Initial should beconsideredinthedifferential diagnosisofendogenoushyperinsulinemic hypoglycemia. observed followedbyimprovement inepisodesofhypoglycemia. Although itisararedisease,IAS In ourcase,after discontinuation ofcaptopril,aninitialdecreaseininsulinautoantibodylevelswas corticosteroids, plasmapheresis, andrituximabhavealreadybeenusedtotreatpatientswithIAS. been induced by captopril. Most cases of IAS are self-limiting. However, dietary management, and exclusionofothercauses,herhyperinsulinemic hypoglycemia was consideredto havelikely female Brazilian patient with a history of postprandial hypoglycemia. After investigation extensive use ofdrugscontainingsulfhydryl radicals,such ascaptopril. This report toa63-year-old refers Japan, withfewcasesreported inwesterncountries. As apossiblecause,itisassociatedwiththe anti-insulin antibodyresults. Thus far, mostcaseshavebeenreported in Asian countries,notably by spontaneoushypoglycemia associatedwithextremelyhighcirculating insulinlevelsandpositive Insulin autoimmunesyndrome(IAS, Hirata’s disease)isararehypoglycemic disordercharacterized SUMMARY Renan MagalhãesMontenegro Junior Eveline GadelhaPereira Fontenele ZaidenRezendeReis Mariella report andliterature review an occidental woman: acase Arch EndocrinolMetab. 2018;62(5):566-70 mellitus or other endocrinopathies, such as insulinoma, mellitus orother endocrinopathies,suchas insulinoma, useof captopril50mg/day.regular and five yearsago,obesityand metabolicsyndrome, diagnosed systemichypertension Comorbidities were months. inthepastthree frequency with increased sugar intake.Theseepisodesbeganfiveyearsago after andsleepiness,which improved blurring, sweating, shakiness and nausea, dizziness, visual a week,withthefollowingsymptoms:palpitation, times three hours afterbreakfast, three approximately bloodglucoseof47mg/dL), capillary (registered episodesofpostprandialhypoglycemia of recurrent A 63yearoldfemaleBrazilianpatientcomplained CASE REPORT medicine inourfield. antihypertensive of captopril,themostprescribed a caseofIASinSouthAmericanpatientafteruse 1 , Virgínia Oliveira Fernandes There was no personal or family history of diabetes ofdiabetes wasnopersonalorfamilyhistory There 1,2 , Ana Paula Abreu Sales Martins 1 , Ana RosaPinto Quidute Arch Metab. Endocrinol 2018;62/5 1 ,

1,4 1,3 ,

Arch Metab. Endocrinol 2018;62/5 Table 1. 1). glucose valuefoundwas48mg/dL(Figure andsleepiness.Thelowest dizziness, visualblurring, symptoms: withneuroglycopenic concordant were and hours after breakfast) postprandial period (three inthelate hours. Episodesofhypoglycemiaoccurred Minneapolis, USA)todetecthypoglycemiawithin72 RealTime System (CGMS)(Guardian monitoring using the Continuous Glucose Monitoring negative. for viralhepatitis,andotherautoimmunediseaseswere serology electrophoresis, nuclear factor, protein serum for anti- outoralhypoglycemicuse.Screening ruled lesions. Anamnesisanddetailedclinical investigation or extra-pancreatic imaging showed no pancreatic ultrasonography andabdominalmagneticresonance <5U/mL)(Tablenon-reactive 1).Endoscopic high levelsofanti-insulinantibodies(294.8U/mL; with hyperinsulinemic hypoglycemiawasobserved fastingtest.After62hoursoffasting, for aprolonged 7.1 ng/mL),respectively. Ourpatientwashospitalized range: 2.6–24.9 range: 65 – 99 mg/dL), 620.9 91mg/dL(reference and C-peptidelevelswere insulin, Initial bloodglucose(8-hourfast),serum of 107cm,andabsenceacanthosisnigricans. lifestyle, BMIof32.2kg/m and fats,withlowfiberintake.Shehadasedentary high consumptionoffoodsrichinsimplecarbohydrates revealed recall orexogenousinsulin.Dietary sulfonylureas suchas useoforalhypoglycemicdrugs or previous ** Resultsobtainedafter suspensionofcaptopril. 2016withsignificantimprovementin thesymptomsofhypoglycemia. ItwasdiscontinuedinFebruary * Resultsobtainedintheprolongedfastingtest (62 hours)afterepisodeofhypoglycemiaaccompaniedbyneuroglycopenic symptoms. Anti-GAD antibody: anti-glutamicaciddecarboxylaseantibody;LDL: low-density lipoprotein;HDL: high-densitylipoprotein;ELISA: enzyme-linkedimmunosorbent assay. Triglycerides HDL LDL Total cholesterol Serum anti-GADantibody Serum anti-insulinantibody Hemoglobin A1c Serum C-peptide Serum pro-insulin Serum insulin Fasting bloodglucose Parameter The patient underwent continuousglucose The patientunderwent inTable presented are results 1. Laboratory Clinical and laboratory resultsduringinitialandsubsequentvisits Clinical andlaboratory µ IU/mL), and3.65ng/mL(0.9– September 25, 2015 123.2 620.9 2 3.65 184 211 91 51 , abdominal circumference , abdominalcircumference - - - - µ IU/mL (reference IU/mL (reference November 6,November 2015* ® ; Medtronic, ; Medtronic, 294.8 246.5 28.2 2.1 2.6 58 - - - - - September 20, 2016** level of5.6%(Table 1). workupshowedanHbA1c was 276mg/dL.Further found tobe110mg/dL,and2-hourglucoseoverload fastingglycemialevelwas (OGTT) wasperformed; mg/dL). A2-hour75gramoralglucosetolerancetest sporadichighglucoselevels(>200 test alsorevealed without symptoms. The hours after breakfast three 2),andthelowestglucosevaluewas66mg/dL (Figure (Table oncepermonth. 1)toapproximately ofhypoglycemicsymptoms frequency reduced of anti-insulinantibodies(100.0U/mL)andreported levels adeclineincirculating the patientpresented and captoprilwasdiscontinued.Sixmonthslater, use, thediagnostichypothesisofIASwasproposed captopril coincidingwithstarting clinical presentation hyperinsulinemia, latepostprandialhypoglycemia,and DQB1*0303 haplotypes. DRB1*0701, DRB1*0901P, DQB1*0202,and for HLA classIItestandobtainedpositiveresults carbohydrates withcomplexones. replacement of simple reduced lipids,and fiber intake, planof1800kcal/day,evaluation anddietary increased nutritional forprofessional The patientwasalsoreferred hypoglycemia, nordidworseningoftheclinicalpicture. inepisodesof anincrease patient didnotpresent in anothercaseofIAS(8).Atsubsequentvisits,the at thedoseof1000mg/day, described aspreviously metformin (7),itwasdecidedtoprescribe syndrome Due to this development and presence of metabolic Due tothisdevelopmentandpresence a new CGMS examination The patient underwent Given highlevelsofanti-insulinantibodies, In due course, we performed high-resolution high-resolution In duecourse,weperformed > 300 164 150 230 100 5.6 47 97 - - - Non-reactive <10IU/mL Non-reactive <5IU/mL Reference Range 2.6–24.9 0.5–3.5 pmol/L 0.9–7.1 ng/mL 65–99 mg/dL < 150mg/dL < 130mg/dL < 200mg/dL < 50mg/dL 4.1–5.7% µ IU/mL Insulin autoimmune syndrome Electrochemiluminescence Enzymatic Colorimetric Chemiluminescence Friedewald Formula GPO - TrinderGPO Hexokinase Enzymatic Methods ELISA ELISA ELISA HPLC 567

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 568 year oldchild withHLADRB1*1104haplotype, thus Brazil, Alvesandcols.(9) described acaseofseven other caseswithpositivity forthesehaplotypes.In and DQB1*0303.We have notfoundintheliterature positive forDRB1*0701,DRB1*0901P, DQB1*0202, DQA1*0301, andDQB1*0302 (2,13).Ourpatientwas associatedwithHLADR4,DRB1*0406, cases are thaninCaucasians(12).Most Japanese andKoreans in prevalent 10-30timesmore II alleles,whichare > 40years(11). inpatientsaged frequent indiscriminately butismore menandwomen inBrazil(8-10).Itaffects reported in 1970(1).To case ourknowledge,this is thefourth hypoglycemia andwasfirstdescribedbyHiratacols. IAS isanuncommonetiologyofspontaneous DISCUSSION of captopril, forthreeconsecutivedays, 24hoursperday. The dottedlinerepresentstheaverageglucoselevelforthreedays. Figure 2. Insulin autoimmune syndrome 24 hperday. The dottedlinerepresentstheaverageglucoselevelforthreedays. Figure 1. Susceptibility to IAS is related to specific HLA class Susceptibility to IAS is related Follow-up continuousglucosemonitoringusingtheContinuousGlucoseMonitoringSystem: Dataobtainedafter13monthsofdiscontinuation Initial continuousglucosemonitoringusingtheContinuousGlucoseMonitoringSystem: Dataofglucoseexcursionsonthreeconsecutivedays, of insulin to its receptors intheliverandperipheral of insulinto its receptors theavailability glycemia. Thisbindingreduces increased to insulininresponse antibodies bindtosecreted mechanism ofinsulinaction. Afterameal,anti-insulin antibody complexes, which hinder the physiological ofinsulin- seem tobeassociatedwith theformation notfullyunderstood.They development ofIASare foranti-insulinantibodies. positive results late postprandialhypoglycemia,highinsulinlevels,and hypoglycemia; however, itisclassicallycharacterizedby countries. western in patientsfrom studiestounderstandthedisease to theneedforfurther thought, leading than previously heterogeneous more and ofIASseemstobebroader the geneticspectrum Suchdatasuggestthat tothesyndrome. far unrelated The pathogenicmechanismsthatleadtothe IAS may occur with fastingorexacerbated exercise Arch Metab. Endocrinol 2018;62/5 140 60 70 140 60 70 Arch Metab. Endocrinol 2018;62/5 enhances sensitivity fortheidentification ofinsulin (GFC) with addition ofexogenous insulin antibody complexes asgel filtration chromatography for insulin- must be used withcautioninscreening withpolyethyleneglycol(PEG) immunoprecipitation andcols.demonstratedthat Church clinical disorders. to cause withbioactivityofthehormones also interfere byimmunoassayandmay ofhormones measurement complexes) mayposeasignificantchallengetothe diagnosis. anti-insulin antibodies,IASseemstobethemostlikely showedhighlevelsofinsulinand results and laboratory acanthosisnigricans, that ourpatientdidnotpresent considering negative(4,15).Therefore, antibodies are anti-insulin usuallypositivewhereas antibodies are insulin hypoglycemia. Inthese cases, anti-receptor resistance andparadoxical in significant insulin resulting of antibodies against the insulin receptor diagnosis.Itiscausedbytheagonisticeffect differential ofthe typeB)isalso part disease (insulinresistance diagnosis for our patient. Autoimmune insulin receptor because it was an unlikely plasma sulfonylureas inourcase.We antibodies observed didnotmeasure which wouldnotjustifythehighlevelsofanti-insulin tumors, outinsulinomaorotherextrapancreatic rule to and endoscopicultrasonographyofthepancreas oftheIgAanti-insulin forinsulin(4,14). affinity weak duetothe relatively available tobinditsreceptor mechanism isdelayedclearanceofinsulin,whichstill lowC-peptide levels. A plausible levels and relatively hypoglycemia associated with high plasma insulin capacity, capableofcausing paraprotein, low-affinity of ahigh- mechanism behindIASisthe presence availability.the insulin,increasing Anotherpossible of hypoglycemiawhentheantibodiesdissociatedfrom endogenous insulin,withsubsequentlateoccurrence period, explainedbytheantibodiesthatboundto hyperglycemia atthebeginningofpostprandial with IAS, wecouldinferthatourpatientpresented with the kinetics of the insulin-antibody complex in postprandial hypoglycemiaoccurs(4,12).Consistent highforglycemia. Thus,late disproportionately insulinconcentrations infree whichresults is released, in bloodglucose,theinsulinboundtoantibodies toanti-insulinlevels.Parallelthedecrease according isdose-dependent of insulin.Thehyperglycemic effect tissues causinghyperglycemia andadditionalsecretion Insulin-immunoglobulin complexes(macro- Initially, imaging magnetic resonance weperformed (Figure 1).Onceweraisedthediagnostichypothesis (Figure detected latepostprandialhypoglycemiainourpatient ofhypertension. use fortreatment prior insulinuse.Theonlypositivefindingwascaptopril of evidence ofotherdiseasesnordidshehaveahistory anyclinicalorlaboratory patient didnotpresent inIAS(4,6,18).Our topotentiallyresult reported penicillin G, imipenem, glutathione, methionine,mercaptans, methimazole, captopril,D-penicillamine,hydralazine, radicals,forexample containing sulfur/sulfhydryl those use ofmedications(5,6,12,17).Amongdrugs, toexogenousinsulin,and exposure diseases, previous diseases (mainlyGraves’Disease),rheumatologic antibodies. andwedidnottestheterophile interference, analytical not considerthepossibilityoflaboratory thatwedid immunocomplexes (16).Itisnoteworthy glucocorticoids, immunosuppressants, andeven immunosuppressants, glucocorticoids, cases, orprolonged severe episodes (11,12).Inmore hypoglycemic orprevent have alsobeenusedtoreduce blood glucose levels (18). Alpha-glucosidase inhibitors absorbed carbohydratesto avoidrapidelevationof ofrapidly- mealsandreduction small, frequent stopping useofthemedication(6). ofthediseasesoonafter IAS can achieve remission (18).Mostpatientswithdrug-induced presentations severe mild,transient,tovery of IAShavevariedfrom in thesepatients common diagnosis ofIAS,andhighHbA1c levels are outa diabetesdonotrule glucose toleranceandovert Impaired contributingtotheclinicalpicture. syndrome insulin antibodylevels.Ourpatienthadmetabolic- evidentwiththefall intheanti- could becomemore which the concomitantpossibilityofinsulinresistance, glucose level:276mg/dL),raisingthequestionof mellitus (fastingglucoselevel:110mg/dL;2-hour consistentwiththediagnosisofdiabetes were results OGTT, and CGMS. Thesefindingsledustoperform theday,throughout whichwasnotseenintheinitial hyperglycemia withvalues>200mg/dL observed 2.Inthefollow-upCGMS, wealso shown inFigure of hypoglycemic episodes, as in the frequency decrease witha intheclinicalpicture improvement reported (captopril) wassuspended.Sixmonthslater, thepatient radical of IAS,themedicationcontainingsulfhydryl Consistent withthepathophysiologyofIAS,wehave associatedwithotherautoimmune IAS isfrequently Nutritional management is recommended with Nutritional managementisrecommended cases clinicalmanifestations,reported Regarding α -lipoic acid, and diltiazem, have been 4 . Insulin autoimmune syndrome 569

Copyright© AE&M all rights reserved. Copyright© AE&M all rights reserved. 570 was reported. relevant tothis article nopotential conflictofinterest Disclosure: -for-profit sector. ornot anyfunding agencyinthepublic,commercial, grant from anyspecific didnot receive Funding statement: this research thefinalmanuscript. andapproved nagement. Allauthorsread wasinvolved inclinicalma diagnostic examinations.APAbreu andRMMJunior contributedtothe al content.VOFernandes themanuscript forintellectu and RMMJuniorcriticallyrevised review.Reis conductedliterature ARPQuidute,EGP Fontenele ofthepatient.ARPQuidute,EGPFontenele andMZR care andwasthenamedphysicianinvolvedin cussion ofthearticle ARPQuidutecontributedtothewritinganddis te thearticle. Acknowledgements and thepatient. from consenthasbeenobtained Patient consent:writteninformed treatment. understanding ofthediseaseandtoimprove neededtoimprove longitudinalstudiesare Long-term forinsulin. drugs forautoimmunity-related be screened andpatientsmust and/or invasivesurgical procedures, expensesinvolvingimagingexaminations unnecessary understood. InitialclinicalsuspicionofIAScanavoid disease whose pathophysiology is still poorly a rare diagnosis of hyperinsulinemic hypoglycemia. It is useinourpatient. which supported (8), male patientwithsuspectedIASgoodresults inthefollow-upofa55yearoldBrazilian metformin the useof Paivaandcols.reported of metformin. weinitiated theuse concomitant insulinresistance, thepossibilityof discussed,toreduce As previously suspension ofthemedicationcaptopril,aknowntrigger. management,and changes withnutritionaldietary weoptedforlifestyle- hemodynamic repercussions, hypoglycemia and without severe with infrequent (11,12). forIAS treatments described asthe most effective were amounts ofcarbohydratesandcorticosteroids mealscontainingreduced in themedicalliterature, andazathioprinetherapy(19).Finally,prednisolone to in a patient with IAS refractory effective reported followed bytwodosesof1grituximabhasbeen againsthumanimmunoglobulin antigens directed adsorbersystemloadedwithsheep using areusable (15).Immunoadsorption diazoxide, andoctreotide includepancreatectomy, alternatives Other reported maybeusefulasadjuvanttherapy(3,15). plasmapheresis Insulin autoimmune syndrome In conclusion, IAS is part of the differential ofthedifferential In conclusion,IASispart Because ourpatienthadamildcondition

author contributions: MZR Reiswro - - - - - 8. 7. 6. 5. 4. 3. 2. 1. REFERENCES 19. 18. 7. 1 16. 15. 14. 13. 12. 11. 10. 9.

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