Autoimmune polyendocrinopathy and hypophysitis after Puumala hantavirus infection

This wo k is licensed unde a C ea i e Commons A ibu ion-NonComme cial-NoDe i s 3.0 Unpo ed License. © 2016 The au ho s h p://www.edmcase epo s.com Published by Bioscien i ica L d Puumala han a i us and polyendoc inopa hy M Ta ainen and o he s Au oimmune polyendoc inopa hy and hypophysi is a e Puumala han a i us in ec ion Ma leneTa ainen1, Sa uMäkelä1,2, JukkaMus onen1,2 and PiaJaa inen1,2,3 1School o Medicine, Uni e si y o Tampe e, Tampe e, Finland, 2Depa men o In e nal Medicine, Tampe e Uni e si y Hospi al, Tampe e, Finland, and 3Di ision o In e nal Medicine, Seinäjoki Cen al Hospi al, Seinäjoki, Finland Summa y Puumala han a i us (PUUV) in ec ion causes neph opa hia epidemica (NE), a ela i ely mild o m o haemo hagic e e wi h enal synd ome (HFRS). Hypophyseal haemo hage and hypopi ui a ism ha e been desc ibed in case epo s on pa ien s wi h acu e NE. Ch onic hypopi ui a ism diagnosed mon hs o yea s a e he acu e illness has also been epo ed, wi hou any signs o a haemo hagic ae iology. The mechanisms leading o he la e-onse ho monal de ec s emain unknown. He e, we p esen a case o NE-associa ed au oimmune polyendoc inopa hy and hypopi ui a ism p esumably due o au oimmune hypophysi is. Thy oid pe oxidase an ibody se ocon e sion occu ed be ween 6 and 12mon hs, and o a ian as well as glu ama e deca boxylase an ibodies we e ound 18mon hs a e acu e NE. B ain MRI e ealed an a ophic adenohypophysis wi h a he e ogeneous, low signal in ensi y compa ible wi h a sequela o hypophysi is. The pa ien de eloped cen al (o mixed cen al and pe iphe al) hypo hy oidism, hypogonadism and diabe es insipidus, all equi ing ho monal eplacemen he apy. This case epo sugges s ha la e-onse ho monal de ec s a e PUUV in ec ion may de elop by an au oimmune mechanism. This hypo hesis needs o be con i med by p ospec i e s udies wi h su icien numbe s o pa ien s. ID: 16-0084; No embe 2016 DOI: 10.1530/EDM-16-0084 10.1530/EDM-16-0084 ID: 15-0028; XXX 2016 Co espondence should be add essed o P Jaa inen Email [email p o ec ed] Lea ning poin s: •Pi ui a y haemo hage esul ing in hypopi ui a ism has been epo ed du ing acu e HFRS caused by PUUV and o he han a i uses. •Cen al and pe iphe al ho mone de iciencies de eloping mon hs o yea s a e HFRS ha e also been ound, wi h an incidence highe han ha in he gene al popula ion. The pa hogenesis o hese la e-onse ho monal de ec s emains unknown. •This case epo sugges s ha he la e-onse hypopi ui a ism and pe iphe al endoc ine de ec s a e HFRS could e ol e ia au oimmune mechanisms. •The sensi i i y o cu en an i-pi ui a y an ibody (APA) es s is low. A cha ac e is ic clinical cou se, oge he wi h ypical b ain MRI and endoc ine indings may be su icien o a non-in asi e diagnosis o au oimmune hypophysi is, despi e nega i e APAs. Backg ound Han a i uses cause haemo hagic e e wi h enal synd ome (HFRS) in Eu asia and han a i us ca diopulmona y synd ome (HCPS) in he Ame icas (1). Puumala han a i us (PUUV) causes a mild HFRS called neph opa hia epidemica (NE). In Finland, annually 1000–3000 cases o NE a e se ologically diagnosed. The M Ta ainen and o he s Puumala han a i us and polyendoc inopa hy ID: 16-0084; No embe 2016 DOI: 10.1530/EDM-16-0084 h p://www.edmcase epo s.com 2 ypical ea u es o NE a e inc eased capilla y pe meabili y, enal in ol emen and h ombocy openia, he la e a ely causing se ious haemo hages (1). The pa ien s commonly su e om high e e , headache, educed isual acui y, abdominal pain, nausea and backache (1). Hypophyseal haemo hage and panhypopi ui a ism ha e been desc ibed in case epo s on pa ien s wi h NE (2, 3, 4, 5, 6, 7, 8). De ec s o he gonadal and/o hy oid axis ha e been ound in mo e han hal o he pa ien s du ing he acu e phase o NE (9). We ha e also epo ed ch onic hypopi ui a ism in 5 o 54 pa ien s, p ima y hypo hy oidism in 5 pa ien s and ch onic subclinical es icula ailu e in 5 o 37 men du ing a median ollow-up o 5 yea s a e NE (9). Ch onic hypopi ui a ism was also iden i ied in 18% o pa ien s wi h a p e ious HFRS in a e ospec i e Se bian s udy o 60 adul s who had eco e ed om HFRS yea s ago (10). Thus, pa ien s wi h HFRS may be a high isk o de eloping hypopi ui a ism o pe iphe al ho mone de iciencies la e on (8, 9, 10). Howe e , no ob ious la e-onse hypopi ui a ism was diagnosed in a coho o 47 pa ien s e-examined 4–8yea s a e NE in No he n Finland (11). The pa hophysiological mechanisms o hypopi ui a ism de eloping as a la e complica ion o NE emain unclea . We p esen a pa ien who de eloped an au oimmune polyendoc ine synd ome and hypopi ui a ism possibly due o au oimmune hypophysi is six o wel e mon hs a e he acu e NE. We also e iew p e ious case epo s on HFRS-induced hypopi ui a ism. Table1 Basic labo a o y es esul s du ing acu e neph opa hia epidemica and a he 1-mon h ollow-up isi . Pa ame e Lowes le el a hospi al Highes le el a hospi al A discha ge A 1-mon h ollow-up Re e ence ange WBC (109/L) 5.5 45 5.8 6.8 3.4–8.2 Pla ele coun (109/L) 5 207 207 260 150–360 Haemoglobin (g/L) 90 202 97 114 117–155 CRP (mg/L) 8.7 57.4 8.7 <1 0–10 ALT (U/L) 13 35 13 N/A 10–45 C ea inine (µmol/L) 206 891 206 89 50–90 U ea (mmol/L) 12.9 35.2 12.9 N/A 2.6–6.4 Po assium (mmol/L) 3.7 5.1 3.9 N/A 3.3–4.8 Sodium (mmol/L) 121 132 130 N/A 137–144 ALT, alanine ansaminase; CRP, C- eac i e p o ein; N/A, no assessed; WBC, whi e blood cells. Table2 Summa y o he ho monal es esul s du ing acu e NE and a he ollow-up isi s. Va iables (uni s) Acu e NE 1-mon h ollow-up 6-mon h ollow-up 12-mon h ollow-up 24-mon h ollow-up Re e ence ange T4 (pmol/L) 10.7 7.7 7.8 18.1116.7111.0–22.0 TSH (mU/L) 9.1 0.64 4.1 <0.0110.2510.27–4.2 Oes adiol (nmol/L) 1.09 0.04 <0.02 0.1720.172* FSH (U/L) 3.0 2.8 4.1 1.521.72* LH (U/L) 12.2 0.9 1.5 0.821.52* GH (mU/L) 59.4 0.5 0.5 0.3 0.33 0.0–11.0 IGF-1 (nmol/L) 13 17 12 16 9** 12–46 10–37** Co isol (nmol/L) 1284 277 356 253 249** 180–680 170–500** ACTH (ng/L) 12 11 19 20 10 0.0–46.0 PRL (mU/L) 439 366 256 283 240 102–496 TPOAb (kU/L) <5 13 23 85 66 <34 1On le o hy oxine subs i u ion, 2on oes ogen–p oges e one subs i u ion, *oes adiol, FSH and LH alues we e e alua ed acco ding o he phase o he mens ual cycle, **IGF-1 and co isol labo a o y es me hods changed du ing he ollow-up. The new e e ence anges and he alues measu ed wi h he new me hods a e ma ked wi h as e isks (**). M Ta ainen and o he s ID: 16-0084; No embe 2016 DOI: 10.1530/EDM-16-0084 Puumala han a i us and polyendoc inopa hy h p://www.edmcase epo s.com 3 Case p esen a ion A 25-yea -old p e iously heal hy woman p esen ed wi h e e o 39°C, oligu ia and lowe back pain. A p esen a ion, he plasma C- eac i e p o ein (CRP) concen a ion was 39 mg/L and u inalysis e ealed p o einu ia (+++) and haema u ia (++). Pyeloneph i is was suspec ed, and she was admi ed o a wa d in he p ima y heal h ca e cen e. In a enous ce u oxime was s a ed. The pa ien began o su e om nausea, omi ing, and isual dis u bances, and she was ans e ed o Tampe e Uni e si y Hospi al. NE was suspec ed, and a poin -o -ca e an i-PUUV an ibody es (Reascan Puumala IgM, Reagena In e na ional, Toi ala, Finland) was e u ned posi i e. The pa ien was anu ic and hypo ensi e, and i. . luids we e adminis e ed. Du ing he nex ew days, she expe ienced headache and dizziness. Diu esis es a ed on day six a e he onse o e e . The highes daily u ina y ou pu was 3700 mL in he polyu ic phase. The mild headache was cu ed by pa ace amol and he isual dis u bances soon subsided. The pa ien was discha ged 14days a e admission. In es iga ions The diagnosis o NE was e i ied by high le els o speci ic an i-PUUV IgM and IgG an ibodies. O he labo a o y indings (Table1) ypical o NE included se e e h ombocy openia, leukocy osis and ele a ed plasma c ea inine and u ea concen a ions, as well as p o einu ia and haema u ia. On he i s ew days o hospi alisa ion, se um le els o co isol and g ow h ho mone (GH) we e high, and ee hy oxine ( T4) was low (Table2). Ou come and ollow-up The pa ien pa icipa ed in a p ospec i e s udy o he ho monal consequences o NE, and w i en in o med consen was ob ained. A he i s ollow-up isi one mon h a e he acu e illness, he pa ien was sligh ly anaemic, bu o he labo a o y indings we e no mal (Table1). She s ill had a igue and an i egula mens ual cycle. Th ee mon hs a e he NE, he pa ien s a ed o su e om ho lushes, mild headache, sleeping diso de s, oedema and ameno hea. Six mon hs a e he acu e illness, cen al hypo hy oidism and hypogonado ophic hypogonadism we e de ec ed (Table 2). The e we e no symp oms o labo a o y indings compa ible wi h diabe es insipidus (DI). Le o hy oxine and oes ogen– p oges e one eplacemen he apy we e s a ed. B ain magne ic esonance imaging (MRI, 3 Tesla) was pe o med 9mon hs a e he acu e NE and showed an a ophic adenohypophysis wi h a he e ogeneous, low signal in ensi y, compa ible wi h a sequela o hypophysi is (Fig.1). The e we e no signs o haemo hage, umou s o o he abno mal indings on he MRI scan. A he 12-mon h ollow-up isi , he pa ien epo ed cons ipa ion, abno mal hi s , polyu ia and loss o appe i e. The labo a o y es s showed high plasma sodium le el (145 mmol/L). DI was suspec ed, and a he apeu ic ial wi h desmop essin p.o. was commenced. Desmop essin subs i u ion (60 µg b.i.d.) co ec ed he polyu ia and o he symp oms and no malised he plasma sodium concen a ion. Plasma hy oid pe oxidase an ibody (TPOAb) le els we e no mal du ing acu e NE and a one-mon h and six- mon h ollow-up isi s, bu inc eased by he 12-mon h ollow-up isi (Table2). Due o he clinical signs o DI Figu e1 B ain MRI scan (T1-weigh ed) 9mon hs a e he acu e NE, showing an a ophic adenohypophysis (a ow) wi h a he e ogeneous, low signal in ensi y, compa ible wi h a sequela o hypophysi is. (A) Co onal plane. The heigh o he hypophysis is 2mm. (B) Sagi al plane. The pa ien de eloped diabe es insipidus la e on, bu a his poin , he ‘b igh spo ’ is s ill isible in he pos e io pi ui a y. M Ta ainen and o he s Puumala han a i us and polyendoc inopa hy ID: 16-0084; No embe 2016 DOI: 10.1530/EDM-16-0084 h p://www.edmcase epo s.com 4 Table3 Summa y o p e ious case epo s on HRFS- ela ed panhypopi ui a ism. S udy Type o ho monal de iciency Time om HFRS o hypopi ui a ism Radiological o his ological indings (imaging modali y) Follow-up ime Ho monal eco e y ACTH TSH LH/FSH GH* AVP Fo slund e al. (2) x x x N/A – 15yea s Emp y sella (CT) N/A No Se e g en e al. (5) x x x xa,c – 6mo – N/A No Suh e al. (14) x x x xcN/A 3mo Haemo hage, la e a ophy (MRI) 3mo No Pa k and Pyo (15) x x x xcN/A Acu e – N/A N/A Kim e al. (16) x x N/A xcN/A 13yea s – 1mo No Hau ala e al. (3) x x x N/A N/A 5mo Acu e: Enla ged pi ui a y gland, haemo hage 10mo No 10mo: Dec eased pi ui a y gland size and pa ial eso p ion o haemo hage (MRI) x x x – N/A Acu e Acu e: Enla ged pi ui a y gland, haemo hage 2mo No 2mo: Dec eased pi ui a y gland size and pa ial eso p ion o haemo hage (MRI) Sane and Fä kkilä (4) x x x xb– 10mo Dec eased pi ui a y enhancemen (CT) 17mo No Pekic e al. (8) x x x xa,b,c N/A 1.5yea s A ophy, emp y sella (MRI) N/A No x x x xa,b,c N/A 2yea s 1mo No? x x x xbN/A 2yea s 15days No? Jos e al. (6) x x x N/A N/A Acu e Acu e: Enla ged pi ui a y gland 5mo Pa ial** 5mo: No mal (MRI) Sa igüzel e al. (17) x x x xb– Acu e Haemo hage, a ophy (MRI) 16mo No Kaybas e al. (18) x N/A x – N/A Acu e No mal (MRI) N/A N/A ACTH, ad enoco ico opic ho mone; AVP, a ginine asop essin; d, days; FSH, ollicle-s imula ing ho mone; GH, g ow h ho mone; LH, lu einizing ho mone; mo, mon hs; N/A, da a no a ailable; TSH, hy oid-s imula ing ho mone; y, yea s. *GH/IGF-1 axis de iciency was diagnosed by de e mining ase um GH le el, o bse um IGF-1 le el o by conduc ing a cGH axis s imula ion es . **Ad enoco ical and hy oid axis eco e ed, and gonadal axis did no . M Ta ainen and o he s ID: 16-0084; No embe 2016 DOI: 10.1530/EDM-16-0084 Puumala han a i us and polyendoc inopa hy h p://www.edmcase epo s.com 5 and b ain MRI indings, hypophysi is was suspec ed and u he e iological in es iga ions we e scheduled. Se um calcium, angio ensin-con e ing enzyme, lysozyme, an inuclea an ibody (ANA) and IgG4 le els we e no mal. An i-pi ui a y an ibodies (APA) we e measu ed by a line blo and a adioimmuno-p ecipi a ion assay (MVZ Labo a o y D Volkmann and Colleagues, Ka ls uhe, Ge many), and he es s yielded no mal esul s. Glu ama e deca boxylase an ibody (GADAb 892.7 IU/mL, e e ence <10 IU/mL), TPOAb (53 kU/L, e e ence <34 kU/L) and o a ian an ibody (O a Ab i e 10, e e ence <1) es s we e all posi i e. The an i-ad enal an ibody (Ad Ab) i e was no mal (<1). The GADAbs we e measu ed by an enzyme immunoassay (Eu oimmune an i-GAD-ELISA, Luebeck, Ge many), whe eas he O a Abs and he Ad Abs we e measu ed by indi ec immuno luo escence (PhD 1xSys em, Bio-Rad Labo a o ies) on sec ions o p ima e o a y and ad enal gland espec i ely, a he ce i ied Huslab Labo a o ies, Helsinki, Finland. O he measu emen s we e pe o med by he ou ine labo a o y me hods o he ce i ied Fimlab Labo a o ies, Tampe e, Finland. A he la es isi , 2 yea s a e NE, he pa ien was asymp oma ic on desmop essin, l- hy oxine and oes ogen–p oges e one subs i u ion. Despi e he oes ogen subs i u ion, he IGF-1 le el was bo de line low and co isol was in he low no mal ange (Table2). The ollow-up is con inued a he Endoc inology Ou pa ien Clinic. Discussion To ou knowledge, his is he i s case epo ed wi h au oimmune polyendoc inopa hy and hypopi ui a ism de eloping soon a e acu e NE. Ou pa ien s a ed o su e om symp oms sugges i e o ho monal de iciencies h ee mon hs a e he NE. Labo a o y es s e ealed hypopi ui a ism six mon hs a e he discha ge om hospi al. Pa ial DI was diagnosed one yea a e NE. Nine mon hs a e he NE, b ain MRI showed a ophy o he adenohypophysis wi h a he e ogeneous, low signal in ensi y, compa ible wi h a sequela o hypophysi is. Au oan ibodies eme ged du ing he i s 18mon hs a e he NE. The APAs we e nega i e, bu he diagnos ic sensi i i y and speci ici y o APA es s a e known o be low (12, 13). P e iously, only one case epo has been published on NE-associa ed hypophysi is (6). The pa ien had ansien panhypopi ui a ism, equi ing ho monal eplacemen he apy wi h l- hy oxine and hyd oco isone du ing he acu e NE. In con as wi h he p esen case, he ho mone le els soon no malised wi h he esolu ion o he acu e PUUV in ec ion and emained no mal du ing he ollow-up o 5 mon hs. In ha case epo , b ain MRI showed enla gemen o he pi ui a y gland, bu no pi ui a y haemo hage o nec osis and no hypo halamic al e a ions (6). Bo h he clinical cou se and he adiological cha ac e is ics o he p e ious case sugges a di ec e ec o he i al in ec ion, a he han an au oimmune mechanism, causing he ansien pi ui a y de ec . Table 3 summa ises ele en p e ious case epo s (2, 3, 4, 5, 6, 8, 14, 15, 16, 17, 18) wi h 14 well-cha ac e ised cases o HFRS- ela ed panhypopi ui a ism. Fi e pa ien s we e diagnosed wi h hypopi ui a ism equi ing ch onic ho monal eplacemen , s a ing om he acu e phase o HFRS (3, 6, 15, 17, 18). Nine pa ien s de eloped la e-onse panhypopi ui a ism mon hs o yea s a e HFRS (2, 3, 4, 5, 8, 14, 16). A le hal case o hypophyseal haemo hage du ing acu e NE was also epo ed (3). In addi ion o he cases o panhypopi ui a ism ep esen ed in Table3, we ound i e cases o ch onic hypogonado ophic hypogonadism, wo wi h cen al hypo hy oidism and h ee isola ed ones, in he p e ious e ospec i e analysis o 54 NE pa ien s (9). In he e ospec i e se ies o 60 pa ien s wi h p e ious HFRS, he e we e six cases o a single pi ui a y ho mone de ici and i e cases o mul iple pi ui a y ho mone de iciencies espec i ely (10). The pa hophysiology o ch onic ho mone de iciencies a e HFRS is s ill unclea . Vi al in ec ions ha e been linked o he pa hogenesis o se e al au oimmune diseases. Fo example, many i uses such as en e o i uses ha e been associa ed wi h ype 1 diabe es (19). I is possible ha an acu e PUUV in ec ion may a ec he pi ui a y and pe iphe al endoc ine glands, as well as he immune sys em, enhancing he p oduc ion o au oan ibodies agains he endoc ine o gans. In ou pa ien , TPO se ocon e sion appea ed be ween 6 and 12mon hs a e NE. Measu ed 18mon hs a e HFRS, TPO, o a ian and GAD an ibody es s we e all posi i e. Se e al lines o e idence sugges ha p ima y hypophysi is may de elop by an au oimmune mechanism (12, 20). P egnancy and childbi h a e known isk ac o s o hypophysi is. Lymphocy ic hypophysi is is commonly associa ed wi h au oimmune diseases, such as Hashimo o’s hy oidi is, G a es’ disease, Addison’s disease, ype 1 diabe es, a ophic gas i is and Sjög en’s synd ome. Such an associa ion has been epo ed in 25–50% o he cases (12, 20). Hypopi ui a ism is he mos common p esen a ion o au oimmune hypophysi is. The ypical o de o ophic ho mone de iciency has been epo ed as ACTH > TSH > FSH/ LH > PRL > GH (12). Howe e , he ecen epo wi h 76 cases M Ta ainen and o he s Puumala han a i us and polyendoc inopa hy ID: 16-0084; No embe 2016 DOI: 10.1530/EDM-16-0084 h p://www.edmcase epo s.com 6 om Ge many ound hypogonado ophic hypogonadism, he mos equen ho monal de ec in p ima y hypophysi is (13). Ou pa ien i s s a ed o expe ience symp oms sugges i e o hypogonadism, h ee mon hs a e NE. Cen al hypo hy oidism and hypogonado ophic hypogonadism we e diagnosed six mon hs a e he acu e NE, and ho monal subs i u ions we e s a ed. He co isol le els ha e been in he low no mal ange, which is likely o e lec an impai ed co isol p oduc ion, in iew o he oes ogen eplacemen he apy inc easing he co isol- binding globulin concen a ion. A he acu e phase o hypophysi is, a sella mass e ec may de elop, p o oking headache, diplopia and isual ield de ici s. In undibula o pos e io pi ui a y de ec s may cause an idiu e ic ho mone (ADH and asop essin) de iciency and cen al DI, p esen ing wi h polyu ia and polydipsia in 20–48% o pa ien s wi h au oimmune hypophysi is (12). In mos cases o hypophysi is, he le el o PRL is no mal o e en low (21), as in ou pa ien . Du ing he anu ic phase o acu e NE, he pa ien had hypona aemia. Fluid e en ion associa ed wi h acu e kidney inju y was p obably an impo an cause o low sodium concen a ion a ha ime. Ne e heless, hypona aemia migh also be caused by excessi e sec e ion o ADH, i.e. an acu e SIADH. The pa ial DI o he pa ien , diagnosed one yea a e NE, e lec ed a sligh de ec o he hypo halamic-in undibulo- neu ohypophyseal sys em, as he in ense signal o he pos e io pi ui a y was s ill isible on MRI, and he e was no isible pa hology in he in undibulum o he hypo halamus, 3mon hs be o e he diagnosis o DI. The b ain MRI o ou pa ien e ealed an a ophic adenohypophysis wi h a he e ogeneous, low signal in ensi y nine mon hs a e acu e NE. These indings a e compa ible wi h a sequela o hypophysi is (12). Haemo hage may also cause a ophy o he adenohypophysis (13). Howe e , ou pa ien p esen ed no symp oms o clinical indings indica i e o hypophyseal haemo hage ei he du ing acu e NE o du ing he ollow-up. A de ini i e diagnosis o hypophysi is equi es his ological e i ica ion om a biopsy specimen, bu a cha ac e is ic clinical cou se, oge he wi h ypical MRI and ho monal indings ha e been sugges ed o su ice o a non-in asi e diagnosis (12, 13). Dis inc i e adiological ea u es in acu e au oimmune hypophysi is a e symme ic enla gemen o he pi ui a y gland, homogenous pos - gadolinium enhancemen , hickened in undibulum in he midline, loss o pos e io ‘b igh spo ’ on T1 imaging and in ac sella loo (12, 22). A cen al hypoin ensi y, ep esen ing nec osis o cys o ma ion, has been epo ed in up o one- hi d o he pa ien s (13, 21). A la e s ages o hypophysi is, pi ui a y a ophy and emp y sella a e ypical indings on MRI (12). Ci cula ing an i-pi ui a y au oan ibodies (APA) may be de ec ed in au oimmune p ocesses o he pi ui a y gland. The low diagnos ic sensi i i y and speci ici y o p esen APA es s un o una ely limi hei diagnos ic u ili y (12, 20). The p esen pa ien was nega i e o APAs, bu he clinical pic u e and he p esence o se e al o he au oan ibodies make au oimmune hypophysi is a plausible cause o he hypopi ui a ism. A di ec e ec o he PUUV in ec ion, inc eased capilla y pe meabili y o a mino haemo hagic damage a e o he possible mechanisms ha may ha e led o he pi ui a y a ophy and panhypopi ui a ism obse ed. In conclusion, we epo he i s case o NE-associa ed au oimmune polyendoc inopa hy and a possible au oimmune hypophysi is. An au oimmune mechanism could explain he la e-onse hypopi ui a ism ha has been epo ed o de elop mon hs o yea s a e HFRS (8, 9, 10). Au oimmune in lamma ion could also explain he insu iciencies o pe iphe al ho monal glands, which seem o be mo e equen a e NE han in he gene al popula ion (9). The case epo s and e ospec i e coho s published so a call o p ospec i e s udies, o cla i y he epidemiology and he mechanisms o ho monal de iciencies a e NE and o he ypes o HFRS. Decla a ion o in e es The au ho s decla e ha he e is no con lic o in e es ha could be pe cei ed as p ejudicing he impa iali y o he esea ch epo ed. Funding This s udy was inancially suppo ed by he Compe i i e Resea ch Funding o he Special Responsibili y A ea o Tampe e Uni e si y Hospi al (9P031) and he Sig id Jusélius Founda ion. Pa ien consen W i en in o med consen has been ob ained om he pa ien o he publica ion o he submi ed a icle and accompanying images. Au ho con ibu ion s a emen D Ma lene Ta ainen examined he pa ien du ing acu e NE and a he ollow-up isi s and d a ed he manusc ip . D Sa u Mäkelä and P o Pia Jaa inen we e in ol ed in he ea men o he pa ien and con ibu ed o he w i ing o he manusc ip . P o Jukka Mus onen con ibu ed o manusc ip w i ing and edi ing. Acknowledgemen s The au ho s hank Esko Väy ynen, MA, o e ising he language o he manusc ip and D Ma ia Juujä i, D Riikka Mäkelä and D Tapio Seiska i, M Ta ainen and o he s ID: 16-0084; No embe 2016 DOI: 10.1530/EDM-16-0084 Puumala han a i us and polyendoc inopa hy h p://www.edmcase epo s.com 7 Fimlab Labo a o ies, Tampe e Uni e si y Hospi al o a anging he au oan ibody es s. Re e ences 1 Vahe iA, Hen onenH, Vou ilainenL, Mus onenJ, Si onenT & Vapalah iO 2013 Han a i us in ec ions in Eu ope and hei impac on public heal h. Re iews in Medical Vi ology 23 35–49. 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