1 7. s l o v e n s k i e n d o k r i n o l o š k i ko n g re s ZDRUŽENJE ENDOKRINOLOGOV SLOVENIJE ZBORNIK PREDAVANJ IN IZVLEÈKOV PROSTIH TEM SLOVENSKO ZDRAVNIŠKO DRUŠTVO 7 th S l o v e n i a n C o n g re s s o f E n d o c r i n o l o g y SLOVENSKO OSTEOLOŠKO DRUŠTVO BOOK OF PROCEEDINGS AND ABSTRACTS Uredniki: Katica Bajuk Studen, Aleš Skvarča, Katarina Mlekuš Kozamernik Založnik: Združenje endokrinologov Slovenije pri Slovenskem zdravniškem društvu in Slovensko osteološko društvo Oblikovalka: Tjaša Štempihar Naklada: 140 izvodov Tisk: Tiskarna Jagraf Trboje Ljubljana, oktober 2022 7. slovenski endokrinološki kongres z mednarodno udeležbo Zbornik predavanj in izvleèkov prostih tem 7th Slovenian Congress of Endocrinology CIP - Kataložni zapis o publikaciji Book of Proceedings Narodna in univerzitetna knjižnica, Ljubljana and Abstracts 616.43(082) SLOVENSKI endokrinološki kongres z mednarodno udeležbo (7 ; 2022 ; Bled) 7. slovenski endokrinološki kongres z mednarodno udeležbo = 7th Slovenian Congress of Endocrinology : zbornik predavanj in izvlečkov prostih tem = book of proceedings and abstracts : Rikli Balance Hotel Bled, 20.–22. oktober 2022 / [uredniki Katica Bajuk Studen, Aleš Skvarča, Katarina Mlekuš Kozamernik]. - Ljubljana : Združenje endokrinologov Slovenije pri Slovenskem zdravniškem društvu : Slovensko osteološko društvo, 2022 ISBN 978-961-95959-0-9 (Združenje endokrinologov Slovenije pri Slovenskem zdravniškem društvu) Rikli Balance Hotel COBISS.SI-ID 123655171 Bled, 20.–22. oktober 2022 2 3 NAGOVOR GREETING 09 MAHKOTOVO PRIZNANJE MAHKOTA’S AWARD 12 STROKOVNI PROGRAM SCIENTIFIC PROGRAMME 15 PREDAVANJA LECTURES 25 Maša Skelin Klemen, Jan Kopecky, Eva Paradiž Leitgeb, Jasmina Kerčmar, KAZALO 27 Lidija Križančić Bombek, Viljem Pohorec, Ismael Valladolid-Acebes, INDEX Andraž Stožer, Jurij Dolenšek FUNCTIONAL CHANGES IN BETA CELLS DURING DEVELOPMENT AND REMISSION OF TYPE 2 DIABETES Mike Lean 31 WEIGHT LOSS AND TYPE 2 DIABETES REMISSION: LESSONS LEARNED? Tomaž Kocjan 35 ACROMEGALY – THE NUMBERS Mojca Jensterle Sever 39 ACROMEGALY: THE NUMBERS OR THE CHAIR? Jasna Šuput Omladič, Primož Kotnik 43 GENETICS OF SHORT STATURE Primož Kotnik, Sončka Jazbinšek 49 NOVEL TREATMENT OPTIONS IN ACHONDROPLASIA Urh Grošelj 55 GENE THERAPY FOR METABOLIC DISORDERS Matej Rakuša 59 FUNCTIONAL HYPOGONADISM: WEIGHT LOSS OR TESTOSTERONE? WEIGHT LOSS Kristina Groti Antonič 63 FUNCTIONAL HYPOGONADISM – TREATMENT WITH TESTOSTERONE THERAPY 4 5 Vilma Urbančič Rovan 69 Mateja Krajc 147 DIABETIC FOOT SCREENING FROM 1996 TO 2022: PANCREATIC CANCER: RISK FACTORS, RISK ASSESSMENT MESSAGES FROM THE DATA-BASE AND SCREENING OF HIGH-RISK INDIVIDUALS Iztok Štotl 75 Antonela Sabati Rajić 151 SCREENING OPTIMIZATION USING PREDICTIVE MODELS HOW DO WE TREAT MILD AUTONOMOUS CORTISOL SECRETION (MACS)? – SURGICAL TREATMENT Katja Zaletel, Katica Bajuk Studen 81 RADIOIODINE UPTAKE Katarina Mlekuš Kozamernik 155 MILD HYPERCORTISOLISM – CONSERVATIVE MANAGEMENT Edvard Pirnat, Andreja Vendramin 87 RADIOIODINE THERAPY Polona Jaki Mekjavić, Daša Šfiligoj Planjšek 95 RADIOIODINE AND GRAVES’ ORBITOPATHY PROSTE TEME FREE COMMUNICATIONS 162 Simona Gaberšček, Nataša Bedernjak Bajuk 99 USTNE PREDSTAVITVE ORALS 163 RADIOIODINE IN ADOLESCENTS POSTERJI POSTERS 191 Nataša Bratina, Ana Gianini, Jana Suklan, Brigita Skela-Savič, 103 Simona Klemenčič, Tadej Battelino, Klemen Dovč QUALITY OF LIFE IN CHILDREN AND ADOLESCENTS WITH TYPE 1 RAZSTAVLJAVCI EXHIBITORS 254 DIABETES USING ADVANCED HYBRID CLOSED LOOP INSULIN DELIVERY Klemen Dovč 107 MODERN TECHNOLOGIES IN THE TREATMENT OF DIABETES AND PHYSICAL ACTIVITY Draženka Pongrac Barlovič 115 MODERN TECHNOLOGIES DURING PREGNANCY Vesna Šalamun 121 THE ROLE OF GLP-1 IN WOMEN’S REPRODUCTIVE HEALTH Nadan Gregorič 129 THE ROLE OF GLP-1 (AGONISTS) IN MALE REPRODUCTIVE HEALTH Eda Vrtačnik Bokal 135 INFERTILITY WORK UP – INTERDISCIPLINARY APPROACH INCLUDING GYNECOLOGIST AND ENDOCRINOLOGIST Vesna Zadnik 141 EPIDEMIOLOGY OF PANCREATIC CANCER 6 7 NAGOVOR GREETING 8 9 Spoštovane kolegice in spoštovani kolegi, Dear colleagues, drage prijateljice in dragi prijatelji, dear friends, v veliko veselje in čast mi je, da vas lahko v imenu Programsko-it is my great pleasure and honour to invite you on behalf of the Program organizacijskega odbora povabim na 7. slovenski endokrinološki kongres and Organizing Committee to the 7th Slovenian Congress of Endocrinology, z mednarodno udeležbo, ki bo potekal na Bledu med 20. in 22. oktobrom which will take place in Bled between October 20th and 22nd, 2022. I 2022. Veselim se, da se bomo lahko ponovno srečali, izmenjali izkušnje in look forward to meeting you again, exchanging experiences and getting se seznanili z najnovejšimi dognanji na področju odrasle in pediatrične acquainted with the latest findings in the field of adult and paediatric endokrinologije, diabetologije in tirologije. endocrinology, diabetology and thyroidology. Pripravili smo razgiban in aktualen strokovni program. Že uvod v četrtek We have prepared a varied and up-to-date scientific program. The bo udaren in ga nikakor ne smete zamuditi, saj se bomo dotaknili večnega introduction on Thursday will be a hit and should not be missed, as vprašanja o reverzibilnosti sladkorne bolezni tipa 2. V nadaljevanju bomo we will touch upon the eternal question of the reversibility of type 2 analizirali pristop k obravnavi akromegalije, pediatri pa nam bodo predstavili diabetes. In the following, we will analyze the approach to the acromegaly obete genskega zdravljenja. Petkov strokovni program prinaša obravnavo treatment, and paediatricians will present the prospects of gene therapy. funkcionalnega hipogonadizma in reproduktivne endokrinologije, prikaz Friday’s scientific program brings a discussion of functional hypogonadism, napredka v presejanju na diabetično nogo, osvetlitev 80 let zdravljenja z reproductive endocrinology and progress in diabetic foot screening. We will radiojodom in vpogled v hiter razvoj na področju sodobnih tehnologij pri highlight 80 years of radioiodine treatment and give an insight into the rapid zdravljenju sladkorne bolezni. Drugi dan kongresa bomo zaključili z vse development of modern technologies in the treatment of diabetes. We will bolj perečo problematiko karcinoma pankreasa v povezavi z debelostjo close the second day of the congress with the critical issue of pancreatic in sladkorno boleznijo. Sobotno dopoldne pa bo namenjeno kortizolu in carcinoma related to obesity and diabetes. Saturday morning will be predstavitvi prostih tem. Vse dni kongresa bodo popestrila zelo zanimiva dedicated to cortisol and oral presentations. All three days of the congress satelitska predavanja naših sponzorjev. will be enriched by the interesting satellite symposia of our sponsors. In nenazadnje – dovolj časa bo tudi za druženje in sprostitev. Če česa, nas je And last but not least – there will also be enough time to socialize and relax. čas pandemije naučil, kakšna vrednota so soljudje, tudi kot večno ogledalo If anything, the time of the pandemic has taught us the value of fellow nas samih. human beings, also as an eternal mirror of ourselves. Se kmalu vidimo na Bledu! See you soon in Bled! Aleš Skvarča Aleš Skvarča Predsednik Združenja endokrinologov Slovenije President of Slovenian Endocrine Society 10 11 MAHKOTOVO PRIZNANJE 2022 Prof. dr. Ciril Kr�išnik Slovenska pediatrična endokrinologija je pogumno stopila na samostojno pot opredelil večjo skupino bolnikov z družinskim panhipopituitarizmom. V v zgodnjih šestdesetih letih po vrnitvi prof. dr. Leva Matajca z izobraževanja sodelovanju z laboratorijem prof. Parksa iz Atlante je opredilil mutacije v genu v Parizu. Prof. dr. Ciril Kržišnik se je tej samostojni poti pridružil zelo kmalu in PROP-1, kar je v devetdesetih letih pomenilo strokovni vrh v endokrinologiji. jo skoraj od začetka soustvarjal. Z izobraževanj v tujini je postopno prinašal Vodil je raziskovalne projekte na področjih tirologije in genetike kongenitalne nove ideje, strokovna dognanja in inovativne pristope k obravnavi pediatrične adrenalne hiperplazije, kjer je Ljubljana dobro desetletje v sodelovanju s prof. populacije. Ob vse večji prepoznavnosti Slovenije kot strokovne entitete na dr. Vito Dolžan predstavljala regionalni center za genetske analize te bolezni področju pediatrične endokrinologije mu je uspelo leta 1989 na Bled pripeljati v okviru Srednjeevropskega združenja za pediatrično endokrinologijo. S kolegi letni svetovni kongres International Society for Pediatric and Adolescent je vodil nacionalne registre redkih bolezni in tudi s tem uvrščal Slovenijo med Diabetes (ISPAD, takrat še ISGD), kar je Slovenijo postavilo na mednarodni države z urejenimi podatki o redkih boleznih, ki so nas uvrščali v številne zelo zemljevid pediatrične endokrinologije. odmevne mednarodne publikacije. Na področju zdravljenja z rastnim hormonom je bila Ljubljana med prvimi Vse te dolgoletne strokovne in raziskovalne aktivnosti so omogočile, da je partnerji v projektu zbiranja človeških kadavrskih hipofiz, iz katerih so potem European Society for Pediatric Endocrinology, naše največje mednarodno v Združenih državah Amerike ekstrahirali rastni hormon, katerega del se je strokovno združenje, prof. dr. Kržišnika izvolilo za svojega predsednika in s kot zdravilo vrnil na našo ustanovo. Po uvedbi rekombinantnerga rastnega tem tudi za organizatorja 42. letnega kongresa v Ljubljani leta 2003. To je bil hormona pa je Ljubljana postala center za sledenje učinkov zdravljenja v resnični praznik endokrinologije s preko 2500 udeleženci z vsega sveta. Sloves okviru več mednarodnih sledilnih raziskav. Prof. dr. Ciril Kržišnik je kot prvi v ljubljanske in slovenske pediatrične endokrinologje in s tem endokrinologije Srednji Evropi zdravil otroka z Laronovim sindromom, sodeloval pa je tudi pri nasploh se je, ob sočasnih vidnih uspehih kolegov endokrinologov internistov, uvajanju prvega presejalnega testiranja novorojenčkov, ki ga je pokojni prof. tako dejansko razširil na vse najbolj imenitne naslove po svetu. dr. Varl takrat lociral v okvir tirologije. Prof. dr. Ciril Kržišnik je iz strokovne megle avtoritarne medicine razvil na Osamosvojitev Slovenije je prinesla številne nove strokovne možnosti. Prof. dr. dokazih temelječo pediatrično endokrinologijo in jo utrdil v strokovnem, Kržišnik je usmeril Oddelek za endokrinologijo, diabetes in bolezni presnove raziskovalnem in organizacijskem pogledu. Z mentoriranjem in stalnim Pediatrične klinike na pot mednarodne uveljavitve in mladim, ki smo se mu na spodbujanjem mlajših kolegov pa je ustvaril generacije univerzitetnih tej poti pridružili, omogočil izobraževanja v najbolj prestižnih tujih ustanovah. učiteljev, ki v novi stavbi Pediatrične klinike, zrasle pod njegovim vodstvom, z Omogočil je tudi začetek sistematičnega raziskovalnega dela, ki je bilo do veseljem nadaljujemo njegovo delo. njegovega vodstva na Pediatrični kliniki pogosto potisnjeno v ozadje. Ohranil je svoje strokovno zanimanje za bolezni hipofize in s kolegom s Hrvaške Prof. dr. Tadej Battelino 12 13 PROGRAMSKO-ORGANIZACIJSKI ODBOR STROKOVNI PROGRAM PROGRAMME AND ORGANIZING COMMITTEE SCIENTIFIC PROGRAMME Aleš Skvarča (predsednik/Chair) Katica Bajuk Studen (sekretarka/Secretary) Nadan Gregorič (blagajnik/Treasurer) Tadej Battelino Simona Gaberšček Andrej Janež Mojca Jensterle Sever Tomaž Kocjan Primož Kotnik Urša Kšela Draženka Pongrac Barlovič Andrej Zavratnik 14 15 Èetrtek, 20. oktober 2022 Petek, 21. oktober 2022 12.00 Registracija in odprtje razstave 08.30–09.00 SATELIT 3 Srebrni sponzor (Gedeon Richter) 13.30–14.30 Kosilo 09.00–10.00 SKLOP 4 Funkcionalni hipogonadizem: hujšanje ali testosteron? 15.00–16.00 SKLOP 1 Reverzibilnost sladkorne bolezni tipa 2 – ali je sploh mogoča? Moderator: Nadan Gregorič Moderator: Draženka Pongrac Barlovič • Hujšanje (Matej Rakuša) • Testosteron (Kristina Groti Antonič) • Funkcionalne spremembe v beta celicah med razvojem in remisijo sladkorne bolezni tipa 2 10.00–10.30 SKLOP 5 Presejanje na diabetično nogo: včeraj, danes, jutri (Andraž Stožer) • Weight loss and type 2 diabetes remission: Moderator: Aleš Pražnikar lessons learned? (Michael Lean) • Presejalni test od leta 1996 do leta 2022: sporočila iz podatkovne baze (Vilma Urbančič Rovan) 16.00–17.00 SKLOP 2 Akromegalija – številke ali stol? • Optimizacija presejanja s pomočjo napovednih Moderator: Urša Kšela modelov (Iztok Štotl) • Številke (Tomaž Kocjan) 11.00–11.30 Odmor • Stol (Mojca Jensterle Sever) 11.30–12.30 SKLOP 6 80 let zdravljenja z radiojodom 17.00–17.30 SATELIT 1 Srebrni sponzor (Pfizer) Moderator: Katica Bajuk Studen 17.30–18.00 Odmor • Privzem radiojoda (Katja Zaletel) • Zdravljenje z radiojodom (Edvard Pirnat) 18.00–18.30 OTVORITEV KONGRESA • Radiojod in ščitnična orbitopatija (Polona Jaki Mekjavić) • Radiojod pri mladostnikih (Simona Gaberšček) Mahkotovo priznanje 12.30–13.30 SKLOP 7 Sodobne tehnologije pri zdravljenju sladkorne 18.30–19.30 SKLOP 3 Obeti genskega zdravljenja bolezni Moderator: Mojca Žerjav Tanšek Moderatorja: Tadej Battelino, • Genetika nizke rasti (Jasna Šuput Omladič) Aleš Skvarča • Nove oblike zdravljenja ahondroplazije (Primož Kotnik) • Glikemija in kakovost življenja z uporabo zaprte • Gensko zdravljenje presnovnih bolezni (Urh Grošelj) zanke pri mladih (Nataša Bratina) • Sodobne tehnologije pri zdravljenju sladkorne bolezni 19.30–20.00 SATELIT 2 Zlati sponzor (Abbott) in telesna dejavnost (Klemen Dovč) • Uporaba sodobnih tehnologij v času nosečnosti 20.30–21.30 Večerja (Draženka Pongrac Barlovič) 16 17 Petek, 21. oktober 2022 Sobota, 22. oktober 2022 13.30–14.00 SATELIT 4 Zlati sponzor (Novo Nordisk) 09.00–09.30 SATELIT 7 Srebrni sponzor (Eli Lilly) 14.00–15.00 Kosilo 09.30–11.00 SKLOP 10 Proste teme Moderatorji: Simona Gaberšček, 15.00–16.00 SKLOP 8 Reproduktivna endokrinologija Mojca Jensterle Sever, Moderator: Mojca Jensterle Sever Andrej Zavratnik, • Vloga GLP-1 v reproduktivnem zdravju žensk Primož Kotnik (Vesna Šalamun) 11.00–11.30 Odmor • Vloga GLP-1 v reproduktivnem zdravju moških (Nadan Gregorič) 11.30–12.30 SKLOP 11 Kako zdravimo blag presežek kortizola? • Interdisciplinarno obravnavanje neplodnosti: Moderator: Tomaž Kocjan endokrinolog in reproduktivni ginekolog • Kirurško zdravljenje (Antonela Sabati Rajić) (Eda Vrtačnik Bokal) • Konzervativno zdravljenje (Katarina Mlekuš Kozamernik) 16.00–16.30 SATELIT 5 Srebrni sponzor (Novartis) 12.30–13.00 SATELIT 8 Srebrni sponzor (AstraZeneca) 16.30–17.00 Odmor 13.00–13.30 ZAKLJUČEK KONGRESA 17.00–18.00 SKLOP 9 Karcinom pankreasa, debelost in sladkorna bolezen 13.30–14.30 Kosilo Moderator: Andrej Janež • Karcinom pankreasa – podatki iz Slovenskega registra raka (Vesna Zadnik) • Nevarnostni dejavniki, ocena ogroženosti in presejanje bolj ogroženih za raka trebušne slinavke (Mateja Krajc) 18.00–19.00 SATELIT 6 Generalni sponzor (Boehringer Ingelheim) 19.30–21.00 Večerja 18 19 Thursday, October 20th, 2022 Friday, October 21st, 2022 12.00 Registration and Exhibition Opening 08.30–09.00 SATELLITE SYMPOSIUM 1 Silver sponsor (Gedeon Richter) 13.30–14.30 Lunch 09.00–10.00 SESSION 4 Functional hypogonadism: weight loss 15.00–16.00 SESSION 1 Reversibility of type 2 diabetes - is it real? or testosterone? Chairperson: Draženka Pongrac Barlovič Chairperson: Nadan Gregorič • Functional beta-cell changes between development • Weight loss (Matej Rakuša) and remission of type 2 diabetes (Andraž Stožer) • Testosterone (Kristina Groti Antonič) • Weight loss and type 2 diabetes remission: lessons learned? (Michael Lean) 10.00–10.30 SESSION 5 Diabetic foot screening: yesterday, today, tomorrow Chairperson: Aleš Pražnikar 16.00–17.00 SESSION 2 Acromegaly - The numbers or the chair? • Screening test from 1996 to 2022: messages Chairperson: Urša Kšela from the database (Vilma Urbančič Rovan) • The numbers (Tomaž Kocjan) • Screening optimization using predictive models • The chair (Mojca Jensterle Sever) (Iztok Štotl) 11.00–11.30 Coffee break 17.00–17.30 SATELLITE SYMPOSIUM 1 Silver sponsor (Pfizer) 11.30–12.30 SESSION 6 80 years of radioiodine treatment Chairperson: Katica Bajuk Studen 17.30–18.00 Coffee break • Radioiodine uptake (Katja Zaletel) 18.00–18.30 CONGRESS OPENING • Radioiodine treatment (Edvard Pirnat) Mahkota’s Award • Radioiodine and Graves’ orbitopathy (Polona Jaki Mekjavić) • Radioiodine in adolescents (Simona Gaberšček) 18.30–19.30 SESSION 2 Prospects for gene therapy Chairperson: Mojca Žerjav Tanšek 12.30–13.30 SESSION 7 Modern technologies in the treatment of diabetes • Genetics of short stature (Jasna Šuput Omladič) Chairpersons: Tadej Battelino • Novel treatments in achondroplasia (Primož Kotnik) Aleš Skvarča • Gene therapy of metabolic diseases (Urh Grošelj) • Glycemic control and quality of life with closed-loop use in youth (Nataša Bratina) 19.30–20.00 SATELLITE SYMPOSIUM 2 • Modern technologies in the treatment of diabetes Golden sponsor (Abbott) and physical activity (Klemen Dovč) • Use of modern technologies during pregnancy 20.30–21.30 Dinner (Draženka Pongrac Barlovič) 20 21 Friday, October 21st, 2022 Saturday, October 22nd, 2022 13.30–14.00 SATELLITE SYMPOSIUM 4 09.00–09.30 SATELLITE SYMPOSIUM 7 Golden sponsor (Novo Nordisk) Silver sponsor (Eli Lilly) 14.00–15.00 Lunch 09.30–11.00 SESSION 10 Oral presentations Chairpersons: Simona Gaberšček, 15.00–16.00 SESSION 8 Reproductive endocrinology Mojca Jensterle Sever, Chairperson: Mojca Jensterle Sever Andrej Zavratnik, • The role of GLP-1 in women’s reproductive health Primož Kotnik (Vesna Šalamun) 11.00–11.30 Coffee break • The role of GLP-1 in men’s reproductive health (Nadan Gregorič) 11.30–12.30 SESSION 11 How do we treat mild autonomous cortisol • Interdisciplinary management of infertility: excess? endocrinologist and reproductive gynaecologist (Eda Vrtačnik Bokal) Chairperson: Tomaž Kocjan • Surgical treatment (Antonela Sabati Rajić) 16.00–16.30 SATELLITE SYMPOSIUM 5 • Conservative treatment Silver sponsor (Novartis) (Katarina Mlekuš Kozamernik) 16.30–17.00 Coffee break 12.30–13.00 SATELLITE SYMPOSIUM 8 Silver sponsor (AstraZeneca) 17.00–18.00 SESSION 9 Pancreatic cancer, obesity and diabetes mellitus 13.00–13.30 CONCLUSION Chairperson: Andrej Janež 13.30–14.30 Lunch • Pancreatic cancer – data from the Cancer Registry of Republic of Slovenia (Vesna Zadnik) • Pancreatic cancer: risk factors, risk assessment and screening of high-risk individuals (Mateja Krajc) 18.00–19.00 SATELLITE SYMPOSIUM 6 Platinum sponsor (Boehringer Ingelheim) 19.30–21.00 Dinner 22 23 PREDAVANJA LECTURES 24 25 01 FUNCTIONAL CHANGES IN BETA CELLS DURING DEVELOPMENT AND REMISSION OF TYPE 2 DIABETES Maša Skelin Klemen 1, Jan Kopecky 1, Eva Paradiž Leitgeb 1, Jasmina Kerèmar 1, Lidija Križančić Bombek 1, Viljem Pohorec 1, Ismael Valladolid-Acebes 3, Andraž Stožer 1,2,3,*, Jurij Dolenšek 1,2,* 1 Institute of Physiology, Faculty of Medicine, University of Maribor, Maribor, Slovenia 2 Faculty of Natural Sciences and Mathematics, University of Maribor, Maribor, Slovenia 3 Karolinska Institutet, Karolinska University Hospital, Solna, Sweden *andraz.stozer@um.si, *jurij.dolensek@um.si Introduction Diet-induced obesity (DIO) mouse models are a common and valuable research tool in studying pathophysiology of type 2 diabetes mellitus (T2D). Currently used animal models (e.g., high fat diet, high fat high sucrose) have some inherent methodological drawbacks, mostly due to beta cell plasticity when used from an early age, and due to the composition of the diet used to induce T2D (1–3). On the other hand, clinical studies by Taylor et al. strongly suggest that caloric restriction results in effective remission of T2D in humans (4, 5). However mechanistic explanation available at the level of beta cell function is inherently limited in human studies (6). We therefore constructed a novel mouse model of DIO that would more closely reflect T2D in humans in an attempt to decipher functional and morphological changes following caloric restriction-induced remission of 26 27 T2D. To this end, 7 days of caloric restriction (i.e., intake of 35% of the and these parameters remained at control values during the following period caloric intake of the control group) were employed in mice previously on CD. In both control and WD mice, active time progressively increased with exposed to WD to attempt to induce DIO and then reverse the diabetic increasing glucose concentrations, as described previously in independent phenotype, with normalization of body mass, normalization of glucose cohorts of mice of different strains (7, 8), but in WD mice, the dose-response handling and insulin sensitivity. To provide a mechanistic explanation for curve was clearly left-shifted, indicating increased sensitivity of beta cells both the DIO and remission following caloric restriction at the level of to glucose in the WD group. In other words, compensatory hyperinsulinemia beta cell function, we performed functional multicellular confocal calcium observed in the WD group can be ascribed to both hyperglycemia and imaging on acute pancreas tissue slices to assess the effects of both DIO increased sensitivity, at least during the early stages of T2D development and caloric restriction on the glucose sensitivity of beta cells. in our model. Similar to in vivo findings obtained by tolerance tests, the in situ changes in sensitivity obtained by calcium imaging were much less pronounced in female mice, yet still clearly detectable. After one week of Methods caloric restriction, the dose-response curve returned to control values. Male and female C57BL/6J were separated into three groups: western diet (WD), control diet (CD), and restricted control diet (RCD). WD and RCD mice Conclusions and outlook were fed WD for 12 weeks starting from the age of 12 weeks. After 7 weeks of WD, the RCD mice received one week of restricted caloric intake (RCD, Our findings further elucidate the impact of caloric restriction on T2D and 35% caloric intake of CD) and then received CD until sacrifice. We measured our animal model provides a novel platform for studying T2D. DIO induced weekly food and water intake, we performed intraperitoneal glucose by WD resulted in T2D with partially compensated insulin resistance, tolerance tests (ipGTT) and insulin tolerance tests (ipITT). Calcium imaging seen as fasting hyperglycemia, impaired glucose tolerance and insulin of islets of Langerhans in acute pancreas tissue slices was performed with resistance. The main mechanism of beta cell adaptation during this partly high temporal and spatial resolution confocal microscopy after stimulating compensated diabetic state was increased activity of calcium oscillations the islets with increasing glucose concentrations (7–16 mM). To quantify and a left shift in the dose-dependence curve. Female mice were more their sensitivity to glucose, the frequency, duration, and active time of resistant to the WD intervention, but still showed clear signs of beta calcium oscillations were determined during the plateau phase of their cell adaptation in the face of developing insulin resistance and glucose responses. intolerance (9). Short-term caloric restriction completely rescued the DIO, with mice exhibiting control values of glucose tolerance, insulin sensitivity, and beta cell responsiveness to glucose, and these parameters remained Results at control values during maintenance on CD. Since first reports on calcium imaging in human islets indicate that the dose-response curves of beta On WD, male mice developed fasting hyperglycemia, glucose intolerance, cells in advanced T2D are right-shifted, i.e., the sensitivity of beta cells to as assessed by the intraperitoneal glucose tolerance tests, and insulin glucose is decreased (10), in future studies, we will attempt to prolong the resistance, as assessed by the intraperitoneal insulin tolerance tests. period of WD to track the temporal evolution of beta cell adaptation and Notably, female mice were more resistant to the development of type possibly detect early dysfunction and thus the time point when caloric 2 diabetes than males. One week of caloric restriction in the RCD group restriction can be expected to become less effective, which is a crucial step reversed fasting glycemia, glucose, and insulin tolerance to control values to make our mouse model translationally more relevant. 28 29 02 References WEIGHT LOSS AND TYPE 2 DIABETES REMISSION: 1. Irles E, Ñeco P, Lluesma M, Villar-Pazos S, Santos-Silva JC, Vettorazzi JF, et al. Enhanced LESSONS LEARNED? glucose-induced intracellular signaling promotes insulin hypersecretion: Pancreatic beta-cell functional adaptations in a model of genetic obesity and prediabetes. Mol Mike Lean Cell Endocrinol. 2015;404:46-55. 2. Gonzalez A, Merino B, Marroqui L, Neco P, Alonso-Magdalena P, Caballero-Garrido School of Medicine, Dentistry and Nursing, E, et al. Insulin hypersecretion in islets from diet-induced hyperinsulinemic obese University of Glasgow, Scotland female mice is associated with several functional adaptations in individual beta-cells. Endocrinology. 2013;154(10):3515-24. mike.lean@glasgow.ac.uk 3. Corezola do Amaral ME, Kravets V, Dwulet JM, Farnsworth NL, Piscopio R, Schleicher WE, et al. Caloric restriction recovers impaired β-cell-β-cell gap junction coupling, calcium oscillation coordination, and insulin secretion in prediabetic mice. Am J Physiol Endocrinol Metab. 2020;319(4):E709-e20. 4. Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018;391(10120):541-51. 5. Xin Y, Davies A, Briggs A, McCombie L, Messow CM, Grieve E, et al. Type 2 diabetes Until recently, teaching about type 2 diabetes (T2D) was from remission: 2 year within-trial and lifetime-horizon cost-effectiveness of the Diabetes endocrinologists. They considered it an unexciting disease which lacked Remission Clinical Trial (DiRECT)/Counterweight-Plus weight management programme. the logical mechanisms of endocrine diseases, and for which hormone Diabetologia. 2020;63(10):2112-22. replacement was not a good solution. It was regarded as inevitable disorder 6. White MG, Shaw JAM, Taylor R. Type 2 Diabetes: The Pathologic Basis of Reversible of ageing, mainly found in elderly people and with few complications β-Cell Dysfunction. Diabetes Care. 2016;39(11):2080-8. compared to type 1 diabetes, where insulin function declines and beta-7. Pohorec V, Križančić Bombek L, Skelin Klemen M, Dolenšek J, Stožer A. Glucose-cell capacity falls, progressively and permanently, not requiring insulin Stimulated Calcium Dynamics in Beta Cells From Male C57BL/6J, C57BL/6N, and NMRI treatment. Treatment was largely symptomatic and the disease and its Mice: A Comparison of Activation, Activity, and Deactivation Properties in Tissue Slices. treatment were largely ignored by many doctors and by most patients. Front Endocrinol (Lausanne). 2022;13:867663. There have been radical changes over the past 30-40 years. T2D now affects 8. Stožer A, Skelin Klemen M, Gosak M, Križančić Bombek L, Pohorec V, Slak Rupnik M, et al. Glucose-dependent activation, activity, and deactivation of beta cell networks in acute 5-10% of western regions, 20-40% in some Asian and indigenous populations. mouse pancreas tissue slices. Am J Physiol Endocrinol Metab. 2021;321(2):E305-e23. Its disabling, painful, life-shortening complications (in increasingly young people) now dominate healthcare budgets. Large numbers of new highly 9. Stožer A, Hojs R, Dolenšek J. Beta Cell Functional Adaptation and Dysfunction in Insulin Resistance and the Role of Chronic Kidney Disease. Nephron. 2019. expensive drugs have been developed and are prescribed to try to modify complications. The change is very clearly through populations gaining 10. Gosak M, Yan-Do R, Lin H, MacDonald PE, Stožer A. Ca2+ oscillations, waves, and weight, at younger ages. T2D is not a primary endocrine disease: it is a networks in islets from human donors with and without type 2 diabetes. Diabetes. 2022 Sep 6;db220004. doi: 10.2337/db22-0004. Online ahead of print. nutritional disease of fat storage, and just one of many chronic disease outcomes which commonly coexist as ‘multi-morbidity’. Not everyone who 30 31 gains weight will develop T2D, but around 40% of western populations do morphology, and maximal insulin production doubles, to become normal have a genetic predisposition for metabolic syndrome, and are likely to again. develop T2D at some stage as they become older and more overweight. DiRECT has thus confirmed that T2D is a disease of ectopic fat accumulation, T2D has been ‘associated’ with overweight and obesity for many years: within the disease-process of ‘obesity’. T2D can develop at almost any BMI the misleading word ‘comorbidity’ has been used. It has astronomical level, if there is already ectopic fat accumulation in vital organs. DiRECT relative risks at high BMI, but even knowing that prediabetes progression showed that T2D is reversible for the majority of people, with weight to diabetes can be prevented by weight loss did not immediately trigger loss soon after diagnosis, and these results have now been repeated for recognition that T2D is actually caused by weight gain with age – and thus Arab and North African people in the DIADEM-1 trial, and in RETUNE with a potentially reversible disease-process. A misunderstanding of ‘obesity’ BMI below 27kg/m2. Remission rate depends on weight loss. Questions (the disease-process of excess body fat accumulation) caused a failure to remain, particularly about how to maintain weight loss after the hard work recognise this as the cause of T2D when body mass index is below the to achieve it, but remission is now a key T2D management target, and epidemiological cut-off of 30kg/m2. weight loss >10-15kg should be encouraged for all, as soon as possible after The DiRECT trial was designed to establish whether T2D remission could diagnosis, using self-help or professionally-supported diet programmes. be achieved, within routine primary-care, by weight loss using an evidence-The COVID-19 experience showed that remote and face-to-face support are based structured diet programme (Counterweight-Plus). Intervention equally effective for Counterweight-Plus. participants lost a mean 13.5kg with 850kcal/day for ~12weeks. New-Further details about the DiRECT trial, and its publications, can be found on style meals with ~50%E carbohydrate were then introduced stepwise, to the website: https://www.directclinicaltrial.org.uk/ maintain mean ~10kg loss at 12 months. Overall, almost half (46%) were no longer diabetic, and not requiring medication for diabetes – ie. in remission. Remission was achievable for the great majority of patients: 86% were in remission if they lost more than 15kg. Sadly, most regained weight, but with weight loss >10kg, over 70% achieved remission, at both 12 and 24 months. About a third of participants were also able to stop their antihypertensive medications, and fatty liver disease, also common in people with T2D, was similarly resolved. With reduced prescriptions and medical consultations and admissions, health economics analysis showed that the intervention would pay for itself in 5–6 years. Patients were estimated to live longer, feel better, and cost less. A subset of DiRECT participants underwent detailed metabolic and MRI investigations, which showed that people with T2D (despite good treatment with UK guidelines) have excess fat in liver and pancreas, and that seems to be driving T2D. With weight loss and remission, liver and pancreas fat falls to normal, the ragged sick-looking pancreas returns to a normal size and 32 33 03 ACROMEGALY – THE NUMBERS Tomaž Kocjan 1,2 1 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia tomaz.kocjan@kclj.si Introduction Acromegaly is a rare, slowly progressive disease resulting from the increased release of growth hormone (GH) and, consequently, insulin- like growth factor I (IGF-1), which in most cases is induced by a GH-secreting pituitary tumor and rarely by ectopic secretion of GH or GH releasing hormone (GHRH). Prolonged exposure to GH excess leads to progressive somatic disfigurement and a wide range of systemic manifestations that are associated with increased mortality (1). Numbers GH and IGF-I assessments are the standard for assessing acromegaly disease activity at diagnosis and follow-up (2). The Endocrine Society recommends measurement of serum IGF-1 in patients with typical clinical manifestations of acromegaly, with several typical associated conditions (e. g. sleep apnea syndrome, type 2 diabetes mellitus, debilitating arthritis, carpal tunnel syndrome, hyperhidrosis, and hypertension) or with a pituitary mass (3). When IGF-1 levels are elevated or equivocal, the diagnosis should 34 35 be confirmed by finding lack of suppression of GH to <0.4 µg/L following necessarily correlate with patient’s well-being, and health-related quality documented hyperglycemia during an oral glucose load (3, 4). Biochemical of life (HRQoL) impairments might persist despite biochemical control. targets of an age normalized IGF-1 value and a random GH <1.0 µg/L are the Therefore, treatment should not only aim to normalize biochemical suggested goals of management of acromegaly (3), as they have each been outcomes but also improve patient-reported outcomes (PROs) (8). To shown to correlate with mortality risk reduction (5). capture the patients’ perspective by measuring symptoms and HRQoL, An important caveat to consider is a lack of consensus for target GH and the use of PRO measures (PROMs) in clinical trials and practice has been IGF-1 levels that correlate with prevention of comorbidities. IGF-1 levels advocated in addition to biochemical evaluation (9–11). correlate with comorbidities better than glucose-suppressed GH levels. A recent meta-analysis found that 34% of studies among patients with IGF-1 levels may be more predictive than nadir GH for predicting insulin acromegaly reported discrepant results between PROs and biochemical sensitivity and clinical symptom score after surgery (3). outcomes. The percentage of discrepant results was slightly higher among studies measuring HRQoL (38%) compared to studies measuring A challenging clinical problem is discrepancy between GH and IGF-1 levels. symptoms (32%). More than half (56%) of the discrepant studies reported Various studies have obtained different discordance rates, ranging from an improvement in biochemical outcomes, without improvement in PROs. 5.4% to 39.5%. Their impacts over mortality and morbidity and the risk No clear determinants of these discrepancies were identified. Studies that of biochemical and/or clinical recurrence are unclear (6). The proposed included participants who had been treated previously showed a tendency mechanisms to explain this phenomenon include early or partially toward higher odds of discrepancy compared to studies in treatment-naïve treated disease, altered dynamics of the GH secretion after surgery, early patients. The authors speculated, the discrepancies may result from the postoperative IGF-1 assay, inappropriate cut-off point for GH suppression fact that PROMs and biochemical parameters measure different aspects in the GH assays, GH nadir values not adjusted to age, sex, and body mass of health and are therefore complementary. Every patient might have index, the influence of concomitant medication, inaccurate or less sensitive an individual optimal hormonal setpoint, making it difficult to rely on tests and laboratory errors, such as pre-analytical and technical pitfalls, and biochemical parameters alone. Furthermore, some symptoms and reduced several co-existing physiologic and pathologic conditions. Such cases should HRQoL may be caused by irreversible damage that is unresponsive to be carefully assessed to avoid misinterpreting the activity of acromegaly treatment. Therefore, both PROMs and biochemical outcome parameters or misdiagnosing a patient with acromegaly. (6, 7). Given the variability are needed to obtain a comprehensive view of disease activity (12). between GH and IGF-1 assays it is critical to maintain the use of the same assay in the same patient if possible throughout management (3). Conclusion Patient-related outcomes A patient-centered approach, accounting for biochemical parameters, comorbidities, treatment complications, and HRQoL measures, should all be Although treatment often results in normalization of GH and IGF-1 levels considered in treatment decisions (8). Scoring systems such as SAGIT (Signs with significant clinical improvement, a proportion of patients still suffer and symptoms, Associated comorbidities, Growth hormone levels, IGF-1 levels, from extensive (irreversible) late effects of acromegaly largely from and Tumor profile) (9) and ACRODAT (10) are useful to assess overall disease musculoskeletal complications and persistent cardiovascular, endocrine, activity while general and acromegaly-specific HRQoL instruments such as metabolic, and oncologic comorbidities (1, 8). Biochemical control does not AcroQoL (11) can be helpful in identifying specific factors for follow-up (8). 36 37 04 References ACROMEGALY: THE NUMBERS OR THE CHAIR? 1. Colao A, Grasso LFS, Giustina A, Melmed S, Chanson P, Pereira AM, et al. Acromegaly. Nat Rev Dis Primer. 2019;5(1):1–17. Mojca Jensterle Sever 1,2 2. Fleseriu M, Biller BMK, Freda PU, Gadelha MR, Giustina A, Katznelson L, et al. A Pituitary Society update to acromegaly management guidelines. Pituitary. 2021;24(1):1–13. 1 Department of Endocrinology, Diabetes and Metabolic Diseases, 3. Katznelson L, Laws ER, Melmed S, Molitch ME, Murad MH, Utz A, et al. Acromegaly: an University Medical Centre Ljubljana, Ljubljana, Slovenia endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(11):3933–51. 2 Faculty of Medicine, 4. Melmed S, Bronstein MD, Chanson P, Klibanski A, Casanueva FF, Wass JAH, et al. A University of Ljubljana, Ljubljana, Slovenia Consensus Statement on acromegaly therapeutic outcomes. Nat Rev Endocrinol. 2018;14(9):552–61. 5. Holdaway IM, Bolland MJ, Gamble GD. A meta-analysis of the effect of lowering serum mojca.jensterlesever@kclj.si levels of GH and IGF-I on mortality in acromegaly. Eur J Endocrinol. 2008;159(2):89–95. mojcajensterle@yahoo.com 6. Zeinalizadeh M, Habibi Z, Fernandez-Miranda JC, Gardner PA, Hodak SP, Challinor SM. Discordance between growth hormone and insulin-like growth factor-1 after pituitary surgery for acromegaly: a stepwise approach and management. Pituitary. 2015;18(1):48–59. 7. Peixe C, Sánchez-García M, Grossman AB, Korbonits M, Marques P. Biochemical Biochemical control of acromegaly is associated with reduced morbidity discrepancies in the evaluation of the somatotroph axis: Elevated GH or IGF-1 levels do and mortality and is recognized as the most important for the long-term not always diagnose acromegaly. Growth Horm IGF Res. 2022;64:101467. prognosis of acromegaly. The numbers are therefore the main-core of the 8. Giustina A, Barkan A, Beckers A, Biermasz N, Biller BMK, Boguszewski C, et al. A disease management. Fortunately, nowadays, a multimodal therapeutic Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities: An Update. J approach allows the achievement of biochemical control in the vast Clin Endocrinol Metab. 2020;105(4):dgz096. majority of patients with acromegaly (1, 2). 9. Giustina A, Bevan JS, Bronstein MD, Casanueva FF, Chanson P, Petersenn S, et al. Based on the biochemical control, the patients are classified as either cured SAGIT®: clinician-reported outcome instrument for managing acromegaly in clinical after surgery, controlled on pharmacotherapy, or uncontrolled. They are practice--development and results from a pilot study. Pituitary. 2016;19(1):39–49. considered cured after transsphenoidal surgery if nadir GH level during an 10. van der Lely AJ, Gomez R, Pleil A, Badia X, Brue T, Buchfelder M, et al. Development of OGTT is <0.4 µg/L and age- and gender-adjusted IGF-1 levels normalized. ACRODAT®, a new software medical device to assess disease activity in patients with acromegaly. Pituitary. 2017;20(6):692–701. When they are not cured by surgery, they are classified controlled on pharmacotherapy, if age- and gender-adjusted IGF-1 levels are up to 1-2-1.3 11. Webb SM, Badia X, Surinach NL, Spanish AcroQol Study Group. Validity and clinical times the upper level of normal (3). Recently, GH and mean GH profile have applicability of the acromegaly quality of life questionnaire, AcroQoL: a 6-month prospective study. Eur J Endocrinol. 2006;155(2):269–77. also been considered as an important number to control in patients that are on pharmacotherapy. In the future, some limitations of biochemical 12. van der Meulen M, Zamanipoor Najafabadi AH, Broersen LHA, Schoones JW, Pereira AM, van Furth WR, et al. State of the Art of Patient-reported Outcomes in Acromegaly assessment still need to be overcome by improving the methodology to or GH Deficiency: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. assess IGF-1 and GH, in particularly for those on pegvisomant, and by better 2022;107(5):1225–38. interpretation of several potential impacts on the biochemical control. 38 39 However, biochemical profiles and clinical features may give discordant References information. Some clinical features do not relief after biochemical normalization. Patients that are biochemical well-controlled might report as poor disease related quality of life (QoL) than those with biochemically 1. Manjila S, Wu OC, Khan FR, Khan MM, Arafah BM, Selman WR. Pharmacological uncontrolled disease. This well-documented discordance between patient-management of acromegaly: a current perspective. Neurosurg Focus. 2010;29(4):E14. and clinician-perception of the disease control could be reduced by using 2. Rowles SV, Prieto L, Badia X, Shalet SM, Webb SM, Trainer PJ. Quality of life (QOL) specific clinician- and patient-reported outcome tools (4, 5). in patients with acromegaly is severely impaired: use of a novel measure of QOL: acromegaly quality of life questionnaire. J Clin Endocrinol Metab. 2005;90(6):3337-41. The clinician-reported outcome tools such as SAGIT Instrument (SAGIT) and 3. Giustina A, Barkhoudarian G, Beckers A, Ben-Shlomo A, Biermasz N, Biller B, et al. ACRODAT provide objective measurement of present signs and symptoms, Multidisciplinary management of acromegaly: A consensus. Rev Endocr Metab Disord. comorbidities, tumour profile, and biochemical parameters (6, 7). On the 2020;21(4):667-678. other hand, the Patient-assessed Acromegaly Symptom Questionnaire 4. Gurel MH, Bruening PR, Rhodes C, Lomax KG. Patient perspectives on the impact of (PASQ), Acromegaly Quality of Life Questionnaire (AcroQoL), the Acromegaly acromegaly: results from individual and group interviews. Patient Prefer Adherence. Treatment Satisfaction Questionnaire (AcroTSQ), the enlargement of 2014;8:53-62. the extremities questionnaire, and the acromegaly comorbidities and 5. Geer EB, Sisco J, Adelman DT, Ludlam WH, Haviv A, Gelbaum D, et al. Observed complaints questionnaire allow patients to give their perspectives on discordance between outcomes reported by acromegaly patients and their treating symptoms and QoL (8, 9). Although these tools were designed to assist endocrinology medical provider. Pituitary. 2020;23(2):140-148. clinicians in acromegaly staging, treatment outcome assessment, and 6. van der Lely AJ, Gomez R, Pleil A, Badia X, Brue T, Buchfelder M, et al. Development of adapting patient management in a standardized way, they are still not ACRODAT®, a new software medical device to assess disease activity in patients with commonly conducted in everyday clinical practice (7, 9). acromegaly. Pituitary. 2017;20(6):692-701. We emphasise the complementary nature of »Clinician- and Patient-7. Giustina A, Bevan JS, Bronstein MD, Casanueva FF, Chanson P, Petersenn S, et al. Reported Outcome« tools in the management of acromegaly. The SAGIT®: clinician-reported outcome instrument for managing acromegaly in clinical correlations between these specific tools could help us to identify practice--development and results from a pilot study. Pituitary. 2016;19(1):39-49. some modifiable parameters that should be further addressed beyond 8. an der Meulen M, Zamanipoor Najafabadi AH, Broersen LHA, Schoones JW, Pereira AM, biochemical control to assure an updated patient-centred personalized van Furth WR, et al. State of the Art of Patient-reported Outcomes in Acromegaly approach in a standardized way (10). In summary, the strategies to or GH Deficiency: A Systematic Review and Meta-analysis. J Clin Endocrinol Metab. improve disease control from both, clinicians’ and patients’ perspective, 2022;107(5):1225-38. should include treatment of the disease, treatment of comorbidities and 9. Giustina A, Bronstein MD, Chanson P, Petersenn S, Casanueva FF, Sert C, et al. addressing individual needs of the patient. International Multicenter Validation Study of the SAGIT® Instrument in Acromegaly. J Clin Endocrinol Metab. 2021;106(12):3555-68. 10. Herman R, Goričar K, Janež A, Jensterle M. Clinical Applicability of Patient- and Clinician-Reported Outcome Tools in the Management of Patients With Acromegaly. Endocr Pract. 2022; 28(7):678-683. 40 41 05 GENETICS OF SHORT STATURE Jasna Šuput Omladič 1, Primož Kotnik 1,2 1 Department of Pediatric Endocrinology, Diabetes, and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia jasna.suputomladic@kclj.si Linear growth in humans is regulated by different factors from the embryonic stage to childhood, adolescence until final height. During fetal stage insulin and growth factors have prevalent influence on growth. Later, in the early childhood growth hormone-insulin like growth factor 1 (GH-IGF-1) axis becomes the main driver of linear growth. During puberty, sex hormones have an important role in the increased growth velocity and are at the same time responsible for the closure of the growth plate, indicating the end of linear growth. Recently the role of non-GH-IGH-1 hormonal factors in linear growth was also determined. Local factors in the growth plate were determined to be important not only in skeletal dysplasia but also in children with so called idiopathic short stature (ISS) (1, 2). Height is a polygenetic trait, and although the environment has an important role in linear growth, it is estimated that genetics explains up to 60% of height variability. There are several hundred loci associated with human height having been identified by genome-wide association studies, and an increasing number of novel monogenic causes of short stature have recently been proposed. Determining the genetic cause of short stature 42 43 is not important only from the diagnostic point-of-view, but also could and psychomotor retardation being the most frequent additional signs. influence the therapeutic decisions at the start of treatment with human Children with GH resistance benefit from human recombinant IGF-1 therapy recombinant GH (hr-GH) and long-term management (1, 2). either as monotherapy or in combination with hr-GH (4). GH-IGF-1 axis defects Non-GH-IGF-1 axis defects Growth can be affected at various levels of the GH-IGF-1 axis. GH deficiency Until recently most of the genetic diagnostic process has focused on the is a major cause of growth failure. Genetic caused associated with GH GH-IGF-1 axis. It was however determined that surprisingly large number of deficiency are pathogenic variants in genes for growth hormone ( GH1) or ISS cases with or without extremities disproportions can be attributed to the GH-releasing hormone receptor ( GHRHR). In addition, several genes non-GH-IGF-1 axis genes (2). associated with the development of pituitary are also associated with GH Pathogenic variants in the FGFR3 gene are associated with skeletal deficiency (and possibly deficiencies of other pituitary hormones), namely dysplasia’s achondroplasia and hypochondroplasia in an autosomal POU1F1, PROP1, LHX3, LHX4, HESX1. Monogenic causes can be determined dominant manner, linked to specific genetic variants. In addition, in up to 10% of subjects diagnosed with GH deficiency, the percentage several heterozygous variants in this gene were also associated with ISS. being even higher if multiple pituitary hormone deficiency was determined. Results regarding rh-GH treatment of children with FGFR3 mutations are Determining the genetic cause of GH deficiency is important for clinical controversial (6). outcomes and GH treatment. E.g. those with identified pathogenic variants in the genes associated with GH deficiency tended to be shorter at recombinant ACAN gene encodes a proteoglycan, that is a key component in the cartilage GH therapy start, however had a better treatment response (3). extracellular matrix of the growth plate. Abnormalities in the ACAN gene are associated with proportionate or mildly disproportionate short stature GH deficiency usually doesn’t affect intrauterine growth. On the other hand, and premature closure of the growth plates. Therapy with hr-GH is reported resistance to GH is associated with impaired intrauterine growth, newborn to be effective (7). being born small for gestational age. Resistance to GH is associated with pathogenic variants in the GH receptor ( GHR) – so called Laron syndrome. One of the genes that is frequently associated with short stature is SHOX, Distally from GHR, pathogenic variants in the STAT5B gene are associated located to the X chromosome. Phenotypically there is a wide variation from with short stature, low IGF-1 levels, normal GH levels and additional clinical skeletal dysplasia of Leri-Weill to short stature without other features. problems as are severe immune deficiency and pulmonary problems. Product of the SHOX gene is a transcription factor that regulated several PAPP-A2 is a newly determined cause of progressive post-natal growth. genes that have important role in the growth plate as are ACAN and FGFR3. Pathogenic variants in the IGF1 and IGF2 genes are a further cause of short Treatment of children with pathological variants in the SHOX gene with stature. Homozygous states are associated with severe short stature and hr-GH was determined to be efficient (8). additional clinical signs, whereas heterozygous states are also determined NPR2 gene is another gene expressed in the growth plate and associated in ISS. Imprinting defects in the IGF2 gene are associated with Silver-Russell with ISS. Homozygous mutations in NPR2 gene are associated with a severe syndrome and Temple syndrome. Further down the GH-IGF-1 axis are defects acromesomelic dysplasia type Maroteaux. Heterozygous mutations are in the IGF1R gene, that are featured by resistance to IGF-1. The clinical linked to ISS. Treatment with hr-GH has been determined as efficient in signs are usually more complex than isolated short stature, microcephaly several studies (9). 44 45 Conclusions References Following the development of molecular-genetic techniques, it is possible to perform more in-depth genetic analysis, more quickly, and more affordably. 1. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, et al. Consensus statement By determining the genetic cause of short stature, the management can be on the diagnosis and treatment of children with idiopathic short stature: A summary targeted, tailored to the individual and safer. It seems that genetic analysis of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine might soon be a standard procedure in the diagnosis of short stature due Society, and the European Society for Paediatric Endocrinology Workshop. J Clin to ever wider spectrum of clinical features linked with short stature. Endocrinol Metab. 2008;93(11):4210–7. 2. Argente J, Tatton-Brown K, Lehwalder D, Pfäffle R. Genetics of Growth Disorders-Which Patients Require Genetic Testing? Front Endocrinol (Lausanne). 2019;10:602(1–15). 3. Wit JM, Oostdijk W, Losekoot M, van Duyvenvoorde HA, Ruivenkamp CA, Kant SG. MECHANISMS IN ENDOCRINOLOGY: Novel genetic causes of short stature. Eur J Endocrinol. 2016;174(4):R145–73. 4. Walenkamp MJ, Losekoot M, Wit JM. Molecular IGF-1 and IGF-1 receptor defects: from genetics to clinical management. Endocr Dev. 2013;24:128–37. 5. Walenkamp MJE, Robers JML, Wit JM, Zandwijken GRJ, van Duyvenvoorde HA, Oostdijk W, Hokken-Koelega ACS, Kant SG, Losekoot M. Phenotypic Features and Response to GH Treatment of Patients With a Molecular Defect of the IGF-1 Receptor. J Clin Endocrinol Metab. 2019;104(8):3157–71. 6. Mamada M, Yorifuji T, Kurokawa K, Kawai M, Momoi T, Nakahata T. Prevalence of Mutations in the FGFR3 Gene in Individuals with Idiopathic Short Stature. Clin Pediatr Endocrinol. 2006;15(2):61–4. 7. Stavber L, Hovnik T, Kotnik P, Lovrečić L, Kovač J, Tesovnik T, et al. High frequency of pathogenic ACAN variants including an intragenic deletion in selected individuals with short stature. Eur J Endocrinol. 2020;182(3):243–53. 8. Faienza MF, Chiarito M, Brunetti G, D’Amato G. Growth plate gene involment and isolated short stature. Endocrine. 2021;71(1):28–34. 9. Stavber L, Gaia MJ, Hovnik T, Jenko Bizjan B, Debeljak M, Kovač J, et al. Heterozygous NPR2 Variants in Idiopathic Short Stature. Genes (Basel). 2022;13(6):1065. 46 47 06 NOVEL TREATMENT OPTIONS IN ACHONDROPLASIA Primož Kotnik 1,2, Sončka Jazbinšek 1 1 Department of Pediatric Endocrinology, Diabetes,and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia primoz.kotnik@mf.uni-lj.si Achondroplasia (ACH) is the most common form of skeletal dysplasia. Incidence is estimated to be 1:25.000–30.000. It is characterized by disproportionate rhizomelic short stature, hypoplasia of the midface, and macrocephaly. Numerous orthopedic and neurological complications are associated with the disease (1). ACH is caused by a gain-of-function mutation in the fibroblast growth factor-3 receptor (FGFR3) gene, a member of the tyrosine kinase receptor family (2). ACH is inherited in an autosomal dominant manner and is characterized by full penetration. Excessive FGFR3 activation results in inhibition of cartilage tissue formation at the level of chondrocyte proliferation, hypertrophy, differentiation, and synthesis of the extracellular matrix (3). Therapy options for achondroplasia are limited. Active follow-up and symptomatic treatment of the complications present the forefront of patient management. Growth hormone supplementation has not shown promising results and is not viewed as a standard treatment for achondroplasia. The progress in the understanding of ACH pathogenesis has led to the development of several therapeutic strategies for 48 49 modulating excessive FGFR3 activation. Approaches are varied and include TransCon CNP inhibiting the tyrosine kinase activity of FGFR3 (infigratinib), producing artificial FGFR3 as a decoy for FGF ligand (recifercept), inhibition of FGFR3 TransCon CNP is another therapeutic option that might soon be available downstream signaling pathways (meclizine, C-type natriuretic peptide for the treatment of children with AP. In TransCon CNP, CNP is conjugated analogs (CNP)), modulation of growth via NPR2 receptor (CNP analogs) and via a cleavable linker to a polyethylene glycol carrier molecule, that prolongs use of aptamers or monoclonal antibodies to prevent binding of FGF to its CNP’s half-life, as a consequence of increased resistance to the action of receptor (aptamer RBM-007, vofamatab). The investigations into analogs neutral endopeptidase and minimizing renal clearance. The cleavage process of CNP, especially vosorotide, are currently the most advanced (4). results in slow, sustained CNP release, leading to continuous exposure of CNP at the growth plate. Its long half-life also allows convenient weekly subcutaneous administrations (12). Vosoritide Preclinical data in healthy cynomolgus monkeys showed that treatment with TransCon CNP subcutaneously once per week resulted in significant Vosoritide is a recombinant CNP analog. Preclinical studies in healthy mice growth increases in body, tail, and long bones compared to controls. An and cynomolgus monkeys have shown the efficacy of daily subcutaneous increase in height was also more pronounced in comparison to the animals vosoritide applications on endochondral bone growth stimulation without receiving a daily dose of CNP analog with the same amino acid sequence causing significant changes in bone quality parameters (5). In 2021, results as vosorotide (5% vs 3%, respectively), and no significant changes in of the extension phase 3 clinical trial in children with ACH aged between 5 to bone quality were observed with both treatments. Moreover, sustained 18, receiving vosoritide 15 µg/kg once daily in subcutaneous injection, were CNP release resulted in lower systemic CNP peak levels and has not been published. An increase in annualized growth velocity was observed, with 3.52 associated with adverse cardiovascular effects in monkeys treated with cm of height gain over a 2-year treatment period in comparison to untreated repeated weekly doses up to 100 µg/kg (12). The safe cardiovascular profile patients. In addition, improvement in the proportionality of body segments has also been recently confirmed in the first human clinical trial in healthy and no acceleration of the bone maturation process was observed (6). Mild adult males receiving single doses of TransCon CNP up to 150 µg/kg (13). adverse effects such as reactions at the injection site occurred in up to 73% of Phase 2 of the TransCon CNP clinical trial to assess its safety, tolerability, patients, and in 23% mild, transient, in majority asymptomatic hypotension and effect on annual growth velocity started in June 2020 is still ongoing. was observed after vosoritide application (7). Vosoritide was approved by TransCon CNP will be administered subcutaneously once per week for 52 both EMA and FDA for the treatment of ACH in children from the age of 2 weeks in children with achondroplasia aged 2–10 years (study identifier years until their growth plates are closed (8, 9). Vosoritide’s effect on final NCT04085523). adult height and prevention of neurological and orthopedic complications requiring surgical interventions is yet to be established. Current ongoing trials investigating its safety and efficacy in infants, young children, and those at risk of requiring cervical-medullary decompression surgery, will provide further insights into treatment effects on growth, proportionality, and other medical complications of ACH (10). In addition, long-acting CNP analogs, that would allow once weekly or once monthly applications, with equal or possibly increased efficiency are in the process of development (11). 50 51 References 12. Breinholt VM, Rasmussen CE, Mygind PH, Kjelgaard-Hansen M, Faltinger F, Bernhard A, et al. TransCon CNP, a sustained-release C-type natriuretic peptide prodrug, a potentially safe and efficacious new therapeutic modality for the treatment of comorbidities 1. Horton WA, Hall JG, Hecht JT. Achondroplasia. Lancet. 2007;370(9582): 162–72. associated with fibroblast growth factor receptor 3–related skeletal dysplasias. J Pharmacol Exp Ther. 2019;370(3):459–71. 2. Rousseau F, Bonaventure J, Legeai-Mallet L, Pelet A, Rozet J-M, Maroteaux P, et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. 13. Bharucha K, Ota S, Christoffersen ED, Mygind P, Viuff D, Leff J. TransCon CNP: Potential Nature. 1994;371(6494):252–4. for a once weekly novel therapy in children with achondroplasia. In: Bone Abstracts. Abstract Book: 9th International Conference on Children’s Bone Health. 2019 Jun 22-3. Kim J-M, Yang Y-S, Park KH, Oh H, Greenblatt MB, Shim J-H. The ERK MAPK pathway is 25, Salzburg, Austria. essential for skeletal development and homeostasis. Int J Mol Sci. 2019;20(8):1803. 4. Wrobel W, Pach E, Ben-Skowronek I. Advantages and disadvantages of different treatment methods in achondroplasia: A review. Int J Mol Sci. 2021;22(11):5573. 5. Wendt DJ, Dvorak-Ewell M, Bullens S, Lorget F, Bell SM, Peng J, et al. Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3–Related Dwarfism. J Pharmacol Exp Ther. 2015;353(1):132–49. 6. Savarirayan R, Tofts L, Irving M, Wilcox WR, Bacino CA, Hoover-Fong J, et al. Safe and persistent growth-promoting effects of vosoritide in children with achondroplasia: 2-year results from an open-label, phase 3 extension study. Genet Med. 2021;23(12):2443-2447. 7. Savarirayan R, Tofts L, Irving M, Wilcox W, Bacino CA, Hoover-Fong J, et al. Once-daily, subcutaneous vosoritide therapy in children with achondroplasia: A randomised, double-blind, phase 3, placebo-controlled, multicentre trial. Lancet. 2020;396(10252):684–92. 8. European Medicines Agency [Internet]. Vosoritide: Summary of Product Characteristics [cited 2021 Oct 22]. Available from: https://www.ema.europa.eu/en/documents/ product-information/voxzogo-epar-product-information_en.pdf. 9. U.S. Food And Drug Association [Internet]. FDA Approves First Drug to Improve Growth in Children with Most Common Form of Dwarfism [cited 2021 Oct 19]. Available from: https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-improve-growth-children-most-common-form-dwarfism. 10. Savarirayan R, Irving M, Maixner W, Thompson D, Offiah AC, Connolly DJA, et al. Rationale, design, and methods of a randomized, controlled, open-label clinical trial with open-label extension to investigate the safety of vosoritide in infants, and young children with achondroplasia at risk of requiring cervicomedullary decompression surgery. Sci Prog. 2021;104(1):368504211003782. 11. S chneider EL, Carreras CW, Reid R, Ashley GW, Santi DV. A long-acting C-natriuretic peptide for achondroplasia. Proc Natl Acad Sci USA. 2022;119(30):e2201067119. 52 53 07 GENE THERAPY FOR METABOLIC DISORDERS Urh Grošelj1,2, Ana Drole Torkar1,2, Mojca Žerjav Tanšek1,2, Tadej Battelino1,2 1 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia urh.groselj@kclj.si Introduction In the last few years, we have witnessed the first major series of clinically useful therapies for certain genetic disorders or for cancer, which are already significantly changing the lives of still very few patients, also in our country (1, 2). At the same time, many research studies in this field are being conducted in various stages of research, with many more new therapies can be expected in the relatively near future. Since 2018, when the first Slovenian patient with inborn error of metabolism (IEM) was referred abroad for experimental gene therapy, several other patients with various rare congenital diseases have been genetically treated at our institution (1, 2). In December 2021, the first successful application of gene therapy in Slovenia was carried out at the University Children’s Hospital, UMC Ljubljana, in a child with spinal muscular atrophy, which represents a new important milestone for our area. It is also worth mentioning the very rapid progress that we are witnessing at the same time in the field of treating certain rare types of blood cancers with genetic therapy (i.e. treatment with CAR-T lymphocytes); in 2019, the first Slovenian pediatric patient was already treated abroad in this way, and it is planned for this 54 55 type of therapies to be produced and administered in our country in a near vivo application of gene therapy was performed with the transplantation future. of hematopoietic stem cells treated with a lentiviral vector (Ospedale San Twelve different gene therapies are currently approved by the European Raffaele, Milan, Italy; sponsored by IRCCS San Raphael). The patient is Medicines Agency (EMA). These include therapies for rare forms of regularly monitored by the study center in Italy and in parallel also at our blindness and leukemia, spinal muscular atrophy, and a type of congenital department, where we currently note a favorable course of the disease, but immunodeficiency. This may be negligible compared to around 8,000 known the final outcome is not yet clear. rare diseases, most of which are genetically determined, but it is expected Patient with MPS IIIA: The diagnosis was made pre-symptomatically, in that the number of approved gene therapies will gradually but steadily the neonatal period, because his older sibling (in whom unfortunately, increase in the coming years (1, 2). the disease was already advanced at that time) had the same diagnosis a In 2012, the first gene therapy approved in Europe was the therapy for short time before. Neonatally, only a coarser facial features were described, recurrent lipoprotein lipase deficiency pancreatitis (Glybera, uniQure), an but otherwise there were no other deviations. The presence of known extremely rare IEM that causes extremely elevated triglyceride levels. This familial genetic alterations of the SHGS gene was confirmed. At the age therapy was later withdrawn (in 2017) due to a lack of commercial interest of 6 months, inclusion in a gene therapy clinical trial in Spain was planned, (due to very few candidates for therapy and also due to a very high price but unfortunately, due to the COVID-19 epidemic, the treatment was not demanded). Nevertheless, the arrival of this drug on the market stimulated carried out until the age of 9 months. A single application of in vivo gene the development of other gene therapies (1,2). therapy with the AAV9 vector was then performed (Hospital Universitario Santiago de Compostela, Santiago de Compostela, Spain; sponsored by Aboena Therapeutics). The patient is regularly monitored by the study center in Spain and, in parallel, at our department, which is included in the Our experiences with gene therapies for metabolic disorders research protocol as an associated study center. For now, we are observing Between 2018 and 2021, we referred four of our patients abroad for a very favorable course of the disease, but the final outcome is not yet experimental gene therapy, one with MPS I, two with MPS IIIa, and one clear. with metachromatic leukodystrophy (in collaboration with pediatric neurologists), who were later successfully treated and continue to be regularly monitored at our institution, in cooperation with both study Conclusions centers. The details of the treatment of two of these patients are briefly Gene therapy represents an important turning point for patients with summarized as follows (1, 2). many hitherto incurable congenital genetic diseases, but is still available Patient with MPS I: Development in the first year was as expected, then for few diseases only. The last decade has brought a great progress in this regression in speech development and unsteady gait were noticed. At the field, including in Slovenia; gene therapy was successfully used in several age of 18 months, he was examined by developmental pediatrician, where Slovenian patients in the last few years. It is expected that in the next hypertelorism, a wide nasal root, a bulging forehead, and sharp facial decade progress in this area will be even more significant, which we must features were noted. Later, hepatomegaly, flexion contractures in the knee, take into account when planning and organizing activities in this area. and umbilical hernia were also found. He was referred to our department, Importanly, an early (i.e. in newborns) detection of the diseases that will where soon after, MPS I was confirmed. Just before the age of two, an ex become “genetically curable “ will become an imperative. We need to 56 57 08 continue following the most developed countries, so that we can introduce FUNCTIONAL HYPOGONADISM: innovations into practice as quickly as possible. WEIGHT LOSS OR TESTOSTERONE? Nevertheless, there remain many ethical challenges and open questions WEIGHT LOSS regarding gene therapy. Among these, it is worth mentioning in particular: the very high price of available therapies (which on the other hand, is in Matej Rakuša most cases lower than the long-term treatment of the same patients with other therapies, such as e.g. enzyme replacement therapy or factor Department of Endocrinology, Diabetes and Metabolic Diseases, therapy in hemophilia); the problem of sufficient production and, especially University Medical Centre Ljubljana, Ljubljana, Slovenia in the case of the ex vivo approach, also of the distribution of gene therapy; Faculty of Medicine, inability to treat diseases caused by changes in several genes or changes University of Ljubljana, Ljubljana, Slovenia at the level of chromosomes; the long-term safety of gene therapy is also not entirely clear due to short follow up periods; the problem of matej.rakusa@kclj.si treating patients who previously have antibodies against the viral vector. Above all, it will probably be possible to treat only few patients for a long time. Consequently, for a while, gene therapy will not yet transform the treatment of the entire group of patients with rare diseases. Functional hypogonadism (FH) usually presents a more subtle clinical picture, with non-specific symptoms and usually no overt signs of androgen deficiency. However, it can present with clinical symptoms or signs similar to classical hypogonadism (1). Although sexual symptoms as decreased frequency of morning erection, decreased frequency of sexual thoughts and erectile dysfunction were more frequently associated with low testosterone (T) in community dwelling middle aged and elderly European males. For the diagnosis of FH, the presence of symptoms and total T <8 nmol/L or total T <11 nmol/L and calculated free T <220 pmol/L should be established (2). References The overall prevalence of FH is estimated to 2.1–4.8%, and increases with age (2, 3). Obesity of all grades, especially World Health Organisation class 1. Lah B, Jalšovec T, Drole Torkar A, Kodrič J, Battelino S, Žerjav Tanšek M, et al. Gensko III obesity (BMI>40 kg/m2), is a major and increasingly common cause zdravljenje pri mukopolisaharidozi tipa IIIa: predstavitev primerov. Slov Pediatr 2022; of low T (1). In meta-analysis of 68 studies and almost 20.000 men with 29(2): 10−15. obesity, 42.8% had serum total T <10.4 nmol/L (4). Based on mendelian 2. Jalšovec T, Lah B, Drole Torkar A, Kodrič J, Žerjav Tanšek M, Avčin SL, et al. Gensko randomisation analysis on 7446 participants, an increase of BMI from zdravljenje otroka z mukopolisaharidozo tipa I - prikaz primera prvega uspešnega 25 kg/m2 to 30 kg/m2 is associated with a decrease in serum testosterone genskega zdravljenja slovenskega pacienta v tujini. Zdrav vestn. In press 2022. concentration of 13–15% (5). 58 59 European Academy of Andrology guidelines on investigation, treatment Weight reduction should be the first line of management and strongly and monitoring of functional hypogonadism in men recommends lifestyle encouraged in all overweight and obese men with low T. Significant changes, including physical exercise and weight reduction, in overweight collateral health benefits may also accrue from these life style changes, and obese men with functional hypogonadism, since weight loss may potentially offering valuable opportunities for preventative care in middle-increase T concentration (1). Longitudinal results of European Male Ageing aged men. Study show that total T increased in men who lost at least 5% weight during mean follow-up of 4.4±0.3 years. T increment was higher with more weight loss, the highest when >15% of weight, with recovery from secondary hypogonadism (6). Meta-analysis of 22 trials assessed the effect of low-calorie diet on hypogonadism. Meta-analysis included 567 patients of average 44.9 years and mean BMI of 36.0 kg/m2, and a mean follow up of 23 weeks. Trials differed in basal total T and types of diets. Low calorie diets result in significant increase in total T, SHBG and free T. Meta-regression analysis References showed that higher weight reduction is associated with a higher T increase, meaning that each 5 kg of weight reduction results in 1 mmol/L increase (7). 1. Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, et al. European Meta-analysis of male patients who underwent bariatric surgery (BS) Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring and reduced BMI from 46.60±6.42 kg/m2 to 30.14±4.6 kg/m2 in 12 months of functional hypogonadism in males. Endorsing organization: European Society of showed a rise in total T (MD 7.32; 95% CI 5.44 to 9.20; P < 0.00001) and Endocrinology. Andrology. 2020;8(5):970-87. free T (SMD 0.99; 95% CI 0.54 to 1.44; P < 0.0001). Also, LH, FSH and 2. Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, et al. EMAS Group. Identification SHBG increased significantly (8). When morbidly obese patients with of late-onset hypogonadism in middle-aged and elderly men. N Engl J Med. hypogonadism were compared with non-hypogonadal patients, total and 2010;363(2):123-35. free T significantly increased only in hypogonadal patients post BS (9). In 3. Rastrelli G, Corona G, Tarocchi M, Mannucci E, Maggi M. How to define hypogonadism? obese adolescent men with subnormal T, reduction of body weight for one-Results from a population of men consulting for sexual dysfunction. J Endocrinol third, which was maximal at 24 months post-surgery, resulted in increased Invest. 2016;39(4):473-84. total and calculated free T up to 5 years (10). In addition to hormone profile 4. van Hulsteijn LT, Pasquali R, Casanueva F, Haluzik M, Ledoux S, Monteiro MP, Salvador also erectile function and symptoms of hypogonadism improved (11). J, Santini F, Toplak H, Dekkers OM. Prevalence of endocrine disorders in obese patients: systematic review and meta-analysis. Eur J Endocrinol. 2020;182(1):11-21. Antihyperglycemic drug liraglutide is a glucagon like peptide-1 analogue. It also induces weight loss. In a 16-week randomised clinical trial 3.0 mg/d 5. Eriksson J, Haring R, Grarup N, Vandenput L, Wallaschofski H, Lorentzen E, et al. Causal relationship between obesity and serum testosterone status in men: A bi-directional liraglutide was compared to 1% T gel. Liraglutide reduced weight by 6%. mendelian randomization analysis. PLoS One. 2017;12(4):e0176277. Both treatments ameliorated sexual symptoms and significantly increased total T, although the increase was more evident with T gel (5.9 vs. 2.6 6. Camacho EM, Huhtaniemi IT, O’Neill TW, Finn JD, Pye SR, Lee DM, et al. EMAS Group. Age-associated changes in hypothalamic-pituitary-testicular function in middle-aged mmol/L). Liraglutide marginally improved LH (0.7 mU/L), in comparison to and older men are modified by weight change and lifestyle factors: longitudinal results T gel which reduced it (12). from the European Male Ageing Study. Eur J Endocrinol. 2013;168(3):445-55. 60 61 09 7. Corona G, Rastrelli G, Morelli A, Sarchielli E, Cipriani S, Vignozzi L, et al. Treatment of FUNCTIONAL HYPOGONADISM – Functional Hypogonadism Besides Pharmacological Substitution. World J Mens Health. 2020;38(3):256-70. TREATMENT WITH TESTOSTERONE THERAPY 8. Al Qurashi AA, Qadri SH, Lund S, Ansari US, Arif A, Durdana AR, et al. The effects of bariatric surgery on male and female fertility: A systematic review and meta-analysis. Ann Med Surg (Lond). 2022;80:103881. Kristina Groti Antonič 1,2 9. Samavat J, Facchiano E, Lucchese M, Forti G, Mannucci E, Maggi M, et al. Hypogonadism 1 as an additional indication for bariatric surgery in male morbid obesity? Eur J Department of Endocrinology, Diabetes and Metabolic Diseases, Endocrinol. 2014;171(5):555-60. University Medical Center Ljubljana, Slovenia 10. Dhindsa S, Ghanim H, Jenkins T, Inge TH, Harmon CM, Ghoshal A, et al. High prevalence 2 Faculty of Medicine, of subnormal testosterone in obese adolescent males: reversal with bariatric surgery. University of Ljubljana, Ljubljana, Slovenia Eur J Endocrinol. 2022;186(3):319-327. 10. Machado FP, Rhoden EL, Pioner SR, Halmenschlager G, de Souza LVB, Lisot BC, et al. kristina.groti@kclj.si Weight Loss Through Bariatric Surgery in Men Presents Beneficial Effects on Sexual Function, Symptoms of Testosterone Deficiency, and Hormonal Profile. Sex Med. 2021;9(4):100400. 12. Jensterle M, Podbregar A, Goričar K, Gregorič N, Janež A. Effects of liraglutide on obesity-associated functional hypogonadism in men. Endocr Connect. 2019;8(3):195-202. Hypogonadism in males is classified as either organic, due to medical disease of the hypothalamic-pituitary-testicular axis (HPT), or as functional (1). Functional hypogonadism (FH) is defined as the coexistence of androgen deficiency clinical features and lowered serum testosterone concentrations occurring in the absence of both intrinsic structural HPT axis pathology (e.g. Klinefelter’s syndrome, pituitary tumor) and specific pathologic conditions suppressing the HPT axis ( e.g. Cushing’s syndrome, prolactinoma) in middle-aged or older men (2). Diagnosis of FH should only be confirmed after the exclusion of organic causes of hypogonadism (3). In contrast to organic hypogonadism, FH may be potentially reversible if underlying causes are identified and adequately treated or removed, whereas organic hypogonadism is generally irreversible (1,2). The vast majority of FH occurrences are associated with aging and comorbidities such as obesity, type 2 diabetes (T2D), or metabolic syndrome (MetS) (4). The community prevalence estimates of FH in middle-aged and older men vary from 2.1% to 12.3% (1). Approximately 50% of males with T2D, aged >40 years, exhibit decreased total testosterone levels (5). As much 62 63 as 45.0-57.5% of male FH prevalence is attributable to obesity and related clinical trials that TTh improves sexual symptoms in hypogonadal men with causes (6). MetS and/or T2D (16–19). Long-term TTh in 823 hypogonadal males (among Diagnostic criteria for FH include the simultaneous presence of low serum which 57.6% were obese) showed that 11 years of therapy improved body testosterone (total testosterone <11 nmol/L and free testosterone <220 weight, waist circumference, and body mass index, along with a significant increase in testosterone levels (8.5 ± 0.2 nmol/L). TTh also decreased fasting pmol/L) and three sexual symptoms (erectile dysfunction, reduced frequency blood glucose and glycated hemoglobin (HbA1c) and improved lipid profiles of sexual thoughts, and morning erections) (3, 7). (20). Another study showed that TTh achieved a statistically significant reduction in fat mass, increase in lean body mass, and HbA1c improvement associated with a 52% improvement in beta-cell function (21). A small Treatment options in middle-aged and older males with FH randomized controlled trial involving 16 subjects with newly diagnosed Obesity-related FH aims to achieve significant weight loss through dietary T2D and MetS demonstrated that the combination of TTh and lifestyle modifications such as caloric restriction, increased physical activity, or by interventions led to greater therapeutic improvements in glycemic control means of bariatric surgery (3, 8). Few randomized clinical studies have and reversed MetS condition after 52 weeks of treatment compared with evaluated the impact of diet and physical activity on testosterone levels lifestyle interventions alone (9). in obese men with FH, with conflicting results. Some of them showed an Other benefits of TTh include improvement in libido and erectile function, increase in testosterone (9), others showed no change (10), and one small volumetric vertebral and femoral mineral bone density, body composition, study has shown a decrease in testosterone levels (11). Longitudinal data anemia, energy, and motivation, and also reduce arterial stiffness, from the European Male Aging Study (EMAS) showed that weight loss can intraabdominal and intramuscular fat, and bone remodeling, which are increase testosterone levels in obese men, and the rise in testosterone level added advantages to the treatment of symptoms of testosterone deficiency is proportional to the extent of weight loss achieved (12). Minor weight (2, 22–25). Low testosterone may contribute to poor motivation to initiate loss (<15%) was associated with a modest increase in total testosterone healthy lifestyle interventions. Few studies have shown that TTh may levels (by 2 nmol/L) and increases in SHBG (due to improvement in insulin increase motivation to diet and exercise (1, 26). In addition, long-duration resistance), while there was no increase in free testosterone levels at this epidemiological studies have found that TTh reduced mortality in T2D (27). degree of weight loss (13). Several clinical trials have evaluated the impact In some men, measures to reverse FH may be unsuccessful, either because of bariatric surgery on testosterone levels in men, showing an increase the implementation of treatment is not feasible (e.g. cessation of opioids in testosterone levels following the procedure, which is more efficient in in chronic pain or antiretroviral therapy for HIV) or they are not achieved achieving weight loss than a low-calorie diet (14). Lifestyle modifications or maintained (e.g. sustained weight loss in obese patients). Even if resulted in a mean weight loss of 9.8%, with an increase in total testosterone successful, such measures may be insufficient to relieve symptoms and of 2.9 nmol/L. In contrast, bariatric surgery achieved a mean weight loss of normalize testosterone levels. In these men, testosterone treatment could 32% with an increase in total testosterone of 8.7 nmol/L (15). be started concomitantly or after these initial measures fail (1). Guidelines The role of testosterone treatment in middle-aged to older men with suggest a trial testosterone treatment for no less than six months in FH remains debatable and controversial because definitive clinical trials these men to determine whether there is a clinical benefit of TTh. The designed and powered to provide conclusive evidence regarding long-term Testosterone Trials clearly showed improvement of most symptoms of FH health benefits and potential risks of testosterone therapy (TTh) are within three months of initiation of testosterone treatment and recovery currently lacking (1, 2). There is a good evidence from larger randomized of testosterone concentrations to the mid-normal range (28). When there 64 65 is no clinical improvement after six months of sufficient testosterone 7. Martits A, Costa E, Nardi A, Nardozza Jr A, Faria G, Facio Jr F, et al. Late-onset replacement, TTh should be discontinued, and other causes of symptoms hypogonadism or ADAM: diagnosis. Rev Assoc Médica Bras. 2014;60:286–94. or alternate testosterone modalities should be considered (1, 3, 8). 8. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone therapy in men with hypogonadism: an Endocrine society clinical practice Whenever testosterone treatment is considered, contraindications must guideline. J Clin Endocrinol Metab. 2018;103(5):1715–44. first be excluded. TTh is contraindicated in men with untreated prostate 9. Heufelder AE, Saad F, Bunck MC, Gooren L. Fifty‐two week treatment with diet and and breast cancer, as well as severe heart failure and recent major acute exercise plus transdermal testosterone reverses the metabolic syndrome and improves CV events. Severe low urinary tract symptoms and hematocrit >48–50% glycemic control in men with newly diagnosed type 2 diabetes and subnormal plasma are relative contraindications for TTh (3, 8, 29). The patient should be fully testosterone. J Androl. 2013;30(6):726–33. informed of potential risks prior to agreeing on the treatment. 10. Reis LO, Favaro WJ, Barreiro GC, De Oliveira LC, Chaim EA, Fregonesi A, et al. Erectile The follow-up of the testosterone treatment in patients with FH is regulated dysfunction and hormonal imbalance in morbidly obese male is reversed after gastric bypass surgery: a prospective randomized controlled trial. Int J Androl. 2010;33(5):736–44. by recommendations made in the Endocrine Society guidelines. 11. KLIBANSKI A, BEITINS IZ, BADGER T, LITTLE R, MCARTHUR JW. Reproductive Function during Fasting in Men*. J Clin Endocrinol Metab. 1981;53(2):258–63. 12. Tajar A, Huhtaniemi IT, O’Neill TW, Finn JD, Pye SR, Lee DM, et al. Characteristics of androgen deficiency in late-onset hypogonadism: results from the European male aging study (EMAS). J Clin Endocrinol Metab. 2012;97(5)(5):1508–16. References 13. Grossmann M. Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab. 2011;96(8):2341–53. 1. Grossmann M, Matsumoto AM. A perspective on middle-aged and older men with 14. Alagna S, Cossu ML, Gallo P, Tilocca PL, Pileri P, Alagna G, et al. Biliopancreatic diversion: functional hypogonadism: focus on holistic management. J Clin Endocrinol Metab. long-term effects on gonadal function in severely obese men. Surg Obes Relat Dis. 2017;102(3)(3):1067–75. 2006;2(2):82–6. 2. Grossmann M, Jones TH. Functional hypogonadism in middle-aged and older men: 15. Corona G, Rastrelli G, Monami M, Saad F, Luconi M, Lucchese M, et al. Body weight loss testosterone treatment or not? Eur J Endocrinol. 2021;185(3):D1–9. reverts obesity-associated hypogonadotropic hypogonadism: a systematic review and 3. Corona G, Goulis DG, Huhtaniemi I, Zitzmann M, Toppari J, Forti G, et al. European meta-analysis. Eur J Endocrinol. 2013;168(6):829–43. Academy of Andrology (EAA) guidelines on investigation, treatment and monitoring of 16. Jones TH, Arver S, Behre HM, Buvat J, Meuleman E, Moncada I, et al. Testosterone functional hypogonadism in males. Andrology. 2020;8(5):970–87. replacement in hypogonadal men with type 2 diabetes and/or metabolic syndrome 4. Louters M, Pearlman M, Solsrud E, Pearlman A. Functional hypogonadism among (the TIMES2 study). Diabetes Care. 2011;34(4):828–37. patients with obesity, diabetes, and metabolic syndrome. Int J Impot Res [Internet]. 17. Hackett G, Cole N, Bhartia M, Kennedy D, Raju J, Wilkinson P, et al. Testosterone 2021 Nov 13; Available from: https://doi.org/10.1038/s41443-021-00496-7 replacement therapy improves metabolic parameters in hypogonadal men with type 5. Hall SA, Esche GR, Araujo AB, Travison TG, Clark RV, Williams RE, et al. Correlates of low 2 diabetes but not in men with coexisting depression: the BLAST study. J Sex Med. testosterone and symptomatic androgen deficiency in a population-based sample. J 2014;11(3):840–56. Clin Endocrinol Metab. 2008;93(10):3870–7. 18. Kalinchenko SY, Tishova YA, Mskhalaya GJ, Gooren Louis J. G., Giltay Erik J., Saad Farid. 6. Calderón B, Gómez-Martín JM, Vega-Piñero B, Martín-Hidalgo A, Galindo J, Luque-Effects of testosterone supplementation on markers of the metabolic syndrome and Ramírez M, et al. Prevalence of male secondary hypogonadism in moderate to severe inflammation in hypogonadal men with the metabolic syndrome: the double‐blinded obesity and its relationship with insulin resistance and excess body weight. Andrology. placebo‐controlled Moscow study. Clin Endocrinol (Oxf). 2010;73(5):602–12. 2016;4(1):62–7. 66 67 10 19. Yassin AA, Alwani M, Talib R, Almehmadi Y, Nettleship JE, Alrumaihi K, et al. Long-term DIABETIC FOOT SCREENING testosterone therapy improves liver parameters and steatosis in hypogonadal men: a prospective controlled registry study. Aging Male. 2020;23(5):1553–63. FROM 1996 TO 2022: 20. Saad F, Doros G, Haider KS, Haider A. Differential effects of 11 years of long-term MESSAGES FROM THE DATA-BASE injectable testosterone undecanoate therapy on anthropometric and metabolic parameters in hypogonadal men with normal weight, overweight and obesity in Vilma Urbančič Rovan 1,2 comparison with untreated controls: real-world data from a controlled registry study. Int J Obes 2005. 2020;44(6):1264–78. 1 Department of Endocrinology, Diabetes and Metabolic Diseases, 21. Dimitriadis GK, Randeva HS, Aftab S, Ali A, Hattersley JG, Pandey S, et al. Metabolic University Medical Centre Ljubljana, Ljubljana, Slovenia phenotype of male obesity-related secondary hypogonadism pre-replacement and 2 post-replacement therapy with intra-muscular testosterone undecanoate therapy. Faculty of Medicine, Endocrine. 2018;60(1):175–84. University of Ljubljana, Ljubljana, Slovenia 22. Corona G, Giagulli VA, Maseroli E, Vignozzi L, Aversa A, Zitzmann M, et al. Therapy of endocrine disease: Testosterone supplementation and body composition: results from vilma.urbancic@kclj.si a meta-analysis study. Eur J Endocrinol. 2016;174(3):R99–116. 23. Snyder PJ, Kopperdahl DL, Stephens-Shields AJ, Ellenberg SS, Cauley JA, Ensrud KE, et al. Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial. JAMA Intern Med. 2017;177(4):471–9. 24. Vlachopoulos C, Ioakeimidis N, Miner M, Aggelis A, Pietri P, Terentes-Printzios D, et Foot ulcers, gangrene and amputation are among the most feared al. Testosterone deficiency: A determinant of aortic stiffness in men. Atherosclerosis. complications of diabetes mellitus that also importantly influence the 2014;233(1):278–83. quality of life. They pose a huge burden on the patient and his relatives 25. Haider A, Gooren LJG, Padungtod P, Saad F. Improvement of the metabolic syndrome as well as on the healthcare system (1). Many foot complications can be and of non-alcoholic liver steatosis upon treatment of hypogonadal elderly men with prevented by interdisciplinary approach, which includes early detection of parenteral testosterone undecanoate. Exp Clin Endocrinol Diabetes. 2010;118(3):167– 71. high-risk patients, treatment of foot ulcers, rehabilitation and prevention of recurrence (2–5). 26. Watts NB, Adler RA, Bilezikian JP, Drake MT, Eastell R, Orwoll ES, et al. Osteoporosis in men: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. The International Working Group on the Diabetic Foot (IWGDF) has 2012;97(6):1802–22. recommended an annual examination of people with diabetes at very low 27. Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency risk of foot ulceration (IWGDF risk 0) to screen for developing risk factors is associated with increased risk of mortality and testosterone replacement improves (history of foot ulcer, foot deformity, loss of protective sensation, absent survival in men with type 2 diabetes. Eur J Endocrinol. 2013;169(6):725–33. pedal pulses) (6). The recommendation of at least 12-month interval of 28. Snyder PJ, Bhasin S, Cunningham GR, Matsumoto AM, Stephens-Shields AJ, Cauley JA, screening is in line with the view of other scientific societies (7) and is et al. Lessons from the testosterone trials. Endocr Rev. 2018;39(3):369–86. largely based on the general expert consensus rather than on strong clinical 29. Minhas S, Bettocchi C, Boeri L, Capogrosso P, Carvalho J, Cilesiz NC, et al. European evidence. A large proportion of people with diabetes do not receive proper Association of Urology Guidelines on Male Sexual and Reproductive Health: 2021 screening due to insufficiencies in health care resources even in developed Update on Male Infertility. Eur Urol 2021;80(5):603–620. countries (8). 68 69 Structured diabetic foot care in Slovenia started around the year 1990; in 1 – normal sensation, no deformity; 2 – loss of protective sensation, no January 1995 a National working group on the diabetic foot was established, deformity; 3 – ischemia without deformity or sensory loss; 4 – combination of a national foot screening protocol was adopted in July 1995. sensory loss and/or deformity and/or absent pedal pulses; history of foot ulcer; Out-patient diabetes clinic in Ljubljana offers care to approximately 9,500 Charcot foot. Adoption of the IWGDF classification is planned in January 2023. registered patients with diabetes. Diabetic foot clinic was established in January 1990. At the beginning, it was running once weekly but gradually TABLE 1: expanded into full-time service, running daily from Monday to Friday, in two The number of successive foot examinations between 1996 and 2022. rooms with 4 examination desks, two full-time and one part-time nurse N and one doctor – consultant (specialist in internal medicine – diabetology). 1st examination 15,812 The activities of the foot clinic are both preventative and curative: foot 2nd examination 8,053 screening, ankle-brachial index measurement, education about foot care, 3rd examination 5,163 wound care and research. Interdisciplinary approach is well established, the 4th examination 3,419 cooperation with surgery and angiology department is running smoothly. 5th examination 2,336 Regular foot screening was introduced in November 1996. A computerized 6th examination 1,631 data base in a form of an Excel file was created at the very beginning and 7th examination 1,162 all data obtained have been recorded. There was no overwriting of the 8th examination 840 entries, the findings of successive foot examinations were entered into 9th examination 621 successive file sheets. In this way, the file currently contains 25 sheets as 10th examination 469 4 patients have had 25 foot examinations during the course of 27 years. 11th examination 313 12th examination 231 According to the recommendations of IWGDF [6], at least 9,500 foot 13th examination 165 screening procedures should be performed every year – on average 36 on 14th examination 114 every of the 260 working days – which is absolutely unfeasible with the 15th examination 82 available resources. In the period from November 1996 till end of August 16th examination 58 2022, 40,634 foot screenings were done, on average 1,505 per year. At least 17th examination 45 one foot examination was done in 15,812 patients. The number of follow-up 18th examination 39 screening procedures is much smaller, with less than 1,000 patients being 19th examination 22 examined 8 times or more and less than 100 patients 15 times or more. 20th examination 18 The average number of first foot examinations is less than 600 per year. 21st examination 14 This number was higher in the first years when we had to screen the whole 22nd examination 10 population attending the clinic. Later on, the majority of the patients are 23rd examination 7 screened immediately after the diagnosis of diabetes is confirmed. The 24th examination 6 detailed figures on the work done are shown in Tables 1, 2 and 3. 25th examination 4 Slovenian foot screening protocol follows the recommendations from Total 40,634 the IWGDF guideline, the only difference is the risk status classification: Average/year 1,505 70 71 TABLE 2: frequency for screening of those with low risk, thus freeing up resources for Summary of the findings at the first foot examination those with higher foot ulcer risk (9). (total 15,812 records). N % History of foot ulcer 683 4,3 Symptoms of neuropathy 6829 43,2 Foot deformity 8877 56,1 Open ulcer 945 6,0 Loss of protective sensation 2511 16,5 References Absent pedal pulses 1151 7,6 1. Armstrong DG, Swerdlow MA, Armstrong AA, Conte MS, Padula WV, Bus SA. Five year mortality and direct costs of care for people with diabetic foot complications are TABLE 3: Risk status classification at the first foot examination comparable to cancer. J Foot Ankle Res. 2020;13(1):16. (total 15,812 records). 2. Schaper NC, van Netten JJ, Apelqvist J, Bus SA, Hinchliffe RJ, Lipsky BA, et al. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 Risk group N % update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3266. 1 9812 62,1 3. Monteiro-Soares M, Russell D, Boyko EJ, Jeffcoate W, Mills JL, Morbach S, et al. Guidelines 2 2011 12,7 on the classification of diabetic foot ulcers (IWGDF 2019). Diabetes Metab Res Rev. 3 0257 1,6 2020;36 Suppl 1:e3273. 4 3732 23,6 4. Rayman G, Vas P, Dhatariya K, Driver V, Hartemann A, Londahl M, et al. Guidelines on use of interventions to enhance healing of chronic foot ulcers in diabetes (IWGDF 2019 An interesting observation is the number of referrals to vascular specialist. update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3283. During the first three years, we have had over 100 referrals per year, later 5. Bus SA, Lavery LA, Monteiro-Soares M, Rasmussen A, Raspovic A, Sacco ICN, et al. this number dropped to values between 20 in 25, representing approximately Guidelines on the prevention of foot ulcers in persons with diabetes (IWGDF 2019 5% of the screened patients. The higher numbers in the first years may be update). Diabetes Metab Res Rev. 2020;36 Suppl 1:e3269. due to longer duration of diabetes at the time of first foot examination. 6. Schaper NC, van Netten JJ, Apelqvist J, et al. Practical Guidelines on the prevention and management of diabetic foot disease (IWGDF 2019 update). Diabetes Metab Res Rev. The messages 2020;36 Suppl 1:e3266. 7. Formosa C, Gatt A, Chockalingam N. A Critical Evaluation of Existing Diabetic Foot Diabetic foot screening not only reveals the patients who are at risk of Screening Guidelines. Rev Diabet Stud. 2016;13(2-3):158-186. developing foot ulceration but also provides a comprehensive overview of 8. Chevreul K, Berg Brigham K, Bouché C. The burden and treatment of diabetes in foot pathology in the observed population. Annual screening of the whole France. Global Health. 2014;10:6. population is not feasible because of limited resources. A risk prediction model which would enables stratification of individuals based on likelihood 9. Štotl I, Blagus R, Urbančič-Rovan V. Individualised screening of diabetic foot: creation of a prediction model based on penalised regression and assessment of theoretical of complications is urgently needed because it would enable extending the efficacy. Diabetologia. 2022;65(2):291-300. 72 73 11 SCREENING OPTIMIZATION USING PREDICTIVE MODELS Iztok Štotl Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia iztok.stotl@guest.arnes.si Diabetic foot disease poses a huge burden on the people with diabetes, including their family, health care system, and society in general (1). Strategies that include elements of screening, prevention, patient and staff education, and interdisciplinary treatment can reduce the load of diabetic foot disease on individual and public level (2). However, implementation of the guidelines and the establishment of multidisciplinary clinics for holistic management of diabetic foot disorders varies and remains sub-optimal (1). Self-assessment of diabetes-related foot problems is unreliable, and self-perceived foot health should be assessed together with foot examination findings (3). Therefore, the International Working Group on the Diabetic Foot (IWGDF) has recommended an annual examination of people with diabetes at very low risk of foot ulceration (IWGDF risk 0) to screen for developing risk factors (2). The recommendation of at least 12 months interval of screening is in line with the view of other scientific societies (4) and is largely based on the general expert consensus and on the results of the study of Litzelman et al. (5) that did not directly address the question of different lengths of the screening interval. 74 75 A large proportion of people with diabetes do not receive proper screening probability for LPP and LOPS (11). The potential for biennial rather than due to insufficiencies in health care resources, even in developed countries. annual screening, for subjects stratified as IWGDF group 0 and a low It was estimated that only 20% of people with diabetes are being probability of complications (using 5% and 10% threshold), was estimated. screened with a monofilament according to ENTRED study in France (6). The decision about the alternative biennial screening interval duration in A multicenter, epidemiological, cross-sectional study from Fernandez et case of low risk was arbitrary and was based on the local estimate of total al. (7) that examined clinical records of 443 people with type 2 diabetes numbers of screenings needed, that would be manageable at our clinic. in primary care in Spain, showed poor diabetic foot screening compliance The individual probability estimation needed for the organizational model (performed in 37%) and infrequent ulcer risk stratification (performed in was calculated on patient population of our clinic. In this proof of the 12.4%). According to the Scottish Diabetes Survey from 2019, 56.7% of concept study, we could demonstrate a 26.5% (cut-off: 5% risk) to 40.5 people with type 1 and 64.8% with type 2 diabetes had their foot scores % (cut-off: 10% risk) reduction of absolute number of screenings needed recorded within 15 months (8). for population with IWGDF risk 0 in two year period, when the screening The probability of foot complications among persons with diabetes interval was extended biennially instead of annually in the low-risk group. can show substantial individualized variability and within different Reduction was even more pronounced when the model was tested with populations (9). This variation is not addressed efficiently with current IWGDF 0 group without foot deformities. recommendations that propose fixed and arbitrary screening frequency (10). Screening interval is increasingly recognized as a public health blind spot that offers many opportunities for improvement of healthcare (10). A Reduction of screenings in 2 years in IWGDF risk group 0 clinical prediction model could be used to tailor the frequency of screening Probability cut-off 5% 10% for each person based on individual probability of complications at the time All screenings 26.5% 40.5% of screening. Without foot deformity 36.9% 46.8% Creation of a proof of the concept organizational model Currently, the patients with diabetes at our center are not screened Our study group has developed a prediction model for diabetic foot according to the guidelines, predominantly due to insufficient capacity and complications that shows good discrimination ability with cross-validated only partial insurance reimbursement. Introduction of the framework that AUC of 0.84 for LOPS (loss of peripheral sensation) and 0.80 for LPP (loss of proposes fewer examinations than currently advised by guidelines would peripheral pulses) (11). The majority of foot screenings not unsurprisingly paradoxically increase the absolute numbers of screenings performed in are performed on patients with low risk at our clinic. Additionally, the patients with IWGDF risk 0 at our center, therefore, safety and efficiency risk for foot complications over years seems to increase more slowly in may improve. people with low baseline risk than in their high baseline risk counterparts, therefore identification of low risk sub-population presents an opportunity for optimizing the screening process. Conclusions As a proof of the concept, we have created a simplified organizational model Diabetes related burden for health care systems is increasing with aging for screening of subjects with IWGDF risk 0 and based on individualized populations, increasing diabetes prevalence and obesity worldwide. 76 77 Improvements in health care systems are urgently needed to enable References adequate care for people with diabetes that is often not optimal because of lack of systemic resources. 1. van Acker K, Léger P, Hartemann A, Chawla A, Siddiqui MK. Burden of diabetic foot A protocol for diabetic foot screening that is enhanced by risk prediction disorders, guidelines for management and disparities in implementation in Europe: a model enables stratification of individuals based on likelihood of systematic literature review. Diabetes Metab Res Rev. 2014;30(8):635–45. complications. Discrimination of low ulcer risk could extend the frequency 2. Schaper C, Van Netten JJ, Bus SA, Hinchliffe RJ, Apelqvist J, Lipsky BA. IWGDF Practical for screening those with low risk, thus freeing up resources for those with guidelines on the prevention and management of diabetic foot disease. IWGDF higher foot ulcer risk. The proposed model requires further refinement and Practical Guidelines [Internet]. 2019; Available from: https://iwgdfguidelines.org/wp-external validation, but it also shows the potential for improving compliance content/uploads/2019/05/01-IWGDF-practical-guidelines-2019.pdf with guidelines for screening which is often not appropriate. 3. Baba M, Foley L, Davis WA, Davis TME. Self-awareness of foot health status in patients with Type 2 diabetes: the Fremantle Diabetes Study Phase II. Diabet Med. 2014;31(11):1439–45. 4. Formosa C, Gatt A, Chockalingam N. A Critical Evaluation of Existing Diabetic Foot Screening Guidelines. Rev Diabet Stud. 2016;13(2–3):158–86. 5. Litzelman DK, Slemenda CW, Langefeld CD, Hays LM, Welch MA, Bild DE, et al. Reduction of lower extremity clinical abnormalities in patients with non-insulin-dependent diabetes mellitus. A randomized, controlled trial. Ann Intern Med. 1993;119(1):36–41. 6. Chevreul K, Berg Brigham K, Bouché C. The burden and treatment of diabetes in France. Global Health. 2014;10:6. 7. Evaluation of diabetic foot screening in Primary Care. - Abstract - Europe PMC [Internet]. [cited 2020 Dec 7]. Available from: https://europepmc.org/article/MED/24582291 8. Scottish Diabetes Data Group. Scottish Diabetes Survey 2019 [Internet]. 2020. Available from: https://www.diabetesinscotland.org.uk/wp-content/uploads/2020/10/ Diabetes-Scottish-Diabetes-Survey-2019.pdf 9. Lu Y, Xing P, Cai X, Luo D, Li R, Lloyd C, et al. Prevalence and Risk Factors for Diabetic Peripheral Neuropathy in Type 2 Diabetic Patients From 14 Countries: Estimates of the INTERPRET-DD Study. Front Public Health [Internet]. Frontiers; 2020 [cited 2021 Mar 2];8. Available from: https://www.frontiersin.org/articles/10.3389/fpubh.2020.534372/full 10. Chiolero A, Anker D. Screening interval: a public health blind spot. Lancet Public Health. 2019; 4(4): e171–2. 11. Štotl I, Blagus R, Urbančič-Rovan V. Individualised screening of diabetic foot: creation of a prediction model based on penalised regression and assessment of theoretical efficacy. Diabetologia. 2022;65(2):291–300. 78 79 12 RADIOIODINE UPTAKE Katja Zaletel 1,2, Katica Bajuk Studen 1,2 1 Department of Nuclear Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia katja.zaletel@kclj.si Eighty years have passed since radioactive iodine-131 (I-131) was successfully used to treat a hyperthyroid patient with Graves' disease in 1941. Since then, countless patients around the world have been diagnosed and treated for both benign and malignant thyroid disorders with different radioiodine isotopes (1). The recognition and function of Na+/I − symporter The ability of thyroid tissue to accumulate iodide (I−), an essential ingredient of thyroid hormones, was recognized as early as 1896. However, the key protein involved in thyroid I− uptake, Na+/I− symporter (NIS), was not discovered until 1996. NIS is a glycoprotein located on the basolateral surface of the thyrocyte. It mediates the active transport of I−into the cell against the electrical and chemical gradients (2). Since NIS cannot differentiate between non-radioactive and radioactive iodine, it provides a powerful tool for the diagnosis and treatment of thyroid disorders using 80 81 different radioiodine isotopes including iodine-123, -124, -125 and -131 (2). In against excessive iodine uptake in patients with thyroid autonomous tissue addition to radioiodine, NIS also transports technetium-99m pertechnetate, or Graves’ disease who are candidates for short-term iodine overload (e.g. a radiopharmaceutical commonly used in diagnostic procedures due to its after the application of iodine contrast) (3). wide availability (3). Radioiodine uptake in thyroid depends on the activity and expression of NIS, both of which increase when thyrotropin receptor (TSHR) is stimulated. In Na+/I − symporter in extra-thyroidal tissues Graves’ disease, TSHR is stimulated by circulating stimulating antibodies, NIS at mRNA and/or protein level is expressed in various extra-thyroidal whilst in thyroid autonomous tissue the receptor is permanently activated tissues. Applying immunohistochemistry methods, NIS protein expression due to a mutation. Our recent experience shows that in patients with was shown in urinary bladder, colon, endometrium, kidney, prostate, and Graves’ disease and thyroid autonomous tissue, the 20-hour uptake of pancreas. However, plasma membrane immunopositivity was confirmed administered I-123 is 69% and 29%, respectively; in comparison to only only in salivary ductal, gastric mucosa, and lactating mammary cells (7, 8). 19% in euthyroid nodular goiter (4). TSHR can also be stimulated by In salivary glands, stomach and intestine, NIS enables efficient absorption the application of recombinant human thyrotropin, which is used in the of I− from the food; in salivary ductal cells (mainly in the parotid glands) treatment of euthyroid goiter or in the ablation of thyroid tissue following and gastric mucosa cells, NIS is expressed on the basolateral membrane thyroid cancer surgery. In both cases the goal is to increase the uptake of and contributes to the transfer of I− from the bloodstream to the lumen I-131 and thus improve the success of treatment (3). of the gastrointestinal tract, and in the intestine, NIS is expressed on the With increased iodine intake, the expression of NIS protein significantly apical membrane of the brush border of small intestine enabling transfer decreases, which reduces uptake of radioiodine in the target thyroid tissue. of I− from the lumen into circulation (9). This observation has been confirmed by several studies comparing I-131 In lactating mammary glands, abundant NIS expression on the basolateral uptake and its applied therapeutic activities before and after the increase membrane of the alveolar cells mediates the transfer of iodine from in iodine supply. In Slovenia, for example, iodine concentration in kitchen the blodstream into the milk to reach a concentration of approximately salt was increased from 10 mg to 25 mg of potassium iodide per kg of salt 150 μg/l. Stimulation of NIS expression during lactation is due to increased in 1999. In the following years, the uptake of radioiodine in patients with levels of various hormones, including oxytocin, prolactin, and estrogens (10, autonomous tissue decreased by an average of 7% (from 45.3% to 31.0%), 11). In contrast, non-lactating normal breast tissue does not express NIS whilst the required therapeutic activity of I-131 increased by an average of protein and is not able to accumulate I−, unless pathological conditions such 10% (from 713 MBq to 791 MBq) (5). Similarly, in Poland, where the iodine as hyperprolactinemia are present. NIS is also expressed in placental cells supply was increased in 1996, studies in Graves’ patients demonstrated a enabling transfer of I− from maternal to fetal circulation. NIS mRNA and 40% reduction in thyroid radioiodine uptake and a 40% increase in applied protein were also demonstrated in human testicular tissues, responsible therapeutic activities of I-131 in subsequent years (6). In addition to for alterations in male patients undergoing radioioidine treatment for increased iodine intake, destruction of thyroid tissue may also reduce the thyroid cancer (8). activity and expression of NIS. This may, for example, be observed in the hyperthyroid phase of Hashimoto's thyroiditis or postpartum thyroiditis. Finally, the action of NIS can also be affected by the competitive inhibitors thiocyanate and perchlorate. Perchlorate is therefore suitable for protection 82 83 Radioiodine therapy for thyroid and References extra-thyroid tumors and future potentials 1. Fahey FH. Celebrating eighty years of radionuclide therapy and the work of Saul Hertz. Radioiodine therapy is a validated treatment effective in benign thyroid J Appl Clin Med Phys. 2021; 22 (1): 4–10. diseases causing increased NIS expression and leading to hyperthyroidism, 2. Portulano C, Paroder-Belenitsky M, Carrasco N. The Na+/I− Symporter (NIS): Mechanism and in differentiated thyroid cancer after TSH-induced increased expression and Medical Impact. Enodocr Rev. 2014; 35 (1): 106–149. of NIS. For radioiodine refractory thyroid cancer, novel therapeutic 3. De la Vieja A, Riesco-Eizaguirre G. Radio-iodide treatment: from molecular aspects to approaches targeting the molecular pathways responsible for the loss of the clinical view. Cancers. 2021; 13 (5): 995. differentiation (and subsequent reduction of NIS) are being investigated. 4. Rot Ž, Zaletel, T, Krković D, Gaberšček S, Zaletel K. The incidence of radioiodine-induced In the future, pharmacologic redifferentiation followed by radioiodine Graves' disease following treatment of thyroid autonomous tissue. Eur J Nucl Med Mol treatment might be one the main therapeutic strategies for such cancers Imaging. 2021; 48 (1): S381. (12). 5. Gaberšček S, Bajuk V, Zaletel K, Pirnat E, Hojker S. Beneficial effects of adequate iodine The characterization of the molecular basis of I supply on character¬istics of thyroid autonomy. Clin Endocrinol (Oxf). 2013; 79: 867– − transport following the 873. cloning of NIS, including its detection in some extrathyroidal tissues, has encouraged a large series of studies aiming to extend radioiodine treatment 6. Baczyk M, Junik R, Ziemicka K, Sowinski J. Iodine prophylaxis intensification. Influence on radioiodine uptake and activity of 131I used in the treatment of hyperthyroid even to extrathyroidal tumors after induction of NIS expression (8). In this patients with Graves' disease. Nuklearmedizin. 2005; 44: 197–199. case, radioiodine uptake and concentration in normal thyrocytes needs to 7. Bruno R, Giannasio P, Ronga G, Baudin E, Travagli JP, Russo D, et al. Sodium iodide be blocked and selective downregulation of NIS expression and inhibition of symporter expression and radioiodine distribution in extrathyroidal tissues. J organification by combination of T3 and methimazole has been described Endocrinol Invest. 2004; 27 (11): 1010–1014. (13). Among the strategies explored to induce NIS expression in cancer cells, 8. Micali S, Bulotta S, Puppin C, Territo A, Navarra M, Bianchi G, et al. Sodium iodide the transfer of NIS gene using vectors (mainly viruses) and constructs able symporter (NIS) in extrathyroidal malignancies: focus on breat and urological cancer. to ensure selective expression in tumor cells or stimulation of the expression BMC Cancer. 2014, 14: 303–315. of a functional endogenous NIS have been reported (8). At the preclinical 9. Nicola JP, Basquin C, Portulano C, Reyna-Neyra A, Paroder M, Carrasco N. The Na+/I-level, significant progress has been made in the development of the NIS symporter mediates active iodide intake in the intestine. Am J Cell Physiol. 2009; 296: C654–C662. gene therapy concept, from local NIS gene delivery to new applications in disseminated disease, such as the use of oncolytic viruses, non-viral 10. Tazebay UH, Wapnir IL, Levy O, Dohan O, Zuckier LS, Zhao QH, et al. The mammary gland iodide transporter is expressed during lactation and in breast cancer. Nat Med. polyplexes, and genetically engineered mesenchymal stem/stromal cells 2000; 6: 871–878. (14). 11. Cho JY, Leveille R, Kao R, Rousset B, Parlow AF, Burak WEJ, et al. Hormonal regulation of radioiodide uptake activity and Na+/I- symporter expression in mammary glands. J Clin Endocrinol Metab. 2000; 85: 2936. 12. Oh JM, Ahn BC. Molecular mechanisms of radioactive iodine refractoriness in differenetiated thyroid cancer: Impaired sodium iodide symporter (NIS) expression owing to altered signaling pathway activity and intracellular localization of NIS. Theranostics. 2021; 11 (13): 6251–6277. 84 85 13 13. Wapnir IL, Goris M, Yudd A, Dohan O, Adelman D, Nowels K, et al. The Na+/I- symporter RADIOIODINE mediates iodide uptake in breast cancer metastases and can be selectively downregulated in the thyroid. Clin Cancer Res. 2004; 10 (13): 4294–4302. THERAPY 14. Spitzweg C, Nelson PJ, Wagner E, Bartenstein P, Weber WA, Schwaiger M, et al. The sodium iodide symporter (NIS): novel applications for radionuclide imaging and Edvard Pirnat, Andreja Vendramin treatment. Endocr Relat Cancer. 2021; 28 (10): T193–T213. Department of Nuclear Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia edi.pirnat@kclj.si Introduction 131I is a beta-emitting radionuclide used for the treatment of thyroid disorders. 131I decays to stable 131Xe, has a physical half-life of 8.02 days, a principal gamma ray of 364 keV, a principal beta particle with a maximum energy of 0.807 MeV and average energy of 0.192 MeV. Beta particles have an average range in tissue of 0.4 mm and the maximum range of about 3 mm. Radiobiological effects of radioiodine on tissues are direct (damage to DNA) or indirect through the production of free radicals that react with critical macromolecules (1). Hertz and Roberts (Massachusetts General Hospital, USA) used the radioiodine for the first time for the treatment of the hyperthyroidism on March 31, 1941. In 1946 the results of two different scientific studies were published in the same issue of the Journal of the American Medical Associations (JAMA) and they both announced the radioiodine therapy as successful treatment for hyperthyroidism (2). The scientific studies of the long-term risk of cancer and other adverse effects after radioiodine treatment also began at that time (2,3). 86 87 Radioiodine therapy is today an established treatment for benign thyroid which have the ability to function autonomously without TSH (7). disease with procedure guidelines by European Association of Nuclear Toxic multinodular goitre and toxic adenoma can cause subclinical Medicine (EANM), regulated by European Commission directives and local hyperthyroidism (8). Despite the normal free thyroxine and total or free regulations and policies based on the recommendations of the International triiodothyronine levels, patients often report palpitations, nervousness, Commission on Radiological Protection (ICRP) (1, 4). tremor, heat intolerance and sweating, which affects their quality of life (8,9). Subclinical hyperthyroidism is associated with an increased risk for atrial fibrillation (10) and ischemic heart disease (11, 12). The risk is higher for TSH level lower than 0.10 mIU/L (11). There is an increased risk for Indications for the radioiodine therapy osteoporotic fractures in postmenopausal women, especially those with a In our article, we will discuss the radioiodine treatment of benign thyroid TSH level lower than 0.10 mIU/L (13, 14), and according to recent studies, disorders. Indications for the radioiodine treatment are Graves’ disease, also for dementia in the elderly (15). Overt hyperthyroidism occurs after toxic multinodular goitre, solitary hyperfunctioning nodule, nontoxic excessive iodine intake (16,17). multinodular goitre and goitre recurrence. There are two methods to When considering treating toxic multinodular goitre and solitary determine the activity of 131I: estimation (based on the volume of the gland, hyperfunctioning nodule with radioiodine, our decision is based on the the so-called “fixed dose”) and calculation (based on radioiodine uptake severity of the subclinical hyperthyroidism, age and presence of symptoms measurements) (1). The range of activities of 131I currently prescribed in and co-morbidities (17). The aim of the radioiodine treatment is the our tertiary centre is between 350 and 925 MBq. destruction of autonomously functioning tissue and achievement of the Graves' disease is a systemic autoimmune disorder caused by stimulating euthyroidism (7). antibodies acting as an agonist on the thyrotropin-receptor (TSH-R) on Surgery is considered standard therapy for large nontoxic goitre. Radioiodine thyroid follicular cells and other TSH-R-expressing tissues. This leads in treatment is indicated in patients with medical contraindications to thyroid thyroid to hyperplasia and unregulated thyroid hormone production and surgery, especially cardiopulmonary diseases, and patients who wish to secretion. Inflammatory changes in orbital tissue (Graves’ orbitopathy - GO) avoid surgery. In patients with large nontoxic goitre causing compressive are present in more than half of patients. Patients with newly diagnosed symptoms surgical treatment is indicated (1, 18, 19). Graves' hyperthyroidism are usually treated with antithyroid drugs. Radioiodine therapy is often recommended for patients with side-effects or allergy to antithyroid drugs, recurrence of the disease after a course of antithyroid drugs, exacerbation of GO and in older patients who have had Side effects of radioiodine treatment atrial fibrillation, cardiac failure, or cardiac ischemic symptoms precipitated The optimal activity for the radioiodine treatment of benign thyroid by hyperthyroidism. Radioiodine therapy or thyroidectomy may be also disorders is determined either by estimation or by calculation but always considered in patients with newly diagnosed Graves' hyperthyroidism that in respect of the principle that exposure to radiation have to be “as low as prefer this approach. Most patients become hypothyroid following the reasonably achievable” (ALARA) (20, 21). radioiodine therapy (5,6). Absolute contraindications for radioiodine treatment are pregnancy and Toxic multinodular goitre and solitary hyperfunctioning nodule (toxic breastfeeding. Relative contraindications are severe hyperthyroidism and adenoma) are the result of diffuse or focal hyperplasia of thyrocytes, active GO (1, 22). The patient has a discussion with a qualified medical 88 89 doctor before radioiodine treatment; has to be familiar with the protective References measures in radiation safety and has to sign an informed consent for the treatment (4, 23). 1. Stokkel M, Handkiewicz Junak D, Lassmann M, Dietlein M, Luster M. EANM procedure There are relatively few side effects from the treatment. In the first guidelines for therapy of benign thyroid disease. Eur J Nucl Med Mol Imaging. 2010; weeks after the application of radioiodine treatment patients with a 37(11): 2218-28. large goitre may notice transient swelling of the goitre, there may be a 2. Sawin C, Becker D. Radioiodine and the treatment of hyperthyroidism: the early history. transient raise in free T4 and free T3 levels and the GO can worsen (1, Thyroid. 1997; 7(2): 163-76. 3). The incidence of radiation thyroiditis after radioiodine treatment of 3. Bonnema SJ, Hegedüs L. Radioiodine Therapy in Benign Thyroid Diseases: Effects, Side hyperthyroidism is approximately 1% (24). Among the acute side effects Effects, and Factors Affecting Therapeutic Outcome. Endocrine Reviews. 2012; 33(6): there are no gastrointestinal symptoms, signs of bone marrow suppression 920–980 or sialadenitis, that occur at higher levels of administered dose used to 4. Beckers C. Regulations and policies on radioiodine 131I therapy in Europe. Thyroid. treat thyroid cancer (1, 3, 25). 1997; 7(2): 221-224. The main side effect of radioiodine treatment is hypothyroidism and its 5. Kahaly GJ, Bartalena L, Hegedüs L, Leenhardt L, Poppe K, Pearce SH. 2018 European incidence continues to increase over time. In 5% of the patients treated Thyroid Association Guideline for the Management of Graves’ Hyperthyroidism. Eur with radioiodine for toxic multinodular goitre or solitary hyperfunctioning Thyroid J. 2018; 7(4): 167-186. nodule Graves’ disease occurs (26). Studies have shown no effect on fertility 6. Fanning E, Inder WJ, Mackenzie E. Radioiodine treatment for graves’ disease: a 10-year or possible teratogenic effects in case of subsequent pregnancy (1, 3). There Australian cohort study. BMC Endocr Disord. 2018;18(1):94. are several cohort studies on cancer risks after radioiodine treatment of 7. Krohn K, Paschke R. Progress in Understanding the Etiology of Thyroid Autonomy. J Clin hyperthyroidism. The selected patients for the studies were treated with Endocrinol Metab. 2001; 86(7): 3336-45. radioiodine from 1946 onward. The studies found that radiation-induced 8. Santos Palacios S, Pascual-Corrales E, Galofre JC. Management of subclinical cancer risks are small and may only be detectable at higher levels of hyperthyroidism. Int J Endocrinol Metab. 2012; 10(2): 490-496. administered dose (27). 9. Biondi B, Palmieri EA, Fazio S, Cosco C, Nocera M, Saccà L. et. al. Endogenous subclinical hyperthyroidism affects quality of life and cardiac morphology and function in young and middle-aged patients. J Clin Endocrinol Metab. 2000; 85(12):4701-5. Conclusions 10. Auer J, Scheibner P, Mische T, Langsteger W, Eber O, Eber B. Subclinical hyperthyroidism as a risk factor for atrial fibrillation. J Auer et al. Am Heart J. 2001; 142(5): 838-42. Radioiodine treatment of benign thyroid disease has an 80-year long history. The treatment is accessible, effective and safe. We can ensure additional 11. Collet TH, Gussekloo J, Bauer DC, et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality. Arch Intern Med. 2012; 172(10): 799-809. safety by carefully selecting patients for the radioiodine treatment, by additional diagnostics, with patient education and with precise treatment 12. Sohn SY, Lee E, Lee MK, Lee JH. The Association of Overt and Subclinical Hyperthyroidism planning. with the Risk of Cardiovascular Events and Cardiovascular Mortality: Meta-Analysis and Systematic Review of Cohort Studies. Endocrinol Metab (Seoul). 2020; 35(4): 786-800. 13. Blum MR, Bauer DC, Collet TH, et al. Subclinical thyroid dysfunction and fracture risk: a meta-analysis. JAMA. 2015; 313(20): 2055-2065. 90 91 14. Vendrami C, Marques-Vidal P, Gonzalez Rodriguez E, Hans D, Waeber G, Lamy O. Thyroid-26. Nygaard B, Faber J, Veje A, Hegedüs L, Hansen JM. Transition of nodular toxic goiter to stimulating hormone is associated with trabecular bone score and 5-year incident autoimmune hyperthyroidism triggered by 131I therapy. Thyroid. 1999; 9(5): 477-81. fracture risk in euthyroid postmenopausal women: the OsteoLaus cohort. Osteoporos 27. Shim SR, Kitahara CM, Cha ES, Kim S, Bang YJ, Lee WJ. Cancer Risk After Radioactive Int. 2022; 33: 195–204. Iodine Treatment for Hyperthyroidism: A Systematic Review and Meta-analysis. JAMA 15. Joy Mathew C, Jose MT, Elshaikh AO, Shah L, Lee R, Cancarevic I. Is Hyperthyroidism Netw Open. 2021; 4(9):e2125072. a Possible Etiology of Early Onset Dementia?. Cureus. 2020;12(9):e10603. Published 2020 Sep 22. 16. Leung AM, Braverman LE. Iodine-induced thyroid dysfunction. Curr Opin Endocrinol Diabetes Obes. 2012; 19(5): 414-419. 17. Biondi B, Bartalena L, Cooper DS, Hegedüs L, Laurberg P, Kahaly GJ. The 2015 European Thyroid Association Guidelines on Diagnosis and Treatment of Endogenous Subclinical Hyperthyroidism. Eur Thyroid J 2015; 4: 149-163. 18. Nygaard B, Hegedüs L, Gervil M, Hjalgrim H, Søe-Jensen P, Hansen JM. Radioiodine treatment of multinodular non-toxic goitre. BMJ. 1993; 307(6908):828-32. 19. Huysmans D, Hermus A, Edelbroek M, Barentsz J, Corstens F, Kloppenborg P. Radioiodine for nontoxic multinodular goiter. Thyroid. 1997; 7(2): 235-9. 20. Van Isselt JW, De Klerk JMH, Lips CJM. Radioiodine treatment of hyperthyroidism: fixed or calculated doses; intelligent design or science?. Eur J Nucl Med Mol Imaging. 2007; 34: 1883–1884. 21. Pravilnik o pogojih za uporabo virov ionizirajočih sevanj v zdravstvu (Uradni list RS, št. 111/03, 75/15, 76/17 – ZVISJV-1 in 33/18) [citirano 27.06.2022]. Dosegljivo na http:// www.pisrs.si/Pis.web/pregledPredpisa?id=PRAV4561 22. Padda IS, Nguyen M. Radioactive Iodine Therapy. StatPearls Publishing; 2022 [citirano 27.06.2022]. Dosegljivo na: https://www.ncbi.nlm.nih.gov/books/NBK557741/ 23. Lazarus JH. Guidelines for the use of radioiodine in the management of hyperthyroidism: a summary. Prepared by the Radioiodine Audit Subcommittee of the Royal College of Physicians Committee on Diabetes and Endocrinology, and the Research Unit of the Royal College of Physicians. J R Coll Physicians Lond. 1995; 29(6): 464-469. 24. Mizokami T, Hamada K, Maruta T, Higashi K, Tajiri J. Painful Radiation Thyroiditis after 131I Therapy for Graves’ Hyperthyroidism: Clinical Features and Ultrasonographic Findings in Five Cases. Eur Thyroid J. 2016; 5(3): 201-206. 25. Sánchez Barrueco A, González Galán F, Alcalá Rueda I, Santillán Coello JM, Barrio Dorado MP, Villacampa Aubá JM et. al. Incidence and risk factors for radioactive iodine-induced sialadenitis, Acta Oto-Laryngologica. 2020; 140(11): 959-962. 92 93 14 RADIOIODINE AND GRAVES’ ORBITOPATHY Polona Jaki Mekjavić 1,2, Daša Šfiligoj Planjšek 3 1 University Eye Hospital, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Department of Nuclear Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia polona.jaki-mekjavic@mf.uni-lj.si Radioiodine (RAI) treatment of Graves' disease (GD) is reported to be a risk factor for the occurrence or worsening of Graves' orbitopathy (GO) in up to 20% of patients (1), which can be prevented with glucocorticoids. The optimal glucocorticoid regimen, however, is yet to be determined (2). The 2021 European Group on Graves' orbitopathy (EUGOGO) recommends the administration of oral prednisone or prednisolone prophylaxis to patients treated with RAI who are at risk of development or progression of GO (smoking, high serum level of thyrotropin receptor antibodies, severe hyperthyroidism, preexisting GO). The proposed regimen for high-risk patients is a starting dose of 0.3–0.5 mg/kg/body weight, tapered, and withdrawn after 3 months. The recommendation for low-risk patients is 0.1–0.2 mg/kg/body weight of prednisone/prednisolone, tapered, and withdrawn after 6 weeks. Patients with a stable inactive GO and without any risk factors for GO progression can receive RAI without prednisone/ prednisolone cover (3). 94 95 At the Department of Nuclear Medicine, UMC Ljubljana, patients with months vs. 9.5±5.1 months, p=0.032); this shows the importance of timely GD are often offered treatment with RAI. Patients with mild active GO RAI treatment. As the duration of GO activity was also significantly longer preventatively receive a short dose of oral methylprednisolone (96 mg on before RAI than after RAI (6.5±4.2 months vs. 2.2±3.3 months, p<0.001), the the 1st, 3rd, and 5th day) concomitant to RAI. Patients with moderate-to-RAI treatment in patients with active GO should be given with concomitant severe and active GO receive longer regimens of oral methylprednisolone steroids soon after medical management of hyperthyrosis. for three weeks, starting with 96 mg every second day, gradually tapering Regarding possible risk factors for GO after RAI (N=552) we concluded that weekly for 32 mg. In patients with more severe GO and risk factors for its it is important to administer the correct RAI dosage for a successful first progression, we administer methylprednisolone intravenously with weekly treatment of GD. A greater proportion of patients who did not develop GO doses of 500 mg for one to two months, followed by weekly doses of 250 after RAI therapy were successfully treated with the first RAI dose (92 % vs mg for one month; a cumulative dose of 3000-5000 mg. 74 %, p =0.008) and were less likely to require a third RAI dose (0.2 % vs 8.7 In a recent dissertation (4) we retrospectively evaluated the beneficial %, p<0,001) than patients who developed GO after RAI therapy. effects of our glucocorticoid regimens prophylaxis given concomitantly with According to our study, the presence of GO at GD presentation or anytime RAI, for the prevention of the occurence or worsening of GO. We also analyzed before but not during RAI treatment is also a risk factor for GO occurrence the connection between the duration of GO activity and RAI treatment, after RAI (3.8 % vs 13 % or 21.7 %, p=0.030 or p<0.001). as well as the risk factors for the occurence of GO after RAI treatment. The study included 724 patients who were diagnosed with GD for the first In our study cohort of 171 patients with GO at the time of RAI, GO worsened time during the years 2005-2009 and were later treated with RAI. Among in only 5 patients after RAI therapy with concomitant steroids treatment, them, 75.8 % (N=549) did not receive glucocorticoid prophylaxis as they did whereas GO improved in 143 patients (84 %). Patients who experienced not have GO. These patients represented the control group; among them, an improvement of GO after treatment were more likely non-smokers only 3.8 % developed GO after RAI which is comparable with published data (p=0.009), received glucocorticoids at the time of RAI (p<0.001), had a (5). Patients with mild GO and patients at risk for the development of GO shorter antithyroid treatment duration (p=0.003), and had a shorter time (N=142, 19.6 %) were given a short dose of methylprednisolone prophylaxis from onset of GD to RAI treatment (p=0.003). concomitantly with RAI treatment; only 4% of them experienced worsening In conclusion, although RAI treatment of GD is a risk factor for de novo of GO which was statistically insignificant compared to the control group. occurrence or worsening of GO, it is, in our experience, a reasonably safe This showcases a beneficial effect of our short-dose methylprednisolone treatment if administered timely and with concomitant appropriate regimen with RAI for the prevention of the occurrence or worsening of methylprednisolone prophylaxis. GO. A group of patients with moderate-to-severe active GO (N=33, 4.6 %) received longer regimens or intravenous methylprednisolone concomitantly with RAI; none of the patients from this group experienced a worsening of GO. Furthermore, in most of them (N=30, 90.9 %) GO improved after the treatment. That implies that the RAI treatment with appropriate glucocorticoid prophylaxis is also safe in patients with moderate-to-severe GO. Patients who received RAI in 6 months or fewer from the onset of GD, showed a significantly shorter duration of GD activity compared to patients who received RAI more than 6 months after the onset of GD (7.8±4.4 96 97 15 References RADIOIODINE IN ADOLESCENTS 1. Acharya SH, Avenell A, Philip S, Burr J, Bevan JS, Abraham P. Radioiodine therapy (RAI) for Graves’ disease (GD) and the effect on ophthalmopathy: a systematic review. Clin Simona Gaberšček 1,2, Nataša Bedernjak Bajuk 1 Endocrinol (Oxf). 2008;69:943–50. 1 Department of Nuclear Medicine, 2. Lazarus JH, Bartalena L, Marcocci C, Kahaly GJ, Krassas G, Wiersinga WM. Glucocorticoid administration for Graves’ hyperthyroidism treated by radioiodine. A questionnaire University Medical Centre Ljubljana, Ljubljana, Slovenia survey among members of the European Thyroid Association. J Endocrinol Invest. 2 Faculty of Medicine, 2010;33:409–13. University of Ljubljana, Ljubljana, Slovenia 3. Bartalena L, Kahaly GJ, Baldeschi L, Dayan CM, Eckstein A, Marcocci C, et al. The 2021 European Group on Graves’ orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves’ orbitopathy. Eur J Endocrinol. 2021;185:43-67. simona.gaberscek@kclj.si 4. Šfiligoj Planjšek D. Potek ščitnične orbitopatije pri bolnikih z Gravesovo boleznijo, zdravljenih z radioaktivnim jodom [PhD Thesis]. Ljubljana: D. Šfiligoj Planjšek; 2019. p. 64-109. 5. Nwatsock JF, Taieb D, Tessonnier L, Mancini J, Dong-A-Zok F, Mundler O. Radioiodine thyroid ablation in Graves’ hyperthyroidism: merits and pitfalls. World J Nucl Med 2012;11:7–11. Introduction In adolescents with Graves' disease (GD), treatment usually starts with antithyroid drugs. If this treatment is not effective, they are left with only two options: thyroid surgery or radioactive iodine 131 (I-131). Surgery is not perceived a good option by many adolescents, as it is associated with a risk of complications. Thyroid autonomy (TA), however, which is rare in adolescents, is usually treated with I-131 only. Treatment goal The goal of treatment of GD in adolescents with I-131 is to establish hypothyroidism. In addition to ensuring permanent hypothyroidism, ablation is also useful for preventing the growth of possible thyroid carcinoma (1). The goal of treatment of TA with I-131 is to establish euthyroidism. In this disease, hypothyroidism occurs later, usually in a few percent of patients annually. 98 99 Treatment dose thyroid volumes than those without nodules. None had thyroid or other malignancies (6). Treating young people with I-131 is safe. The efficacy of I-131 therapy is dose related. It also depends on the iodine supply in a certain area. Therefore, various successful doses have been reported. In Japan, for example, a dose of 300 μCi of I-131/g of thyroid tissue provided fairly reliable ablation of thyroid tissue (1). When the dose was too Our experience low (several mCi), retreatment was needed (2). In the USA, the reported Between March 2013 and January 2022, we treated 56 adolescents (46 I-131 doses in children and adolescents have ranged from 100 to 250 μCi/g girls and 10 boys) aged between 14 and 20 with I-131. Among them, 41 of thyroid tissue (3). After administering a dose of 150–200 μCi/g of tissue, had GD and 15 TA. Patients with GD were significantly older than patients the long term cure rates of hyperthyroidism were 90% or greater (3). On the with TA (18.5±1.5 and 17.5±1.5 years, respectively, p=0.024). Before I-131, other hand, with the I-131 dose of 220 μCi/g of thyroid tissue, a successful all GD patients were treated with antithyroid drugs for 30 (1–84) months treatment rate of 65.6% was reported (4). An I-131 dose close to 250 μCi/g (median, range). No patient with TA was treated with antithyroid drugs of thyroid tissue had a higher likelihood of achieving hypothyroidism (5). before I-131. Thyroid volume in GD patients was significantly larger than With the median dose of 13 mCi (range 3.6 to 29.8 mCi) 91% of 117 juvenile the volume of thyroid autonomous tissue in TA patients (median, range, patients from Japan developed overt hypothyroidism, 2% subclinical 24.4 (6.5–75) and 7.7 (0.7–24.6) mL, respectively, p<0.001). GD patients hypothyroidism, 5% euthyroidism, and 2% subclinical hyperthyroidism (6). were treated with significantly lower dose of I-131 than TA patients Ultrasound measurement of thyroid volume three months after treatment (median, range, 724 (500–950) and 902 (572–950) MBq, respectively, with I-131 is clinically useful for predicting hypothyroidism. Around 90% of p=0.0001). First dose of I-131 was successful in 92.7% of GD patients. adolescents whose thyroid volume decreased by 50% three months after Three patients needed the second dose of I-131. Time to the onset of I-131 treatment became hypothyroid within one year (1). hypothyroidism was in GD patients 2 (1–11) months (median, range). As for TA, hypothyroidism after I-131 occurred in 46.7% of patients after 3 (1–24) months (median, range). Treatment safety No increased risk of adverse events was reported in young GD patients under the age of 20 years who had been treated with I-131 between Conclusions 1953 and 1973 (2). At the time of treatment with I-131, their ages Treatment with radioiodine is a simple, effective and safe treatment option ranged between 3 years, 7 months and 19 years, 9 months. A follow-for adolescents with GD and TA. up was performed in 107 patients after 26.1 years, and in 98 of them also after 36.2 years. No patient developed thyroid cancer or leukemia. Pregnancies were not associated with higher frequency of complications such as congenital anomalies or spontaneous abortions (2). The follow-up time of 117 juvenile patients aged 10 to 18 years who had been treated with the median dose 13 mCi I-131 ranged between 4 and 226 months (6). New thyroid nodules were detected in 9 patients after 4 to 17 years. These patients received lower doses of I-131 and had larger residual 100 101 16 References QUALITY OF LIFE IN CHILDREN AND ADOLESCENTS WITH TYPE 1 DIABETES USING ADVANCED HYBRID CLOSED 1. Nakatake N, Fukata S, Tajiri J. Prediction of post-treatment hypothyroidism using changes in thyroid volume after radioactive iodine therapy in adolescent patients with LOOP INSULIN DELIVERY Graves’ disease. Int J Pediatr Endocrinol. 2011;2011(1):14. 2. Read CH Jr, Tansey MJ, Menda Y. A 36-year retrospective analysis of the efficacy and Nataša Bratina 1,2, Ana Gianini 1,2, Jana Suklan 3, safety of radioactive iodine in treating young Graves’ patients. J Clin Endocrinol Metab. Brigita Skela-Savič 4, Simona Klemenčič 1, 2004;89(9):4229–33. Tadej Battelino 1,2, Klemen Dovč 1,2 3. Rivkees SA, Sklar C, Freemarks M. The management of Graves’ disease in children, with special emphasis on radioiodine treatment. J Clin Endocrinol Metab. 1998;83(11):3767– 1 Department of Pediatric Endocrinology, Diabetes, and Metabolic Diseases, 76. University Children’s Hospital, 4. Namwongprom S, Dejkhamron P, Unachak K. Success rate of radioactive iodine University Medical Centre Ljubljana, Ljubljana, Slovenia treatment for children and adolescent with hyperthyroidism. J Endocrinol Invest. 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 2021;44(3):541–5. 3 NIHR Newcastle In Vitro Diagnostics Co-operative, 5. Kaplowitz PB, Jiang J, Vaidyanthan P. Radioactive iodine therapy for pediatric Graves’ disease: a single-center experience over a 10-year period. J Pediatr Endocrinol Metab. Translational and Clinical Research Institute, Faculty of Medical Sciences, 2020;33(3);383–9. William Leech Building, Newcastle University, United Kingdom 6. Mizokami T, Hamada K, Maruta T Higashi K, Tajiri J. Long-term outcomes of radioiodine 4 Angela Boškin Faculty of Health Care, Jesenice, Slovenia therapy for juvenile Graves’ disease with emphasis on subsequently detected thyroid nodules: a single institution experience from Japan. Endocr Pract. 2020;26(7):729–37. natasa.bratina@mf.uni-lj.si Background Type 1 diabetes (T1D) is one of the most common chronic conditions in children and adolescents all over the world, and the incidence of T1D is increasing by approximately 3.4 % per year in Europe. The goal in the management of T1D is to maintain blood glucose levels as close to normal as possible with the aim of avoiding or delaying disease-related micro- and macrovascular complications. Major guidelines suggest glycated hemoglobin (A1C) below 7 % (53 mmol/mol), but not all patients can achieve this goal. The use of technology in the management of T1D is increasing, and we can 102 103 start with a continuous glucose monitor followed by an insulin pump. In the References last decade, the two are combined into an automated closed-loop insulin delivery system. There is increasing evidence that the use of advanced hybrid closed loop (AHCL) systems can improve glycemic control irrespective 1. Patterson CC, Harjutsalo V, Rosenbauer J, et al. Trends and cyclical variation in the of baseline A1C, with fewer hypoglycemic events. Most of the studies using incidence of childhood type 1 diabetes in 26 European centres in the 25 year period 1989–2013: a multicentre prospective registration study. Diabetologia. 2019;62(3):408–17. AHCL show stable glycemic control overnight. This is also important for families since fear of undetected hypoglycemia and hyperglycemia can be 2. Lind M, Svensson AM, Kosiborod M, et al. Glycemic control and excess mortality in type the biggest during sleep. Recent data also confirm the ability of the AHCL 1 diabetes. N Engl J Med. 2014;371:1972–1982. insulin delivery systems to safely achieve a significant overall improvement 3. Battelino T, Danne T, Bergenstal RM, et al. Clinical targets for continuous glucose in glucose control in T1D. monitoring data interpretation: Recommendations from the international consensus on time in range. Diabetes Care. 2019;42(8):1593–1603. 4. Martin CT, Criego AB, Carlson AL, Bergenstal RM. Advanced technology in the management of diabetes: which comes first-continuous glucose monitor or insulin Methods pump? Curr Diab Rep. 2019;19(8):50. 24 young people with T1D (14 female) aged 10 to 18 years participated. 5. Dovc K, Piona C, Mutlu GY, et al. Faster Compared With Standard Insulin Aspart During Data collection before and at the end of AHCL (a period of 4 months) use Day-and-Night Full Closed-Loop Insulin Therapy in Type 1 Diabetes: A Double-Blind were analyzed. Qualitative data were obtained with modeled interviews of Randomized Crossover Trial. Diabetes Care. 2020;43(1):29-36. four focus groups before and at the end of the period. Clinical data were 6. Tauschmann M, Thabit H, Leelarathna L, et al. Factors Associated With Glycemic collected from electronic medical records. Control During Free-Living Overnight Closed-Loop Insulin Delivery in Children and Adults With Type 1 Diabetes. J Diabetes Sci Technol. 2015;9(6):1346-47. 7. Strandberg RB, Graue M, Wentzel-Larsen,T, et al. The relationships among fear of hypoglycaemia, diabetes-related quality of life and psychological well-being in Results Norwegian adults with Type 1 diabetes. Diabetes Res Clin Pract. 2017;124:11−19. The use of AHCL significantly improved the quality of life in terms of 8. Hood KK, Laffel LM, Danne T, et al. Lived Experience of Advanced Hybrid Closed–Loop decreased fear of hypoglycemia (p<0.001), decrease in diabetes-related Versus Hybrid Closed–Loop: Patient–Reported Outcomes and Perspectives. Diabetes emotional distress (p<0.001), and increased well-being (p=0.003). The mean Technol Ther. 2021;23(12):857-61. A1C decreased from 8.55± 1.34 % (69.9 mmol/mol) to 7.73± 0.42 % (61.0 9. Abraham MB, Bock M, Smith GJ, et al. Effect of a Hybrid Closed-Loop System on Glycemic mmol/mol) (p=0.002) at the end of the study. Mean TIR was 68.22 % (± and Psychosocial Outcomes in Children and Adolescents With Type 1 Diabetes. JAMA 13.89) before and 78.26 (± 6.29) % (p<0.001) at the end of the study. Pediatr. 2021;175(12):1227-35 Conclusion The use of AHCL significantly improved the quality of life and metabolic control in children and adolescents with T1DM. 104 105 17 MODERN TECHNOLOGIES IN THE TREATMENT OF DIABETES AND PHYSICAL ACTIVITY Klemen Dovč 1,2 1 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 2 Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, Ljubljana, Slovenia klemen.dovc@mf.uni-lj.si • Regular physical activity is recommended for all individuals with diabetes, as the health-related benefits of being physically active are well established. • Physical activity has long been proposed as a major hurdle for glucose-responsive insulin therapy as there are numerous factors affecting glucose homeostasis. • Various clinical guidelines and strategies exist, incorporating recommendations based on current insulin delivery and glucose monitoring modality, that assist maintaining precise glucose control during and after physical activity. Regular physical activity is recommended for individuals with diabetes, performed as often as possible since the health-related benefits of being physically active are well established (1, 2). Data from the Swedish pediatric diabetes quality registry has also indicated a positive impact of physical activity on glycemic control, regardless of age and gender (3), and its association with improved quality of life (4). More recently, higher amounts 106 107 of physical activity were associated with improvements in time in range AID combines rtCGM with a modern insulin pump and a sophisticated without significantly increasing the risk for hypoglycemia (5). On the computer algorithm, which directs insulin (single-hormone) or insulin other hand, physical activity is overall associated with an increased risk and glucagon (dual-hormone or bihormonal system) delivery in response of glycemic excursions and hypoglycemia, particularly during the physical to sensor glucose data. The autonomous graduated modulation of insulin activity and the night following it (6–8). Consequently are individuals (and glucagon) delivery below and above the amount preset in a glucose-with type 1 diabetes reportedly less active than recommended; less than responsive manner differentiates AID from conventional insulin pump 20% manage to do aerobic exercise more than two times per week, and therapy with or without low-glucose suspend or suspend before low feature about 60% do not engage in structured exercise at all (9). Additionally, an (15, 16). AID is now a part of regular clinical reality for many individuals living accomplishment of optimal glucose control is complicated by the variability with type 1 diabetes and its performance during and after physical activity in insulin requirements from one day or night to another and might be has been extensively evaluated, especially in a controlled environment. difficult to overcome with conventional therapeutic tools (2). AID has been challenged with different exercise protocols of different Modern technologies for diabetes care, including continuous subcutaneous durations and intensities, using faster insulin formulation, glucagon, insulin infusion (insulin pump), continuous glucose monitoring (CGM) in heterogeneous age groups, with additional devices to detect physical devices, either real–time (rtCGM) that is continuously displaying glucose activity, such as activity and heart rate monitoring, and adding glucagon concentration in the interstitial fluid or intermittently scanned CGM to prevent hypoglycemia. These studies have demonstrated reduced (isCGM), which is a variety displaying glucose values only on demand, have frequency and the overall proportion of time spent in hypoglycemia during re-shaped the management of diabetes. These devices are enabling many and after physical activity, including nocturnal hypoglycemia, and generally individuals with type 1 diabetes to optimize their glycemic control, improve improved time in range with AID (17–21). There are less published data quality of life, and reduce the burden of type 1 diabetes and there has regarding physical activity in unsupervised or less-supervised settings and been reported a global increase in uptake into everyday clinical practice future research is needed (22–24). (10–13). Glucose-responsive insulin therapy, such as sensor augment pump, Several strategies for insulin adjustments and additional carbohydrate predictive low glucose suspend and automated insulin delivery (AID) might consumption regarding physical activity have been suggested and these further facilitate the situation and reduce some of the challenges during recommendations should be individualized and tailored based on above-and after physical activity in type 1 diabetes. mentioned factors and treatment modalities (25–30). Due to differences Physical activity has long been proposed as a major hurdle for glucose and in modalities and duration of physical activity, activity-related hormonal studies are now looking into how these systems are performing. Exercise responses, different gender and age responses to physical activity, a duration, modality, relative and absolute intensity, and fitness capacity all personalized glucose management plan should be made. This plan should affect glucose homeostasis in people living with type 1 diabetes. Previous include advice on glucose monitoring, exercise timing, carbohydrate intake, studies have demonstrated that the use of predictive low glucose insulin-insulin dose modification and avoiding injecting insulin at sites involved in suspend (PLGS) function could reduce the risk of hypoglycaemia after the muscular activity (31). Most common aerobic activities lasting more physical activity and can reduce the risk of nocturnal hypoglycaemia (14). than 30 minutes are likely to require a reduction in insulin dose during These benefits were, however, achieved at the expense of mildly elevated exercise and up to 90 minutes before (32). In addition to this, the risk of glucose levels or increased time in moderate hyperglycemia without an nocturnal hypoglycemia is increased following afternoon exercise. For insulin increased risk for severe rebound hyperglycemia or diabetic ketoacidosis pump users, a combination of pump suspension, or a temporary decrease after the PLGS. in basal insulin infusion rate (e.g. 50%) implemented at least 90 minutes 108 109 before starting exercise to give a reduced basal effect can be advised. A References temporary basal reduction of approximately 20% at bedtime for 6 hours helps reduce the risk of nocturnal hypoglycemia. Some differences in AID strategies for physical activity include the importance of pump suspension 1. Riddell MC, Gallen IW, Smart CE, Taplin CE, Adolfsson P, Lumb AN, et al. Exercise if disconnecting during physical activity, fewer grams of uncovered management in type 1 diabetes: a consensus statement. Lancet Diabetes Endocrinol. 2017;5(5):377–90. carbohydrates before physical activity (taken close to activity onset to avoid a rise in automatically initiated insulin delivery) and continuing the 2. Adolfsson P, Riddell MC, Taplin CE, Davis EA, Fournier PA, Annan F, et al. ISPAD Clinical exercise (temporal) target for several hours after activity or potentially Practice Consensus Guidelines 2018: Exercise in children and adolescents with diabetes. Pediatr Diabetes. 2018;19:205–26. overnight to avoid hypoglycemia (33). 3. Beraki Å, Magnuson A, Särnblad S, Åman J, Samuelsson U. Increase in physical activity In conclusion, it is vital that most individuals with type 1 diabetes are is associated with lower HbA1c levels in children and adolescents with type 1 diabetes: regularly engaged in physical activity. Current data underscore the Results from a cross-sectional study based on the Swedish pediatric diabetes quality synergistic effect of advanced diabetes technologies used concomitantly registry (SWEDIABKIDS). Diabetes Res Clin Pract. 2014;105(1):119–25. that should be more readily available to individuals with type 1 diabetes 4. 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Diabetes Care. 2013;36(4):838–44. diabetes. Lancet Diabetes Endocrinol. 2017;5(7):493. 20. Jayawardene DC, McAuley SA, Horsburgh JC, Gerche A La, Jenkins AJ, Ward GM, et al. 31. Moser O, Riddell MC, Eckstein ML, Adolfsson P, Rabasa-Lhoret R, van den Boom L, et Closed-Loop Insulin Delivery for Adults with Type 1 Diabetes Undertaking High-Intensity al. Glucose management for exercise using continuous glucose monitoring (CGM) and Interval Exercise Versus Moderate-Intensity Exercise: A Randomized, Crossover Study. intermittently scanned CGM (isCGM) systems in type 1 diabetes: position statement Diabetes Technol Ther. 2017;19(6):340–8. of the European Association for the Study of Diabetes (EASD) and of the International Society f. Pediatr Diabetes. 2020;21(8):1375–93. 112 113 18 32. Zaharieva DP, McGaugh S, Pooni R, Vienneau T, Ly T, Riddell MC. Improved open-MODERN TECHNOLOGIES loop glucose control with basal insulin reduction 90 minutes before aerobic exercise in patients with type 1 diabetes on continuous subcutaneous insulin infusion. In: DURING PREGNANCY Diabetes Care. 2019. p. 824–31. 33. Zaharieva DP, Messer LH, Paldus B, O’Neal DN, Maahs DM, Riddell MC. Glucose Draženka Pongrac Barlovič 1,2 control during physical activity and exercise using closed loop technology in type 1 diabetes. Can J Diabetes [Internet]. 2020; Available from: https: //doi.org/10.1016/j. 1 Department of Endocrinology, Diabetes and Metabolic Diseases, jcjd.2020.06.003 University Medical Centre Ljubljana, Slovenia 2 Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia drazenka.pongrac@kclj.si Introduction Pregnancy is a challenging life period, characterized by dynamic changes of insulin sensitivity and glucose tolerance and demands the achievement of tight glycemic control (1). Recently, continuous glucose monitoring (CGM) systems with and without insulin pump therapy are revolutionizing diabetes care (2). In particular, new algorithm-controlled insulin delivery systems based on real-time CGM have changed the clinical landscape by providing new therapeutic targets, as well as an increase in the proportion of people with type 1 diabetes safely achieving these goals (3). However, the value of these systems in pregnant women with type 1 diabetes is still not well characterized. In addition, there is a lack of data on target glucose range, derived from the CGM systems, in pregnant women with type 2 diabetes or gestational diabetes (4). 114 115 Continuous glucose monitoring during pregnancy infant growth from the early gestation onwards (8). Moreover, it has been demonstrated that normal birth weight was associated with TBR well Continuous glucose monitoring systems can be broadly divided into two above the recommended international consensus target of ≤4%, never types: falling below 8% in women with normal-sized babies (8). 1. systems for continuous measurement of glucose in the intercellular In Slovenia, we can prescribe RT-CGM sensor systems at the expense of the space (RT-CGM: "real-time continuous glucose monitoring"); Health Insurance Institute to pregnant women with type 1 diabetes, while 2. systems for intermittent glucose monitoring (IS-CGM: "intermittent IS-CGM can be prescribed also to pregnant women with type 2 diabetes or system for continuous glucose monitoring" or "flash glucose gestational diabetes, if they are treated with insulin. monitoring"). According to international guidelines, both are recommended in pregnancy as an adjunct and not as a substitute for capillary blood glucose Insulin pump therapy measurement (4). Insulin pump therapy in women with type 1 diabetes was not conclusively The recent randomized multicenter study CONCEPTT showed that the use associated with better perinatal outcomes in meta-analyses, but was of RT-CGM for capillary blood glucose measurement during pregnancy in associated with greater treatment satisfaction and dietary freedom (9). type 1 diabetes slightly lowers HbA1c (-0.19%) without an increased risk of In the CONCEPTT study (5), the effect of CGM was the same regardless hypoglycemia, while reducing the risk of macrosomia of the fetus, neonatal of the way insulin was administrated (continuous delivery of glucose in hypoglycemia and shortening the duration of hospitalization compared the subcutaneous tissue or multiple daily insulin injections). Some newer to only capillary blood glucose concentration measurement (5). In a large systems, where CGM is combined with the continuous delivery of glucose cohort study, perinatal outcomes did not differ by sensor system type (IS-by the help of advanced mathematical computer algorithms, the so-called CGM or RT-CGM), while pregnant women with type 1 diabetes spent less "closed-loop system", have enabled pregnant women with type 1 diabetes time hypoglycemic when RT-CGM was used (6). International guidelines to survive a higher percentage of time in the target glucose range between have outlined the goals for the treatment of type 1 diabetes during 3.5 and 7.8 mmol/l (10) or a lower percentage of time in the hypoglycemic pregnancy (2) with more than 70% of the time spent in the target range range (11). We are still waiting for the results of a randomized controlled ("time in range", TIR), i.e. between 3.5 and 7.8 mmol/l; less than 4% of the study in pregnant women with type 1 diabetes using the Minimed 780G time spent in the glucose range of less than 3.5 mmol/l ("time below range”, system that includes an advanced hybrid closed loop algorithm, already in TBR) and less than 25% of the time spent in the range above 7.8 mmol/l clinical use in Slovenia. ("time above range", TAR). Intriguingly, a recent large cohort study of type 1 diabetes pregnancies from the Joslin diabetes center has pointed out that although CGM use Gestational diabetes and continuous glucose monitoring was associated with better glycemic control (reflected by lower HbA1c), it did not translate into a significant improvement of any of the maternal Gestational diabetes is characterized by the increased glycaemia compared or neonatal outcomes (7). Of note, a detailed analysis of >10.5 million to normal pregnancy, but usually not reaching glucose concentrations CGM glucose measures from two large multicenter trials has shown that typical for pregnancies in women with preexistent diabetes (12). Sensor maternal glucose has the central role in the pathogenesis of excessive systems have not yet been tested in large randomized clinical trials in type 116 117 2 diabetes or in gestational diabetes. The guidelines therefore point out References that in these cases it is not yet clear what the glycemic targets are when using the sensor system, nor whether the use of sensors improves glycemic or perinatal outcomes (4). However, the hypothesis is that CGM devices 1. García-Patterson A, Gich I, Amini SB, Catalano PM, de Leiva A, Corcoy R. Insulin may be more user friendly to women with GDM compared to capillary blood requirements throughout pregnancy in women with type 1 diabetes mellitus: three changes of direction. Diabetologia. 2010;53(3):446-51. glucose measurements, may help in improving lifestyle and in gaining less gestational weight (13). 2. Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. Clinical Targets for Continuous Glucose Monitoring Data Interpretation: Recommendations From the International Consensus on Time in Range. Diabetes Care. 2019;42(8):1593-603. 3. Silva JD, Lepore G, Battelino T, Arrieta A, Castañeda J, Grossman B, et al. Real-World Performance of the MiniMed™ 780G System: First Report of Outcomes from 4120 Users. Diabetes Technol Ther. 2022;24(2):113-9. 4. American Diabetes Association. 14. Management of Diabetes in Pregnancy: Standards of Medical Care in Diabetes—2021. Diabetes Care. 2021;44(Supplement 1):S200-S210. 5. Feig DS, Donovan LE, Corcoy R, Murphy KE, Amiel SA, Hunt KF, et al. Continuous glucose monitoring in pregnant women with type 1 diabetes (CONCEPTT): a multicentre international randomised controlled trial. Lancet. 2017;390(10110):2347-59. 6. Kristensen K, Ögge LE, Sengpiel V, Kjölhede K, Dotevall A, Elfvin A, et al. Continuous glucose monitoring in pregnant women with type 1 diabetes: an observational cohort study of 186 pregnancies. Diabetologia. 2019;62(7):1143-53. 7. Wang Z, James-Todd TM, Isganaitis E, O’Connell J, Helman S, Wyckoff JA, et al. Associations of insulin pump and continuous glucose monitoring use with pregnancy-related outcomes in women with type 1 diabetes. Diabetes Research and Clinical Practice. 2022;187:109854. 8. Scott EM, Murphy HR, Kristensen KH, Feig DS, Kjölhede K, Englund-Ögge L, et al. Continuous Glucose Monitoring Metrics and Birth Weight: Informing Management of Type 1 Diabetes Throughout Pregnancy. Diabetes Care. 2022;45(8):1724-34. 9. Lawton J, Kirkham J, Rankin D, White DA, Elliott J, Jaap A, et al. Who gains clinical benefit from using insulin pump therapy? A qualitative study of the perceptions and views of health professionals involved in the Relative Effectiveness of Pumps over MDI and Structured Education (REPOSE) trial. Diabetic Medicine. 2016;33(2):243-51. 10. Stewart ZA, Wilinska ME, Hartnell S, Temple RC, Rayman G, Stanley KP, et al. Closed-Loop Insulin Delivery during Pregnancy in Women with Type 1 Diabetes. N Engl J Med. 2016;375(7):644-54. 11. Stewart ZA, Wilinska ME, Hartnell S, O’Neil LK, Rayman G, Scott EM, et al. Day-and-Night Closed-Loop Insulin Delivery in a Broad Population of Pregnant Women With Type 118 119 19 1 Diabetes: A Randomized Controlled Crossover Trial. Diabetes Care. 2018;41(7):1391-9. THE ROLE OF GLP-1 12. Nigam A, Sharma S, Varun N, Munjal Y, Prakash A. Comparative analysis of 2-week IN WOMEN’S REPRODUCTIVE glycaemic profile of healthy versus mild gestational diabetic pregnant women using HEALTH flash glucose monitoring system: an observational study. BJOG. 2019;126(S4):27-33. 13. Huhn EA, Linder T, Eppel D, Weißhaupt K, Klapp C, Schellong K, et al. Effectiveness of real-time continuous glucose monitoring to improve glycaemic control and pregnancy Vesna Šalamun outcome in patients with gestational diabetes mellitus: a study protocol for a randomised controlled trial. BMJ Open. 2020;10(11):e040498. Department of Human Reproduction, Division of Obstetrics and Gynecology, University Medical Centre Ljubljana, Ljubljana, Slovenia vesna.salamun@icloud.com There is much research-supported evidence about the connection between energy balance and fertility. On one end of the calorie consumption spectrum, chronic energy deficiency has been connected with amenorrhea and infertility (1, 2). On the other end, studies have continuously proven a link between obesity and anovulation, subfertility, infertility and a higher miscarriage rate (3, 4, 5). By some studies, weight loss alone improves the chances of a successful IVF treatment and of successful pregnancy (6, 7, 8, 9, 10). It is speculated that the amount of energy available to the body impacts fertility and inhibits reproductive capacity during poor nutrition conditions (11). Hormones of the gut (glucagon-like peptide-1 (GLP-1), insulin, ghrelin, obestatin, insulin, peptide YY, glucose-dependent insulinotropic peptide, oxyntomodulin and cholecystokinin) and the adipose tissue (leptin, adiponectin, resistin, omentin, chemerin) control this phenomenon. All of the above-mentioned hormones have been found to be involved in the regulation of human reproduction (12). 120 121 GLP-1 is an incretin hormone produced by post-translational processing models varied in a time- and tissue-specific manner through the oestrous of proglucagon in enteroendocrine L-cells (13). Its most important role cycles. The highest expression level of GLP-1R mRNA in the hypothalamus is to regulate insulin secretion, which enables adequate maintenance (27) and the plasma concentrations of GLP-1 were detected during the proof postprandial glucose levels (13, 14). It is secreted as one of the gut oestrous phase. The hypothalamic GLP-1 content and plasma LH were also hormones within minutes after food intake (15, 16). It further stimulates responding to the nutritional status (26). insulin production and improves insulin sensitivity, increases pancreatic GLP-1 also has an effect on the ovaries. In addition to the GLP-1 receptors β-cell proliferation and protects them from apoptosis. It inhibits glucagon expressed in the ovary (25), GLP-1 has also been demonstrated in follicular secretion and gastric emptying and suppresses food intake (13, 17–20), fluid (32). Based on pre-clinical and clinical irradiation studies, GLP-1 is most which has been shown to be beneficial in weight reduction. GLP-1 binds to likely to affect steroidogenesis, gametogenesis and gonadal morphology. the GLP-1 receptor (GLP-1R), which is a member of the G protein-coupled Most clinical studies show the impact of GLP-1 RAs on hyperandrogenism receptor (GPCR) family (21). GLP-1R has also been detected in the lung, with reduction of androgens and increase of SHBG in PCOS patients (23). stomach, hypothalamus, heart, intestine, ovary and endometrium (22). Studies on the effect of GLP-1 on the menstrual cycle in PCOS patients are Recently, the GLP-1’s role as a modulatory molecule in fertility is becoming also important in determining the impact of GLP-1 on women’s reproductive increasingly apparent (12, 23, 24). GLP-1 receptors (GLP-1R) are distributed health. Elkind-Hirsch et al. looked at the effect of GLP-1A on menstrual throughout the reproductive system, and the effects of GLP-1 are seen frequency in anovulatory women with PCOS in three randomised groups at the level of reproduction in both preclinical models and some clinical treated with exenatide, metformin or a combination of the two (33). trials (25) thus suggesting, GLP-1 plays a role in the interaction between They found improved ovulation rates in all groups, and the combination the reproductive and metabolic systems (23). Preclinical results suggest treatment led to the best results, with the establishment of ovulation in that GLP-1 predominantly has a stimulatory effect on the hypothalamic-86%. Body weight decreased in all groups, and weight reduction was also pituitary axis (26, 27, 28, 29). It was also suggested that GLP-1 and GLP-associated with improved menstrual cycle. 1 agonists (GLP-1A) have anti-inflammatory and antifibrotic effects on Recent studies on the GLP-1RA’s plausible therapeutic role in human various reproductive tissues, such as the ovaries, endometrium, and testes, infertility treatment showed the positive impact of GLP-1RA on weight loss which are altered in obesity, diabetes, and polycystic ovary syndrome and improved fertility rate (6, 34). Liu et al. observed the effects of 24 (PCOS) (23). weeks of GLP-1RA (Exenatide) treatment on the spontaneous pregnancy GLP-1 modulates the activity of hypothalamic GnRH neurons (26, 27, 28, rate in obese or overweight women with PCOS. After 24 weeks of treatment, 29). Further investigations in preclinical models have shown that GLP-1 they observed significant weight loss, central adiposity reduction and an acts through the modulation of presynaptic excitatory γ -aminobutyric acid improvement in insulin resistance (IR), menstrual cycle and a decrease (GABA)-ergic inputs and via kisspeptin-1 neurons (29) in the hypothalamus. in inflammatory markers (34). Our research team conducted a study in These are neurons that are essential for fertility (30), as they are key which we observed liraglutide’s influence on IVF outcomes in infertile, regulators of the pulsatile release of GnRH from GnRH neurons (31). obese, women with PCOS. A 12-week preconception treatment with low-GLP-1 induces an increase in serum LH concentration in the most dose liraglutide in combination with metformin was superior to metformin functional studies (26, 27, 28). GLP-1 related increase in GnRH is being alone in increasing IVF pregnancy rates and the cumulative pregnancy rate applied as a principal mechanism to stimulate LH secretion from the including also spontaneous pregnancies after IVF. Suggested mechanisms pituitary. Importantly, the hypothalamic expression of GLP-1R in animal for the improved pregnancy rate were attributed to weight-loss mechanisms, 122 123 improvement of insulin resistance, and the possible effect of GLP-1 on the References hypothalamic-pituitary-ovarian axis (6, 34). In addition, the possible effect of liraglutide on the endometrium was also 1. Vale B, Brito S, Paulos L, Moleiro P. Menstruation disorders in adolescents with eating proposed relating to significantly better implantation rate in the group that disorders-target body mass index percentiles for their resolution. Einstein (Sao Paulo). was given the combination of metformin and liraglutide (6). 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Am J stress, glucose metabolism and energy consumption according to the Epidemiol. 2000;151(11):1072-1079. functional transcriptomic analysis of the endometrium. These processes 5. Diamanti-Kandarakis E, Bergiele A. The influence of obesity on hyperandrogenism and could represent potential mechanisms for optimizing the endometrial infertility in the female. Obes Rev. 2001;2(4):231-238. environment for implantation and embryo development to successful 6. Šalamun V, Jensterle M, Janež A, Vrtačnik Bokal E. Liraglutide increases IVF pregnancy pregnancy (35). rates in obese PCOS women with poor response to first-line reproductive treatments: The distribution of GLP-1R in the reproductive system and the described a pilot randomized study. Eur J Endocrinol. 2018;179(1):1-11. actions of GLP-1 in preclinical and clinical studies suggest that GLP-1 may 7. Sim KA, Dezarnaulds GM, Denyer GS, Skilton MR, Caterson ID. Weight loss improves be an influential signaling link between the reproductive and metabolic reproductive outcomes in obese women undergoing fertility treatment: a randomized systems. GLP-1A has the potential for novel therapeutic strategies in the controlled trial. Clin Obes. 2014;4(2):61-68. treatment of infertility associated with obesity, diabetes and PCOS. 8. Moran L, Tsagareli V, Norman R, Noakes M. Diet and IVF pilot study: short-term weight loss improves pregnancy rates in overweight/obese women undertaking IVF. Aust N Z J Obstet Gynaecol. 2011;51(5):455-459. 9. Espinós JJ, Polo A, Sánchez-Hernández J, et al. Weight decrease improves live birth rates in obese women undergoing IVF: a pilot study. Reprod Biomed Online. 2017;35(4):417-424. 10. Palomba S, Falbo A, Valli B, et al. Physical activity before IVF and ICSI cycles in infertile obese women: an observational cohort study. Reprod Biomed Online. 2014;29(1):72-79. 11. Kennedy GC & Mitra J. Body weight and food intake as initiating factors for puberty in the rat. J Physiol. 1963;166(2):408-418. 12. Comninos AN, Jayasena CN, Dhillo WS. The relationship between gut and adipose hormones, and reproduction. Hum Reprod Update. 2014;20(2):153-174. 13. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409-1439. 14. Drucker DJ. The biology of incretin hormones. Cell Metab. 2006;3(3):153-165. 124 125 15. Lovshin JA, Drucker DJ. Incretin-based therapies for type 2 diabetes mellitus. Nat Rev 28. Farkas I, Vastagh C, Farkas E, et al. Glucagon-Like Peptide-1 Excites Firing and Increases Endocrinol. 2009;5(5):262-269. GABAergic Miniature Postsynaptic Currents (mPSCs) in Gonadotropin-Releasing Hormone (GnRH) Neurons of the Male Mice via Activation of Nitric Oxide (NO) and 16. Hayes MR, Kanoski SE, Alhadeff AL, Grill HJ. Comparative effects of the long-acting Suppression of Endocannabinoid Signaling Pathways. Front Cell Neurosci. 2016;10:214. GLP-1 receptor ligands, liraglutide and exendin-4, on food intake and body weight suppression in rats. Obesity (Silver Spring). 2011;19(7):1342-1349. 29. Heppner KM, Baquero AF, Bennett CM, et al. GLP-1R Signaling Directly Activates Arcuate Nucleus Kisspeptin Action in Brain Slices but Does not Rescue Luteinizing 17. Huang Y, Wilkinson GF, Willars GB. Role of the signal peptide in the synthesis and Hormone Inhibition in Ovariectomized Mice During Negative Energy Balance. processing of the glucagon-like peptide-1 receptor. Br J Pharmacol. 2010;159(1):237-251. eNeuro. 2017;4(1):ENEURO.0198-16.2016. Published 2017 Jan 20. doi:10.1523/ 18. Li Y, Tweedie D, Mattson MP, Holloway HW, Greig NH. Enhancing the GLP-1 receptor ENEURO.0198-16.2016 signaling pathway leads to proliferation and neuroprotection in human neuroblastoma 30. Gianetti E, Seminara S. Kisspeptin and KISS1R: a critical pathway in the reproductive cells. J Neurochem. 2010;113(6):1621-1631. system. Reproduction. 2008;136(3):295-301. 19. Montrose-Rafizadeh C, Yang H, Wang Y, Roth J, Montrose MH, Adams LG. Novel signal 31. Han SY, McLennan T, Czieselsky K, Herbison AE. Selective optogenetic activation of transduction and peptide specificity of glucagon-like peptide receptor in 3T3-L1 arcuate kisspeptin neurons generates pulsatile luteinizing hormone secretion. Proc adipocytes. J Cell Physiol. 1997;172(3):275-283. Natl Acad Sci U S A. 2015;112(42):13109-13114. 20. Quoyer J, Longuet C, Broca C, et al. GLP-1 mediates antiapoptotic effect by 32. Bou Nemer L, Shi H, Carr BR, Word RA, Bukulmez O. Effect of Body Weight on Metabolic phosphorylating Bad through a beta-arrestin 1-mediated ERK1/2 activation in Hormones and Fatty Acid Metabolism in Follicular Fluid of Women Undergoing In Vitro pancreatic beta-cells. J Biol Chem. 2010;285(3):1989-2002. Fertilization: A Pilot Study. Reprod Sci. 2019;26(3):404-411. 21. Nauck MA, Meier JJ. Incretin hormones: Their role in health and disease. 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Transkriptom celic kumulusa in endometrija pri neplodnih bolnicah 24. Lamos EM, Malek R, Davis SN. GLP-1 receptor agonists in the treatment of polycystic z debelostjo in s sindromom policističnih jajčnikov zdravljenih z metforminom in ovary syndrome. Expert Rev Clin Pharmacol. 2017;10(4):401-408. liraglutidom [online]. 2021. [Cited 2022 Sep 2]. Available from: https://repozitorij.uni-lj. 25. Nishiyama Y, Hasegawa T, Fujita S, et al. Incretins modulate progesterone biosynthesis si/IzpisGradiva.php?lang=slv&id=132787 by regulating bone morphogenetic protein activity in rat granulosa cells. J Steroid Biochem Mol Biol. 2018;178:82-88. 26. Beak SA, Heath MM, Small CJ, et al. Glucagon-like peptide-1 stimulates luteinizing hormone-releasing hormone secretion in a rodent hypothalamic neuronal cell line. J Clin Invest. 1998;101(6):1334-1341. 27. Outeiriño-Iglesias V, Romaní-Pérez M, González-Matías LC, Vigo E, Mallo F. GLP-1 Increases Preovulatory LH Source and the Number of Mature Follicles, As Well As Synchronizing the Onset of Puberty in Female Rats. Endocrinology. 2015;156(11):4226-4237. 126 127 20 THE ROLE OF GLP-1 (AGONISTS) IN MALE REPRODUCTIVE HEALTH Nadan Gregorič Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana, Slovenia nadan.gregoric@gmail.com Introduction The reproductive system and energy metabolism are closely interconnected processes in human biology. For a human to reproduce the energy homeostasis needs to be adequately balanced. Prolonged scarcity or energy surplus can disrupt the human reproductive system through complex signalling pathways which are yet to be fully understood. Due to extreme energy abundance, we are currently living in the obesity epidemic which coincides with the rise of male hypogonadism and infertility (1, 2). Obesity and insulin resistance are major contributors to male hypogonadism, with some studies reporting up to 50 % of obese diabetic men to have low levels of circulating testosterone (3). The extensive research on type 2 diabetes and its treatment gave rise to antidiabetic agents based on the incretin system, particularly, glucagon-like-peptide 1 (GLP-1) agonists, which further defined the role of incretins in glucose homeostasis and energy metabolism. Ensuing studies revealed widespread effects of GLP1 throughout the human body and were not limited to the pancreas and glucose and energy homeostasis. Of particular interest has been the effect of GLP-1 on the male reproductive system. Prolonged treatment with GLP1 agonists has improved testosterone levels via weight reduction in obese men with hypogonadism. There has also been demonstrated a direct effect of GLP-1 on male gonads and gametes. 128 129 The GLP-1 and the incretin system The direct role of GLP-1 on male gonads The incretin system has been extensively studied in the treatment of The presence of the GLP-1 receptor in male gonads indicates a direct role type 2 diabetes where the effects of GLP-1 agonists have been proven of GLP-1 in the reproductive system but the role remains to be determined. to be particularly successful in improvement of glucose homeostasis by A study has demonstrated the presence of GLP-1 receptors in rodent and enhancement of insulin secretion and reduction of caloric intake through human male Leydig cells, but absent in tumour Leydig cells suggesting a appetite regulation and decreasing gut motility thereby achieving role in cell oncogenesis (11). Recognized for its anti-apoptotic and anti-significant weight reduction (4). The widespread presence of GLP-1 inflammatory role in other tissues GLP-1 could have a similar role in male receptors on multiple human tissues, namely lungs, kidneys, heart, and gonads (5). The absence of GLP-1 function has led to the decreased size central nervous system, indicates far greater physiological reach than of gonads in GLP-1 receptor knockout mice compared to controls (12). glucose and energy homeostasis (5). In several different tissues, GLP-1 Conversely, treatment with a GLP-1 agonist has led to improve the quallity carries out a protective role in preserving cell mass mainly due to its anti-and motility of sperm as well as improve the inflammatory status of the apoptotic and anti-inflammatory function (5). gonads in hypogonadal obese mice models (13). Finally, the direct effect of GLP-1 on human male gametes has been thoroughly demonstrated by Rago et al. The in vitro treatment of gametes with a GLP-1 agonist, exendin-4, Energy metabolism and the male reproductive health demonstrated the effect on several metabolic processes such as an increase in cholesterol influx and lipid metabolism, an increase in gamete insulin The relationship between energy metabolism and the reproductive system secretion and glucose metabolism as well as an increase in sperm motility is complex and remains to be fully elucidated. Current evidence points (14). These findings are consistent with the intensification of metabolic to peripheral adipokine inhibition of gonadotropin-releasing hormone activity and sperm maturation during the capacitation state, indicating a secretion via kisspeptin neurons in the hypothalamus (6). The adipokine crucial role of GLP-1 in male fertility. It is worth noticing that, in the same formation is most pronounced in obese and insulin-resistant states (7). study, reduced GLP-1 receptor expression was observed in sperm samples of Consequentially, the downregulation of the hypothalamic-pituitary-gonadal patients with oligoastenospermia (14). (HPG) axis reduces spermatogenesis and testosterone production (6). Interestingly, the HPG axis is reinstated again when the body weight and Despite mostly favourable outcomes from laboratory studies, a few insulin resistance are reduced. The extent of weight loss and testosterone clinical reports are suggesting the negative effects of GLP-1 agonists on level elevation seem to be in a reciprocal relationship (8). The role of GLP-sperm quality. A case report of a 35-year-old man examined for infertility 1 through its regulation of appetite and reduction of energy intake has demonstrated no sperm motility after a few months of treatment with proven to be significant in the coupling of the two physiological processes. a GLP-1 agonist, liraglutide, and a complete improvement after the drug A study on obese individuals with functional hypogonadism demonstrated discontinuation (15). Up to July 2022, of 38 415 people that reported adverse significant increase of circulating testosterone levels through the recovery side effects when taking liraglutide only 2 had a decreased sperm count of the HPG axis when continually treated with GLP-1 agonists (9). However, (16). So far, no other concerns have been raised despite GLP-1 agonists in healthy individuals such treatment, albeit acute, did not affect luteinizing being one of the most widely prescribed antidiabetic agents worldwide. hormone and testosterone levels (10). 130 131 References 14. Rago V, De Rose D, Santoro M, Panza S, Malivindi R, Andò S, et al. Human Sperm Express the Receptor for Glucagon-like Peptide-1 (GLP-1), Which Affects Sperm Function and Metabolism. Endocrinology. 2020;161(4):bqaa031. 1. Rolland M, Le Moal J, Wagner V, Royère D, De Mouzon J. Decline in semen concentration 15. Fontoura P, Cardoso MC, Erthal-Martins MC, Werneck C, Sartorio C, Ramos CF. The effects and morphology in a sample of 26,609 men close to general population between 1989 of liraglutide on male fertility: a case report. Reprod Biomed Online. 2014;29(5):644–6. and 2005 in France. Hum Reprod. 2013;28(2):462–70. 16. Victoza and Sperm count decreased - a phase IV clinical study of FDA data. Mountain 2. Dhindsa S, Prabhakar S, Sethi M, Bandyopadhyay A, Chaudhuri A, Dandona P. Frequent View, CA: eHealthMe; 2022 [cited 2022 Sep 8]. Available from: https://www.ehealthme. occurrence of hypogonadotropic hypogonadism in type 2 diabetes. J Clin Endocrinol com/ds/victoza/sperm-count-decreased/ Metab. 2004;89(11):5462–8. 3. Dhindsa S, Miller MG, McWhirter CL, Mager DE, Ghanim H, Chaudhuri A, et al. Testosterone concentrations in diabetic and nondiabetic obese men. Diabetes Care. 2010;33(6):1186–92. 4. Nauck MA, Quast DR, Wefers J, Meier JJ. GLP-1 receptor agonists in the treatment of type 2 diabetes - state-of-the-art. Mol Metab. 2021;46:101102. 5. Zhao X, Wang M, Wen Z, Lu Z, Cui L, Fu C, et al. GLP-1 Receptor Agonists: Beyond Their Pancreatic Effects. Front Endocrinol. 2021;12:721135. 6. Roseweir AK, Millar RP. The role of kisspeptin in the control of gonadotrophin secretion. Hum Reprod Update. 2009;15(2):203–12. 7. Rabe K, Lehrke M, Parhofer KG, Broedl UC. Adipokines and insulin resistance. Mol Med. 2008;14(11-12):741–51. 8. Grossmann M. Low testosterone in men with type 2 diabetes: significance and treatment. J Clin Endocrinol Metab. 2011;96(8):2341–53. 9. Jensterle M, Podbregar A, Goricar K, Gregoric N, Janez A. Effects of liraglutide on obesity-associated functional hypogonadism in men. Endocr Connect. 2019;8(3):195–202. 10. Izzi-Engbeaya C, Jones S, Crustna Y, Machenahalli PC, Papadopoulou D, Modi M, et al. Effects of Glucagon-like Peptide-1 on the Reproductive Axis in Healthy Men. J Clin Endocrinol Metab. 2020;105(4):1119–25. 11. Caltabiano R, Condorelli D, Panza S, Boitani C, Musso N, Ježek D, et al. Glucagon-like peptide-1 receptor is expressed in human and rodent testis. Andrology. 2020;8(6):1935-45. 12. MacLusky NJ, Cook S, Scrocchi L, Shin J, Kim J, Vaccarino F, et al. Neuroendocrine function and response to stress in mice with complete disruption of glucagon-like peptide-1 receptor signaling. Endocrinology. 2000;141(2):752–62. 13. Zhang E , Xu F , Liang H , Yan J , Xu H , Li Z , et al. GLP-1 receptor agonist exenatide attenuates the detrimental effects of obesity on inflammatory profile in testis and sperm quality in mice. Am J Reprod Immunol 2015;74(5):457–66 . 132 133 21 INFERTILITY WORK UP – INTERDISCIPLINARY APPROACH INCLUDING GYNECOLOGIST AND ENDOCRINOLOGIST Eda Vrtačnik Bokal Department of Obstetrics and Gynecology, University Medical Centre, Ljubljana, Slovenia eda.bokal@guest.arnes.si Nowadays, in the absence of relevant medical history or physical findings, a complete systematic infertility workup should be advised after 12 months of conceptual failure in women aged <35 years. In women >35 years, this interval is commonly shortened to 6 months and even less in women aged >40 years. In the infertility workups, the treatment of 4 areas should be included: the assessment of oocyte quantity and quality; assessment of ovulation, ovulatory disorders, and amenorrhea; assessment of other endocrine disorders, which may compound infertility; and genetic screening and in future maybe expanded carrier screening (ECS). 1. Assessment of oocyte quantity and quality using different clinical markers is needed for optimizing ovarian stimulation (OS). 1.1. Clinical biomarkers 1.1.1 Age Women are born with a given number of nongrowing follicles (NGFs), and this number is progressively declining with age. However, the NGF decline rate may widely vary among individuals, but around 80% of the variance in the NGF populations is because of age alone. Ovarian surgery, gonadotoxic therapy, and genetic or 134 135 idiopathic causes may be associated with an accelerated decline in of patients with infertility. Being produced by the granulosa cells the number of NGFs, leading to primary ovarian insufficiency (POI). of large preantral and antral follicles, AMH has proven to be an Still, age is by far the most reliable biomarker for the prediction of excellent biomarker of ovarian reserve with an excellent ability to oocyte quality. Embryo euploidy rates show a consistent continuous predict the extremes of ovarian response. It has low intercycle and decline with age starting from approximately the age of 36 years (1). intracycle variability and remains same at least up to 12 months. Smoking and the use of combined contraceptives, may suppress 1.1.2 Body mass index BMI is not independently associated with ovarian the serum AMH levels, and seems to be reversible. AMH is not a reserve. However, BMI does affect response to stimulation because biomarker associated with oocyte quality. it is inversely associated with the circulating follicle-stimulating hormone (FSH) level after exogenous administration. Women with 1.2.5. Androgens testosterone levels may be lower in women with DOR obesity are at increased risk of an inadequate response leading to because of the reduction of the number of follicles. It is also known ART cancellation. Altered follicular environment, due to lipotoxicity that the androgens decline with age. and increased production of reactive oxygen species causes oocyte On the other hand, serum androgens may be associated with oocyte organelle damage. It is assumed that obesity also negatively affects quality in women with PCOS. Hyperandrogenism alters intrafollicular endometrial receptivity (2). microenvironment, leading to abnormal folliculogenesis and premature arrest of immature developing oocytes. The most 1.2. Hormonal biomarkers common provocative factors of ovarian hyperandrogenism appear to be obesity and insulin resistance, which occur in 50% of the 1.2.1. Basal FSH has been one of the first biomarkers for the pretreatment patients. In this context, obesity up-regulates ovarian androgen assessment of ovarian function. It is elevated in women with production primarily via insulin-resistant hyperinsulinemia and, to diminished ovarian reserve (DOR) and is not biomarker of oocyte some extent, via inflammatory cytokines (3). quality. 1.2.2. Basal estradiol (E2) alone should not be used as a marker of ovarian 1.3. Functional Biomarkers reserve. However, it is essential for the correct interpretation of a Antral follicle count (AFC) is one of the best biomarkers of ovarian reserve normal basal FSH value. An elevated serum E2 level in advanced-age and response to stimulation with an excellent ability to predict low and patients can lower an otherwise elevated basal FSH level into the excessive response to stimulation. Its low intercycle and intracycle normal range, thereby causing a misinterpretation of the test. variability makes it, along with AMH, a very reliable biomarker. Regarding, 1.2.3. The basal LH levels are not associated with ovarian reserve and oocyte quality AFC is a weak biomarker (4). oocyte quality. Low basal LH levels are associated with a suboptimal oocyte yield after trigger with a GnRH agonist, and thus, it may be 1.4. Genetic Biomarkers considered when a freeze-all strategy is planned. Fragile X mental retardation 1 (FMR1) (>200 CGG repeats) can cause 1.2.4. Antimullerian hormone (AMH) has undeniably been one of the intellectual disability, and premutation (approximately 55–200 repeats) most important pretreatment biomarkers of the general workup has been associated with POI (5). 136 137 2. Assessment of ovulation, ovulatory disorders, and conditions, such as congenital adrenal hyperplasia (CAH), non-amenorrhea classic NCAH or late-onset CAH which tend to manifest later, with more discrete signs, ranging from premature adrenarche and/or various degrees of masculinization. Ovulation can be detected by transvaginal ultrasonography, urinary LH kits and progesterone level of > 3 ng/mL in the mid-luteal phase. They are In addition, Cushing syndrome, a disorder of cortisol excess, can be classified by the nonfunctioning level in the reproductive axis. confused with PCOS because symptoms of hyperandrogenism, such as hirsutism, and menstrual irregularities are often present (6). World Health Organization (WHO) type I includes disorders of hypothalamic and pituitary origin. Central nervous system abnormalities and/or pituitary tumors should be excluded. The most common ovulatory disorders are WHO type II disorders, which refer to oligo-anovulation or PCOS. Classically, there have been 3 sets of criteria for diagnosing PCOS, androgen excess, ovulatory dysfunction, or polycystic ovaries. Owing to the fact that PCOS is a more complex metabolic disorder, associated with various degrees of insulin resistance References and metabolic syndrome (commonly associated with hyperandrogenism), general workup may require additional examinations. Disorders that mimic the clinical features of PCOS: thyroid disease, hyperprolactinemia; and 1. Franasiak JM, Forman EJ, Hong KH, Werner MD, Upham KM, Treff NR, et al. The nature non-classic congenital adrenal hyperplasia (NCAH) should be excluded. of aneuploidy with increasing age of the female partner: a review of 15,169 consecutive trophectoderm biopsies evaluated with comprehensive chromosomal screening. Fertil World Health Organization type III ovulatory disorders— with or without Steril. 2014;101:656–63.e1. amenorrhea—are associated with elevated gonadotropin levels. This is often associated with autoimmune alterations (3). 2. Broughton DE, Moley KH. Obesity and female infertility: potential mediators of obesity’s impact. Fertil Steril. 2017;107:840–7. 3. Polyzos NP, Ayoubi JM, Pirtea P. General infertility workup in times of high assisted 3. Assessment of other endocrine disorders reproductive technology efficacy. Fertil Steril. 2022;118:8-18. 4. van Disseldorp J, Lambalk CB, Kwee J, Looman CW, Eijkemans MJ, Fauser BC, et al. 3.1. Screening for thyroid disorders has become a standard, given their Comparison of inter- and intra-cycle variability of anti- Mullerian hormone and antral potential association with early miscarriage rates. follicle counts. Hum Reprod. 2010;25: 221–7. 3.2. Other hormonal markers Apart from estrogens and progesterone, 5. Murray A, Schoemaker MJ, Bennett CE, Ennis S, Macpherson JN, Jones M, et al. the measurement of other steroid hormones should be limited to Population-based estimates of the prevalence of FMR1 expansion mutations in women specific patients’ categories. Androgens play a role in women with with early menopause and primary ovarian insufficiency. Genet Med. 2014;16:19–24. PCOS and may be associated with oocyte quality. 6. Carmina E, Dewailly D, Escobar-Morreale HF, Kelestimur F, Moran C, Oberfield S, et al. Non-classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency revisited: 3.3. Determination of cortisol and other hormones involved in the an update with a special focus on adolescent and adult women. Hum Reprod Update. steroidogenic pathway is essential in cases of suspicion of specific 2017;23: 580–99. 138 139 22 EPIDEMIOLOGY OF PANCREATIC CANCER Vesna Zadnik Epidemiology and Cancer Registry, Institute of Oncology Ljubljana, Slovenia vzadnik@onko-i.si Introduction Cancer epidemiology studies the distribution of cancer in populations and its changes over time. It looks at characteristics of different population groups, not only those who get the disease but also those who do not, to find out how these groups differ. The continuous and systematic collection, storage, and analysis of data on all cancer patients is the basis for controlling this significant public health problem. The population-based cancer registries play a crucial role in this. In this abstract, we present the data on new cancer cases (incidence), mortality, and survival of pancreatic cancer patients in Slovenia, Europe, and globally. In the last part, we also give a short overview of known and possible risk factors for developing pancreatic cancer. The burden of pancreatic cancer With almost half a million new cases annually, pancreatic cancer is estimated to be the 12th most common cancer worldwide in 2020; more 140 141 than half of the new cases occurred in countries at high or very high levels the histological type was not specified. The disease was most commonly of human development (1). The geographical differences within Europe are diagnosed in the distant stage (55%), one-third of patients were diagnosed not so pronounced; the highest crude incidence rates in 2020 were noted with the regional disease (6). in Germany, Hungary, and Finland (app. 25/100,000) and the lowest (app. 15/100,000) in Poland, Ireland, and Cyprus (2). In Slovenia, the pancreatic cancer incidence is around 400 (20/100,00) which represents 2.5% of all Survival new cancers. The estimated lifetime risk of being diagnosed with pancreatic cancer is 1% for those born after 2010 in Slovenia. The estimated annual According to the Concord-3 global research of patients diagnosed with change of crude incidence rate over the latest ten years in Slovenia was cancer during the 15 years between 2000 and 2014 in 71 countries, 2,7% (3). Along with risk factors, the differences in access to health care can pancreatic cancer has the lowest survival of all common cancers, with a affect the reported rates (4). The incidence of pancreatic cancer is projected five-year survival of less than 7% (7). Early diagnosis is crucial to improve to rise in the next two decades by more than 60%, and the rise will be survival outcomes for people with pancreatic cancer; with one-year survival steeper in the currently less developed areas (1). There were an estimated in those diagnosed at an early stage six times higher than one-year survival 466,000 deaths from pancreatic cancer in 2020, and because of its very in those diagnosed at stage four (6, 7). Very important is also the age at high fatality, pancreatic cancer is the seventh most common cause of death diagnosis. A study by Huang et al. et al. comparing survival by stage and from cancer worldwide (1). Given the overall mortality-to-incidence ratio of patient age in four European countries (Norway, the Netherlands, Belgium, 0.98, the geographical patterns and trends for mortality are very similar and Slovenia) and the United States shows that the three-year survival of to those observed for incidence (4). Finally, on the global scale, there was a patients with stage I–II who were younger than 60 years at diagnosis was two-times increase in disability-adjusted life-years due to pancreatic cancer, 20-34%, in patients aged 60-69 years 14-25%, and in patients over 70 years increasing from 4.4 million in 1990 to 9.1 million in 2017 (5). 9-13%. In patients with stage III-IV, survival was in the range of 2-5% (under 60 years), 1-2% (60-59 years), and 1% (over 70 years) (8). Characteristics of patients and their disease Risk factors and prevention possibilities Pancreatic cancer is most frequent in elderly people. The risk of developing pancreatic cancer increases as people age: about 85% are at least 60 years Without effective screening methods, options for primary prevention of old; pancreatic cancer is unusual in people younger than 45 years (3). pancreatic cancer are of significant importance. Risk factors such as age, Pancreatic cancer affects men and women equally. In Slovenian patients race, and family history cannot be modified. Still, primary prevention by with pancreatic cancer diagnosed between 1997 and 2016, most cases altering modifiable risk factors has the potential to decrease the overall risk (40%) occurred in the head of the pancreas, in 6%, the disease occurred of pancreatic cancer and warrants further study. Potentially modifiable risk in the tail of the pancreas, and in 5%, in the body of the pancreas. In 4% factors include smoking, obesity, diabetes, diet, and alcohol consumption. of cases, the disease occurred as an overlapping lesion of the pancreas. The best strategy for risk reduction is lifestyle modification: smoking In 35% of cases of pancreatic cancer, the site was not specified. Around cessation, maintaining a healthy weight, a diet high in fruits and vegetables, 40% of patients did not have their disease confirmed microscopically. The regular physical activity, and avoiding heavy alcohol consumption (4). most common histological type among all microscopically confirmed cases was adenocarcinoma, which occurred in 87% of cases. In 10% of cases, 142 143 Conclusion References Pancreatic cancer is among the deadliest types of cancer. Part of the reason lies in the fact that the stage of most patients at diagnosis is locally 1. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A, et al. Cancer advanced or disseminated cancer due to the non-specific symptoms and statistics for the year 2020: An overview. Int J Cancer. 2021;149:778–89. signs of the disease and the aggressiveness of the disease. All professions 2. ECIS - European Cancer Information System, European Union, 2022. [cited 2022 July involved in the study, monitoring, diagnosis, and treatment of pancreatic 25]. Available from: https://ecis.jrc.ec.europa.eu. cancer can, by working together, contribute to efforts to reduce the number 3. Zadnik, V, Primic Žakelj M, Lokar K, Jarm K, Ivanuš U, Žagar T. Cancer burden in Slovenia of patients and improve the prognosis of patients with pancreatic cancer. with the time trends analysis. Radiol Oncol. 2017;51:47–55. 4. Wild CP, Weiderpass E, Stewart BW, eds. World cancer report. Cancer research for cancer prevention. Lyon: IARC, 2020. p. 367–74. 5. GBD 2017 Pancreatic Cancer Collaborators. The global, regional, and national burden of pancreatic cancer and its attributable risk factors in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet Gastroenterol Hepatol. 2019;4:934–47. 6. Zadnik V, Žagar T, Lokar K, Tomšič S, Konjević Duratović A, Zakotnik B. Trends in population-based cancer survival in Slovenia. Radiol Oncol. 2021;55:42–9. 7. Allemani C, Matsuda T, Di Carlo V, Harewood R, Matz M, Nikšić M, et al. Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37 513 025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries. Lancet. 2018;391:1023–75. 8. Huang L, Jansen L, Balavarca Y, Babaei M, van der Geest L, Lemmens V, et al. Stratified survival of resected and overall pancreatic cancer patients in Europe and the USA in the early twenty-first century: a large, international population-based study. BMC Medicine. 2018;16:125. 144 145 23 PANCREATIC CANCER: RISK FACTORS, RISK ASSESSMENT AND SCREENING OF HIGH-RISK INDIVIDUALS Mateja Krajc Cancer Genetics Clinic, Institute of Oncology Ljubljana, Ljubljana, Slovenia mkrajc@onko-i.si Introduction Pancreatic cancer is one of the cancers with the fastest increasing incidence. It is a leading cause of cancer death worldwide (1). At the same time, survival is still among the lowest. Five years after diagnosis, only a few percent of patients are still alive, which makes it one of the five deadliest cancers (2). The medical profession around the world is currently looking for solutions to this problem and an investment in the research of risk prediction, prevention and early detection of pancreatic cancer is fully encouraged. Given that treatment outcomes are better in localized disease, we expect that personalized screening and diagnosing of asymptomatic, potentially curable pancreatic cancers could improve overall survival. Risk factors Ageing of the worldwide populations represents an important factor for the increase in the incidence. Anyway, there are other known non-modifiable and also modifiable risk factors. Both may act either independently or jointly. Many modifiable risk factors such as cigarette smoking, obesity, diabetes and alcohol intake are well known and researched. On the other side, we are aware that there are some families where the clustering of pancreatic 146 147 cancer is detected. This may be attributed either to common environmental Conclusion factors or to an underlying genetic predisposition. The proportion of pancreatic cancers that are due to inherited genetic risk factors has been Pancreatic cancer incidence is increasing. The main causes are ageing of the estimated to be between 21.4–36% (3, 4). Lately, several studies have population, as well as increase in the prevalence of modifiable pancreatic revealed both, high-penetrance rare variants ( i.e. BRCA2, PALB2, BRCA1, risk factors like obesity, diabetes and cigarette smoking (11). The burden of ATM, STK11, CDKN2A, PRSS1, MLH1, MSH2, MSH6 and PMS2), and also low-this disease may be therefore reduced by public health interventions such penetrance common variants that are associated with an increased risk of as smoking cessation, obesity prevention and weight loss. On the other pancreatic cancer (5-8). However, the identified genetic variations explain side, the inherited genetic pathogenic variants also play an important role only 20–25% of the heritability (4–5% of all pancreatic cancers) (3). For in pancreatic cancer risk. Identifying high-risk individuals and offering the 20% of familial pancreatic cancers for which a causative mutation has them pancreatic cancer screening in a research setting, might provide been identified, knowledge of the precise genetic variation can help guide opportunities for earlier detection. Furthermore, the identification of the therapeutic decisions for those who develop pancreatic cancer and prompt genetic changes that underlie pancreatic cancer may provide insight into early detection screening choices for at-risk relatives. the etiology of this cancer and the opportunity to implement personalized treatment for cancer patients and screening, early detection and cascade genetic testing for relatives at risk (11). Pancreatic Cancer Screening Our ability to detect pancreatic cancer and its precursor lesions is slowly improving. Understanding the underlying risk factors and their interactions will enable prevention efforts, like primary prevention strategies, to reduce exposures and to identify high risk individuals. At the moment, screening of the general population for pancreatic cancer is not recommended, since no screening test has proven to be effective in lowering the incidence and/or mortality. Individuals who are at higher risk of developing pancreatic cancer, on the basis of a family burden of pancreatic cancer or a proven genetic predisposition, could be suitable candidates for selective personalized screening with endoscopic ultrasound (EUS) and/or magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography. The International Cancer of the Pancreas Screening Consortium have agreed that screening should be conducted as part of a clinical trial, or if that is not possible, at a center with experience in pancreatic cancer screening (9). The consensus statements support screening using EUS or MRI (9). EUS-based screening trials in both the USA and Europe have shown that asymptomatic precursor lesions as well as cancers, can be detected at an earlier stage. Yet additional research is needed to prove that early detection screening improves pancreatic cancer outcomes (9, 10). 148 149 24 References HOW DO WE TREAT MILD AUTONOMOUS CORTISOL SECRETION (MACS)? – 1. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Piñeros M, Znaor A et al. Cancer SURGICAL TREATMENT statistics for the year 2020: An overview. Int J Cancer. 2021;149:778–89. 2. Zadnik, V, Primic Žakelj M, Lokar K, Jarm K, Ivanuš U, Žagar T. Cancer burden in Slovenia Antonela Sabati Rajić with the time trends analysis. Radiol Oncol. 2017;51:47–55. Department of Endocrinology, Diabetes and Metabolic Diseases, 3. Chen F et al. Analysis of heritability and genetic architecture of pancreatic cancer: a University Medical Centre Ljubljana, Ljubljana, Slovenia PanC4 study. Cancer Epidemiol. Biomarkers Prev. 2019; 28:1238–1245. 4. Lichtenstein P et al. Environmental and heritable factors in the causation of cancer– analyses of cohorts of twins from Sweden, Denmark, and Finland. N Engl J Med. 2000; asabatirajic@gmail.com 343:78–85. 5. Jones S et al. Exomic sequencing identifies PALB2 as a pancreatic cancer susceptibility gene. Science. 2009; 324: 217 6. Roberts NJ et al. Whole genome sequencing defines the genetic heterogeneity of familial pancreatic cancer. Cancer Discov. 2016; 6:166–175. 7. Petersen GM et al. A genome-wide association study identifies pancreatic cancer Who is the patient with mild autonomous cortisol secretion (MACS)? A patient susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. Nat Genet. 2010; 42: with an adrenal mass and biochemical evidence of hypercortisolemia but 224–228. without the classical clinical manifestations of overt Cushing’s syndrome. 8. Wolpin BM et al. Genome-wide association study identifies multiple susceptibility loci MACS encompasses subclinical Cushing’s syndrome (CS), subclinical for pancreatic cancer. Nat Genet. 2014; 46: 994–1000. hypercortisolemia, pre-clinical Cushing’s, and subclinical autonomous 9. Goggins M et al. Management of patients with increased risk for familial pancreatic glucocoricoid hypersecretion. Up to 50% of benign adenomas present cancer: updated recommendations from the International Cancer of the Pancreas some degree of cortisol excess depending on diagnostic criteria applied. Screening (CAPS) Consortium. Gut. 2020; 69: 7–17. Prevalence of MACS is estimated to be 1–2% in general population. The 10. Canto MI et al. Risk of neoplastic progression in individuals at high risk for pancreatic main diagnostic criterion is the result of the 1 mg overnight dexamethasone cancer undergoing long-term surveillance. Gastroenterology. 2018; 155:740–751. suppression test. Possible autonomous cortisol secretion is diagnosed if the 11. Klein AP. Pancreatic cancer epidemiology: understanding the role of lifestyle and morning cortisol level is in the range 1.9–5 µg/dL (51–138 nmol/L) (1). inherited risk factors. Nat Rev Gastroenterol Hepatol. 2021;18(7):493-502. Just under 1% of patients with mild autonomous adrenal cortisol secretion will progress to overt CS in the following years. Comorbidities potentially related to MACS are: glucose intolerance or type 2 diabetes mellitus, dyslipidemia, increased visceral fat and low muscle mass, hypertension, increased left ventricular mass, osteoporosis (2, 3, 4). Based mostly on retrospective observational studies, MACS is reported to be associated with an increased risk of cardiovascular events, increased 150 151 mortality, and increased risk for bone fractures. Adrenalectomy or intensive and cost of healthcare for extensive follow-up should be considered as medical treatment of comorbidities? Should all patients with subclinical important factors. After surgical treatment of MACS, quality of life of Cushing’s syndrome undergo unilateral adrenalectomy? In the absence of these patients improves; however, it remains below that of age and gender a prospective randomized study, it is reasonable to consider that younger controls without MACS for up to 15 years (9). patients and those who have disorders potentially attributable to excess glucocorticoid secretion and have well documented glucocorticoid secretory autonomy are candidates for adrenalectomy. If adrenalectomy is performed, perioperative glucocorticoid coverage should be administered because of the risk of adrenal insufficiency, hemodynamic crisis, and death. Is adrenalectomy effective? Adrenalectomy results in improvement of cardiovascular risk factors, improved blood preassure, and metabolic control in patients with possible autonomous cortisol secretion (5). When compared to conservative management, patients with MACS undergoing adrenalectomy experienced improvement in hypertension (RR 11, 95% CI 4.3–27.8), diabetes mellitus (RR 3.9, 95% CI 1.5–9.9) but not in dyslipidemia or obesity. Adrenalectomy is the way to improve the bone mineral density. In the study of 32 MACS surgically treated patients and 23 MACS non-surgical patients, surgically treated patients showed 30% reduction in vertebral fractures; in the conservatively treated group, follow-up showed 15 times higher risk of new vertebral fractures (6, 7). Optimal management of MACS is still a matter of debate. The problems are identification of patients likely to benefit, active approach to screening for comorbidities, discussion of treatment options and lack of evidence-based data. In conclusion, adrenalectomy as a treatment option for MACS is safe and effective. A surgeon experienced in adrenal surgery who will be able to minimize the risk of complications should be engaged. Adrenalectomy may be done laparoscopically, endoscopically via the posterior approach, or as an open procedure. Laparoscopic adrenalectomy, compared with open adrenalectomy, is associated with less pain, shorter hospitalization time, less blood loss, and faster recovery (8). Furthermore, patient’s anxiety 152 153 25 References MILD HYPERCORTISOLISM – CONSERVATIVE 1. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of MANAGEMENT adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline in collaboration with the European Network for the Study of Adrenal Tumors. Eur J Katarina Mlekuš Kozamernik 1,2 Endocrinol 2016; 175(2): G1–G34. 2. Morelli V, Reimondo G, Giordano R, Della Casa S, Policola C, Palmieri S, et al. Long-term 1 Department of Endocrinology, Diabetes and Metabolic Diseases, follow-up in adrenal incidentalomas: an Italian multicenter study. J Clin Endocrinol University Medical Centre Ljubljana, Ljubljana, Slovenia Metab. 2014;99(3):827-34. 2 Faculty of Medicine, 3. Di Dalmazi G, Vicennati V, Garelli S, Casadio E, Rinaldi E, Giampalma E, et al. University of Ljubljana, Ljubljana, Slovenia Cardiovascular events and mortality in patients with adrenal incidentalomas that are either non-secreting or associated with intermediate phenotype or subclinical Cushing’s syndrome: a 15-year retrospective study. Lancet Diabetes Endocrinol. katarina.mlekuskozamernik@kclj.si 2014;2(5):396-405. 4. Androulakis II, Kaltsas G, Piaditis G, Grossman AB. The clinical significance of adrenal incidentalomas. Eur J Clin Invest. 2011;41(5):552-60. 5. Morelli V, Frigerio S, Aresta C, Passeri E, Pugliese F, Copetti M, et al. Adrenalectomy Improves Blood Pressure and Metabolic Control in Patients With Possible Autonomous Mild hypercortisolism (mHC) describes an excessive cortisol secretion in Cortisol Secretion: Results of a RCT. Front Endocrinol (Lausanne). 2022;13:898084. doi: patients without the classical clinical manifestations (especially without 10.3389/fendo.2022.898084. [cited 2022 Aug 31]. catabolic characteristics, e.g., proximal muscle weakness, striae, skin 6. Salcuni AS, Morelli V, Eller Vainicher C, Palmieri S, Cairoli E, Spada A, et al. Adrenalectomy fragility, etc.) of Cushing’s syndrome (CS) (1). It is also named “subclinical reduces the risk of vertebral fractures in patients with monolateral adrenal hypercortisolism” or “subclinical CS” (2). However, the term “subclinical” incidentalomas and subclinical hypercortisolism. Eur J Endocrinol. 2016;174(3):261-9. is misleading, as these patients have a higher prevalence of diabetes 7. Morelli V, Eller-Vainicher C, Palmieri S, Cairoli E, Salcuni AS, Scillitani A, et al. Prediction mellitus type 2 (DM type 2), hypertension, hyperlipidemia, osteoporosis, of Vertebral Fractures in Patients With Monolateral Adrenal Incidentalomas. J Clin cardiovascular events, neuropsychologic disorders, and increased mortality Endocrinol Metab 2016; 101 (7): 2768–75. (3). In some patients, mHC may also be completely hidden, meaning they 8. Elfenbein DM, Scarborough JE, Speicher PJ, Scheri RP. Comparison of laparoscopic only have biochemical (and no clinical) evidence of hypercortisolism. In this versus open adrenalectomy: results from American College of Surgeons-National case, the term “hidden hypercortisolism” (HidHyCo) has been proposed (4). Surgery Quality Improvement Project. J Surg Res. 2013;184(1):216-20. The term “mild autonomous cortisol secretion” (MACS) defines the presence 9. Lindsay JR, Nansel T, Baid S, Gumowski J, Nieman LK. Long-term impaired quality of of mHC in patients with adrenal incidentalomas (AI) (5). Patients with mHC life in Cushing’s syndrome despite initial improvement after surgical remission. J Clin rarely progress towards CS; therefore, mHC is a distinctive chronic disorder Endocrinol Metab. 2006;91(2):447-53. rather than a pre-step of CS (3). The diagnostic criteria used for defining mHC are inconsistent. Most guidelines agree that the first-line test is a 1 mg overnight dexamethasone suppression test (DST), but the cutoff level of cortisol after the test is still 154 155 a matter of debate. Suggested cutoff values are 50 nmol/L (1.8 µg/dL), 51 Medical therapy in mHC is required in most patients with bilateral nmol/L (1.9 µg/dL) and 138 nmol/L (5.0 µg/dL) (6). The European guidelines adrenal adenomas, in patients refusing surgery, or in whom surgery is not suggest that cortisol levels between 1.9 and 5.0 µg/dL indicate “possible” reasonable or safe (e.g., due to advanced age and the high risk of surgical autonomous cortisol secretion (7). In the presence of mHC, the ACTH levels complications). In rare patients with pituitary mHC, scarce data have been above 4.4 pmol/L (20 pg/mL) suggest a pituitary origin (1). provided on the medical therapy with somatostatin analog pasireotide The estimated prevalence of mHC is up to 2% in individuals older than 60 and dopamine agonist cabergoline (1). In the MACS, data are available for and even higher in patients with uncontrolled hypertension, DM type 2, and some steroidogenesis inhibitors and glucocorticoid receptor antagonists. osteoporosis (4, 8). It is frequently associated with AI, with high variability Metyrapone successfully restored normal cortisol circadian rhythm in six in prevalence ranging between 5 and 50% (the high variability results from patients with MACS. They also noted a reduced cardiovascular risk marker different criteria for diagnosing this condition) (9). It is even more frequent IL-6 (17). Metyrapone treatment was also used in a prospective study (about 22–42%) in patients with bilateral AI and with larger adrenal tumors on seven patients with MACS who received a short-term (a few months) (i.e., above 2.4 cm) (9, 10). Mild hypercortisolism has also been described in metyrapone course as preoperative therapy. In this study, all patients patients with pituitary incidentalomas with an estimated prevalence of 5% normalized UFC levels and reduced serum and salivary cortisol levels (18). (11). The use of ketoconazole in mHC was reported in a case report of a Patients with mHC have a higher prevalence of osteoporosis and 48-year-old woman with bilateral macronodular adrenal hyperplasia cardiovascular risk factors (hypertension, DM type 2, dyslipidemia, and (BMAH). Ketoconazole therapy caused rapid normalization of cortisol obesity). Therefore, they have increased cardiovascular events and mortality and ACTH that persisted over ten years of treatment, with no adrenal rates (3, 12, 13). Some data suggest that the extent of comorbidities in mHC changes in size (19). We have no data on levoketoconazole and depends not only on the amount of adrenal glucocorticoid (GC) production osilodrostat in patients with mHC. Nowadays, two glucocorticoid receptor but also on the peripheral activation of cortisone-to-cortisol by the 11 beta-antagonists are available: mifepristone and relacorilant. Mifepristone hydroxysteroid dehydrogenase (11BHSD) enzymes and by the GC receptor was first studied in six patients with MACS, who were treated for four (GR) sensitivity (14, 15). weeks. There was a significant reduction in insulin resistance and Treatment of mHC can be surgical or conservative. Guidelines from 2016 cardiovascular benefit in two patients (20). These results were confirmed recommend adrenalectomy in patients with MACS (cortisol after DST >138 by the second study performed on eight patients who were treated with nmol/L or 5.0 µg/dL) who have at least two comorbidities potentially related mifepristone for six months (21). In the same year, another study showed to cortisol excess (e.g., DM type 2, hypertension, obesity, osteoporosis), that mifepristone improved cardiometabolic parameters two weeks after of which at least one is poorly controlled (7). In patients with bilateral treatment initiation in 4 patients with BMAH, who also experienced an adrenal masses and MACS, 2016 guidelines recommend against bilateral amelioration of glycemic control and hypertension as well as weight adrenalectomy and suggest unilateral adrenalectomy of the dominant loss (22). Relacorilant is a selective GR antagonist that does not bind to lesion in selected patients (considering age, degree of cortisol excess, the progesterone receptor. Presently, a phase III, randomized, double-general condition, comorbidities, and patient preference) (7). However, the blind, placebo-controlled study (GRADIENT, NCT04308590) is in progress adrenalectomy of the dominant lesion is associated with a high number assessing the efficacy and safety of relacorilant to treat hypercortisolism of relapses of hypercortisolism (16). The surgical treatment (i.e., removal in patients with cortisol secreting adrenal adenoma or hyperplasia of the pituitary adenoma and/or pituitary surgical exploration) in patients associated with impaired glucose metabolism and uncontrolled systolic with mHC of pituitary origin has never been investigated (1). hypertension. 156 157 When deciding on the type of medical therapy in patients with mHC, we 8. Bülow B, Jansson S, Juhlin C, Steen L, Thorén M, Wahrenberg H, et al. Adrenal must consider the side effects of steroidogenesis inhibitors. For example, incidentaloma – follow-up results from a Swedish prospective study. Eur J Endocrinol. ketoconazole can be a better choice than metyrapone in women to avoid 2006;154(3):419–23. hirsutism, whereas metyrapone is a better choice in men to prevent 9. Delivanis DA, Athimulam S, Bancos I. Modern Management of Mild Autonomous Cortisol hypogonadism. We must avoid ketoconazole in patients taking medication Secretion. Clin Pharmacol Ther. 2019;106(6):1209–21. that affects CYP3A4 P450 metabolism. If hepatic aminotransferases 10. Vassilatou E, Vryonidou A, Ioannidis D, Paschou SA, Panagou M, Tzavara I. Bilateral significantly increase on ketoconazole, we can use metyrapone as a adrenal incidentalomas differ from unilateral adrenal incidentalomas in subclinical substitute (23). cortisol hypersecretion but not in potential clinical implications. Eur J Endocrinol. 2014;171(1):37–45. 11. Toini A, Dolci A, Ferrante E, Verrua E, Malchiodi E, Sala E, et al. 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Eur J Endocrinol. 2015;172(6):R263-280. 160 161 ODBOR ZA PROSTE TEME PROSTE TEME ABSTRACTS COMMITTEE FREE COMMUNICATIONS Simona Gaberšček USTNE PREDSTAVITVE ORALS Mojca Jensterle Sever Primož Kotnik Andrej Zavratnik 162 163 01 THE MULTIDISCIPLINARY ADRENAL TUMOR BOARD: FIRST EIGHT YEARS OF EXPERIENCE IN UMC LJUBLJANA Vladimir Božić 1, Valerija Oblak 2, Peter Popović 2,3, Tomaž Kocjan 1,3 1 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana 2 Clinical Institute of Radiology, University Medical Centre Ljubljana, Ljubljana 3 Faculty of Medicine, University of Ljubljana, Ljubljana vladimir.bozic@kclj.si Introduction Adrenal tumors are among the most common tumors in humans. In addition to defining hormonal activity, the radiological appearance of the tumor is crucial for the patient. Therefore, we introduced a multidisciplinary endocrinological and radiological adrenal tumor board at the UMC Ljubljana in 2014. Analysis of the work of the board In the first eight years, we discussed 786 patients (469 women (59%), average age 61.47 ± 13.74 years) at 196 meetings (average 2.1 per month). There were mostly unilateral tumors (572, 73%), of which 336 were on the left side (59%). The mean tumor size was 36.21 mm±24.88 mm. Most of the growths appeared benign, i.e., adenomas (n = 382, 48%), myelolipomas (n = 79, 10%), hyperplasia (n = 56, 7%) or cysts (n = 25, 3%). There were 164 165 02 39 nodules defined as a pheochromocytoma (5%), 27 as an adrenocortical ANALIZA EKONOMSKEGA BREMENA carcinoma (3%) and 15 as metastases (2%). In 57 cases the change was too SLADKORNE BOLEZNI V SLOVENIJI KOT small for a precise diagnosis, or it was not visible at all (7%). In 106 cases PODLAGA ZA NAÈRTOVANJE BODOÈIH STROŠKOV there was a formation of another or unexplained etiology or a tumor was outside the adrenal gland (13%). SLADKORNE BOLEZNI IN PRESOJO UKREPOV ZA NJENO OBVLADOVANJE Conclusion Petra Došenović Bonča 1, Dalibor Gavrić 2, Karmen Janša 2,3 Adrenal tumors are predominately benign. If their nature can be reliably 1 Ekonomska fakulteta, Univerza v Ljubljani, Ljubljana confirmed at the tumor board, additional examinations or surgical 2 Zavod za zdravstveno zavarovanje Slovenije, Ljubljana treatment can be spared for relatively rare patients with suspicious tumors. 3 Splošna bolnišnica Jesenice, Jesenice karmen.jansa@zzzs.si Uvod Ekonomsko breme posameznih bolezni zajema njihove neposredne References zdravstvene in nezdravstvene stroške, posredne stroške zaradi izgub produktivnosti ter neotipljive stroške (1, 2). Gre za stroške, ki bremenijo 1. Fassnacht M, Arlt W, Bancos I, Dralle H, Newell-Price J, Sahdev A, et al. Management of vse relevantne deležnike, torej bolnike, njihove družine, zdravstveni sistem, adrenal incidentalomas: European Society of Endocrinology Clinical Practice Guideline delodajalce itd. Upoštevanje družbenega vidika omogoča ugotavljanje in collaboration with the European Network for the Study of Adrenal Tumors. Eur J razporeditve ekonomskega bremena med deležnike, načrtovanje bodočih Endocrinol. 2016;175(2):G1-G34. stroškov glede na demografske in druge trende, z identifikacijo različnih 2. Savitz A, Fong B, Hochberg A, Rumore G, Chen C, Yun J, et al. Endocrine Tumor Board: učinkov na različne deležnike pa tudi ustreznejše zasnove analiz upravičenosti Ten Years’ Experience of a Multidisciplinary Clinical Working Conference. Perm J. ukrepov za obvladovanje bolezni. Pregled tujih raziskav o ekonomskem 2020;24:19.140. bremenu sladkorne bolezni (SB) kaže na precejšnjo variabilnost ocenjenega 3. Chiapponi C, Santos DPD, Hartmann MJM, Schmidt M, Faust M, Wahba R, et al. Adrenal bremena, kar je posledica razlik v uporabljeni metodologiji, zajemu zapletov Surgery in the Era of Multidisciplinary Endocrine Tumor Boards. Horm Metab Res. ter naboru upoštevanih stroškov, pri čemer večina rezultatov kaže, da so 2022;54(5):294-299. neposredni stroški SB višji od njenih posrednih stroškov (3, 4). 1 Ekonomska fakulteta Univerze v Ljubljani, Kardeljeva ploščad 17, 1000 Ljubljana 2 Zavod za zdravstveno zavarovanje Slovenije, Miklošičeva cesta 24, 1000 Ljubljana 3 Splošna bolnišnica Jesenice, Cesta maršala Tita 112, 4270 Jesenice in Zavod za zdravstveno zavarovanje Slovenije, Miklošičeva cesta 24, 1000 Ljubljana, karmen.jansa@zzzs.si 166 167 Podobne razlike razkrivajo tudi obstoječe raziskave posameznih elementov References ekonomskega bremena SB v Sloveniji (5–8). 1. Larg A, Moss JR. Cost-of-Illness Studies: A Guide to Critical Evaluation. Namen Pharmacoeconomics. 2011;29(8): 653–671. V tem članku na podlagi primerjave obstoječih analiz stroškov SB v Sloveniji 2. Jo C. Cost-of-illness studies: concepts, scopes, and methods. Clin Mol Hepatol. predlagamo razširjen zajem neposrednih zdravstvenih stroškov SB z vidika 2014;20(4): 327–337. plačnika in podajamo oceno tega bremena na podlagi podatkov ta leto 2019. 3. Seuring T, Archangelidi O, Suhrcke M. The Economic Costs of Type 2 Diabetes: A Global Systematic Review. PharmacoEconomics. 2015;33(8):811–831. Metode 4. Šalehar A. Analiza ukrepov in spodbud za boljše obvladovanje ekonomskega bremena sladkorne bolezni tipa 2 v Sloveniji. Magistrsko delo. 2018; Ljubljana: Ekonomska Ocena stroškov je pripravljena na podlagi administrativne baze podatkov fakulteta. ZZZS o izdatkih za zdravila in medicinske pripomočke, izdatkih za zunajbolnišnično dejavnost diabetologije, za prejemnike zdravil za zniževanje 5. NIJZ, Ekonomsko breme sladkorne bolezni v Sloveniji 2012. 2014; Ljubljana: NIJZ. glukoze v krvi pa tudi o izdatkih v splošni in drugih zunajbolnišničnih 6. Nerat T; Kos M. Breme sladkorne bolezni tipa 2 s stališča plačnika zdravstvenega specialističnih dejavnostih. Prav tako so na podlagi relevantnih diagnoz varstva v Sloveniji. Zdravstveno varstvo. 2012;52(3):162–180. upoštevani izdatki za bolnišnične obravnave oseb s SB in njenih akutnih ter 7. Janša K, Stariha J, Lotrič Dolinar A, Došenović Bonča P. Prikaz bremena srčno-kasnih zapletov. Ocenjeni so tako skupni stroški kot njihova struktura, pa žilnih dogodkov pri sladkornih bolnikih. 2017; Redni strokovni sestanek Združenja tudi spolno-starostni profili izdatkov. endokrinologov Slovenije. 8. Grelewska J, Jakubczyk M, Niewada M, Lipka I, Petrova G, Tcharaktchiev D, et al. Rezultati The cost of macro- and microvascular diseases in patients with diabetes mellitus in selected Central and Eastern European countries. J Health Policy Outcomes Research. V Sloveniji so leta 2019 neposredni zdravstveni stroški SB znašali 197,7 milijona 2019;1:1–18. evrov, od tega 18,3% za zdravila iz skupine A10, 12,3% za zdravila za zdravljenje zapletov, 10,7% za medicinske pripomočke, 26,4% odstotkov za dejavnost Finančna podpora in konflikt interesov: Zasnovo raziskave ekonomskega bremena splošnih in specialističnih ambulant ter 32,2% za bolnišnično dejavnost. sladkorne bolezni z opredelitvijo različnih razpoložljivih administrativnih baz in podatkov v Sloveniji, ki omogočajo oceno tega bremena (npr. NIJZ, ZZZS, ZPIZ,…), je Razprava in zakljuèek financiral Mednarodni forum znanstvenoraziskovalnih farmacevtskih družb, GIZ, izvedena pa je bila preko Centra poslovne odločnosti Ekonomske fakultete. Izvedba Ocenjevanje neposrednih zdravstvenih stroškov SB bi bilo smiselno izvajati raziskave na podlagi podatkov ZZZS pa ni bila finančno podprta in avtorji tako podajajo letno, kar bi na podlagi spolno-starostnih profilov izdatkov omogočalo izjavo o odsotnosti konflikta interesov. načrtovanje bodočih izdatkov za plačnika. Za potrebe celovite presoje ukrepov za obvladovanje SB pa bi bilo nujno razviti tudi metodologijo za zajem neposrednih stroškov ostalih deležnikov, zlasti pacientov, ter predvsem posrednih stroškov, ki jih je do sedaj v omejenem obsegu naslovila zgolj analiza NIJZ (5). 168 169 03 VLOGA ELASTOGRAFIJE PRI mediano vrednost desetih meritev nad obema režnjema ščitnice. Za OPREDELITVI HIPERTIROTIÈNE FAZE primerjavo skupin preiskovancev smo uporabili test Mann-Whitney. Za HASHIMOTOVEGA TIROIDITISA izračun uporabne vrednosti metode SWE smo uporabili analizo ROC ter točnost metode SWE izrazili z meritvijo AUC. Anže Jarc 1, Katja Zaletel 1,2 1 Medicinska fakulteta, Rezultati Univerza v Ljubljani, Ljubljana Meritev SWE je bila pri HHT 18,2 kPa (9,0–31,3), pri bazedovki 22,3 kPa 2 Klinika za nuklearno medicino, (4,8–41,1 kPa), pri zdravih preiskovancih pa 13,2 kPa (5,8–35,0). Med HHT in Univerzitetni klinični center Ljubljana, Ljubljana bazedovko nismo ugotovili statistično pomembne razlike v rezultatih SWE (p=0,332). Če smo za razlikovanje med HHT in bazedovko določili mejno anze.jarc19@gmail.com vrednost 21,7 kPa, je bila občutljivost metode SWE 57,6 %, specifičnost pa 75,0 % (AUC=0,587). Pri bolnikih s HHT je bila vrednost SWE značilno višja kot pri zdravih preiskovancih (p<0,001). Če smo za razlikovanje med HHT in kontrolno skupino določili mejno vrednost 16,5 kPa, je bila občutljivost Izhodišèa metode SWE 81,3 %, specifičnost pa 73,5% (AUC=0,778). Tudi pri bolnikih z bazedovko je bila vrednost SWE značilno višja kot pri zdravih preiskovancih Hashimotov tiroiditis je najpogostejša avtoimunska bolezen ščitnice, pri (p<0,001). Če smo za razlikovanje med bazedovko in kontrolno skupino kateri so v zgodnjem poteku možna kratkotrajna obdobja hipertiroze. določili mejno vrednost 18,5 kPa, je bila občutljivost metode SWE 63,6 %, Razlikovanje hipertirotične faze HT (HHT) od bazedovke je težavno, saj se specifičnost pa 91,2 % (AUC=0,770). klinični sliki prekrivata, laboratorijsko diagnosticiranje ni vedno zanesljivo, ultrazvočna ocena morfologije žleze pa se ne razlikuje značilno. Elastografija je novejša metoda za oceno elastičnosti tkiva ščitnice, ki nima prepoznane vloge pri opredelitvi HHT. Zato smo želeli ugotoviti, ali elastografija ščitnice Zakljuèek pripomore k razlikovanju HHT od bazedovke. Z metodo elastografije ščitnice ne moremo zanesljivo razlikovati med HHT in bazedovko, lahko pa razlikujemo HHT in bazedovko od ščitnično zdravih preiskovancev. Za točnejšo opredelitev vloge elastografije bo potrebna Metode vključitev večjega števila preiskovancev. V prospektivno raziskavo smo med oktobrom 2021 in julijem 2022 vključili 16 bolnikov s HHT (starost, 41,5±13,9 let) in 33 bolnikov z bazedovko (starost, Konflikt interesov: ni konflikta interesov 36,9±10,5 let) pred pričetkom zdravljenja. V kontrolno skupino smo vključili 34 ščitnično zdravih preiskovancev (starost, 49,7±15,3 let). Ultrazvočno smo izmerili elastičnost parenhima ščitnice z metodo elastografije strižnih valov (»shear-wave« elastografija, SWE). Za izračun SWE smo uporabili 170 171 04 FINAL ADULT HEIGHT IN CHILDREN Population and Methods WITH CENTRAL PRECOCIOUS PUBERTY – A retrospective study included 93 children (12 boys and 81 girls) with CPP or A RETROSPECTIVE STUDY menarche before 10 years, that reached their FAH (68 with idiopathic (iCPP) and 25 with an identified likely cause of CPP (nCPP)). Clinical characteristics Taja Knific 1, Melisa Lazarevič 1, Janez Žibert 2, Nika Obolnar 3, including FH between the two groups were compared. We also compared FH Nataša Aleksovska 4, Jasna Šuput Omladič 5, between the children treated with triptorelin depo (n=71) and untreated Tadej Battelino 1,5 Magdalena Avbelj Stefanija 1,5 children (n=22). Finally, to determine predicting factors for FH, a multiple regression analysis including 48 treated girls with iCPP was conducted. 1 Faculty of Medicine, Target height (TH) was calculated based on parental heights. Predicted University of Ljubljana, Ljubljana adult height (PAH) was calculated based on bone age, chronological age, 2 Centre for Health Informatics and Statistics, height at diagnosis and ethnicity. Faculty of Health Sciences, University of Ljubljana, Ljubljana Results 3 Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana Children with iCPP reached higher FH than children with nCPP (p=0.002). Negative FH SDS in both groups indicated children with CPP are smaller 4 Izola General Hospital, Izola compared to the general population. There was no significant difference 5 Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, in FH between the treated and untreated children. However, the study University Children’s Hospital, was retrospective and not randomised. Nonetheless, the treated group University Medical Centre Ljubljana, Ljubljana gained 31.2 cm since diagnosis compared to 23.7 cm in the untreated group. Predicting factors for FH were bone age at diagnosis, BMI SDS at taja.knific@gmail.com diagnosis, basal LH, age at initiation and cessation of treatment, height at cessation of treatment, TH SDS and PAH SDS. Our model explained 72% of FH variance (R2=0.72). Background Central precocious puberty (CPP) is a premature activation of the Conclusion hypothalamic-pituitary-gonadal axis. Important negative consequence Children with nCPP reached lower FH compared to iCPP group. From CPP is compromised final height (FH) due to premature growth plate fusion. diagnosis, the treated children gained 7.5 cm more than the untreated; GnRH analogues (GnRHa) act by suppressing the HPG axis and stopping the yet, the FAH was not different. Factors that influence FAH are numerous, progression of puberty and prolonging growth period. and should be considered at individualized decision-making. The most important factors that can be influenced are timely diagnosis and therapy, Objectives height at treatment cessation and prudent selection of children that can We aimed to evaluate the effect of the GnRHa on FH and identify factors benefit from treatment. that predict FH in children with CPP. 172 173 05 References A PATIENT WITH INTRACTABLE 1. Chen M, Eugster EA. Central Precocious Puberty: Update on Diagnosis and Treatment. RIGHT LEG PAIN AND Pediatr Drugs. 2015;17(4):273–81. PERIMALLEOLAR EDEMA 2. Latronico AC, Brito VN, Carel JC. Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol. 2016;4(3):265–74. Andrijana Koceva 1, Katarina Mlekuš Kozamernik 2,3, 3. Bereket A. A Critical Appraisal of the Effect of Gonadotropin-Releasing Hormon Analog Tomaž Kocjan 2,3 Treatment on Adult Height of Girls with Central Precocious Puberty. J Clin Res Pediatr Endocrinol. 2017;9(Suppl 2):33–48. 1 Department of Endocrinology and Diabetes, University Medical Center Maribor, Maribor 2 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana 3 Faculty of Medicine, University of Ljubljana, Ljubljana andrijana_koceva@yahoo.com Background Endocrine myopathy refers to muscle symptoms such as weakness, myalgia, or flexion contractures, caused by endocrine disorders. Edema can occur in systemic diseases, including endocrinopathies. We present a 42-year-old male with myopathy and edema who has remained without diagnosis and proper treatment for two years despite several examinations. Case report A 42-year-old male presented to the emergency unit with intractable chronic pain in the right leg and bilateral perimalleolar edema. An angiologist, neurologist, and orthopedist were unable to resolve his problems. Two years ago, he also started to notice reduced body and facial hair, low libido, and erectile dysfunction. On physical examination the patient was hemodynamically stable, but pale, with reduced facial and body hair, and bilateral perimalleolar edema. Antalgic gait with protective guarding and 174 175 06 partial flexion contracture of the right hip were noted. Initial laboratory IZRA�ENOST ŠÈITNIÈNIH BOLEZNI tests were notable for increased myoglobin, CK, and liver function tests. MED EPIDEMIJO COVID-19 Chest X-rays showed accentuated hilar shadows. After confirming panhypopituitarism, we initiated hydrocortisone and levothyroxine, which resolved the edema. Testosterone was added in due course. A pituitary Nastja Medle 1, Tim Medved 1, Simona Gaberšček 1,2 MRI was suspicious for neurosarcoidosis. Enlarged hilar, mediastinal, and 1 Medicinska fakulteta, mesenteric lymph nodes were visible on CT scans and on PET/CT. An enlarged Univerza v Ljubljani, Ljubljana lymph node was noted in the region of the right obturator muscle. Mild sensory and motor polyneuropathy was diagnosed with EMG. MRI revealed 2 Klinika za nuklearno medicino, mild bilateral hip osteoarthrosis. Sarcoidosis was pathohistologically Univerzitetni klinični center Ljubljana, Ljubljana confirmed after mediastinoscopy with lymphadenectomy. After introduction of methylprednisolone, there was rapid and significant amelioration of right nastja.medle@gmail.com leg pain. Conclusions Izhodišèa Clinical manifestations of sarcoidosis are heterogeneous, so diagnostics SARS-CoV-2, ki povzroča koronavirusno bolezen 19 (COVID-19), vstopa v celice is challenging. Our patient presented with severe right leg pain, which preko receptorja za angiotenzin konvertazo 2. Izraženost tega receptorja je subsided with methylprednisolone, probably due to shrinkage of the celo večja v ščitnici kot v pljučih, zato bi lahko bila tudi ščitnica tarča SARS-enlarged lymph node in the region of the right obturator muscle. However, CoV-2. Z raziskavo smo želeli ugotoviti, ali je bila v času epidemije COVID-19 since musculoskeletal symptoms might occur in 6–13% of hypoadrenalism izraženost ščitničnih bolezni drugačna kot pred epidemijo. cases, panhypopituitarism could have also contributed not only to perimalleolar edema, but also to myalgia. In patients with unexplained Metode general complaints, such as pain and edema, we should always search for accompanying clinical symptoms and signs that might reveal an underlying Raziskava je bila retrospektivna in klinična. Primerjali smo izraženost endocrine or other systemic etiology. ščitničnih bolezni pri bolnikih, ki so bili prvič v življenju pregledani v Ambulanti za bolezni ščitnice na Kliniki za nuklearno medicino Univerzitetnega kliničnega centra Ljubljana med 1. 4. 2019 in 29. 2. 2020 (pred epidemijo COVID-19) ter med 1. 4. 2020 in 28. 2. 2021 (med epidemijo COVID-19). Primerjali smo References izraženost subakutnega tiroiditisa, Hashimotovega tiroiditisa, bazedovke 1. Hoshino C, Satoh N, Narita M, Kikuchi A, Inoue M. Painful hypoadrenalism. BMJ Case in avtonomnega tkiva v ščitnici. V analizi smo upoštevali koncentracijo Reports. 2011. tirotropina (TSH), prostega tiroksina (pT4) in prostega trijodtironina (pT3), 2. Voortman M, Drent M, Baughman RP. Management of neurosarcoidosis: A clinical vrednost razmerja pT4/pT3, pri subakutnem tiroiditisu pa tudi hitrost challenge. Curr Opin Neurol. 2019;32(3):475–483. sedimentacije eritrocitov, pri bazedovki pa še koncentracijo protiteles proti 3. Bradshaw MJ, Pawate S, Koth LL, Cho TA, Gelfand JM. Neurosarcoidosis: Pathophysiology, receptorju za TSH. Primerjali smo tudi ultrazvočno izmerjen volumen Diagnosis, and Treatment. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1084. ščitnice. Za statistično obdelavo smo uporabili Mann-Whitneyev test. 176 177 07 Rezultati EFFECTIVENESS OF TELEMEDICINE CARE Ugotovili smo, da so imeli bolniki s subakutnim tiroiditisom med epidemijo REPLACING STANDARD CARE COVID-19 statistično značilno večji volumen ščitnice kot pred epidemijo IN GESTATIONAL DIABETES: (p=0,003). Bolniki s hipotirozo zaradi Hashimotovega tiroiditisa so imeli A RANDOMIZED CONTROLLED TRIAL med epidemijo statistično značilno višjo koncentracijo TSH (p=0,001), višjo koncentracijo pT3 (p=0,005) in nižje razmerje pT4/pT3 (p=0,031) kot bolniki Ana Munda 1, Zala Mlinarič 2, Petra Ana Jakin 2, pred epidemijo. Bolniki z bazedovko so imeli med epidemijo statistično Mojca Lunder 1, Drazenka Pongrac Barlovič 1,2 značilno višjo koncentracijo pT4 (p=0,007) in pT3 (p=0,028). Ugotovili pa smo tudi, da je bila pri bolnikih z avtonomnim tkivom v ščitnici v obdobju med 1 University Medical Centre Ljubljana, Ljubljana epidemijo koncentracija TSH značilno nižja (p=0,0003) kot pred epidemijo. 2 Faculty of Medicine, University of Ljubljana, Ljubljana Zakljuèek Zaključimo lahko, da sta bili med epidemijo COVID-19 bolj izraženi hipotiroza ana.munda@kclj.si zaradi Hashimotovega tiroiditisa in hipertiroza zaradi bazedovke in avtonomnega tkiva v ščitnici, kar bi lahko pripisali zakasnjeni obravnavi bolnikov v Ambulanti za bolezni ščitnice. To pa bi lahko bila posledica slabše dostopnosti do zdravstvenih storitev na primarni ravni v opazovanem obdobju. Background Telemedicine improves glycemic and perinatal outcomes when used as an adjunct to standard in-person care in gestational diabetes (GDM). However, little is known about its effectiveness when used instead of standard in-person care. Therefore, we aimed to compare the outcomes of the telemedicine care and the standard care in women with GDM. Methods In a single-centre, parallel, randomized controlled trial, women were randomized to: (1) telemedicine group, sending glucose readings via an application installed on a smartphone and monthly individual videocalls replacing on-site visits or (2) standard care group with routine monthly on-site visits. The primary outcome was the effectiveness of glycemic control. Reference The secondary outcomes were gestational weight gain, perinatal data, 1. Naguib R. Potential relationships between COVID-19 and the thyroid gland: an update. including birth weight, gestational age, incidence of the offspring large for J Int Med Res 2022; 50(2):3000605221082898. gestational age, preterm birth, preeclampsia and caesarean section. 178 179 08 Results IMMUNE CHECKPOINT INHIBITOR-ASSOCIATED A total of 106 women were randomized to the telemedicine (n=54) and AUTOIMMUNE DIABETES PRESENTING the standard care group (n=52). The telemedicine group demonstrated less AS DIABETIC KETOACIDOSIS: postprandial measurements above the glycemic target (10.4% [3.9–17.9] A SINGLE-CENTRE CASE SERIES vs. 14.6% [6.5–27.1]; p=0.015), together with lower average postprandial glucose (5.6±0.3 vs. 5.9±0.4; p=0.004). Percentage of caesarean section was Eva Podbregar Kolar 1, Mojca Lunder 1,2, Miodrag Janić 1,2 lower in the telemedicine group (9 (17.3%) vs. 18 (35.3%); p=0.038), with no other differences in perinatal outcomes detected. 1 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana Conclusions 2 Faculty of Medicine, Telemedicine offers an effective alternative of delivering care in women University of Ljubljana, Ljubljana with GDM. Research, focused on optimizing the tele-care delivery, limiting the extent of health professional’s involvement with the use of automated evapodbregar@gmail.com decision support tools is needed to achieve optimal prenatal care via telemedicine and at the same time to alleviate the burdened health system. Introduction Immune checkpoint inhibitor (ICI) therapy transformed oncologic care (1). Its use increased due to outstanding efficiency and a significant improvement in patient prognosis (2). The key representatives are monoclonal antibodies targeting programmed cell death protein 1 (pembrolizumab, nivolumab) and its ligand and cytotoxic T lymphocyte-associated protein 4 (ipilimumab) (3). One of their immune-related adverse effects is irreversible pancreatic β-cell failure leading to the so-called ICI-associated autoimmune diabetes (CIADM). Although rare, it usually presents with diabetic ketoacidosis (DKA) (4). We review the clinical characteristics of patients hospitalized in our department for DKA and CIADM to explore possible predictive factors for CIADM. 180 181 Presentation of cases References Three patients (2 men, 1 woman; aged 56±15 years; body mass index 1. Goldman JW, Mendenhall MA, Rettinger SR. Hyperglycemia Associated With Targeted 31±4 kg/m2) were hospitalized in our clinical department with newly Oncologic Treatment: Mechanisms and Management. Oncologist. 2016;21(11):1326-1336. diagnosed CIADM and DKA. Two were treated with pembrolizumab (malignant melanoma), one received ipilimumab and nivolumab (renal 2. Naidoo J, Page DB, Li BT, Connell LC, Schindler K, Lacouture ME, et al. Toxicities of the cell carcinoma). Before confirmation of diabetes, they received 12.5 doses anti-PD-1 and anti-PD-L1 immune checkpoint antibodies. Ann Oncol. 2015;26(12):2375-91. [4–21] of pembrolizumab; 3 doses of ipilimumab and 6 doses of nivolumab. The median time from the last immunotherapy to the presentation of 3. The Joint British Diabetes Societies (JBDS) for Inpatient Care Group. The Management of Glycaemic Control in People with Cancer: Guidance for the oncology and diabetes diabetes was 20 days [7–39]. A personal history of diabetes was negative multidisciplinary team. Available at: https://abcd.care/resource/jbds-17-management-with normal fasting blood glucose prior to immunotherapy. The 3 patients glycaemic-control-people-cancerAccessed Sept 2021. Accessed: 21/07/2022. presented with DKA. At the presentation of DKA, the median HbA1c was 10.6 4. Wu L, Tsang VHM, Sasson SC, Menzies AM, Carlino MS, Brown DA, et al. Unravelling % [7.8–12.2]; the plasma glucose 31.6 mmol/L [18.9–42.2], the pH 7.18±0.2, Checkpoint Inhibitor Associated Autoimmune Diabetes: From Bench to Bedside. Front HCO3- 9.7±4.6 mmol/L, with an anion gap of –17.6±9.4 mmol/L. 2/3 patients Endocrinol (Lausanne). 2021;12:764138. had positive ketones urinalysis. Low levels of C-peptides and negative pancreatic autoantibodies were determined. In one patient, asymptomatic COVID-19 infection was confirmed at the time of presentation of the DKA. Ketoacidosis was treated according to the standard protocol and resolved in all patients. They were discharged with multiple daily subcutaneous insulin injections. Conclusions In the three patients, ICI-associated autoimmune diabetes and DKA were confirmed; no other predictive parameters were found. To avoid life-threatening DKA, insulin treatment is suggested after confirmation of diabetes (4). Guidelines for the detection of hyperglycemia must be strictly followed during the use of ICI to diagnose diabetes and begin treatment promptly (3). 182 183 09 STRUKTURIRANI IZOBRA�EVALNI PROGRAM Metode ZA OSEBE, KI BODO NUDILE LAIÈNO V Zdravstvenem domu (ZD) Ljubljana in ZD Slovenj Gradec smo pridobili PODPORO BOLNIKOM S SLADKORNO 36 bolnikov s SB in/ali AH, ki so se v manjših skupinah udeležili 15-urnega BOLEZNIJO IN ARTERIJSKO HIPERTENZIJO strukturiranega izobraževanja. 31 posameznikov je uspešno zaključilo NA PRIMARNI ZDRAVSTVENI RAVNI V SLOVENIJI program, ki je obsegal 2 skupinski in 2 individualna izobraževanja z edukatorico. Udeleženci so pred in po zaključku edukacije izpolnili vprašalnike Tina Virtič 1,2 , Majda Mori Lukančič 1, Matic Mihevc 1,3 , o socio-demografskih in kliničnih podatkih, poznavanju SB (5) in AH (6), Črt Zavrnik 1,3 , Zalika Klemenc Ketiš 1,2,3 , Antonija Poplas Susič 1,3 kakovosti življenja s SB (7) in sprejemljivosti intervencije (8). 1 Inštitut za raziskave in razvoj osnovnega zdravstva (IRROZ), Rezultati Zdravstveni dom Ljubljana, Ljubljana Za nudenje laične podpore bolnikom s SB in AH se je usposobilo 10 moških in 2 Katedra za družinsko medicino, Medicinska fakulteta, Univerza v Mariboru, Maribor 21 žensk. Njihova povprečna starost je bila 63,9 ± 8,9 let, za SB so se zdravili 14,3 ± 11,7 let in za AH 7,9 ± 8,1 let. V primerjavi z znanjem ob vstopu v 3 Katedra za družinsko medicino, Medicinska fakulteta, raziskavo se je pomembno povečalo njihovo znanje o SB (p<0,001) kot tudi o Univerza v Ljubljani, Ljubljana AH (p=0,022). Vpliv na kvaliteto življenja je bil nepomembno boljši (p=0,146). Udeleženci so izobraževalni program ocenili kot visoko sprejemljiv v vseh 7 tina.virtic@gmail.com domenah sprejemljivosti. Skupna povprečna ocena na 5-stopenjski lestvici je bila 4,45 ± 0,50. Zakljuèki Uvod Protokol izobraževalnega programa za usposabljanje oseb, ki bodo nudile Za dobro presnovno urejenost bolnika s sladkorno boleznijo (SB) in arterijsko laično podporo bolnikom s SB in AH, se je izkazal za visoko sprejemljivega in hipertenzijo (AH) je potrebno kontinuirano spremljanje bolnikovega učinkovitega, kar nakazuje velik potencial za uspešno implementacijo laične zdravstvenega stanja in pridruženih bolezni, pri čemer sta ključna podpore na primarni zdravstveni ravni. vseživljenjsko izobraževanje in podpora, ki bosta bolnika opolnomočila, da bo lahko samostojno in optimalno skrbel za svojo bolezen (1–3). Uporaba modela integrirane oskrbe je pokazala, da je v Sloveniji najslabše implementirano prav področje samoobvladovanja bolezni in samopomoči (4). Ena izmed možnih rešitev, kako nadgraditi obstoječi model celostne oskrbe kroničnih bolnikov s SB in AH, je uvedba in ustrezna organizacija laične podpore bolnikom in njihovim oskrbovalcem s pomočjo posebej usposobljenih oseb, ki bodo svoje znanje, izkušnje in podporo prostovoljno prenašali na druge bolnike s SB in AH. 184 185 10 Reference HEALTH RELATED QUALITY OF LIFE 1. Powers MA, Bardsley JK, Cypress M, Funnell MM, Harms D, Hess-Fischl A, et al. Diabetes IN OLDER PATIENTS WITH Self-management Education and Support in Adults With Type 2 Diabetes: A Consensus TYPE 1 AND TYPE 2 DIABETES Report of the American Diabetes Association, the Association of Diabetes Care & Education Specialists, the Academy of Nutrition and Dietetics, the American Academy of Family Physicians, the American Academy of PAs, the American Association of Špela Volčanšek 1,2, Mojca Lunder 1,2, Andrej Janež 1,2 Nurse Practitioners, and the American Pharmacists Association. Diabetes Care. 2020;43(7):1636–49. 1 Clinical Department of Endocrinology, Diabetes and Metabolic Diseases, 2. Pongrac Barlovič, Draženka. Slovenske smernice za klinično obravnavo sladkorne University Medical Centre Ljubljana, Ljubljana bolezni tipa 2. Ljubljana: Diabetološko združenje Slovenije, 2022; 2022. 2 Medical Faculty, 3. Davis J, Fischl AH, Beck J, Browning L, Carter A, Condon JE, et al. 2022 National University of Ljubljana, Ljubljana Standards for Diabetes Self-Management Education and Support. Diabetes Care. 2022;45(2):484–94. spela.volcansek@gmail.com 4. Klemenc-Ketis Z, Stojnić N, Zavrnik Č, Ružić Gorenjec N, Danhieux K, Lukančič MM, et al. Implementation of Integrated Primary Care for Patients with Diabetes and Hypertension: A Case from Slovenia. Int J Integr Care. 2021;21(3):15. Background 5. Prevolnik Rupel V, Ogorevc M, Poplas-Susič A. PMU99 Knowledge of Disease Among Patients with Type 2 Diabetes and Hypertension in Slovenia. Value Health. 2020 Diabetes is widely present in older adults and consequently this chronic Dec;23:S620. disease is affecting health and emotional wellbeing of a vast portion of 6. Turk Eva, Palfy M., Prevolnik Rupel V. General knowledge about diabetes in the elderly worlds’ population. Health related quality of life (HRQOL) is an independent diabetic population in Slovenia. Zdr Vest. 2012;81:517–25. predictor of health outcomes that predicts mortality in patients with 7. Carey MP, Jorgensen RS, Weinstock RS, Sprafkin RP, Lantinga LJ, Carnrike CL, et al. diabetes, even more prognostic than some physiological diabetes specific Reliability and validity of the appraisal of diabetes scale. J Behav Med. 1991;14(1):43–51. factors. The aim of the present study was to determine differences in 8. Sekhon M, Cartwright M, Francis JJ. Acceptability of healthcare interventions: an Health-related quality of life (HRQOL) and self-rated mental health between overview of reviews and development of a theoretical framework. BMC Health Serv older adults of both diabetes types and associations of diabetes control, Res. 2017;17(1):88. complications, and comorbidities with HRQOL domains. Methods We included type 1 (T1D) and type 2 diabetes (T2D) patients, aged ≥ 60 years (n=56), age- and HbA1c- matched. They completed validated Raziskava poteka v okviru mednarodnega raziskovalnega projekta SCUBY (SCale-Up diaBetes Questionnaires (Short Form-36, The EuroQol-5 Dimensions/Visual Analog and hYpertension care), ki je financiran iz programa Evropske unije za raziskave in inovacije Scale, The Hospital Anxiety and Depression Scale, The Problem Areas in - Obzorja 2020; in sicer po pogodbi št. 825432. Diabetes). The outcomes were compared between diabetes types by independent sample t-test. Univariate linear regression analysis was used Avtorica in soavtorji izjavljamo, da ne obstaja konflikt interesov. to establish disease-related factor’s impacts on self-rated health scores. 186 187 Results References The average age of patients was 68.9 ± 7.8 years, 55% had T2D. General health assessment differed between diabetes types in older T2D and T1D, 1. Alonso J, Ferrer M, Gandek B, Ware JE, Aaronson NK, Mosconi P, et al. Health-related that reported of better outcomes, while no differences in self-reported quality of life associated with chronic conditions in eight countries: Results from the diabetes distress, anxiety or depression were proven. Mean EQ-5D VAS International Quality of Life Assessment (IQOLA) Project. Qual Life Res. 2004;13:283– 98. score was significantly lower in T2D (61.6 ± 17.2 vs. 77.5 ± 16.2, p=0.002) indicating worse overall impression of self-rated health compared to T1D 2. Anderson BJ, Laffel LM, Domenger C, Danne T, Phillip M, Mazza C, et al. Factors (Figure 1). Most of the domains of HRQOL were not associated with HbA1c Associated With Diabetes-Specific Health-Related Quality of Life in Youth With Type 1 Diabetes: The Global TEENs Study. Diabetes Care. 2017;40:1002–9. and neither presence of complications. However, multiple regression model suggested that BMI is a predictor of HRQOL. 3. Feng Y, Parkin D, Devlin NJ. Assessing the performance of the EQ-VAS in the NHS PROMs programme. Qual Life Res. 2014;23:977–89. Conclusion Older T1D patients rated their general health better compared to their T2D counterparts. Most of the domains od HRQOL were not associated with HbA1c or presence of complications, BMI could be a predictor of some physical health domains. Given the complex nature of interaction of diabetes- related factors with HRQOL, this research argues that HRQOL and glycaemic control are central outcomes in clinical diabetes care but should be evaluated separately. Figure 1. EQ-VAS score according to diabetes type. Legend: EQ-VAS – EuroQoL-Visual analog scale, T1D Type 1 diabetes patients, T2D Type 2 diabetes patients, values are presented as mean ± SD, *Denotes statistical significance at P < 0.05 188 189 PROSTE TEME FREE COMMUNICATIONS POSTERJI POSTERS 190 191 01 SEVERE POSTMENOPAUSAL HYPERANDROGENISM AND A PITUITARY TUMOR: A DIAGNOSTIC CHALLENGE? Živa Dolenšek 1, Katarina Mlekuš Kozamernik 1, 2, Tina Krokter Kogoj 1,2, Tomaž Kocjan 1,2 1 Faculty of Medicine, University of Ljubljana, Ljubljana 2 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana zdolens1@gmail.com Postmenopausal hyperandrogenism results from absolute or relative androgen excess. It presents with hirsutism, acne, and androgenetic alopecia, in most severe cases with virilisation. We must differentiate between rare tumorous, and common, nontumorous (functional) causes. Diagnosis is based on detailed history and clinical examination, followed by measurement of dehydroepiandrosterone-sulphate and testosterone with additional hormone testing and imaging when necessary (1). We present a 51-year-old postmenopausal patient with severe, rapidly progressing hyperandrogenism and substantially elevated total testosterone. She was diagnosed with acromegaly due to elevated insulin-like growth factor 1 and pituitary tumour on MRI, despite lacking acromegalic features and appropriate growth hormone suppression after glucose load (2). A second opinion was requested by neurosurgeon. We found a Leydig cell tumour of the right ovary. After bilateral salpingo-oophorectomy, testosterone levels normalised and hyperandrogenism subsided. Since insulin growth 192 193 02 factor 1 also normalised, we concluded that its high levels were caused IMPROVEMENT IN GLYCEMIC CONTROL by the stimulatory effect of testosterone on the somatotropic axis (3). WITH THE USE OF THE ADVANCED HYBRID The pituitary tumour was recognized as macroprolactinoma. Prolactin normalised with a dopaminergic agonist. A follow-up MRI is scheduled to CLOSED-LOOP MINIMED 780G SYSTEM confirm the tumour shrinkage. IN PATIENTS WITH TYPE 1 DIABETES: FIRST EXPERIENCE IN AN OUTPATIENT CLINIC If hyperandrogenism is clinically suspected in a postmenopausal female, a diagnostic algorithm should be followed. In addition to serum androgen value, the timing of onset, progression and severity of hyperandrogenism Miodrag Janić 1,2, Mojca Mesojedec 1, Mojca Lunder 1,2 are also very important (1). When there is a combination of aetiologies 1 Department of Endocrinology, Diabetes and Metabolic Diseases, for hyperandrogenism, the diagnosis can be challenging – as it was in the University Medical Centre Ljubljana, Ljubljana presented case. Only testing of all pituitary-peripheral axes enables optimal management of patients with a pituitary tumour (2). 2 Faculty of Medicine, University of Ljubljana, Ljubljana miodrag.janic@kclj.si Background Long-term glycemic control can be challenging with long-lasting type 1 diabetes. Advanced technology, the MiniMed 780G system with an advanced hybrid closed-loop (AHCL) algorithm, enables automated delivery of basal and correction bolus insulin, thus overcoming several obstacles to reach optimal glycemic control (1). Our objective was to evaluate the effect of the introduction of the AHCL system on glycemic parameters in eligible middle-aged patients with type 1 diabetes. References 1. Markopoulos MC, Kassi E, Alexandraki KI, et al. MANAGEMENT OF ENDOCRINE DISEASE: Methods Hyperandrogenism after menopause. European Journal of Endocrinology. 2015;172(2): Seventeen patients with type 1 diabetes were included, 53 % were women, R79–R91 the mean age was 48.4 ± 2.9 years, and the mean duration of diabetes 2. Freda PU, Beckers AM, Katznelson L, et al. Pituitary Incidentaloma: An Endocrine was 22.5 ± 3.9 years. The parameters analyzed were glycated hemoglobin Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2011;96(4): 894–904. (HbA1c), time in range (TIR), time above range (TAR) and time below range 3. Birzniece V. Hepatic actions of androgens in the regulation of metabolism. Curr Opin (TBR). In addition, associations were established between the use of the Endocrinol Diabetes Obes. 2018;25(3): 201–208. SmartGuard function and glycemic parameters. 194 195 03 Results FIRST CLINICAL EXPERIENCE Before the introduction of the AHCL system, glycemic control was poor OF THE EFFICACY AND SAFETY (HbA1c 7.7 ± 0.3 %; TIR 58.4 ± 3.3 %). Sixty days after the introduction OF ORAL SEMAGLUTIDE IN POORLY of the AHCL system, the HbA1c level decreased to 6.8 ± 0.1 % (P=0.001), CONTROLLED TYPE 2 DIABETES while TIR increased to 76.2 ± 1.7 % (P=0.03). After the introduction of the AHCL system, the average TAR was 21.2 ± 1.9 % and the TBR 2.5 ± 0.6 Marija Jovanović 1, Miodrag Janić 1,2, %. The patients used the SmartGuard function 83.9 ± 5.9 % of the time. Andrej Janež 1,2, Mojca Lunder 1,2 SmartGuard use was associated with improved HbA1c (R=-0.49; P=0.05). HbA1c after the introduction of the AHCL system correlated with TIR (R=- 1 Faculty of Medicine, 0.63; P=0.01). Most patients evaluated the use of the new AHCL system as University of Ljubljana, Ljubljana easy while providing satisfactory glycemic control results. 2 Clinical Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana Conclusion The introduction of the new AHCL MiniMed 780G system resulted in a mojca.lunder@kclj.si significant improvement in glycemic control in middle-aged patients with type 1 diabetes in our outpatient clinic; the results were similar to those in other studies (2, 3), but the data are limited. Optimal glycemic control was Background and aim already achieved 60 days after the introduction of the new device. These Recently, the first oral glucagon-like receptor agonist (GLP-1RA), oral results are promising and merit longer-term studies to further explore the semaglutide (1), became available in Slovenia, thus allowing the removal of new AHCL system in the population with type 1 diabetes. the frequent treatment barrier of injectable therapy (2). Oral semaglutide proved effective in glycaemia control and body mass reduction in randomised controlled trials (3). However, data from everyday clinical practice are missing. Therefore, we explored the efficacy and safety of oral semaglutide References in our outpatient clinic in the first patients with poorly controlled type 2 1. Ferrito L, Passanisi S, Bonfanti R, Cherubini V, Minuto N, Schiaffini R, et al. Efficacy diabetes who received oral semaglutide. of advanced hybrid closed loop systems for the management of type 1 diabetes in children. Minerva Pediatr (Torino). 2021;73(6):474-85. Methods 2. Silva JD, Lepore G, Battelino T, Arrieta A, Castaneda J, Grossman B, et al. Real-World Performance of the MiniMed 780G System: First Report of Outcomes from 4120 Users. In this analysis, the first 20 patients with poorly controlled type 2 diabetes Diabetes Technol Ther. 2022;24(2):113-9. (11 men, 9 women) were included in whom oral semaglutide was prescribed 3. Beato-Vibora PI, Gallego-Gamero F, Ambrojo-Lopez A, Gil-Poch E, Martin-Romo I, in our outpatient clinic. The baseline average HbA1c was 9.4 ± 0.3%. We Arroyo-Diez FJ. Rapid Improvement in Time in Range After the Implementation of an followed glycated haemoglobin (HbA1c), fasting blood glucose, and body Advanced Hybrid Closed-Loop System in Adolescents and Adults with Type 1 Diabetes. weight after oral semaglutide introduction. Adverse effects were also Diabetes Technol Ther. 2021;23(9):609-15. recorded. 196 197 04 Results NIZKE PORODNE MERE V POVEZAVI The mean age of the included patients was 59.9 ± 1.5 years, the mean S CENTRALNO PREZGODNJO PUBERTETO – duration of diabetes 8.5 ± 1.4 years, and the mean body mass index was RETROSPEKTIVNA RAZISKAVA 34.6 ± 1.4 kg/m2. Seven patients received two antidiabetic medications (metformin + sulphonylurea) while 13 patients received three medications Taja Knific 1, Melisa Lazarevič 1, Janez Žibert 2, Nika Obolnar 3, (metformin + sulphonylurea + SGLT-2 or DPP-4 inhibitor) prior to oral Nataša Aleksovska 4, Jasna Šuput Omladič 5, Tadej Battelino 1, 5, semaglutide introduction. Oral semaglutide at doses of 7 mg or 14 mg daily Magdalena Avbelj Stefanija 1, 5 significantly improved glycaemic parameters: HbA1c (-1.2%; p<0.05 and -1.6%; p<0.01, respectively) and fasting blood glucose values (-17.8% and 1 Medicinska fakulteta, -20.4%; both p<0.05), respectively). Body weight decreased significantly Univerza v Ljubljani, Ljubljana during oral semaglutide treatment at a dose of 14 mg daily (-11.9%; 2 Center za zdravstveno informatiko in statistiko, p<0.05). Gastrointestinal adverse effects (particularly reduced appetite, Zdravstvena fakulteta, Univerza v Ljubljani Ljubljana nausea, and obstipation) were recorded in half of the patients; they were 3 Infekcijska klinika, Univerzitetni klinični center Ljubljana, Ljubljana mainly mild and transient. 4 Splošna bolnišnica Izola, Izola Conclusions 5 Oddelek za pediatrično endokrinologijo, diabetes in metabolne bolezni, Pediatrična klinika, UKC Ljubljana, Ljubljana Oral semaglutide, the first GLP-1RA available for oral administration, improved glycaemic parameters and decreased body weight in daily clinical taja.knific@gmail.com practice in our outpatient clinic, even in patients with poorly controlled type 2 diabetes and in addition to substantial previous oral antidiabetic therapy. Therefore, oral semaglutide appears to be an effective and safe treatment option in uncontrolled type 2 diabetic patients. References 1. Chan M, Dimitriou A, Lam S. Semaglutide: A Novel Oral Glucagon-Like Peptide Receptor Izhodišèe Agonist for the Treatment of Type 2 Diabetes Mellitus. Cardiol Rev. 2021;29(2):100-8. Centralna prezgodnja puberteta (CPP) je prezgodnja aktivacija hipotalamo-2. Byrne J, Willis A, Dunkley A, Fitzpatrick C, Campbell S, Sidhu MS, et al. Individual, hipofizno-gonadne (HHG) osi. Različna bolezenska stanja, predvsem v healthcare professional and system-level barriers and facilitators to initiation and adherence to injectable therapies for type 2 diabetes: A systematic review and meta-povezavi z osrednjim živčevjem, lahko pozvročijo CPP, večinoma pa je ethnography. Diabet Med. 2022;39(1):e14678. idiopatska. Dejavniki tveganja za razvoj CPP niso natančno opredeljeni. Nizka porodna teža je povezana z večjim pridobivanjem telesne teže v otroštvu, 3. Thethi TK, Pratley R, Meier JJ. Efficacy, safety and cardiovascular outcomes of once-daily oral semaglutide in patients with type 2 diabetes: The PIONEER programme. kar lahko sproži prezgodnjo adrenarho in pubarho, vendar povezava s CPP v Diabetes Obes Metab. 2020;22(8):1263-77. literaturi zaenkrat ni opisana 198 199 Namen References Želeli smo opredeliti, ali imajo otroci s CPP nižje porodne mere kot splošna 1. Latronico AC, Brito VN, Carel JC. Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol. 2016;4(3):265–74. populacija in, ali je nizka porodna teža lahko dejavnik tveganja za CPP. 2. Hernández MI, Mericq V. Impact of being born small for gestational age on onset and progression of puberty. Best Pract Res Clin Endocrinol Metab. 2008;22(3):463–76. Metode 3. Ibáñez L, Potau N, Francois I, de Zegher F. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J Clin Endocrinol Retrospektivno smo analizirali klinične podatke 142 otrok s CPP, ki smo jih Metab. 1998;83(10):3558-62. razdelili na skupino z idiopatsko CPP (iCPP) (n=104) in neidiopatsko CPP (nCPP) (n=38) ter primerjali klinične značilnosti med skupinama z metodami opisne statistike. Prevalenco nizke porodne teže in nizke gestacijske starosti smo primerjali s populacijskimi nacionalnimi podatki s testom za testiranje enakosti deleža. Rezultati Otroci z nCPP so imeli značilno nižjo gestacijsko starost od otrok z iCPP (p=0,031). Med otroci s CPP je bil delež nedonošenih 11%. Med iCPP so največji delež predstavljali zmerno nedonošeni (32-36 tednov), med nCPP pa izjemno nedonošeni (<28 tednov). Pod 50. percentilom porodne teže je bilo 70% otrok z iCPP in 62% z nCPP. Pod 50. percentilom porodne dolžine je bilo 53% otrok z iCPP in 73% otrok z nCPP. Razlika med skupinama ni bila statistično značilna. V primerjavi s slovensko populacijo novorojenčkov rojenih leta 2015, so imeli otroci s CPP nižjo porodno težo in porodno dolžino glede na gestacijsko starost. Med nCPP je bil značilno večji delež izjemno nedonošenih. Med CPP je bil večji delež otrok z nizko porodno težo neodvisno od gestacijske starosti: pri iCPP je bila razlika pri nizki (2499–1400g) in pri zelo/izjemno nizki (<1500g) porodni teži, pri nCPP pa le pri zelo/izjemno nizki porodni teži. Zakljuèek Porodna teža in dolžina pri otrocih s CPP sta pomaknjeni k nižjim vrednostim v primerjavi s slovensko populacijo. Izrazita nedonošenost je značilna le za nCPP in je povezana s spremembami OŽ ter tudi etiološko s CPP. Nizka porodna teža je bolj pogosto prisotna pri otrocih s CPPkot v splošni populaciji in lahko predstavlja dejavnik tveganja za njen nastanek. 200 201 05 PARATHYROID CARCINOMA: serum calcium and iPTH concentrations after surgery were normal (Ca 2.12 A RARE CAUSE OF HYPERCALCEMIA mmol/l, iPTH 30 ng/l). There were no other complications of the disease. During 5 years of follow-up, his condition has been stable, there has not been any other endocrine disorder. Genetic testing (for mutation of HRPT2) Urša Kšela, Mitja Krajnc has not yet been completed. Department of Endocrinology and Diabetology, Maribor University Medical Centre, Maribor Conclusions urska.ksela@ukc-mb.si Primary hyperparathyroidism is often recognized as a result of biochemical screening. Most patients are asymptomatic with mildly elevated serum calcium. Although there is overlap in the clinical in biochemical presentation Primary hyperparathyroidism is usually caused by parathyroid adenoma or of benign parathyroid disease and parathyroid cancer, there are some hyperplasia. Parathyroid carcinoma is a rare cause of hyperparathyroidism, features that increase likelihood of parathyroid cancer, one of them is accounting for approx. 0.74% of cases. Features that increase the likelihood tumor size. Follow-up is indicated as the recurrence rate is high. of parathyroid carcinoma in patients with primary hyperparathyroidism are larger tumor size, symptomatic disease, marked hypercalcemia and very high serum parathyroid hormone (iPTH) concentrations. Preoperative localization studies do not reliably distinguish carcinoma from adenoma, a definitive diagnosis is made if there is local invasion or lymph node or distant metastases. Case report 65-year-old asymptomatic patient with diabetes mellitus and arterial hypertension was referred to our outpatient clinic because of accidentally found hypercalcemia, with calcium 2.79 mmol/l (normal range 2.2-2.6 mmol/l), ionized-calcium 1.40 mmol/l (1.12-1.23 mmol/l) and intact parathyroid hormone 194 ng/l (10-65 ng/l). We performed ultrasonography of neck region and subtraction thyroid scan. Investigations did not confirm neck mass. We performed choline PET CT that showed larger cystic mass on the right side of thyroid gland, suspicious for parathyroid carcinoma. Before surgery he did CT scan of neck and thorax, which showed large 4x3x5 cm tumor of parathyroid gland, without distant metastases. The patient was referred to a thoracic surgeon. Histological findings of resected tumor confirmed parathyroid carcinoma, TNM stage was T1N0M0. His 202 203 06 REDEK VZROK ZASTOJA SRCA: Ob 4 tirni antihipertenzivni terapiji je bil krvni pritisk dobro urejen. Napadov PARAGANGLIOM tipičnih za feokromocitom ni navajal. V statusu z izjemo prekomerne telesne teže ni bilo posebnosti. Aleksandra Kukovič, Urška Kšela Ambulanto smo 2x določili plazemske metanefrine in normetanefrine, ki so bili negativni. Oddelek za endokrinologijo in diabetologijo, Opravil je PET CT (F-18 FDG), ki je pokazal nizko metabolno aktivno formacijo UKC Maribor, Maribor pred desnim m. psoas. Glede na karakteristike je sprememba predstavljala NET ali paragangliom. aleksandra.kukovic@ukc-mb.si Priporočen je bil PET/CT z 68Ga-DOTATAT, ki je potrdil paragangliom. Sprememba v desni nadledvičnici ni bila metabolno aktivna. Ponovno smo določili kateholamine in dopamin v 24 urnem urinu 2x. V enkratnem vzorcu sta bila povišana metanefrin 2,07 (do 1,62) in Uvod normetanefrin 7,32 (do 2,13). Povišan je bil tudi kromogranin A: 1094,0 (ref. območje 19,4 - 101,9). Feokromocitom in paragangliom sta redka nevroendokrina tumorja, ki izločata kateholamine. Povzročata različne srčno-žilne zaplete, ki so lahko Bolnika smo predstavili na urološkem konziliju, priporočena je laparoskopska usodni: ventrikularne aritmije, akutni miokardni infarkt, hipertenzivo krizo odstranitev paraganglioma po ustrezni predoperativni pripravi. in kardiogeni šok. Razprava Prikaz primera S kateholamini povzročena kardiomiopatija je redek, vendar nevaren zaplet 51- letni bolnik, ki se je več let zdravil zaradi AH z večtirno terapijo, je bil feokromocitoma in paraganglioma. Nenadno sproščanje kateholaminov napoten v endokrinološko ambulanto zaradi suma na sekundarno AH. iz tumorja poviša srčni utrip, sistemsko žilno upornost, kontraktilnost miokarda in zmanjša vensko komplianco. Ob preveliki adrenergični V januarju 2022 je doživel zunajbolnišnični srčni zastoj, prvi ritem VF. S stimulaciji pride do hude vazokonstrikcije in koronarnega vazospazma. preiskavami v času hospitalizacije so izključili kardialne vzroke srčnega zastoja in zaradi zastoja srca nejasnega vzroka vstavili ICD. Zaradi visokih Smernice priporočajo slikovno diagnostiko ob sumu na feokromocitom/ vrednosti krvnega pritiska so postavili sum na sekundarno AH. Določili so paragangliom le ob pozitivnih biokemičnih testih. Pri bolniku smo, kljub kateholamine v 24 urnem urinu 3x. V enem vzorcu je bil mejno povišan negativnim biokemičnim testom, ob visokem sumu na endokrini vzrok normetanefrin (2,48 umol/dan, meja 2,13). hipertenzije opravili slikovno diagnostiko, s katero smo potrdili paragangliom in s tem verjeten vzrok srčnega zastoja. Opravil je CT trebuha, kjer je bila vidna 12 mm velika okrogla sprememba v desni nadledvičnici, ki po radioloških kriterijih ni predstavljala maščobno bogatega adenoma. Ob tem je bila vidna mehkotkivna sprememba pred desnim m. psoas - sum na NET. 204 205 07 References EPIDEMIOLOGY OF CENTRAL PRECOCIOUS PUBERTY, PREMATURE ADRENARCHE 1. Lenders JWM, Duh QY, Eisenhofer G, Gimenez-Roqueplo AP, Grebe SKG, Murad MH, AND ISOLATED TELARCHE IN SLOVENIA et al. Pheochromocytoma and paraganglioma: an endocrine society clinical practice guideline J Clin Endocrinol Metab. 2014;99(6):1915-42. Melisa Lazarevič1, Taja Knific1, Janez Žibert2, Nika Obolnar3, 2. Santos JRU, Bruna AB, Pacak VK. Catecholamine-Induced Cardiomyopathy in Nataša Aleksovska4, Jasna Šuput Omladič5, Tadej Battelino1,5, Pheochromocytoma: How to Manage a Rare Complication in a Rare Disease? Horm Metab Res. 2019;51(07):458–469. Magdalena Avbelj Stefanija1,5 1 Faculty of Medicine, University of Ljubljana, Ljubljana 2 Centre for Health Informatics and Statistics, Faculty of Health Sciences, University of Ljubljana, Ljubljana 3 Department of Infectious Diseases, University Medical Center Ljubljana, Ljubljana 4 Izola General Hospital, Izola 5 Department of Pediatric Endocrinology, Diabetes and Metabolic Diseases, University Children’s Hospital, University Medical Centre Ljubljana, Ljubljana melisa.lazarevic@outlook.com Background Decreasing age at the onset of puberty, but stable age at menarche is observed in recent decades in several populations (1). In line with this observation, a rising incidence of central precocious puberty (CPP) is identified in some countries (2). Precocious adrenarche is in most cases an isolated condition of early rise in adrenal androgens, commonly associated with childhood obesity (3). Precocious telarche sometimes occure as an isolated temporal or persistent condition unrelated to activated hypothalamic-pituitary-gonadal axis. 206 207 Objectives References We aimed to define the national incidence and trends of CPP, isolated 1. Eckert-Lind C, Busch AS, Petersen JH, Biro FM, Butler G, Bräuner EV, Juul A. Worldwide precocious adrenarche (PA) and isolated persistent precocious telarche (PT). Secular Trends in Age at Pubertal Onset Assessed by Breast Development Among Girls: A Systematic Review and Meta-analysis. JAMA Pediatr. 2020;174(4):e195881. 2. Bräuner EV, Busch AS, Eckert-Lind C, Koch T, Hickey M, Juul A. Trends in the Incidence of Population and Methods Central Precocious Puberty and Normal Variant Puberty Among Children in Denmark, 1998 to 2017. JAMA Netw Open. 2020;3(10):e2015665. In a retrospective study, the data on Slovenian national incidence on 3. Rosenfield RL. Normal and Premature Adrenarche. Endocr Rev. 2021;42(6):783-814. CPP, PA and PT was collected from an electronic system at the national referral center for pediatric pubertal disorders, Department of Pediatric Endocrinology, Diabetes and Metabolic diseases of the University Children’s Hospital of Ljubljana for the time frame between 2011 and 2021. The population of risk was defined as girls of 7 years of age or younger and boys of 8 years of age or younger that lived in Slovenia in a specific year. Results The national incidence of CPP was 12.97/100,000 (23.11/100,000 girls, 4.42/100,000 boys). The incidence in girls was rising from 12.57/100,000 in 2011 up to 34.31/100,000 in 2021. In 83.25% of girls, CPP was idiopathic (iCPP), while in boys, the potential cause of the condition was found in 77% of the cases (non-idiopathic CPP - nCPP). There was no sex difference in the incidence of nCPP. The incidence of PA in girls was 35.33/100,000 and in boys 4.195/100,000 and showed no rising trend. The Incidence of PT in girls was 6.04/100,000 and remained stable during observation period. Conclusions It is possible that better CPP recognition due to ameliorated education of primary pediatricians impacted rising numbers of identified children with CPP. However, rising CPP incidence during short observation period could also suggest important contribution of yet unidentified environmental factors in iCPP etiology, particularly in girls. However, these may not have the same effect on PA and PT incidence. Earlier pubertal maturation should be acknowledged as an increasing need for care by the national health system. 208 209 08 ENDOCRINE DYSFUNCTION AFTER IPILIMUMAB maintenance chemotherapy with nivolumab was hospitalized after a newly AND NIVOLUMAB CANCER IMMUNOTHERAPY: discovered diabetes presented as diabetic ketoacidosis (DKA). In the weeks A CASE PRESENTATION following his last round of chemotherapy, he noticed general weakness, headaches, and dizziness. Polydipsia, nocturia, and urinary frequency became more evident days before hospitalization. When examined, he Sara Lovšin,1,2 Katarina Černač,2 Mojca Lunder,2,3 was hypotensive and nauseous with episodes of vomiting; laboratory Miodrag Janić 2,3 tests showed hyponatremia, hyperkalemia, hyperglycaemia, and metabolic acidosis (low bicarbonate and pH). Ketoacidosis was treated according to 1 Division of Surgery, University Medical Centre Ljubljana, Ljubljana the standard protocol and resolved completely. However, the patient tested 2 Faculty of Medicine, positive for COVID-19 and received remdesivir, remaining asymptomatic University of Ljubljana, Ljubljana throughout the infection. During hospitalization, hypothyroidism, and 3 Department of Endocrinology, Diabetes and Metabolic Diseases, adrenal insufficiency (basal cortisol 40 nmol/L and 98 nmol/L 30 minutes University Medical Centre Ljubljana, Ljubljana after stimulation, respectively) were diagnosed. Substitution treatment with levothyroxine and hydrocortisone was introduced. Hyperglycemia sara.marinko@gmail.com was regulated with multiple daily insulin injections. Higher sodium values found in the urine suggested the concomitant syndrome of inappropriate antidiuretic hormone secretion (SIADH). This, among hypophysitis, hypothyroidism and diabetes, could also be a side effect of nivolumab Introduction immunotherapy. Anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) and anti-programmed cell death protein 1/programmed death-ligand 1 (anti-PD-1/ Conclusions PD-L1) immune checkpoint inhibitors (ICI) have significantly improved cancer outcomes (1). However, due to their mechanism of action, immune-In the case presented, we confirmed multiple endocrinopathies (diabetes, related adverse events, most often endocrine dysfunctions (thyroiditis, hypothyroidism, and probably secondary adrenal insufficiency due to hypophysitis, adrenal gland disorders, diabetes) can be triggered (2). hypophysitis) as a consequence to ICI oncological immunotherapy treatment. Combined therapy has shown the highest risk of occurrence of adverse Therefore, in patients who receive this class of immunotherapy, caution events (3). We present a patient who suffered insufficiency of three is advised for endocrinopathies due to possible life-threatening adverse endocrine glands after combined immunotherapy with ipilimumab (anti-events (ketoacidosis, adrenal crisis, etc.) and appropriate substitution CTLA-4) and nivolumab (anti-PD-1). therapy should be introduced promptly (3). Case presentation A 58-year-old man with a history of several chronic non-communicable diseases and metastatic clear cell renal carcinoma of the right kidney on 210 211 09 References CLINICAL CHARACTERISTICS OF 1. Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science. FIRST SLOVENIAN PATIENTS 2018;359(6382):1350-5. WITH TYPE 2 DIABETES 2. Barroso-Sousa R, Barry WT, Garrido-Castro AC, Hodi FS, Min L, Krop IE, Tolaney SM. WHO WERE TREATED WITH ORAL Incidence of Endocrine Dysfunction Following the Use of Different Immune Checkpoint Inhibitor Regimens: A Systematic Review and Meta-analysis. JAMA Oncol. 2018;4(2):173-SEMAGLUTIDE: A MULTICENTER STUDY 82. 3. Ovčariček T. Imunoterapija. Onkologija (Ljubljana). 2018;22(1):18-22. Mojca Lunder1,2, Marjan Kristanc3, Rajko Svilar4, Zorančo Trpkovski5, Miodrag Janić1,2, Andrej Janež1,2 1 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana 2 Faculty of Medicine, University of Ljubljana, Ljubljana 3 University Clinic Golnik, Golnik 4 General Hospital »Dr. Franc Derganc« Nova Gorica, Šempeter pri Gorici 5 General Hospital Murska Sobota, Murska Sobota mojca.lunder@kclj.si Background and aim GLP-1 receptor agonists (GLP-1RA) are suggested in patients with type 2 diabetes at increased cardiovascular risk or with established atherosclerotic cardiovascular disease (ASCVD) (1, 2). Until recently, GLP-1RA was only available in injectable form, which frequently caused treatment barriers from the patient or medical personnel (3). Oral semaglutide, the first GLP1-RA in oral form, could overcome these barriers (4). The purpose of the present study was to analyse the clinical characteristics of the first patients who received oral semaglutide in Slovenia in four different hospitals. 212 213 Methods References The first 45 patients (23 women, 22 men) with type 2 diabetes who were treated with oral semaglutide were analysed. We establish background 1. American Diabetes Association Professional Practice Committee; Boris Draznin, antidiabetic treatment, the reason for the introduction of oral semaglutide, Vanita R Aroda, George Bakris, Gretchen Benson, Florence M Brown, RaShaye Freeman, and their risk of ASCVD. Glycated haemoglobin (HbA1c) and fasting blood Jennifer Green, Elbert Huang, Diana Isaacs, Scott Kahan, Jose Leon, Sarah K Lyons, Anne L Peters, Priya Prahalad, Jane E B Reusch, Deborah Young-Hyman. 9. Pharmacologic glucose were also collected at the start of the study. Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2022. Diabetes Care, 2022;45(Suppl 1):S125-S143. Results 2. Draženka Pongrac Barlovič, et al. Slovenske smernice za klinično obravnavo sladkorne bolezni tipa 2, 2022. The patients were 61.9 ± 1.5 years old, obese (stage 3, mean body mass index 3. Kruger DF, LaRue S, Estepa P. Recognition of and steps to mitigate anxiety and fear of 35.8 ± 0.8 kg/m2) with a duration of type 2 diabetes of 9.8 ± 1.6 years. Most pain in injectable diabetes treatment. Diabetes Metab Syndr Obes. 2015;8:49–56. 4. Bucheit JD, Pamulapati LG, Carter N, Malloy K, Dixon D, Sisson EM. Oral Semaglutide: A patients received a triple combination of metformin, gliclazide, and SGLT-2 Review of the First Oral Glucagon-Like Peptide 1 Receptor Agonist. Diabetes Technol inhibitor (45%) or a dual combination of metformin and gliclazide (40%), Ther. 2020;22(1):10-18. others received a combination of metformin and SGLT-2 inhibitor (8%) or metformin, gliclazide, and DPP-4 inhibitor (7%) prior to oral semaglutide introduction. In most patients, oral semaglutide was introduced due to poorly controlled glycemia (45%), fear of injections (20%), obesity (22%). 11 patients (24.5%) had known ASCVD; 19 patients (42.2%) had a high risk of ASCVD. The mean HbA1c at the introduction of oral semaglutide was 9.3 ± 0.3% and fasting blood glucose 10.8 ± 0.5 mmol/l. Conclusion In a Slovenian cohort of the first 45 patients with type 2 diabetes who received oral semaglutide, the main reasons for its introduction were poorly controlled glycemia, fear of injections, and obesity. Most of the patients had received triple antidiabetic treatment before and were at high cardiovascular risk. Due to the change in the insurance policy in Slovenia, we expect more patients to benefit from oral semaglutide sooner after the diagnosis of type 2 diabetes. 214 215 10 PROTECTION OF THE VASCULAR SYSTEM Methods THROUGH THE ANTIOXIDANT AND Forty male patients with type 1 diabetes were randomly assigned to four ANTI-INFLAMMATORY ACTION OF groups: (1) control (placebo), (2) empagliflozin 25 mg daily, (3) metformin THE EMPAGLIFLOZIN-METFORMIN 2000 mg daily, and (4) empagliflozin-metformin combination (25 mg and COMBINATION 2000 mg daily, respectively) in addition to their regular insulin therapy (multiple daily injections or continuous subcutaneous insulin infusion). Their average age was 44.7 ± 2.5 years and the average duration of diabetes was Mojca Lunder1,2, Mišo Šabovič2,3, Andrej Janež1,2, 22.6 ± 3.9 years. Blood samples were collected to determine the parameters Miodrag Janić1,2 of oxidative stress (total antioxidative status (TAS), superoxide dismutase 1 Department of Endocrinology, Diabetes and Metabolic Diseases, (SOD), glutathione peroxidase (GPx), uric acid, advanced oxidation University Medical Centre Ljubljana, Ljubljana protein products (AOPP), advanced glycosylation end products ((AGE) and isoprostane), and inflammation parameters (C-reactive protein (CRP) and 2 Faculty of Medicine, University of Ljubljana, Ljubljana interleukin-6 (IL-6)) parameters at inclusion and after 3 months of therapy. 3 Department of Vascular Diseases, University Medical Centre Ljubljana, Ljubljana Results The empagliflozin-metformin combination increased antioxidant levels miodrag.janic@kclj.si (TAS, SOD and GPx up to 1.1-fold; P < 0.01), decreased pro-oxidant levels (AOPP and isoprostanes up to 1.2 times, P < 0.01; AGE up to 1.5-fold, P < 0.01), and decreased inflammatory parameters (up to 1.5-fold, CRP P < 0.01; IL-6 P < 0.001). The antioxidant action was associated with an improvement in arterial function in the empagliflozin-metformin combination group. Background Conclusions Cardiovascular benefits of antihyperglycemic drugs have become one The empagliflozin-metformin combination had a strong antioxidant and of the key criteria for choosing the type 2 diabetes treatment (1). The anti-inflammatory action, which was greater compared to individual drugs empagliflozin-metformin combination improved endothelial function and in patients with type 1 diabetes. In addition, the antioxidant activity of the reduced arterial stiffness, thus proving functional cardiovascular benefit (2). empagliflozin-metformin combination could at least partially explain the However, the mechanisms behind this finding are not yet fully understood. improvement in arterial function. We propose that these results could be Therefore, the purpose of our study was to explore the possible antioxidant extrapolated to patients with type 2 diabetes. and anti-inflammatory action of empagliflozin-metformin combination in patients with type 1 diabetes, naive to any antihyperglycemic therapy with cardiovascular protection. 216 217 11 References DINAMIKA TELESNE TE�E PRI SLADKORNIH BOLNIKIH, ZDRAVLJENIH Z GLP1-RA 1. American Diabetes Association Professional Practice C, Draznin B, Aroda VR, Bakris G, Benson G, Brown FM, et al. 9. Pharmacologic Approaches to Glycemic Treatment: (ANALIZA PODATKOV IZ VSAKDANJE Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S43. KLINIÈNE PRAKSE) 2. Lunder M, Janic M, Japelj M, Juretic A, Janez A, Sabovic M. Empagliflozin on top of metformin treatment improves arterial function in patients with type 1 diabetes mellitus. Cardiovasc Diabetol. 2018;17(1):153. Jana Makuc Bolnišnica Topolšica, Topolšica jana.makuc@b-topolsica.si Uvod Bolniki s sladkorno boleznijo (SB) tipa 2 so pogosto prekomerno prehranjeni ali debeli. V tuji literaturi se tako vse pogosteje uporablja skovanka »diabesity« (1). Zmerna izguba telesne teže ugodno vpliva na urejenost glikemije, zato smernice bolnikom priporočajo izgubo vsaj 5% telesne mase, pri izbiri zdravil za zdravljenje SB pa njihov učinek na telesno težo. Med novejša zdravila z ugodnim učinkom ne telesno težo spadajo tudi agonisti receptorjev GLP1 (GLP1-RA) (2). Namen, cilji in metode Da bi pridobili osnovni vpogled v učinek GLP1-RA na telesno težo naših bolnikov, smo v diabetološki ambulanti Bolnišnice Topolšica retrospektivno analizirali podatke o telesni teži pri bolnikih s SB tipa 2 in predpisanim enim od GLP1-RA, ki so v zadnjih 6 mesecih prišli na redni kontrolni pregled. Drugih pomembnih dejavnikov, ki bi lahko vplivali na rezultate, nismo preverjali (urejenost glikemije, sočasna terapija, doslednost jemanja zdravil, frekvenca kontrolnih pregledov ipd.). Analiza je potekala z vgrajenimi osnovnimi statističnimi funkcijami programa Microsoft Excel. Rezultati Skupaj smo pregledali podatke za 89 bolnikov, med katerimi je 28 prejemalo 218 219 dulagutid, 18 liraglutid (vsi v kombinaciji z inzulinom), 23 semaglutid s.c. in Zakljuèek 20 semaglutid p.o. Rezultati kažejo začeten ugoden učinek na znižanje izhodiščne telesne teže Dinamiko telesne teže bolnikov skozi čas prikazuje Graf 1. za vse GLP1-RA z izjemo liraglutida (v kombinaciji z inzulinom). V nadaljevanju zdravljenja učinek izzveni. Pri interpretaciji podatkov je potrebno upoštevati, GRAF 1. da predstavlja naša analiza zaradi številnih omejitev (majhen vzorec, Spremembe izhodiščne telesne teže pri bolnikih s SB tip 2, zdravljenih z GLP1-RA. manjkajoči podatki, sočasna terapija, doslednost jemanja zdravil, kratka 40 prisotnost peroralnega semaglutida na domačem tržišču) zgolj omejen 30 vpogled v učinek različnih GLP1-RA na telesno težo pri bolnikih s SB tipa 2. 20 10 0 0 3 6 12 18 24 30 36 48 60 72 Čas zdravljenja (meseci) -10 -20 -30 -40 Primeri bolnikov -50 (kg) Gibanje telesne teže za posamezne GLP1-RA med trajanjem zdravljenja prikazuje Tabela 2. TABELA 2. Gibanje telesne teže za posamezne GLP1-RA med trajanjem zdravljenja. Reference 1. Ng ACT, Delgado V, Borlaug BA, Bax JJ. Diabesity: the combined burden of obesity and diabetes on heart disease and the role of imaging. Nat Rev Cardiol. 2021;18(4):291-304. 2. Lazzaroni E, Ben Nasr M, Loretelli C, Pastore I, Plebani L, Lunati ME, et al. Anti-diabetic drugs and weight loss in patients with type 2 diabetes. Pharmacol Res. 2021;171:105782. Prispevek ni sponzoriran. Konflikt interesov: Avtorica je občasna pogodbena sodelavka podjetja NovoNordisk. 220 221 12 POJAVNOST SUBAKUTNEGA TIROIDITISA Rezultati MED PANDEMIJO COVID-19 V obdobju enajstih mesecev pred COVID-19 je bilo pregledanih 4844 bolnikov (1139 moških in 3705 žensk) s povprečno starostjo 54±22,9 let, v Tim Medved 1, Nastja Medle 1, Simona Gaberšček 1,2 enajstih mesecih med COVID-19 pa je bilo pregledanih 4048 bolnikov (1042 moških in 3006 žensk) s povprečno starostjo 53,6±18,6 let. Med obdobjema 1 Medicinska fakulteta, nismo ugotovili razlik v starosti (p=0,438), je pa bil delež moških večji med Univerza v Ljubljani, Ljubljana pandemijo COVID-19 kot pred njo (p=0,030). V obdobju pred COVID-19 smo 2 Klinika za nuklearno medicino, odkrili 65 primerov subakutnega tiroiditisa (1,2 % vseh diagnoz), medtem ko Univerzitetni klinični center Ljubljana, Ljubljana smo v obdobju med COVID-19 zabeležili 81 primerov subakutnega tiroiditisa (2 % vseh diagnoz). Pojavnost subakutnega tiroditisa je bila statistično tim.medved1@gmail.com značilno večja med pandemijo COVID-19 kot pred njo (p = 0,022). Uvod Zakljuèki SARS-CoV-2, ki povzroča COVID-19, vstopa v celice preko receptorja za Ugotovili smo, da je pojavnost subakutnega tiroiditisa statistično angiotenzin konvertazo 2, čigar izraženost je celo večja v ščitnici kot v značilno porasla med pandemijo COVID-19. Domnevamo, da je to posledica pljučih. Poleg tega se pri okužbi s SARS-CoV-2 močno odzove imunski sistem, neposrednega vpliva virusa SARS-CoV-2 na ščitnične celice ter vpliva okužbe kar lahko vpliva tudi na pojavnost bolezni ščitnice. V literaturi so opisane na imunski sistem. možne povezave med okužbo s SARS-CoV-2 in subakutnim tiroiditisom, zato smo želeli raziskati vpliv pandemije COVID-19 na pojavnost subakutnega tiroiditisa. Metode V klinični retrospektivni raziskavi smo pregledali zdravstveno dokumentacijo vseh bolnikov, ki so bili prvič v življenju pregledani v Ambulanti za bolezni ščitnice na Kliniki za nuklearno medicino Univerzitetnega kliničnega centra Ljubljana med 1. 4. 2019 in 29. 2. 2020 (obdobje pred COVID-19) ter med 1. 4. 2020 in 28. 2. 2021 (obdobje med COVID-19). V to ustanovo že leta prihajajo bolniki iz polovice Slovenije, v kateri živi približno milijon prebivalcev. Zaradi stabilnega področja zajemanja bolnikov lahko iz števila novih primerov Reference ugotavljamo pojavnost posamezne bolezni. Pri vsakem bolniku so po opravljenem kliničnem pregledu, ultrazvoku ščitnice in laboratorijskih 1. Naguib R. Potential relationships between COVID-19 and the thyroid gland: an update. meritvah specialisti za bolezni ščitnice postavili diagnozo ščitnične bolezni. J Int Med Res. 2022; 50(2):3000605221082898. 222 223 13 ATTACHMENT STYLES AND PERCEPTION Results OF GESTATIONAL DIABETES MELLITUS The expressiveness of the fearful attachment style (n=21) was associated with a more negative experience of GDM. It was associated with higher Ana Munda 1, Katarina Lia Kompan Erzar 2, impact of GDM to their everyday life (r=0.378; p<0.001), more concerns Draženka Pongrac Barlovič 1,3 about GDM (r=0.324, p=0.001) and higher emotional burden of the disease (r=0.329, p=0.001). Moreover, even though GDM is known as an 1 University Medical Centre Ljubljana asymptomatic disease, fearful attachment style was positively associated 2 Faculty of Theology, University of Ljubljana, Ljubljana with experiencing the symptoms attributed to GDM (r=0.225, p=0.022). 3 Faculty of Medicine, University of Ljubljana, Ljubljana Expressions of other attachment styles were not significantly associated with dimensions of illness perception. ana.munda@kclj.si Conclusions For the first time, our results show an association of attachment styles with GDM perceptions. These could affect coping with illness and could have consequences on glycemic control and pregnancy outcomes. Background Based on the Attachment theory and the Common Sense Model of illness perceptions, the current study focused on the identifying potential differences in the formation of perception about gestational diabetes mellitus (GDM) according to four attachment styles - secure, fearful, preoccupied and dismissing. Namely, illness perception can significantly influence the management of the disease, which can be a problem in GDM requiring immediate adjustment and treatment. Method The sample consisted of 107 women (age 32.5±4.7 years) newly diagnosed with GDM. Participants completed the Brief Illness Perception Questionnaire (BIPQ) and the Relationship Questionnaire (RQ). The Spearman correlation coefficient was used to determine the association between variables and the Mann Whitney U test was used to compare the difference among attachment styles. 224 225 14 MIDDS (MATERNALLY INHERITED DIABETES hospital admission also lactatemia of unknown origin was confirmed . Two AND DEAFNESS SYNDROME ) years after that sensorineural deafness was proved. He also manifest WITH CARDIOMYOPATHY, ENDOCRINE erectile dysfunction we confirmed hypogonadotropic hypogonadism and after one year also pituitary hypothyroidism. Cardiac disease started DISORDERS AND SOME OVERLAPPING with paroxysmal arrithmia as WPW syndrome . At age of 37 years he SYMPTOMS OF MELAS (MITOCHONDRIAL manifest cardiogenic shock during pneumonia. His coronary angiography ENCEPHALOMYOPATHY, LACTIC ACIDOSIS, was normal, on cardiac echosonography hypertophic cardiomyopathy with STROKE SYNDROME) – CASE REPORT diastolic dysfunction was confirmed. Cardiac muscle biopsy was done and confirm the A3243G mutation in the mitochondrial gene MT-TL1 compatible with MIDDS diagnosis of very rare phenotypic mitochondrial mutation Maja Navodnik Preložnik, Lidija Benedičič, Aleksandra Šauperl manifestation, which manifest de novo – there were no diabetes, deafness Department of Diabetes and Endocrinology, or cardiac disease in his family history. The patient is treated with insulin, General Hospital Celje, Celje hormonal replacement, ACE inhibitors , spironolactone and empagliflozine with good clinical response. maja.navodnik@gmail.com Discussion This rare mitochondrial disease decline mitochondrial oxidation and increase ROS** which affect organs depending on energy, such as central nervous system, skeletal muscle, heart, kidney, and endocrine glands (3). Mutation Introduction could be asymptomatic or can manifest with different syndromes, some MIDDS is a rare monogenic disease due to a mitochondrial DNA mutation mitochodrial disease phenotypes overlap as in our patient who also has - A to G transition at position 3243 within MT-TL1 gen*. MIDDS could some symptoms of MELAS – except strokes (4, 5). In UK Cohort Study 6% also be associated with neuromuscular and psychiatric manifestations, patients were associated with combined MELAS/MIDDS overlap syndromes cardiomyopathy as well as renal disease, macular dystrophy and endocrine (6). The disease remains progressive and fatal, with lower mortality with and gastrointestinal disorders and short or thin statue (1). The most adult disease onset. There is no curative treatment, but some antioxidants common phenotype of this mutation (80% of cases) manifest as MELAS can lower ROS and rise NO production, SGLT 2 inhibitors could have promising syndrome (2). role. MT-TL1* gene for tRNA (Leu UUR) in mitochondria Case report ROS** – reactive oxygen species We report the case of a 42-year-old thin male who suffer from insuline dependent DM, which started at age 27 years with ketoacidosis (c peptid level was 0.14 nmol/l), complaining of muscle cramps and myalgia with normal electrolyte and myoglobin levels), headaches and depressia, at 226 227 15 References COPPER-BASED WOUND DRESSINGS 1. Esterhuizen K, Lindeque JZ, Mason S, van der Westhuizen FH, Rodenburg RJ, de Laat P, AS A NEW INTERVENTION IN CHRONIC et al. One mutation, three phenotypes: novel metabolic insights on MELAS, MIDD and NON-HEALING DIABETIC FOOT ULCERS myopathy caused by the m.3243A > G mutation. Metabolomics. 2021;12;17(1):10. 2. Sproule DM, Kaufmann P. Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes: basic concepts, clinical phenotype and therapeutic management of MELAS Urška Perc 1, Miodrag Janić 1,2, Mojca Lunder 1,2 syndrome. Ann N Y Acad Sci. 2008;1142:133–58. 3. Hayashi G, Cortopassi G. Oxidative Stress in Inherited Mitochondrial Diseases. Free 1 Department of Endocrinology, Diabetes and Metabolic Diseases, Radic Biol Med. 2015;88:10–17. University Medical Centre Ljubljana, Ljubljana 4. Gerbitz KD, van den Ouweland JM, Maassen JA, Jaksch M. Mitochondrial diabetes 2 Faculty of Medicine, mellitus: a review. Biochim Biophys Acta1995;1271(1):253–60. University of Ljubljana, Ljubljana 5. Yatsuga S, Povalko N, Nishioka J, Katayama K, Kakimoto N, Matsuishi T. MELAS: a nationwide prospective cohort study of 96 patients in Japan. Biochim Biophys Acta. 2012;1820(5):619–24. urskap0703@gmail.com 6. Nesbitt V, Pitceathly RDS, Turnbull DM, Taylor RW, Sweeney MG, et al. The UK MRC Mitochondrial Disease Patient Cohort Study: Clinical Phenotypes Associated With the M.3243A>G Mutation–Implications for Diagnosis and Management. J Neurol Neurosurg Psychiatry. 2013;84(8):936–8. Introduction Chronic non-healing ulcers do not progress through the normal phases of healing in an orderly and timely manner (1). The selection of dressings is very important for the ulcer healing process; a new available option are copper-based wound dressings. Copper is known to modulate several cytokine and growth factor mechanisms and plays a key role in skin regeneration and angiogenesis (2). It enhances hypoxia inducible factor (HIF-1α) expression, which was recognized as a critical factor in wound healing (3). The purpose of the present analysis was to review the potential of copper-based wound dressings (MEDCu) in chronic non-healing diabetic foot ulcers. Presentation of cases Five patients (3 men and 2 women with a mean age of 65 ± 7.8 years and an average duration of type 2 diabetes of 13.6 ± 1.6 years) with chronic non-healing diabetic foot ulcers (persisting from four months to two years) were prescribed MEDCu wound dressing and included in the analysis. A standard chronic wound management protocol (debridement, local treatment, systemic antibiotic treatment, offloading and supportive angiology, 228 229 16 dermatology or surgical care) was followed. The wound characteristics were DIABETIC KETOACIDOSIS IN PATIENTS WITH followed during the use of MEDCu, patient satisfaction was also observed. TYPE 2 DIABETES RECEIVING SGLT-2 INHIBI- The mean observation period was 29.4 ± 4.0 days. In four patients, the use of MEDCu accelerated the ulcer healing process, which was observed by TORS: A SINGLE-CENTRE CASE SERIES reducing wound surface area (WSA) by up to 46.3 ± 10.3%. In one patient, WSA and wound characteristics did not change during the use of MEDCu, Tina Pučnik 1, Mojca Lunder 1,2, Miodrag Janić 1,2 which could be due to intense physical activity. Furthermore, in three 1 patients, a regression of the wound inflammation process was observed Faculty of Medicine, with the use of MEDCu. All patients were very satisfied with the use of University of Ljubljana, Ljubljana MEDCu dressings. 2 Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana Conclusions miodrag.janic@kclj.si The use of MEDCu wound dressings improved chronic diabetic foot ulcer healing, which was observed as WSA reduction and attenuation of surrounding tissue inflammation. The patients were very satisfied with the MEDCu dressings. Therefore, MEDCu dressings represent a potentially Introduction effective option in the treatment of chronic diabetic ulcers. Sodium-glucose cotransporter-2 inhibitors (SGLT-2i) have changed in the last 5 years from convenient to ultimate treatment in type 2 diabetes (1). Their safety profile is generally good (2). Diabetic ketoacidosis (DKA) rarely occurs during SGLT-2i treatment, but can be a major concern, as a life-threatening condition. The purpose of the present study was to review the clinical cases of DKA associated with using SGLT-2i in our department to explore possible causal risk factors. Presentation of cases References Seven patients (4 men and 3 women, aged 60±6 years; average body mass index 27.2±3.5 kg/m2) with DKA associated with SGLT-2i were hospitalised in 1. Werdin F, Tennenhaus M, Schaller HE, Rennekampff HO. Evidence-based management our department in the last 4 years. Four received empagliflozin and three strategies for treatment of chronic wounds. Eplasty. 2009;9:e19. dapagliflozin. All were previously diagnosed with type 2 diabetes (median 2. Sen CK, Khanna S, Venojarvi M, Trikha P, Ellison EC, Hunt TK, et al. Copper-induced duration 18 years [8–33]); median HbA1c at the presentation was 8.6 % vascular endothelial growth factor expression and wound healing. Am J Physiol Heart Circ Physiol. 2002;282(5):H1821-7. [6.9–11.6]). DKA occurred 4 days to several years after the introduction of 3. Ruthenborg RJ, Ban JJ, Wazir A, Takeda N, Kim JW. Regulation of wound healing and SGLT-2i. One patient received SGLT-2i in monotherapy, others additionally fibrosis by hypoxia and hypoxia-inducible factor-1. Mol Cells. 2014;37(9):637-43. received metformin (6/7), sulfonylurea/repaglinide (5/7), basal insulin 230 231 17 (2/7) and/or incretin therapy (2/7). The median plasma glucose at the POJAVLJANJE SRÈNO-�ILNIH DOGODKOV presentation of DKA was 14.6 mmol/L [8.2–40.2], the mean pH was 7.0±0.2, PRI BOLNIŠNIÈNO OBRAVNAVANIH BOLNIKIH HCO3- 4.2±1.8 mmol/L, with an anion gap of 27.3±4.3 mmol/L. 4/7 patients underwent urinalysis, all positive for ketones. In 4 patients, the infection S HIPERTIROZO ZARADI BAZEDOVKE was recognized as the cause of the DKA. Ketoacidosis was treated according to the standard protocol and resolved in all patients. The median fasting Ana Šešek 1, Katica Bajuk Studen 1,2 C-peptide was 0.29 nmol/L [0.03–0.35] and 0.40 nmol/L [0.03–0.79] after 1 Medicinska fakulteta, food stimulation. Autoantibodies were determined in 4/7 patients and Univerza v Ljubljani, Ljubljana were negative. In all patients, SGLT-2i was withdrawn without attempted rechallenge. 2 Klinika za nuklearno medicino, Univerzitetni klinični center Ljubljana, Ljubljana Conclusions ana.sesek134@gmail.com Based on our case series analysis, one of the critical triggers for the development of DKA associated with the use of SGLT-2i is infection. Therefore, general educational measures must be strictly followed, particularly stopping SGLT-2i in the setting of any acute illness or major event (surgery, etc.) (3). Other factors for the increased risk of developing Znana je vzročna povezanost hipertiroze z razvojem nekaterih srčno-žilnih DKA associated with the use of SGLT-2i could not be defined from our dogodkov (SŽD). Hipertiroza se značilno pojavlja tudi pri bazedovki, ki analysis; therefore, more studies are needed. v primeru težjega poteka oz. potrebe po določenih terapevtskih ukrepih (intravenski tirostatik, radiojodno zdravljenje, tiroidektomija) zahteva bolnišnično obravnavo. Želela sem preveriti, če pri bolnišnično obravnavanih bolnikih (BOB) s hipertirozo zaradi bazedovke obstaja povečano tveganje za SŽD. V retrospektivno raziskavo sem vključila v obdobju 01.01.2018-31.12.2021 prvič obravnavane bolnike z bazedovko na Kliniki za nuklearno medicino Univerzitetnega kliničnega centra Ljubljana (1113 bolnikov). Hipertirotičnih References (znižan TSH, povišana pT4 in pT3) je bilo 781 bolnikov, 210 (26,9 %) BOB 1. American Diabetes Association Professional Practice C, Draznin B, Aroda VR, Bakris in 571 (73,1%) ambulantno obravnavanih bolnikov (AOB). Skupini sem s G, Benson G, Brown FM, et al. 9. Pharmacologic Approaches to Glycemic Treatment: Pearsonovim χ2-testom oz. t-testom za neodvisna vzorca primerjala po Standards of Medical Care in Diabetes-2022. Diabetes Care. 2022;45(Suppl 1):S125-S43. pojavnosti akutnih SŽD in prisotnosti dejavnikov tveganja. 2. Donnan JR, Grandy CA, Chibrikov E, Marra CA, Aubrey-Bassler K, Johnston K, et al. Comparative safety of the sodium glucose co-transporter 2 (SGLT2) inhibitors: a BOB so bili glede na AOB značilno starejši (50,8±16,1 proti 44,4±14,4 let, systematic review and meta-analysis. BMJ Open. 2019;9(1):e022577. p<0,001), prevladovali so moški (28,6 proti 20,7 %, p=0,017), imeli so večjo 3. Bashir J, Nalla P, Peter R, Bain SC, Chudleigh R. A case series of DKA occurring in patients pojavnost arterijske hipertenzije (23,3 proti 8,2 %, p<0,001), hiperlipidemije receiving treatment with SGLT-2 inhibitors. Diabetes Obes Metab. 2018;20(7):1800-1. (17,6 proti 8,1 %, p=0,001) in kajenja (35,2 proti 23,6 %, p<0,001). Indeks 232 233 18 telesne mase (24,6±4,5 proti 24,3±5,6 kg/m2, p=0,851), pojavljanje sladkorne TELEMEDICINE AND DIABETES CARE bolezni (6,2 proti 6,7 %, p=0,127), ravni TSH, pT4, pT3, antiTg in antiTPO se DURING COVID-19 PANDEMIC med skupinama niso značilno razlikovali, značilno višja pri BOB kot pri AOB IN SLOVENIA je bila raven antiTSH-R (24,3±44,1 proti 9,9±16,0 IU/L, p<0,001). SŽD je doživelo 74 (9,4 %) bolnikov (Tabela 1), značilno več BOB (54,0 % Brina Šket 1, Karmen Janša 2,3, Ana Munda 1, dogodkov) kot AOB (46,0 % dogodkov), p<0,001. Med skupinama v starosti ob SŽD (63,5±11,8 proti 60,8±17,9 let, p=0,063) ni bilo značilne razlike. Draženka Pongrac Barlovič 1,4 Najpogostejši zaplet bazedovke, AF, je bil pogostejši pri BOB (p=0,034). 1 Clinical Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana 2 Health Insurance Institute of Slovenia, Ljubljana TABELA 1. 3 Pojavljanje srčno-žilnih dogodkov. General hospital Jesenice, Jesenice 4 Faculty of Medicine, University of Ljubljana, Ljubljana brina.sket@kclj.si Introduction Precautionary measures during the COVID-19 pandemic facilitated use of telemedicine for routine diabetes care. Therefore, we aimed to assess the implementation of telemedicine in diabetes out-patient care nationally and across different Slovenian regions during the COVID-19 pandemic. Izsledki kažejo, da so se SŽD in dejavniki tveganja zanje pri BOB z bazedovko pojavljali statistično značilno pogosteje kot pri AOB. Methods We analysed national and regional data of the Health Insurance Institute of Slovenia about on–site and telemedicine visits from years 2019 to 2021. Moreover, healthcare professionals’ experience on telemedicine was collected using an online questionnaire, sent to all members of the Diabetology Association of Slovenia. 234 235 Results FIGURE 1. In the year 2020, the number of all diabetes out-patient visits in Slovenia Number of on-site and telemedicine visits in Slovenia and its regions between was lower (n =158,339) than in year 2019 (n =173,375) or 2021 (n =168,462). years 2019 and 2021. The number of telemedicine visits increased 5- times from the year 2019 (n = 6,118; 3.5% of all visits) to 2020 (n = 29,695; 18.8% of all visits) with a 1.8% 2021 2020 ZASAVSKA REGION decline from the year 2020 to 2021. The extent of telemedicine practices 2019 2021 2020 SAVINJSKA REGION varied across Slovenia (Figure), with the highest share of telemedicine 2019 2021 visits in 2020 in Podravska (37.1%) and the lowest in Savinjska region 2020 PRIMORSKO-NOTRANJSKA REGION 2019 2021 (2.1% of all visits). The most frequently tool used was telephone call and 2020 POSAVSKA REGION 2019 e-mail. Telemedicine was most commonly used for elderly and pregnant 2021 2020 POMURSKA REGION 2019 women. Healthcare professionals experienced both advantages (mainly 2021 2020 PODRAVSKA REGION good accessibility for patients and cost–effectiveness) and disadvantages 2019 2021 2020 OSREDNJE SLOVENSKA REGION (mainly personal burden and worse treatment control) with telemedicine 2019 2021 approach. 2020 OBALNO-KRAŠKA REGION 2019 2021 2020 KOROŠKA REGION 2019 2021 2020 JUGOVZHODNA SLOVENIJA Discussion and conclusion 2019 2021 2020 GORIŠKA REGION During the COVID-19 pandemic, use of telemedicine increased profoundly, 2019 2021 2020 GORENJSKA REGION however, its implementation in daily clinical practice is not increasing 2019 2021 after the year 2020. Experience and implementation rate varied across 2020 SLOVENIA 2019 regions and practices. Nevertheless, telemedicine offers useful tools that 0 5.000 10.000 15.000 20.000 25.000 30.000 35.000 40.000 45.000 50.000 can be well implemented in diabetes care also outside the COVID-19 frame, Legend: complementary to on-site visits, in certain groups of individuals and specific Every region has its own color for on-site (first part of the row) and telemedicine (second settings, yet improvements in many aspects are needed. part of the row) visits. The columns of regions represent absolute number of visits, but the column Slovenia represents the average absolute number of all regions. 236 237 19 REAL WORLD DATA CONFIRMS ASSOCIATION Methods OF FLASH GLUCOSE MONITORING-DERIVED Included subjects (n=32, age 59 ± 17 years) were both Type 1 (64%) and TIME IN RANGE AND HBA1C Type 2 diabetes patients, treated with insulin, who had central-laboratory measurements of HbA1c. They were monitored for a up to 20-month period Brina Šket 1, Špela Volčanšek 1,2, Mojca Lunder 1,2, in their daily life through commercial FGM devices, reimbursed by the Andrej Janež National Health System. FGM metrics were calculated and compared with 1,2 each other and with HbA1c cross-sectionally. Paired FGC metrics and HbA1c 1 Clinical Department of Endocrinology, Diabetes and Metabolic Diseases, were evaluated by Pearson’s correlation coefficient. University Medical Centre Ljubljana, Ljubljana 2 Faculty of Medicine, Results Univesity of Ljubljana, Ljubljana The average TIR and HbA1C were 63.9 ± 20.4 % and 7.5 ± 1.2 %, respectively, and were linearly correlated. The correlation coefficient (R) of mean TIR spela.volcansek@kclj.si with mean HbA1C was −0.802; P<0.01 (2-tailed). For every absolute 10% change in %TIR, there was a 0.85 % change in HbA1c (Figure 1). TIR was strongly correlated with TAR (R= −0.995; P<0.01), but, not with TBR (R= −0.066, NS). HbA1c was strongly correlated with TAR (R= −0.790; P<0.01), but not significantly with TBR (R= −0.025, NS). Background and aims Conclusions Flash glucose monitoring (FGM) has become widely used and recognized as Real world data demonstrated a strong linear correlation between %TIR a “beyond glycated haemoglobin (HbA1c)” tool. According to the consensus captured by FGM and HbA1c. The assessment of device-specific TIR–HbA1c recommendations, several metrics, such as time in range (TIR), time above relationship in real-life conditions is important for diabetologists to gain range (TAR) and time below range (TBR) can be used. Associations between trust and rely on FGM-derived metrics in every day clinical practice. TIR (70 – 180 mg/dL; 3.9 – 10 mmol/L) and diabetes complications have been investigated to corroborate the relationship between TIR and HbA1c. However, most data were gathered by paired HbA1c and %TIR metrics from frequent self-monitoring of blood glucose (SMBG) data or data provided by continuous glucose monitoring (CGM). Currently, the most frequently used device in clinical practice is FGM. Therefore, device (e.g., FGM) specific TIR-HbA1c relations should be established. This pilot study aimed to establish real world data-based correlations between several metrics measured by FGM and well-established laboratory parameter of glycaemic control, HbA1c. 238 239 20 KRONIÈNA LEDVIÈNA BOLEZEN 100% PRI SLADKORNEM BOLNIKU – 90% JO PODCENJUJEMO? 80% Ajda Urbas, Jana Komel, Mojca Mir 70% Ambulanta za diabetike, ZD Koper, Koper TIR 60% 50% ajda.urbas@zd-koper.si 40% 30% 20% 5,0 5,5 6,0 6,5 7,0 7,5 8,0 8,5 9,0 9,5 HbA1C FIGURE 1. Correlation between %TIR (Flash Glucose Monitoring-Derived Time In Range) and HbA1c. Uvod Sladkorna bolezen je kronična metabolna bolezen, njena pojavnost pa po svetu vse bolj narašča (1). Osebe s sladkorno boleznijo ogrožajo zapleti, najbolj pogosto srčno-žilna obolenja, retinopatija in okvara ledvic (1). Slednja predstavlja glavni vzrok kronične ledvične bolezni, njeno zdravljenje pa predstavlja velik zdravstveni izziv (2). Pristop mora biti multidisciplinaren, pri zdravljenju pa sledimo sodobnim smernicam Združenja za nefrologijo (KDIGO) (2). Osebe s sladkorno boleznijo in ledvično boleznijo zdravimo z References novejšimi antihiperglikemičnimi zdravili, predvsem so se na tem področju izkazali zaviralci natrij-glukoznih transporterjev (SGLT2 zaviralci) (3). 1. Battelino T, Danne T, Bergenstal RM, Amiel SA, Beck R, Biester T, et al. Clinical Targets Raziskave s SGLT2 zaviralci so pokazale odlične ledvične izide ter manjšo for Continuous Glucose Monitoring Data Interpretation: Recommendations From the umrljivost pri osebah s kronično ledvično boleznijo. (3) International Consensus on Time in Range. Diabetes Care. 2019;42:1593–603. 2. Yaron M, Roitman E, Aharon-Hananel G, Landau Z, Ganz T, Yanuv I, et al. Effect of Flash Glucose Monitoring Technology on Glycemic Control and Treatment Satisfaction Ali na ledvièno bolezen pomislimo dovolj pogosto? in Patients With Type 2 Diabetes. Diabetes Care. 2019;42:1178–84. V Ambulanti za diabetike v Kopru smo se odločili, da na vzorcu bolnikov 3. Karter AJ, Parker MM, Moffet HH, Gilliam LK, Dlott R. Association of Real-time Continuous Glucose Monitoring With Glycemic Control and Acute Metabolic Events preverimo, koliko dejansko je ledvične okvare in ali bolniki prejemajo Among Patients With Insulin-Treated Diabetes. JAMA. 2021;325:2273–84. sodobna zdravila z ugodnimi učinki na ledvice*. 240 241 Metode Literatura Med 1. 5. in 31. 7. 2022 smo pregledali kartoteke naključno izbranih bolnikov. 1. WHO - Diabetes. Pridobljeno 30.8. 2022 s spletne strani https://www.who.int/health- Številka predstavlja približno 10% bolnikov, zdravljenih v naši ambulanti. topics/diabetes Pregledali smo laboratorijske izvide kreatinina in ocenjene glomerulne 2. Garabed Eknoyan, Norbert Lameire, David C. Wheeler, Michel Jadoul, Wolfgang C. filtracije (CKD-EPI), morebitno že postavljeno diagnozo ledvične bolezni ter Winkelmayer, et al. KDIGO 2022 Clinical practice guidelines for diabetes management in chronic kidney disease. Pridobljeno s spletne strani 30.8. 2022 https://kdigo.org/ napotitev k nefrologu, bolnikove ostale zaplete in zdravila, ki jih prejema. wp-content/uploads/2022/03/KDIGO-2022-Diabetes-Management-GL_Public-Review-draft_1Mar2022.pdf 3. Heerspink HJL, Stefánsson BV, Correa-Rotter R, et al. Dapagliflozin in Patients with Rezultati Chronic Kidney Disease. N Engl J Med. 2020;383(15):1436-1446. Analizirali smo 700 kartotek bolnikov. Povprečna starost bolnikov je bila *Pregled bolnikov smo opravili v sodelovanju s podjetjem AstraZeneca 68 let, 57% je bilo moških, povprečni Hba1c je bil 7,2 %. Sladkorna bolezen je v povprečju trajala 12,5 let. Diagnoza ledvične bolezni je bila postavljena pri 91 bolnikih (13%), po pregledu podatkov pa je kriterijem za postavitev diagnoze (po KDIGO) ustrezalo 234 bolnikov (34%). Manj kot četrtina je imela še ostale zaplete (ASŽB n=170 (24%), SP n=103 (15%) in retinopatija n=81 (12%)). Pogledali smo še, ali bolniki prejemajo terapijo, ki ugodno vpliva na ledvične bolezni. Od bolnikov, ki so imeli postavljeno diagnozo ledvičnega zapleta, je terapijo s SGLT2 zaviralci prejemalo 34 bolnikov (37%), od tistih, ki ustrezajo kriterijem, vendar diagnoze še nimajo zavedene, pa je SGLT2 zaviralec prejemalo 98 bolnikov (42%). Zakljuèek Rezultati so pokazali, da (pre)pogosto ne postavimo diagnoze kronične ledvične okvare dovolj zgodaj. Postavitev zgodnje diagnoze kronične ledvične bolezni in uvedba terapije s SGLT2 zaviralci pa je pomembna pri preprečevanju progresa ledvičnih zapletov. Verjamemo, da nam bodo rezultati pregleda pomagali k boljši obravnavi bolnikov s sladkorno boleznijo in kronično ledvično okvaro. 242 243 21 SPREMEMBA NOHTA NA NOGI – POT DO DIAGNOZE Ajda Urbas, Jana Komel, Mojca Mir Ambulanta za Diabetike ZD Koper ajda.urbas@zd-koper.si Uvod Ob obravnavi v naši ambulanti je bila na nohtu prisotna razjeda nohta-Težave z nohti so pri diabetikih pogoste. Navadno so posledica okvare noht je deloval »požrt«, rana je bila brez sekrecije ali znakov vnetja. Ob prvi živcev ali prekrvitve spodnjih okončin. Na njih se lahko razvijejo tudi okužbe, obravnavi smo opravili diagnostiko nevropatije, ki ni bila prisotna, stopalni najpogosteje glivične(1). Včasih pa na pogled nedolžna okužba razvije težke pulzi so bili dobro tipni. Napotili smo ga na pregled h kirurgu. Opravljen je posledice. bil RTG prsta, ki je pokazal znake akutnega osteomielitisa. Uvedena je bila dvotirna antibiotična terapija, ki jo je gospod prejemal 8 tednov. Odvzet je bil tudi bris, iz katerega so porasle številne bakterije, ki so bile občutljive Prikaz primera na uvedeno terapijo. Svetovana je bila kontrola pri žilnem kirurgu, ki pa je 63-letni bolnik se v Ambulanti za Diabetike Koper obravnava od leta 2011. gospod ni opravil. Kljub terapiji, se stanje ni izboljševalo, zato smo gospoda Pri zdravljenju ne potrebuje terapije, upošteva nefarmakološke ukrepe. V napotili še na dermatološki pregled. Ta je svetoval dodatno diagnostiko ter letošnjem letu je ambulanto obiskal zaradi sprememb na nohtu prvega antibiotična mazila. Ob ponovni napotitvi k žilnemu kirurgu, so gospodu prsta leve noge. Preden je obiskal našo ambulanto, je bila sprememba amputirali del prsta. Izvid histopatološkega pregleda govori, da gre za nohta prisotna že približno pol leta, prejemal je antibiotike. Stanje se ni invazivni ploščatocelični karcinom, ki je bil odstranjen v zdravo. Zaradi blage izboljševalo. limfocitne infiltracije je svetovana še odstranitev varovalne bezgavke. 244 245 22 Zakljuèek SELF-REPORTED PHYSICAL ACTIVITY Rakava obolenja so pri sladkornih bolnikih pogostejša kot v populaciji AND SEDENTARY BEHAVIOUR brez sladkorne bolezni. Zaradi slabšega celjenja ran in pogostejših okužb, IN OLDER ADULTS WITH DIABETES se pogosteje pojavljajo kožni malignomi. V primerjavi z zdravo populacijo je preživetje pri kožnih karcinomih slabše (2), zato je pomembno, da ob Špela Volčanšek 1,2, Mojca Lunder 1,2, Andrej Janež 1,2 nenavadnih ranah pomislimo tudi na to diagnozo. Zgodnje prepoznavanje je ključno. 1 Clinical Department of Endocrinology, Diabetes and Metabolic Diseases, University Medical Centre Ljubljana, Ljubljana 2 Medical Faculty, University of Ljubljana, Ljubljana spela.volcansek@gmail.com Background Despite proven benefits of regular physical activity (PA) in diabetes patients, physical inactivity and sedentary lifestyle is increasing across all age groups. The aim of the present study was to examine self-reported PA and sedentary behaviour in older adults with type 1 diabetes (T1D) and type 2 diabetes (T2D) patients and possible differences between diabetes types. The associations of PA and sitting time (ST) with glycaemic control and BMI were also explored. Methods This cross-sectional cohort non-exposure study included 117 patients, aged ≥60 years, treated with insulin regimens. Statistical analyses were conducted on data gathered by the International Physical Activity Questionnaire - IPAQ. Literatura Data was presented as mean ± standard error of mean (SEM). 1. Rich, P. Nail Changes due to diabetes and other endocrinopathies. Dermatol Ther. 2002;15:107-110. Results 2. Ederaine SA, Lopez-Dominguez J, Harvey JA, Mangold AR, Cook CB, et al. Survival and Patients were aged 71.6 ± 1.1 years, majority had T2D (75%). T1D patients glycemic control in patients with co-existing squamous cell carcinoma and diabetes mellitus. Future Sci OA. 2021;7(5):FSO683. were active 162 ± 32 minutes weekly and sedentary 4.45 ± 0.7 hours daily, 246 247 23 while T2D were active 72 ± 12 min and sedentary 6.71 ± 0.9 h (p <0.01 for STAROSTNO POGOJENE SPREMEMBE both). T1D patients had longer duration of vigorous PA (up to 7.2-fold; p V NIVOJIH KRVNIH MAŠÈOB IN GLUKOZE <0.05). PA and BMI were associated in subjects with T1D (r = -0.5; p <0.01), however, in T2D subjects sitting time (ST) and BMI were associated (r = 0.2; p TER NJIHOVA POVEZAVA Z UPORABO ZDRAVIL <0.05). Regular physical activity was not associated with improved glycaemic IN SMRTNOSTJO: OPAZOVALNA RAZISKAVA control. Only the patients achieving >1500 metabolic equivalent-minutes weekly had significantly lower HbA1c (7.9% ± 1.6% vs. 7.3% ± 1.2% (p <0.05). Rene Markovič 1,2, Vladimir Grubelnik 2, Helena Blažun Vošner 3,4,5, Peter Kokol 2, Matej Završnik6, Karmen Janša 7, Marjeta Zupet 7, Conclusion Jernej Završnik 1,3,5,8, Marko Marhl 1,9,10 The results suggest that older age itself is not a barrier to engagement in PA. 1 Fakulteta za naravoslovje in matetematiko, Older T1D patients were in general more active and less sedentary compared Univerza v Mariboru, Maribor to T2D counterparts and performed longer duration of vigorous PA, whereas 2 Fakulteta za elektrotehniko, računalništvo in informatiko, T2D patients engaged in mostly low or moderate PA, e.g. walking. The Univerza v Mariboru, Maribor expected beneficial affect of PA on glycaemic control was observed only in 3 Zdravstveni dom Dr. Adolfa Drolca Maribor, Maribor the very active older diabetic patients. Therefore, tailored advice targeting physical inactivity is important during lifelong diabetes education, since 4 Fakulteta za zravstvene in socialne vede, Slovenj Gradec it can guide older adults of both diabetes types towards better metabolic 5 Alma Mater Europaea - Evropski center Maribor, Maribor health. 6 Oddelek za endokrinologijo in diabetologijo, Univerzitetni klinični center Maribor, Maribor 7 Zavod za zdravstveno zavarovanje Slovenije, Ljubljana 8 Znanstveno-raziskovalno središče Koper, Koper 9 Pedagoška fakulteta, Univerza v Mariboru, Maribor 10 References Medicinska fakulteta, Univerza v Mariboru, Maribor 1. Saint-Maurice PF, Graubard BI, Troiano RP, Berrigan D, Galuska DA, Fulton JE, et al. matej.zavrsnik1@gmail.com Estimated Number of Deaths Prevented Through Increased Physical Activity Among US Adults. JAMA Intern Med. 2022. 182(3):349–352. 2. Bohn B, Herbst A, Pfeifer M, Krakow D, Zimny S, Kopp F, et al. Impact of Physical Activity on Glycemic Control and Prevalence of Cardiovascular Risk Factors in Adults With Type Predstavljamo analizo dinamike krvnih maščob (KM) in glukoze (G) glede na 1 Diabetes: A Cross-Sectional Multicenter Study of 18,028 Patients. Diabetes Care. starost in spol, pri čemer so nas zanimali vplivi uporabe antidiabetičnih in 2015;38(8):1536–1543. hipolipemičnih zdravil ter smrtnosti na analizirane meritve. Osnovna analiza 3. Johansen MY, MacDonald CS, Hansen KB, Karstoft K, Christensen R, Pedersen M, et al. Effect of an Intensive Lifestyle Intervention on Glycemic Control in Patients With Type temelji na anonimiziranih podatkih Zdravstvenega doma Dr. A. Drolca za 2 Diabetes: A Randomized Clinical Trial. JAMA. 2017;318:637–46. holesterol (celokupni holesterol, LDL, HDL, TG) in glukozo v obdobju 2008– 248 249 24 2019 (506.083 laboratorijskih testov, 63.606 pacientov). Glede na znano ORAL SEMAGLUTIDE IN COMBINATION WITH povezavo dislipidemije in hiperglikemije (1) smo se vprašali ali se motnji METFORMIN IS AN EFFECTIVE TREATMENT OF pojavljata sočasno in ali je razlika po spolu. V drugi fazi raziskave smo vključili SYMPTOMATIC HYPERGLYCEMIA IN PATIENTS anonimizirane podatke porabe zdravil Zavoda za zdravstveno zavarovanje Slovenije za obdobje 2013–2018 za dve anatomsko terapevstski skupini (ATC WITH NEWLY DIAGNOSED TYPE 2 DIABETES A10 – zdravila za sladkorno bolezen in ATC C10 – hipolipemiki) (392.171 različnih pacientov). Zanimalo nas je, ali in kako se laboratorijski podatki Klara Zorko 1, Nadan Gregorič 1,2 spreminjajo glede na porabo omenjenih skupin zdravil. V zadnji fazi raziskave smo dodali še podatke o smrtnosti Statističnega urada republike Slovenije za 1 Department for Endocrinology, Diabetes and Metabolic Diseases, leto 2018 z namenom analize vpliva umrljivosti na statistiko meritev KM in G. University Medical Centre Ljubljana, Ljubljana 1,2 Faculty of Medicine, University of Ljubljana, Ljubljana Zakljuèki Ugotovili smo, da se najvišji procent populacije s povišanimi vrednostmi G klara.zorko@kclj.ci pojavlja približno 20 let kasneje kot največji procent populacije z hiperlipidemijo. Uporabili smo tri različne podatkovne baze, kar ni dopuščalo longitudinalne raziskave, vendar je omogočalo dokazati, da so profili KM in G v populacijski statistiki kvalitativno spremenjeni z zdravili in s smrtnostjo. Zaznali smo dve Introduction prelomni točki, prva v starosti 55-59 let ustreza največjemu porastu uporabe zdravil in druga sovpada z naglim porastom smrtnosti v starosti 75-79 let Symptomatic hyperglycemia in newly diagnosed type 2 diabetes (2). V kasnejši, dodatni študiji smo z metodo matematičnega modeliranja demands prompt pharmacological treatment, generally with a dual oral opozorili še na nekatere ključne celične mehanzme v celicah beta, ki lahko ob antihyperglycemic regime or insulin (1). Due to good effectiveness, relative kroničnih pogojih hiperlipidemije vodijo v povišano bazalno izločanje inzulina safety and low cost, sulphonylureas are preferable antihyperglycemic agents in pomanjkanje inzulinske sekrecije po hrani (3). in addition to metformin. Renal impairment and high risk of hypoglycemia limit its use and frequent dose adjustment is required. Oral semaglutide is a novel antihyperglycemic with proven clinical effectiveness and safety even in case of renal or liver impairment (2). Due to its mechanism through the incretin system, it does not cause hypoglycemia. Could oral semaglutide be an References alternative choice along with metformin for the treatment of symptomatic hyperglycemia in newly diagnosed type 2 diabetes? 1. Roden M, Shulman GI. The integrative biology of type 2 diabetes. Nature. 2019;576:51–60. 2. Markovič R, Grubelnik V, Vošner HB, Kokol P, Završnik M, Janša K, Zupet M, Završnik J, Marhl M. Age-Related Changes in Lipid and Glucose Levels Associated with Drug Use Methods and Mortality: An Observational Study. J Pers Med. 2022;12(2):280. 3. Grubelnik V, Zmazek J, Završnik M, Marhl, M. Lipotoxicity in a Vicious Cycle of Pancreatic The study was conducted from April 2022 to August 2022 in the outpatient Beta Cell Exhaustion. Biomedicines. 2022;10:1627. diabetes clinic of the University Medical Centre Ljubljana. Nine patients with 250 251 newly diagnosed type 2 diabetes and symptomatic hyperglycemia without References previous antihyperglycemic treatment were enrolled and put on a dual therapeutic regimen with metformin and oral semaglutide. The titration 1. Janež A. Zdravljenje hiperglikemije z zdravili. Urednica Pongrac Barlovič D. Slovenske was performed according to the protocol provided by the manufacturer. The smernice za klinično obravnavo sladkorne bolezni tipa 2. Ljubljana: Diabetološko združenje Slovenije; 2022. follow-up was scheduled between 30 and 45 days after the initial visit. For 2. Aroda VR, Rosenstock J, Terauchi Y, Altuntas Y, Lalic NM, Morales Villegas EC, the statistical analysis, we used the t-test. Jeppesen OK, Christiansen E, Hertz CL, Haluzík M; PIONEER 1 Investigators. PIONEER 1: Randomized Clinical Trial of the Efficacy and Safety of Oral Semaglutide Monotherapy in Comparison With Placebo in Patients With Type 2 Diabetes. Diabetes Care. Results 2019;42(9):1724-1732. Of nine patients three were females. The mean age was 44 years (SD+/-7,6). Mean baseline blood glucose was 13,8 mmol/L (SD+/-1,7). All patients reported symptoms of hyperglycemia. At the follow-up, six patients had received a Disclaimer cumulative daily dose of metformin 2000 mg, three 1000 mg. Five patients received oral semaglutide 7 mg and four patients 3 mg per day. Hyperglycemic The authors declare that the research was conducted in the absence of any treatment was effective. Baseline HbA1c 10,7 % (SD+/-2,0) has decreased to commercial or financial relationships that could be construed as a potential 8,9 % (SD+/-1,3), change -1,9% (SD+/-1,5; 95 % CI 0,7, 3,0; p<0,006). The effect conflict of interest. on bodyweight was evident, albeit statistically not significant, with baseline body mass index 35,9 kg/m2 (SD +/- 7,1) reduced to 33,6 kg/m2 (SD +/-6,0), change -2,3kg/m2 (SD +/-3,4; 95 %, CI -0,6, 5,1; p=0,104). All the reported hyperglycemia-associated symptoms resolved. Treatment was generally well tolerated. One patient complained of mild gastrointestinal symptoms. No patients discontinued with treatment. Conclusions Oral semaglutide in combination with metformin offers a safe and effective alternative treatment of symptomatic hyperglycemia in patients with newly diagnosed type 2 diabetes. 252 253 ABBOTT LABORATORIES d.o.o. AMGEN ZDRAVILA d.o.o. ASTRAZENECA UK LIMITED, Podružnica v Sloveniji BAYER d.o.o. BOEHRINGER INGELHEIM RCV, Podružnica Ljubljana DEXCOM INTERNATIONAL Ltd. ELI LILLY FARMACEVTSKA DRUŽBA, d.o.o. GEDEON RICHTER d.o.o. RAZSTAVLJAVCI KRKA, d.d., Novo mesto EXHIBITORS LEK d.d. MEDIAS INTERNATIONAL d.o.o. MEDIS-M d.o.o. MED TRUST d.o.o. MERCK d.o.o. NOVARTIS PHARMA SERVICES INC. NOVO NORDISK d.o.o. PFIZER, Podružnica v Sloveniji ROCHE FARMACEVTSKA DRUŽBA d.o.o. Ljubljana SWIXX BIOPHARMA d.o.o. VIATRIS d.o.o. VPD, BLED, d.o.o. WÖRWAG PHARMA ZALOKER & ZALOKER d.o.o. 254 255 256