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After successful treatment for Cushing's syndrome (CS), secondary adrenal insufficiency develops as a result of the prior suppression of the hypothalamic-pituitary-adrenal (HPA) axis by excess cortisol in the body. Until the recovery of the HPA axis, glucocorticoid replacement therapy is required to enable normal functioning of the body and prevent adrenal crisis. Significant variation in the median time of recovery of the HPA axis is found in various cohorts of CS patients ranging from several weeks to years. Despite the use of physiological glucocorticoid replacement, after cure for CS, patients often experience symptoms of glucocorticoid withdrawal syndrome (GWS). The optimal glucocorticoid regimen to reduce GWS needs to be established and requires an individualized approach aiming to avoid overtreatment at one side and minimize the risk of undertreatment and possible adrenal crisis and GWS on the other side.

Objective: Indices based on aldosterone/cortisol (A/C) concentration in the successfully cannulated adrenal vein (AV) and in the inferior vena cava (IVC) (AV/IVC) appear to be possible markers to verify the subtype of primary aldosteronism (PA) in the case of inconclusive results of adrenal vein sampling (AVS). The variability of results in previous studies encouraged us to calculate AV/IVC and adrenal A/C cutoff values that could predict the aetiology of PA. Methods: This retrospective study included 96 patients who underwent AVS due to PA between 2015 and 2020. The derivation cohort ultimately consisted of 60 patients with bilaterally successful AVS and a clear diagnosis of unilateral or bilateral disease. Receiver operating characteristic analysis was used to find the optimal A/C and AV/IVC cutoff values predicting the subtype of PA. The validation cohort consisted of 11 patients with either unsuccessful cannulation or a borderline lateralization index (LI), those patients underwent adrenalectomy because their indices were suggestive of unilateral disease based on the derivation cohort data. Results: The cutoff values of A/C ≤ 0.63 or AV/IVC ≤ 0.37 identified unaffected glands with a sensitivity of 91.2% and 97.1%, respectively, and a specificity of 90.7% and 88.4%, respectively. Unilateral ipsilateral gland involvement was characterized by A/C ≥ 3.5 or AV/IVC ≥ 3.4 with a corresponding specificity of 100%. All patients in the validation cohort achieved biochemical remission postoperatively. Conclusions: A/C and AV/IVC cutoff values could be a useful tool to determine the subtype of PA in patients with unilateral successful AVS as well as in patients with a borderline LI.

Background\ud \ud The association between cortisol secretion and mortality in patients with adrenal incidentalomas is controversial. We aimed to assess all-cause mortality, prevalence of comorbidities, and occurrence of cardiovascular events in uniformly stratified patients with adrenal incidentalomas and cortisol autonomy (defined as non-suppressible serum cortisol on dexamethasone suppression testing).\ud \ud \ud \ud Methods\ud \ud We conducted an international, retrospective, cohort study (NAPACA Outcome) at 30 centres in 16 countries. Eligible patients were aged 18 years or older with an adrenal incidentaloma (diameter ≥1 cm) detected between Jan 1, 1996, and Dec 31, 2015, and availability of a 1 mg dexamethasone suppression test result from the time of the initial diagnosis. Patients with clinically apparent hormone excess, active malignancy, or follow-up of less than 36 months were excluded. Patients were stratified according to the 0800–0900 h serum cortisol values after an overnight 1 mg dexamethasone suppression test; less than 50 nmol/L was classed as non-functioning adenoma, 50–138 nmol/L as possible autonomous cortisol secretion, and greater than 138 nmol/L as autonomous cortisol secretion. The primary endpoint was all-cause mortality. Secondary endpoints were the prevalence of cardiometabolic comorbidities, cardiovascular events, and cause-specific mortality. The primary and secondary endpoints were assessed in all study participants.\ud \ud \ud \ud Findings\ud \ud Of 4374 potentially eligible patients, 3656 (2089 [57·1%] with non-functioning adenoma, 1320 [36·1%] with possible autonomous cortisol secretion, and 247 [6·8%] with autonomous cortisol secretion) were included in the study cohort for mortality analysis (2350 [64·3%] women and 1306 [35·7%] men; median age 61 years [IQR 53–68]; median follow-up 7·0 years [IQR 4·7–10·2]). During follow-up, 352 (9·6%) patients died. All-cause mortality (adjusted for age, sex, comorbidities, and previous cardiovascular events) was significantly increased in patients with possible autonomous cortisol secretion (HR 1·52, 95% CI 1·19–1·94) and autonomous cortisol secretion (1·77, 1·20–2·62) compared with patients with non-functioning adenoma. In women younger than 65 years, autonomous cortisol secretion was associated with higher all-cause mortality than non-functioning adenoma (HR 4·39, 95% CI 1·93–9·96), although this was not observed in men. Cardiometabolic comorbidities were significantly less frequent with non-functioning adenoma than with possible autonomous cortisol secretion and autonomous cortisol secretion (hypertension occurred in 1186 [58·6%] of 2024 patients with non-functioning adenoma, 944 [74·0%] of 1275 with possible autonomous cortisol secretion, and 179 [75·2%] of 238 with autonomous cortisol secretion; dyslipidaemia occurred in 724 [36·2%] of 1999 patients, 547 [43·8%] of 1250, and 123 [51·9%] of 237; and any diabetes occurred in 365 [18·2%] of 2002, 288 [23·0%] of 1250, and 62 [26·7%] of 232; all p values

Complete surgical removal of adrenocortical carcinoma (ACC) represents the only chance of long-term cure. In this study, we compared the long-term outcomes of ACC patients depending on whether they had adrenal surgery performed in a high-volume (HVC) or in a low-volume (LVC) center. This retrospective study included 49 patients from the Croatian ACC Registry with the European Network for the Study of Adrenal Tumors (ENSAT) stage I–III ACC, of which 35 underwent surgery in a HVC whereas 14 of them were operated in one of the LVCs. Patients operated in the LVCs had a significantly higher rate of ACC recurrence (57.1% vs. 22.9%; p = 0.02). Accordingly, RFS was significantly longer in patients operated on in HVC (p = 0.04). The difference in RFS remained significant after controlling for age, gender, tumor size, Ki-67 index, Weiss score, and type of surgery (HR 4.55; 95% CI 1.16–17.88; p = 0.03). In addition, there is a tendency towards longer DSS in patients in the HVC group compared to those in the LVC group (p = 0.05). These results point to the centralization of adrenal surgery as a key prerequisite for improving the outcomes of ACC patients.

Background: Benign adrenal tumors are commonly discovered on cross-sectional imaging. Mild autonomous cortisol secretion (MACS) is regularly diagnosed, but its effect on cardiometabolic disease in affected persons is ill defined. Objective: To determine cardiometabolic disease burden and steroid excretion in persons with benign adrenal tumors with and without MACS. Design: Cross-sectional study. Setting: 14 endocrine secondary and tertiary care centers (recruitment from 2011 to 2016). Participants: 1305 prospectively recruited persons with benign adrenal tumors. Measurements: Cortisol excess was defined by clinical assessment and the 1-mg overnight dexamethasone-suppression test (serum cortisol: 138 nmol/L and absence of typical clinical Cushing syndrome [CS] features, definitive MACS [MACS-2]). Net steroid production was assessed by multisteroid profiling of 24-hour urine by tandem mass spectrometry. Results: Of the 1305 participants, 49.7% had NFAT (n = 649; 64.1% women), 34.6% had MACS-1 (n = 451; 67.2% women), 10.7% had MACS-2 (n = 140; 73.6% women), and 5.0% had CS (n = 65; 86.2% women). Prevalence and severity of hypertension were higher in MACS-2 and CS than NFAT (adjusted prevalence ratios [aPRs] for hypertension: MACS-2, 1.15 [95% CI, 1.04 to 1.27], and CS, 1.37 [CI, 1.16 to 1.62]; aPRs for use of ≥3 antihypertensives: MACS-2, 1.31 [CI, 1.02 to 1.68], and CS, 2.22 [CI, 1.62 to 3.05]). Type 2 diabetes was more prevalent in CS than NFAT (aPR, 1.62 [CI, 1.08 to 2.42]) and more likely to require insulin therapy for MACS-2 (aPR, 1.89 [CI, 1.01 to 3.52]) and CS (aPR, 3.06 [CI, 1.60 to 5.85]). Urinary multisteroid profiling revealed an increase in glucocorticoid excretion from NFAT over MACS-1 and MACS-2 to CS, whereas androgen excretion decreased. Limitations: Cross-sectional design; possible selection bias. Conclusion: A cardiometabolic risk condition, MACS predominantly affects women and warrants regular assessment for hypertension and type 2 diabetes.

Purpose of review: Adrenocortical carcinoma (ACC) is a rare tumor with variable prognosis depending mostly on the disease stage and tumor grade. The staging system proposed by the European Network for the Study of Adrenal Tumors has a reliable prognostic potential and defines ACC stages I-IV. Due to the absence of extraadrenal tissue invasion, patients with stage I-II have a lower recurrence rate and better prognosis. This article elaborates on the current understanding of the clinical approach to this group of patients. ----- Recent findings: Concerning the treatment, complete surgical resection of the tumor provides the only chance for cure. However, even after tumor removal, the risk of recurrence remains high and the main predictors of recurrence include tumor stage, grade (measured by Ki-67 proliferative index), and the tumor resection status. Adjuvant mitotane and/or adjuvant radiotherapy should be considered in patients with high risk of recurrence taking into account potential harmful effects of such treatment. Accordingly, careful selection of patients who may benefit from adjuvant treatment is of the utmost importance both for improving disease outcome and for avoiding potential overtreatment in patients who are at low risk of disease recurrence. ----- Summary: Many aspects of the management of patients with ACC stages I and II are not entirely evidence-based, and treatment decisions rely mostly on expert opinions and data from retrospective studies. Therefore, the treatment of these patients should be restricted to specialized centers with high expertise in ACC.

Background: Chronic Graft-versus-Host disease (cGvHD) is the leading cause of late non- relapse morbidity and mortality following allogeneic hematopoietic stem cell transplantation (alloHSCT). Metabolic bone disease is frequently seen after alloHSCT and is related to vitamin D deficiency and to GvHD – especially corticosteroids therapy and gastrointestinal (GIT) involvement. Elevated parathyroid hormone levels (PTH>6 pmol/L) were noticed alongside vitamin D deficiency presumably causing excessive bone resorption. However, high PTH level could be also a marker of systemic inflammation in cGvHD. In this study we investigated an association of cGvHD and vitamin D with PTH levels among long-term alloHSCT survivors. Methods: Data were collected on a prospective cross-sectional study protocol in patients who underwent alloHSCT and were evaluated by the institutional multidisciplinary cGvHD team from 6/2013 to 11/2019. Laboratory tests and detailed history were obtained, and patients with cGvHD were evaluated according to NIH 2005 criteria. Exclusion criteria were active acute GvHD, and for non-cGvHD group of patients also ongoing immunosuppressive treatment. Results: Study population consisted of 89 alloHSCT survivors (46% female), median age 48 (11-72) years, median of 672 (77-9478) days after alloHSCT. 62 (69.7%) had cGvHD and were evaluated at median of 376 (0-8869) days after the diagnosis was established. Majority of cGvHD patients had severe (38.7%) or moderate (38.7%) NIH global score, 41.9% had active cGvHD by clinician impression, and 58.1% were receiving systemic immunosuppression (41.6% of them corticosteroids). Median number of organs involved by cGvHD was 3, and most frequently involved organs were skin (58.0%), eyes (53.2%), and mouth (51.6%). GIT was involved in 11.3% of the patients. There was significantly more patients with history of acute GvHD (p

Objective To collect outcome data in a large cohort of patients with aggressive pituitary tumours (APT)/carcinomas (PC) and specifically report effects of temozolomide (TMZ) treatment. Design Electronic survey to ESE members Dec 2015–Nov 2016. Results Reports on 166 patients (40 PC, 125 APT, 1 unclassified) were obtained. Median age at diagnosis was 43 (range 4–79) years. 69% of the tumours were clinically functioning, and the most frequent immunohistochemical subtype were corticotroph tumours (45%). Ki-67 index did not distinguish APT from PC, median 7% and 10% respectively. TMZ was first-line chemotherapy in 157 patients. At the end of the treatment (median 9 cycles), radiological evaluation showed complete response (CR) in 6%, partial response (PR) in 31%, stable disease (SD) in 33% and progressive disease in 30%. Response was more frequent in patients receiving concomitant radiotherapy and TMZ. CR was seen only in patients with low MGMT expression. Clinically functioning tumours were more likely to respond than non-functioning tumours, independent of MGMT status. Of patients with CR, PR and SD, 25, 40 and 48% respectively progressed after a median of 12-month follow-up. Other oncological drugs given as primary treatment and to TMZ failures resulted in PR in 20%. Conclusion This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.

Incidentalomi nadbubrežne žlijezde jesu tumori otkriveni tijekom dijagnostičke evaluacije nekoga drugog kliničkog stanja. Tehnološki napredak radioloških uređaja i njihova sve veća upotreba u svakodnevnoj kliničkoj praksi doveli su do češćeg otkrivanja ovih tumora čineći njihovu dijagnostiku i liječenje jednim od najvažnijih izazova moderne endokrinologije. Radi racionalnog pristupa ovim bolesnicima radna skupina koju su činili vodeći hrvatski stručnjaci iz područja bolesti nadbubrežne žlijezde, na temelju relevantne znanstvene literature i postojećih smjernica europskih i svjetskih društava, donijela je preporuke za dijagnostiku i liječenje incidentaloma nadbubrežne žlijezde., Adrenal incidentalomas are tumours of adrenal glands discovered during diagnostic workup for other clinical condition unrelated to adrenal glands. Improvement in imaging techniques and their widespread use in everyday practice have increased detection of adrenal incidentalomas making their management one of the most important challenges of modern endocrinology. Based on the relevant medical literature and guidelines of other international societies a panel of Croatian leading experts in adrenal gland disorders provide practical recommendations for the diagnostics and treatment of adrenal incidentaloma.

The aim of the study was to compare bone properties of two groups of students which strongly differ in the level of their everyday physical activity; the School of Medicine (SM) students and the Faculty of Physical Education (FPE) students, University of Zagreb. Quantitative ultrasound parameters--broadband ultrasound attenuation (BUA) and speed of sound (SOS) were measured. Quantitative ultrasound index (QUI) and estimated bone mineral density (BMD) were calculated by the device software. The final study sample consisted of 165 students from SM (94 males and 71 females) and 215 students from the FPE (164 males, 51 females). Sixty eight percent of FPE students and 21% of SM students reported a high level of everyday physical activity (P < 0.001). All ultrasound parameters were significantly higher in FPE students than in SM students (at the P < 0.001 level). The multiple regression model of the QUI confirmed that the school students attended was the single significant predictor variable for both genders. Our data indirectly showed the beneficial role of physical activity on bone properties.

The aim of the study was to establish the normative QUS data in a healthy sample of Croatian males and estimate the prevalence of osteoporosis. A total of 1002 male participants, aged 20-99, were recruited in seven study centers (Zagreb, Ivanić-grad, Koprivnica, Sibenik, Pula, Slavonski Brod, Vukovar). In each subject broadband ultrasound attenuation (BUA), speed of sound (SOS) and quantitative ultrasound index (QUI) of the calcaneus were measured using the Sahara ultrasound device. Significant declining with age was found for all three parameters (p0.001). The peak SOS (1562.8 +/- 28.5 m/s) and QUI (103.6 +/- 16.5) values were observed in the third decade, whereas the peak BUA value (86.2 +/- 19.2 db/MHz) was observed in the fourth decade of life. Using the World Health Organization diagnostic criteria for DXA the rates of osteoporosis in the males aged 50 and older were 5.8%, 3.4 and 4.2% for QUI, BUA, and SOS respectively. However, when we used the cut-off value of the Tor = -l.8, prevalence of osteoporosis in Croatian males older than 50 years was 16.2%, 11.7% and 17.2%.

Metabolic syndrome is a constellation of interrelated abnormalities that increase the risk for the development of cardiovascular disease and type 2 diabetes. Together with obesity and dyslipidaemia, hypertension is one of the basic elements of the metabolic syndrome. Current guidelines do not provide specific recommendation for pharmacological management of the hypertensive patients with metabolic syndrome. Recent trials have consistently shown that therapy involving beta-blockers and diuretics may have some negative impact on metabolic and haemodynamic disorders present in metabolic syndrome. Several lines of evidence support the use of angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers as the appropriate first-line therapy and calcium channel blockers, as the second, in the patients with metabolic syndrome.

The clinical and molecular data of a patient with triple A syndrome are reported.A 21-year-old male who was diagnosed for adrenal insufficiency at the age of 2 years after a severe attack of adrenal crisis. At the age of 4 years, achalasia and alacrima were diagnosed. Puberty started at the age of 17 years. At the same time, symptoms of central, peripheral, and autonomic nervous system dysfunction were noted. Later on, at the age of 20 years, a bone age delay of 6 years and severe osteoporosis was diagnosed.A compound heterozygous AAAS mutation consisting of two mutations was found: a CT transition in exon 7 resulting in a change of arginine at amino acid position 194 into a stop codon (Arg194X) at one allele, and a CT transition in exon 12 resulting in a change of glutamine at amino acid position 387 into a stop codon (Gln387X) on the other allele.The mutation in exon 7 (p.R194X) of the AAAS gene is a novel mutation which has not been found in any other family so far, whereas the second was already found in some other families. This case adds to the clinical and molecular spectrum of triple A syndrome and may provide a new insight into the functions of AAAS gene.

The aim of our study was to evaluate the proposed Croatian scale for grading the disease severity in patients with hemorrhagic fever with renal syndrome (HFRS). The aim was also to determine whether the infection with Dobrava virus (DOBV) in Croatia was associated with a more severe illness than the infection with Puumala virus (PUUV).To evaluate the scale, case records of 62 HFRS patients hospitalized at the University Hospital for Infectious Diseases in Zagreb from 1995 till 2000 were reviewed. ELISA IgM and IgG tests were used for the detection of specific IgM and IgG antibodies to PUUV or DOBV.HFRS caused by hantaviruses is a zoonotic disease spread worldwide, posing a major public health problem of global dimensions. Recent epidemiologic studies show that almost all parts of Croatia are endemic regions for two hantaviruses, Puumala and Dobrava. The disease severity ranges from subclinical infection to severe illness with fatal outcome. Clinical picture is predominated by fever, myalgia, vomiting, hemorrhagic manifestation, visual impairment and kidney affection. There is still a lack of knowledge concerning all the parameters involved in the disease severity. Besides the type of virus and genetic material, host genes are also associated with the variable clinical course. HLA alleles B8, DR3, and DQ2 are strongly associated with severe outcome of PUUV infection, white HLA B27 allele is associated with a mild course. Whether similar genetic factors also operate in DOBV infection remains to be determined. Recently, a Croatian scale for grading the disease severity was proposed. The disease severity is graded by a scoring system (points attributed to specific clinical symptoms and laboratory findings) as 1--mild, 2--moderate, 3--severe, and 4--very severe. We found 60% of HFRS patients to be infected with PUUV and 40% with DOBV. In our study, 65% of patients infected with PUUV had mild, and 24% moderate disease. Severe and very severe disease was recorded in 11% of PUUV infected patients. In contrast, only 44% of patients infected with DOBV had mild disease, whereas 40% of patients showed a moderate clinical picture. Severe and very severe clinical picture was recorded in 16% of patients with DOBV infection. Statistical analysis showed a significant number of pa (p0.01) with PUUV infection to have mild disease, whereas a significant number of HFRS patients infected with DOBV had moderate (p0.01) and severe or very severe (p0.01) disease.Our results clearly indicate that in Croatia DOBV infection is associated with a more severe disease than PUUV infection. However, we confirmed previous findings that even PUUV infection could lead to a severe disease. Our initial experience in the evaluation of the proposed grading scale for disease severity demonstrated the proposed Croatian scale to be a useful tool in grading disease severity in patients infected with PUUV or DOBV. Moreover, the proposed scale may also prove highly useful for the prognostic purpose.

To compare the teaching programs of European medical schools with the minimum requirement medical curriculum recommended by the European University Association. Methods. Information on the curricula was gathered from the websites of 32 medical schools from 18 European countries. The data collected were the number of courses and proportion of each course in the study plan according to the class hours or credits. Each curriculum was compared with the standard medical curriculum recommended by the European University Association. Courses were clustered in 3 large groups: preclinical, clinical, and public health.The proportion of preclinical subjects was the highest at the Medical Schools in Brussels, Dublin, Milan, and Madrid, and the lowest in Athens, London, Lund, and Bucharest. The proportion of clinical subjects was the highest at the Medical Schools in London, Bucharest, and Genoa, and the lowest in Brussels, Dublin, and Milan. Croatian Medical Schools (Zagreb, Osijek, Split, and Rijeka) and the Medical School in Milan had the highest proportion of public health and humanistic subjects in their curricula. Neuroscience was found in less than half of the analyzed medical school curricula, and Psychology in about two-thirds. Nuclear Medicine course was found only in 7 out of 28 schools. Intensive Care, Anesthesiology, and Urology courses were found in less than half of the curricula. Two-thirds of analyzed curricula offered Primary Care course within the group of public health and humanistic courses. Epidemiology and Social Medicine courses were taught at more than half, and Anthropology at one-sixth of the medical schools.The lack of uniform curriculum in European medical schools makes mutual accreditation and mobility of students very difficult. Great deviations from the standard, ie, medical curriculum recommended by the European University Association, question the possibility of a quick medical curricula reform.