Camurati-Engelmann disease in a family from Croatian Island: an old bone scan confirmed pattern of inheritance.

34-year old patient had history of muscular wasting, easy fatigability, pain in extremities and waddling gait since age of four. During the time, neuromuscular disease was suspected, but not confirmed. Elevated bone alkaline phosphatase as well as other bone turnover markers (osteocalcin, procollagen, telopeptide) indicated further skeletal evaluation. Symmetrical enhanced uptake on technetium methylene diphosphonate [99mTc]MPD bone scintigraphy at diaphyses of longitudinal bones and scull matched cortical thickening of long bones and sclerosis of the scull seen at radiograms. Those findings pointed to Camurati-Engelmann disease misdiagnosed for the long time. This rare genetic autosomal dominant disorder was retrospectively diagnosed in asymptomatic father too on the basis of bone scans done long time ago. Old family member scans confirmed heredity pattern of the disease.

[Croatian Society of Endocrinology guidelines for the diagnosis and treatment of acromegaly]. / Smjernice Hrvatskoga endokrinoloskog drustva za dijagnostiku i lijecenje akromegalije.

The working group of the Croatian Society of Endocrinology met in September 2011 to discuss the diagnostic and therapeutic dilemmas in patients with acromegaly. The group comprised 9 pituitary specialists including endocrinologists, neurosurgeons, and medical biochemistry specialist. After a critical analysis of published scientific papers the group has developed guidelines for the diagnosis and treatment of acromegaly.

Gene expression in visceral and subcutaneous adipose tissue in overweight women.

Excess weight and obesity are common health problems with multifactorial and polygenic causes. Abdominal or visceral obesity is associated with a higher risk of obesity related complications. The aim of the study was to evaluate differentially expressed genes in visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of 10 overweight women undergoing elective laparoscopic cholecystectomy. Following expression profiling using microarrays, a set of 294 genes that exhibited differential expression between VAT and SAT was further analyzed to test the functional correlation of gene sets using the Gene Set Enrichment Analysis method. To confirm the functional pathways involved in differential expression between SAT and VAT, additional pathway analysis was done using the GeneGo MetaCore software and the Ingenuity Pathway Analysis. Ten differentially expressed genes were selected according to the microarray data, with seven exhibiting significant differential expression in the RT-PCR experiments. The data from this preliminary study suggest enrichment of inflammation and oxidative stress related pathways in VAT, while insulin homeostasis pathways as well as pathways pertaining to several growth factors are enriched in SAT.

Prevalence and five-year cumulative incidence of abdominal obesity in Croatian women of childbearing age: the CroHort study.

Generalised obesity is increasing in prevalence globally, however trends in abdominal obesity are less well known. In 2003, 1,999 women of childbearing age participated in the Croatian Adult Health Survey, of whom 598 (29.9%) participated in the second cycle in 2008. For 2008, the prevalence of abdominal obesity using the International Diabetes Federation (IDF) criterion (waist circumference > or = 80 cm) was estimated at 70.3% (95% CI 61.8% to 75.7%), whereas the prevalence of abdominal obesity using the National Cholesterol Education Program, Adult Treatment Panel III (NCEP ATP III) criterion (waist circumference > or = 88 cm) was estimated at 48.6% (42.6% to 54.7%). The preceding five-year cumulative incidence was 54.3% (44.5% to 64.2%) and 35.2% (28.0% to 42.4%) using the IDF and NCEP ATP III criteria, respectively. The burden of abdominal obesity is high and rapidly increasing in Croatian women of childbearing age, the key population subgroup for obesity control.

Simultaneous analysis of mitotane and its main metabolites in human blood and urine samples by SPE-HPLC technique.

Adrenocortical carcinoma (ACC) is a rare malignancy with an incompletely understood pathogenesis and a poor prognosis. The adrenalytic activity of mitotane has made it the most important single drug in the treatment of ACC. Unfortunately, the exact mechanism of mitotane action is still unknown. It is believed that mitotane belongs to the class of drugs that require metabolic transformation by cytochrome P450 for therapeutic action; therefore determination of plasma levels of not only mitotane but also its metabolites would help in carrying out the treatment. The objective of this work was to develop and validate an SPE-HPLC method for simultaneous determination of mitotane and its metabolites in different biological fluids. The sample preparation consisted of a solid-phase extraction on a Discovery DSC(18) cartridge, while analysis of extracts was performed on a Symmetry C(18) column. The usefulness of the proposed method was confirmed by analysis of plasma, red cell and urine samples from patient chronically treated with 1.5 g of mitotane. The patient involved in this study had a high plasma concentration of mitotane and none of the investigated metabolites were found. In order to investigate whether the polymorphism of CYP2C9 and CYP2C19 enzymes could be related to the metabolism of mitotane, RT-PCR analysis was performed.

[Visceral obesity]. / Visceralna debljina.

Some studies indicate that visceral obesity may be a better predictor of morbidity and mortality related to cardiovascular diseases and type 2 diabetes than general obesity measured by the body mass index. A causal relationship seems to exist between the accumulation of visceral fat and occurence of cardiovascular diseases and type 2 diabetes. Assessment of cardiometabolic risk comprises information on intra-abdominal obesity, as well as traditional risk factors. Visceral fat acts as a large endocrine gland, excreting cytokines and adipokines which leads to insulin resistance and proinflammatory state, whereas subcutaneous fat may act as a protective metabolic sink. Of anthropometric measures, waist circumference seems to best correlate with visceral fat.

[Vitamin D: vitamin from the past and hormone of the future]. / Vitamin D: vitamin proslosti, hormon buducnosti.

In the last decade there has been a rising recognition of potential clinical significance of the vitamin D. Vitamin D regulates about 3% of the human genome. Thus, vitamin D deficiency is common and high in various populations across the world including Croatia. In this paper vitamin D metabolism and up to date knowledge of vitamin D function in calcium metabolism, muscular function and in prevention of infection, malignancy, autoimmune and cardiovascular diseases is presented. Reasons for pandemic vitamin D deficiency and guidelines for vitamin D supplementation are given.

Monthly or weekly bisphosphonate? Evaluation of satisfaction in patients with postmenopausal osteoporosis using OPSAT-Q questionnaire during the BOOSTER study in Croatia.

A prospective, open-labelled, multicentre 6-month study was designed to assess three categories that have high impact on Health-Related Quality of Life (HR-QoL). These categories were: satisfaction, preference and drug tolerability in postmenopausal patients with osteoporosis in Croatia, at first treated with weekly oral bisphosphonates, followed by monthly oral ibandronate. Three hundred eighty-five postmenopausal women who were treated with one of the weekly bisphosphonates for at least 6 months were included into the study and after they had signed written informed consent, the therapy was changed to monthly ibandronate. Satisfaction with the treatment was assessed with the Osteoporosis Patient Satisfaction Questionnaire (OPSAT-Q). Patients completed OPSAT-Q at the baseline visit before the change of therapy (visit 1) and 6 months after the change of therapy (visit 2). Following 6 months ibandronate therapy, the values in all four domains of the OPSAT-Q (convenience, confidence with daily activities, overall satisfaction, side effects) as well as in the Composite Satisfaction Score were higher in visit 2 (p < 0.001). Values in subjects enrolled into the patient assistance programme did not differ significantly from the values in subjects that were not (p = 0.399) except for the domain convenience (p = 0.026). This study demonstrates significantly higher satisfaction in patients who switched from the weekly bisphosphonate therapy regimen to monthly ibandronate in all observed aspects of treatment. Patients expressed preference for monthly bisphosphonate (ibandronate) in comparison with weekly bisphosphonates and found it to be a more convenient method of treatment. At the time of study, however, it was not known that the anti-fracture effect of ibandronate was smaller for hip fractures than with other bisphosphonates.

Health-related quality of life and fatigue in patients with adrenal incidentaloma.

The objective of the present study was to examine several dimensions of quality of life (QoL) and fatigue in patients with adrenal incidentaloma. This was a case-control study designed to analyze patient outcomes using three validated generic QoL questionnaires, EQ-5D, SF-36, and MFI-20, the results of which were compared to those obtained for age- and sex-matched controls. The study population comprised 139 consecutive patients with nonfunctioning adrenal masses (104 females, 35 males; age 59.1 ± 10.8) and 139 age- and sex-matched controls. Reduced QoL was found in patients with adrenal incidentaloma as compared to controls. Dimensions of QoL that were notably affected included mobility (P = 0.03), performance of usual activities (P = 0.002), and anxiety/depression (P = 0.04) as evaluated using the EQ-5D; physical functioning (P < 0.001), physical role (P < 0.001), general health (P < 0.001), vitality (P = 0.001), social functioning (P = 0.001), and emotional role (P < 0.001) as evaluated using the SF-36; and physical fatigue (P = 0.04) as assessed using the MFI-20 questionnaire. In addition, perceived health on a visual analogue scale was also significantly lower in patients than in controls (64.8 ± 19.2 vs. 77.1 ± 15.1; P < 0.001). Patients with adrenal incidentaloma reported reduced QoL and a higher level of physical fatigue compared to age- and sex-matched controls. This subject will benefit from further studies comparing QoL outcomes of laparoscopic adrenalectomy versus no treatment in patients with adrenal incidentaloma.

Health-related quality of life among patients with postmenopausal osteoporosis treated with weekly and monthly bisphosphonates.

OBJECTIVE: The present study was designed to assess the effect of monthly ibandronate on health-related quality of life (HR-QoL) in patients with postmenopausal osteoporosis previously treated with weekly bisphosphonates. METHODS: HR-QoL was assessed by Euroqol (EQ-5D) and Osteoporosis Targeted Quality of Life (OPTQoL) questionnaires. RESULTS: The EQ-5D questionnaire showed significant improvement associated with ibandronate treatment, occurring in mobility (p < 0.01), usual activity (p < 0.01), pain/discomfort (p < 0.05), and anxiety/depression (p < 0.05). In addition, ibandronate treatment considerably improved patients' perceived health on a visual analog scale (p < 0.001). For the OPTQoL questionnaire, patients reported less physical difficulty (p < 0.001), fewer adaptations in their lives (p < 0.001), and less fear (p < 0.001) with ibandronate than with weekly bisphosphonates. CONCLUSION: The study demonstrated that patients who were transferred from weekly bisphosphonates to a monthly ibandronate experienced improved HR-QoL.

[Management of adrenal incidentaloma: the position statement of the Croatian referral center for adrenal gland disorders]. / Dijagnostika i lijecenje incidentaloma nadbubrezne zlijezde: preporuke referentnog centra ministarstva zdravstva za bolesti nadbubrezne zlijezde.

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.

Vitamin D status, dependence on age, and seasonal variations in the concentration of vitamin D in Croatian postmenopausal women initially screened for osteoporosis.

Vitamin D deficiency is associated with secondary hyperparathyroidism, increased bone turnover, and bone loss, leading to increased risk for osteoporotic fractures. The objective of this study was to investigate the prevalence of inadequate (insufficient or deficient) serum vitamin D levels in Croatian postmenopausal women initially screened for osteoporosis. Assessment of 25-hydroxyvitamin D (25(OH)D) was performed in 120 Croatian postmenopausal women aged > or =50 years. Three cut-off levels of vitamin D inadequacy were investigated: <75, <50, and <30 nmol/L. Among the included patients, only 14.2% of women complied with diagnostic criteria for osteoporosis. A total of nine (7.5%) had vitamin D levels greater than 75 nmol/L, suggesting that 92.5% of postmenopausal women had inadequate vitamin D status. The prevalence of two different cut-off point groups was 63.3% (<50 nmol/L) and 14.2% (<30 nmol/L). Mean (+/-SD) serum level of 25(OH)D was 46.94 (16.77) nmol/L. Vitamin D was exhibiting declining values with increasing age (r = -0.28; P = 0.002). The prevalence of vitamin D levels below 30 nmol/L was high in patient aged > or =65 years (23.8%). The highest mean level of vitamin D was detected in summer, with significant differences from spring and winter (P = 0.015 and P = 0.022, respectively). The results of this study indicate a high prevalence of vitamin D inadequacy in Croatian postmenopausal women initially screened for osteoporosis. High prevalence coupled with the rising recognition of potential clinical significance of the vitamin D inadequacy makes this highly interesting intervention target, suggesting that the attempts to increase the awareness on this issue are needed.

[Obesity as a medical and public health problem]. / Debljina, medicinski i javnozdravstveni problem.

Obesity is one of the leading public health problems. Fat tissue is an organ with intensive metabolic activity whose function is to store unused energy. At the same time, it is a gland with internal secretion which secretes cytokines (adipokines) which have an endocrine, paracrine and autocrine function. Receptors for numerous hormones and cytokines are found on adipocytes. In such a way a functional connection between fat tissue and other tissues and organs is ensured. Fat tissue is part of a system of neuroendocrine regulation of body mass and metabolism. An increase in fat tissue, especially in visceral fat tissue, leads to an increase in adipokine blood concentration, which results in changes in the functioning of distant tissues and organs with which fat tissue is hormonally linked. The consequent comprehensive changes in the metabolism are termed metabolic syndrome, and are linked with further complications. The consequences of these complications are a diminished quality of life and a rise in mortality. The treatment of obesity is a long term and often unsuccessful process. Better results of treatment are achieved by a multidisciplinary approach.

Hypercoagulability in Cushing's syndrome: the role of specific haemostatic and fibrinolytic markers.

OBJECTIVE: Hypercoagulability is a commonly described complication in patients with Cushing's syndrome. Recent clinical studies have indicated various abnormalities of coagulation and fibrinolysis parameters which may be related to that phenomenon. The aim of this study was to investigate the mechanisms underlying the hypercoagulable state in patients with Cushing's syndrome. RESEARCH METHODS AND PROCEDURES: A wide range of serum markers involved in the processes of blood coagulation and fibrinolysis was measured in a group of 33 patients with Cushing's syndrome and 31 healthy controls. No participant was taking medication which could influence the result or had known diseases, except hypertension and diabetes, which could affect blood coagulation or fibrinolysis parameters. RESULTS: Patients with Cushing's syndrome had higher levels of clotting factors II (P = 0.003), V (P < 0.001), VIII (P < 0.001), IX (P < 0.001), XI (P < 0.001) and XII (P = 0.019), protein C (P < 0.001), protein S (P < 0.001), C1-inhibitor (P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) (P = 0.004). The activity of fibrinolytic markers, plasminogen (P < 0.001), antithrombin (P < 0.001) and antithrombin antigen (P = 0.001) was also increased in the patient group. CONCLUSION: The study has demonstrated hypercoagulability in patients with Cushing's syndrome manifest as increased prothrombotic activity and compensatory activation of the fibrinolytic system. We propose the introduction of thromboprophylaxis in the preoperative and early postoperative periods, combined with a close follow-up in order to prevent possible thromboembolic events in patients with Cushing's syndrome.

Platelet serotonin concentration and monoamine oxidase activity in hypothyroid patients.

BACKGROUND/AIM: The relationship between the hypothalamic-pituitary-thyroid (HPT) axis and the serotonergic (5-hydroxytryptamine, 5-HT) system is not clear. The aim of the study was to determine platelet biochemical markers (5-HT concentration and monoamine oxidase B, MAO-B, activity) in hypothyroid patients. METHODS: The study included 25 medication-free female hypothyroid patients in postoperative follow-up after total thyroidectomy due to papillary thyroid carcinoma, who had not been treated with synthetic thyroxine (T(4)) for 4 weeks, and 44 age-matched euthyroid healthy women. The platelet 5-HT concentration, platelet MAO-B activity, total T(4) and thyroid-stimulating hormone (TSH) levels were determined using spectrofluorimetric methods, radioimmunoassay and fluoroimmunoassay, respectively. RESULTS: Hypothyroid patients had significantly higher TSH, significantly lower T(4) levels and platelet 5-HT concentrations, and unchanged platelet MAO-B activity than healthy subjects. A positive correlation was found between the 5-HT concentration and platelet MAO-B activity, and between the platelet MAO-B activity and T(4) in control subjects. CONCLUSIONS: Reduced platelet 5-HT concentrations in hypothyroid patients suggests a complex interaction between the 5-HT system and HPT axis activity, which could be related to the frequent occurrence of depressive symptoms in hypothyroid patients. The determination of platelet 5-HT concentrations should be considered a diagnostic tool for the evaluation of depressive symptoms in hypothyroid patients during the hormone withdrawal procedure.

The role of estrogen receptor-alpha gene TA polymorphism and aromatase gene TTTA polymorphism on peak bone mass attainment in males: is there an additive negative effect of certain allele combinations?

Idiopathic osteoporosis in males is influenced predominantly by low peak bone mass as a feature under a strong genetic control. Among a number of candidate genes, alpha-estrogen receptor (ERalpha) and CYP19 genes are of particular interest due to important role of estrogen in pathophysiology of osteoporosis. In the present study we examined the association of certain allelic combinations of ERalpha gene thymine-adenine (TA) polymorphism and aromatase gene TTTA polymorphism on bone mineral density (BMD) in young men. The study sample consisted of 92 unrelated healthy male volunteers, aged 21-35. In each subject, lumbar spine and proximal femur BMD, parameters of bone turnover and 25-OHD level were measured. Two ERalpha (TA)( n ) alleles, allele 19 and allele 21, were found to be associated with lower BMD. The presence of allele 19 was associated with significantly lower lumbar spine (P = 0.006) and trochanter (P = 0.02) BMD while the subjects positive for allele 21 had significantly lower lumbar spine (P = 0.04), trochanter (P = 0.02) and total hip (P = 0.03) BMD. Men with CYP19 (TTTA)(7-3)/ERalpha (TA)(19) allele combination had significantly lower lumbar spine BMD (P = 0.02) and those with CYP19 (TTTA)(7-3)/ERalpha (TA)(21) allele combination had significantly lower BMD for all three measurements, i.e. lumbar spine (P = 0.02), femoral neck (P = 0.02) and total hip (P = 0.008). These particular combinations of high-risk alleles were associated with lower median lumbar spine, femoral neck and total hip BMD than either of the allele alone suggesting that negative effect of two risk alleles on peak bone mass add up.

Proinflammatory cytokines and receptor activator of nuclear factor kappaB-ligand/osteoprotegerin associated with bone deterioration in patients with Crohn's disease.

OBJECTIVES: The high incidence of bone disease and the increasing evidence of Crohn's disease (CD) bone decline in corticosteroid users and nonusers suggest that bone metabolism is affected by inflammatory process. The aim of the study was to compare serum levels of proinflammatory cytokines, markers of bone turnover and regulatory molecules of osteoclast biogenesis, receptor activator of nuclear factor kappaB-ligand (RANKL) and osteoprotegerin (OPG), between naïve and long-standing CD patients. METHODS: The study included 95 CD patients, 15 of them with newly diagnosed and previously untreated CD. The spine and hip bone mineral density was measured by dual-energy X-ray absorptiometry. Biochemical markers were determined by immunoassay. RESULTS: Osteopenia was recorded at diagnosis in 53% of naïve patients and osteoporosis was found in 26% of long-standing CD patients. The newly diagnosed patients showed correlation between TNF-alpha and soluble RANKL (sRANKL) (r=0.5; P=0.04), and this positive relationship characterized the study population as a whole (r=0.3; P=0.003). Analysis of the OPG and sRANKL relationship showed absence of correlation in patients with healthy skeleton, whereas an inverse correlation was found in those with osteopenia (r=-0.31; P=0.033) and osteoporosis (r=-0.48; P=0.028). In naïve patients with reduced T score, the correlation between sRANKL and OPG was highly inverse (r=-0.8; P=0.02) and these patients were characterized by lower BMI, significantly higher level of proinflammatory cytokines, elevated C-reactive protein, and increased activity of free sRANKL and OPG. CONCLUSION: Bone disease that accompanies CD at diagnosis suggests that bone metabolism is affected by the underlying inflammatory process per se, as probably confirmed by our finding of the central proinflammatory cytokine TNF-alpha being strongly associated with the osteoclastogenic mediator RANKL, and inversely with bone density.

Preference for weekly and monthly bisphosphonates among patients with postmenopausal osteoporosis: results from the Croatian PROMO Study.

The PROMO (preference for once monthly bisphosphonate) Study, conducted in seven hospital centres in Croatia between June 2007 and June 2008, was designed to analyse patient preference for weekly and monthly bisphosphonates in everyday clinical practice where the significant proportion of patients are not completely satisfied with the current osteoporosis treatment. Eligible participants were women with postmenopausal osteoporosis taking weekly bisphosphonates for the last 6 months. Those who agreed to be enrolled were transferred from weekly to monthly ibandronate for the next 6 months. There was no washout period between the two treatment regimens. At the baseline, patients expressed their satisfaction with the weekly treatment. At the end of the study, all patients were asked to complete the five-question survey specially designed for this study. Study population comprised 258 participants. Among 248 patients who completed the study, 244 (98.4%) declared their preference for one of the regimens or they had no preference. Once-monthly regimen was preferred by 231 patients (94.7%), whereas once-weekly regimen was preferred by five patients (2.0%). Eight patients (3.3%) indicated no preference. Furthermore, 93.0% of patients thought that monthly dosing was more convenient. Compared to weekly regimen, monthly dosing was associated with significantly higher satisfaction with the treatment and with significantly less adverse events. In line with these data, 85.9% of patients stated improved quality of life with monthly ibandronate. In summary, the PROMO Study demonstrated strong patient preference for monthly over weekly dosing which is expected to improve suboptimal adherence to weekly bisphosphonates.

Nutrition and lifestyle in relation to bone health and body weight in Croatian postmenopausal women.

The objective was to investigate the association of nutrients and lifestyle modifiers with bone mineral density (BMD) and weight and/or body mass index (BMI) in 120 healthy Croatian postmenopausal women. The hip and spine BMD was assessed by Lunar Prodigy (GE Medical Systems). Nutrient assessment from 3-day records was analyzed using the US Department of Agriculture Food Composition Tables and the Croatian National Institute of Public Health database. Subjects were asked to record the consumption of alcohol, coffee, tea and mineral waters, the amount of salt added to foods and smoking habits, as well as involvement in recreational activities, walking and heavy housework. Spot urine samples were analyzed for calcium, magnesium, sodium, potassium and zinc and were normalized by creatinine. Alcohol showed statistically significant positive association with femur and spine BMD and its consumption was higher in subjects without osteoporosis. Urinary sodium/creatinine was significantly positively associated with femoral neck and trochanter BMD, while urinary calcium/creatinine was significantly negatively associated with trochanter, total femur and spine BMD. Consumption of mineral waters was inversely associated with weight/BMI and so were dietary fiber and magnesium. In conclusion, moderate alcohol consumption and urinary sodium were positively associated while urinary calcium was negatively associated with either hip and/or spine BMD. Mineral waters, higher fiber and magnesium intake were beneficial for weight/BMI in this population of apparently healthy Croatian women.

[Croatian Thyroid Society guidelines for rational detection of thyroid dysfunction]. / Smjernice hrvatskog drustva za stitnjacu za racionalnu dijagnostiku poremecaja funkcije stitnjace.

Thyroid dysfunction is common in the population, especially in women, and thyroid diagnostic tests are among the most often used diagnostic procedures nowadays. Many thyroid societies developed guidelines for the detection of thyroid dysfunction. An interdisciplinary team of experts from the Croatian Thyroid Society studied guidelines of other thyroid societies and international publications, and according to our tradition and clinical practice developed guidelines for rational detection of thyroid dysfunction; hypothyroidism and hyperthyroidism. The aim of these guidelines is to recommend evidence-based and rational approach to the detection of thyroid dysfunction.