Treatment of Obesity with Thyroid hormones in Europe. Data from the THESIS* Collaboration.

PURPOSE: The use of thyroid hormones (TH) to treat obesity is unsupported by evidence as reflected in international guidelines. We explored views about this practice, and associations with respondent characteristics among European thyroid specialists. METHODS: Specialists from 28 countries were invited to a survey via professional organisations. The relevant question was whether "Thyroid hormones may be indicated in biochemically euthyroid patients with obesity resistant to lifestyle interventions". RESULTS: Of 17,232 invitations 5695 responses were received (33% valid response rate; 65% women; 90% endocrinologists). Of these, 290 (5.1%) stated that TH may be indicated as treatment for obesity in euthyroid patients. This view was commoner among non-endocrinologists (8.7% vs. 4.7%, p < 0.01), private practice (6.5% vs. 4.5%, p < 0.01), and varied geographically (Eastern Europe, 7.3%; Southern Europe, 4.8%; Western Europe, 2.7%; and Northern Europe, 2.5%). Respondents from Northern and Western Europe were less likely to use TH than those from Eastern Europe (p < 0.01). Gross national income (GNI) correlated inversely with this view (OR 0.97, CI: 0.96-0.97; p < 0.001). Having national guidelines on hypothyroidism correlated negatively with treating obesity with TH (OR 0.71, CI: 0.55-0.91). CONCLUSIONS: Despite the lack of evidence, and contrary to guidelines' recommendations, about 5% of respondents stated that TH may be indicated as a treatment for obesity in euthyroid patients resistant to life-style interventions. This opinion was associated with (i) respondent characteristics: being non-endocrinologist, working in private practice, treating a small number of hypothyroid patients annually and (ii) national characteristics: prevalence of obesity, Eastern Europe, low GNI and lack of national hypothyroidism guidelines.

Rabies in the world and the Zero by 30 strategy.

Rabies is a viral disease that occurs in more than 150 countries worldwide. According to the World Health Organisation, this zoonotic disease causes an estimated 59 000 human deaths each year, with 95% occuring in Africa and Asia. The most common route of transmission is through the bite of an infected dog. The disease is preventable by vaccination, and effective prophylaxis is also available after animal bite injury. However, if the patient develops clinical signs, the disease is almost always fatal. The aim of this brief report is to summarise information on the global impact of rabies and to present the Zero by 30 strategy, which aims to achieve the elimination of human deaths due to rabies transmission from infected dogs by 2030.

Current trends in the epidemiology of malaria.

Malaria is one of the worlds most important infectious diseases, occurring in many tropical and subtropical countries. The causative agent is a parasitic protozoan of the genus Plasmodium, transmitted to humans by infected mosquitoes. More than 200 million people get malaria every year worldwide, and hundreds of thousands of them, mostly children under 5 years of age, die of it. Thanks to prevention programmes implemented by various organisations headed by the World Health Organisation (WHO) with the aim of eliminating malaria, cases have been declining in recent years. However, particularly in African countries, malaria continues to be a health and economic issue.

Point-of-care ultrasound in internal medicine: A position paper by the ultrasound working group of the European federation of internal medicine.

Point-of-care ultrasound (POCUS) is increasingly used to assess medical patients. It has many uses in daily clinical practice, including improved diagnostic timeliness and accuracy, and providing information about a patient's prognosis and follow-up. It has been integrated into numerous specialities, but remains relatively undefined in internal medicine training programs. Ultrasonography is a useful tool in the standard clinical practice of internists in numerous clinical scenarios (Emergency Department, hospital ward, general and specific consultations, and home care). Although POCUS has been recently included in the European curriculum of internal medicine, there are differences between European internists in its use, ranging from not at all to well structured educational programs. The use of POCUS needs to be widespread in internal medicine departments, and to accomplish this we must encourage structured training. This document details the consensus-based recommendations by the European Federation of Internal Medicine (EFIM) Ultrasound working group. We establish POCUS core competencies and clinical settings for internists in a symptom-based approach. We also propose training requirements, providing a framework for training programs at a national level.

Insulin-like growth factor axis in pregnancy and gestational diabetes mellitus.

The insulin-like growth factor (IGF) is involved in the regulation of growth and metabolism. The aim of this study was to determine selected parameters of IGF system at systemic and local levels [subcutaneous (SAT) and visceral adipose tissue (VAT)] to assess its possible role in gestational diabetes mellitus (GDM). 37 pregnant women (21 with GDM and 16 without GDM) and 15 age-matched non-pregnant females were included in the study. Blood samples were taken in 28-32 and 36-38 weeks of gestation and 6-12 months after delivery. SAT and VAT samples were obtained during delivery or surgery. Compared with non-pregnant women, serum IGF-1 and IGFBP-3 were increased in both groups of pregnant women. IGF-2 was elevated only in GDM women from 36 weeks of gestation culminating 6 months after delivery (p=0.003). Serum IGFBP-3 was increased and IGFBP-4 decreased in GDM women vs. pregnant women without GDM during the whole study (IGFBP-3: p?0.001 for GDM vs. non-GDM; IGFBP-4: p=0.004 for GDM vs. non-GDM). Pregnant women with GDM had decreased mRNA expression of IGF-1, IGF-1R and IGF-2R and IGFBP-4 in VAT and IGF-1R in SAT compared to pregnant women without GDM. Changes in local activity of IGF are associated with the development of GDM.

Changes in plasma concentrations and mRNA expression of hepatokines fetuin A, fetuin B and FGF21 in physiological pregnancy and gestational diabetes mellitus.

We measured plasma concentrations, adipose tissue and placental mRNA expression of hepatokines fetuin A, fetuin B and fibroblast growth factor 21 (FGF21) in 12 healthy pregnant women (P group), 12 pregnant women with gestational diabetes (GDM) and 10 healthy non-pregnant women (N group) to explore their potential role in the etiopathogenesis of GDM. GDM and P group had comparable BMI, C-reactive protein (CRP) and glycated hemoglobin levels while IL-10 and TNF-alpha levels were higher in GDM group. Fetuin A and fetuin B levels were higher in pregnancy as compared to N group and decreased after delivery with no apparent influence of GDM. In contrast, the pattern of changes of circulating FGF21 levels differed between GDM and P group. Fetuin A concentrations positively correlated with CRP, TNF-alpha mRNA expression in adipose tissue and IL-6 mRNA expression in placenta. Fetuin B positively correlated with CRP. FGF21 levels correlated positively with IFN-gamma mRNA in adipose tissue and inversely with IL-8 mRNA in the placenta. Taken together, fetuin A and fetuin B levels were increased during pregnancy regardless of the presence of GDM. In contrast, FGF21 patterns differed between healthy pregnant women and GDM patients suggesting a possible role of this hepatokine in the etiopathogenesis of GDM.

Pitfalls in screening for gestational diabetes in the Czech Republic - patient survey.

OBJECTIVE: The aim of our survey was to investigate gestational diabetes (GDM) screening policy in the Czech Republic with regards to the correct methodology of the screening. MATERIALS AND METHODS: 1100 anonymous questionnaires were distributed among patients of a tertiary level obstetric department from July 2015 to September 2015. RESULTS: 958 (87.0%) questionnaires were found eligible for analysis. 794 (82.9%) of participants had at least one risk factor for GDM development. The oGTT was performed in 751 (94.6%) women at risk of GDM and 153 (93.3%) women at low risk of GDM. From the 904 performed oGTT, 154 (17.0%) were performed completely by recommended standards. In the remaining cases, at least one deviation from standard was noted. The results of oGTT were provided by 364 (40.3%) of respondents. In this subgroup, 71 (19.5%) matched International Association of Diabetes in Pregnancy Study Groups (IADPSG) criteria for GDM diagnosis. However, these women were often not those who were evaluated as screening positive by the office gynaecologist. CONCLUSION: The screening for GDM was frequently not performed in accordance with the national guidelines and the diagnostic criteria used were not uniform.

Can the gold standard be beaten? How reliable are various modifications of the Synacthen test compared to the insulin tolerance test.

Criteria for the evaluation of the insulin tolerance test (ITT) and Synacthen test are still a matter of debate. The objective of the study was to make a comparison of serum and salivary cortisol during four stimulation tests. Sixty four healthy volunteers underwent the ITT, the Synacthen test with 1 (LDST), 10 (MDST) and 250 (HDST) microg dose of ACTH. Maximum serum cortisol response was observed at the 90 min of the ITT (49 %), HDST (89 %) and MDST (56 %) and at the 40 min of the LDST (44 %). Results expressed as 95 % confidence intervals: 408.0-843.6 and 289.5-868.1 nmol/l in the IIT at 60 and 90 min. In the HDST and the MDST serum cortisol reached the maximum at 90 min 542.6-1245.5 and 444.2-871.3 nmol/l. Levels of salivary cortisol followed the same pattern as serum cortisol. Salivary cortisol reached the maximum response in the HDST and the MDST at 90 min and at 40 min in the LDST. We confirmed good reliability of all tests with respect to timing of response and maximum response compared to the ITT. We proved that the MDST test can provide the similar response in serum cortisol to the HDST. Measuring either salivary cortisol or ACTH levels did not provide any additional benefit then measuring serum cortisol by itself.

The effect of very-low-calorie diet on mitochondrial dysfunction in subcutaneous adipose tissue and peripheral monocytes of obese subjects with type 2 diabetes mellitus.

Mitochondrial dysfunction is a potentially important player in the development of insulin resistance and type 2 diabetes mellitus (T2DM). We investigated the changes of mRNA expression of genes encoding main enzymatic complexes of mitochondrial respiratory chain in subcutaneous adipose tissue (SCAT) and peripheral monocytes (PM) of 11 subjects with simple obesity (OB), 16 obese patients with T2DM and 17 healthy lean subjects (C) before and after very low-calorie diet (VLCD) using quantitative real time PCR. At baseline in SCAT, both T2DM and OB group had decreased mRNA expression of all investigated mitochondrial genes with the exception of 2 complex I (NDUFA 12) and complex IV (COX 4/1) enzymes in OB subjects. In contrast, in PM only the expression of complex I enzymes NDUFA 12 and MT-ND5 was reduced in both T2DM and OB subjects along with decreased expression of citrate synthase (CS) in T2DM group. Additionally, T2DM subjects showed reduced activity of pyruvate dehydrogenase and complex IV in peripheral blood elements. VLCD further decreased mRNA expression of CS and complex I (NT-ND5) and II (SDHA) enzymes in SCAT and complex IV (COX4/1) and ATP synthase in PM of T2DM group, while increasing the activity of complex IV in their peripheral blood elements. We conclude that impaired mitochondrial biogenesis and decreased activity of respiratory chain enzymatic complexes was present in SCAT and PM of obese and diabetic patients. VLCD improved metabolic parameters and ameliorated mitochondrial oxidative function in peripheral blood elements of T2DM subjects but had only minor and inconsistent effect on mitochondrial gene mRNA expression in SCAT and PM.

The possible role of mRNA expression changes of GH/IGF-1/insulin axis components in subcutaneous adipose tissue in metabolic disturbances of patients with acromegaly.

We explored the effect of chronically elevated circulating levels of growth hormone (GH)/insulin-like-growth-factor-1 (IGF-1) on mRNA expression of GH/IGF-1/insulin axis components and p85alpha subunit of phosphoinositide-3-kinase (p85alpha) in subcutaneous adipose tissue (SCAT) of patients with active acromegaly and compared these findings with healthy control subjects in order to find its possible relationships with insulin resistance and body composition changes. Acromegaly group had significantly decreased percentage of truncal and whole body fat and increased homeostasis model assessment-insulin resistance (HOMA-IR). In SCAT, patients with acromegaly had significantly increased IGF-1 and IGF-binding protein-3 (IGFBP-3) expression that both positively correlated with serum GH. P85alpha expression in SCAT did not differ from control group. IGF-1 and IGFBP-3 expression in SCAT were not independently associated with percentage of truncal and whole body fat or with HOMA-IR while IGFBP-3 expression in SCAT was an independent predictor of insulin receptor as well as of p85alpha expression in SCAT. Our data suggest that GH overproduction in acromegaly group increases IGF-1 and IGFBP-3 expression in SCAT while it does not affect SCAT p85alpha expression. Increased IGF-1 or IGFBP-3 in SCAT of acromegaly group do not appear to contribute to systemic differences in insulin sensitivity but may have local regulatory effects in SCAT of patients with acromegaly.

Response of cortisol metabolites in the insulin tolerance test and Synacthen tests.

Determination of response of cortisol and its metabolites to different stimuli may be important for adrenal gland disorders. To date, only one metabolite, cortisone, has been followed in stimulation tests of the adrenal gland. We aimed to describe a response of cortisol metabolites to the standard short Synacthen test (HDST), insulin tolerance test (ITT), low dose Synacthen test (LDST) and medium dose Synacthen test (MDST). Sixty healthy subjects were investigated: 30 men and 30 women. Plasma for measurements of cortisol and its metabolites was obtained before and 30th and 60th min after Synacthen and insulin administration. The cut-off 500 nmol/l of cortisol was reached after stimulation in all of tests, the maximal stimulation level was reached in 60th min in all of the tests except for LDST. The response of cortisol and its metabolites at 30th and 60th min strongly correlated in all of the tests except for LDST. Cortisol and its metabolites increased after stimulation; in contrast, cortisone and its metabolites decreased. We showed that the response of the cortisol metabolites during the Synacthen tests and ITT well correlated, and the MDST showed similar response compared to HDST. The decrease in cortisone metabolites may correspond to the regeneration of cortisol from cortisone in response to stimulation test.

Biochemical Testing After Pheochromocytoma Removal: How Early?

Pheochromocytomas are catecholamine-producing tumors with typical clinical presentation. Tumor resection is considered as an appropriate treatment strategy. Due to its unpredictable clinical behavior, biochemical testing is mandatory to confirm the success of tumor removal after surgery. The aim of the study was to investigate the feasibility of a shorter interval of postoperative testing (earlier than the recommended 2-4 weeks according to recently published Guidelines). We investigated 81 patients with pheochromocytoma before and after surgery. Postoperative examination was performed of stable subjects after their transport from the surgical to the internal ward (7.1±2.2 days after surgery). Plasma metanephrines were used for the diagnosis of pheochromocytoma and confirmation of successful tumor removal. All subjects with pheochromocytoma had markedly elevated plasma metanephrines before surgery. No correlation between postoperative interval (the shortest being 3 days) and plasma metanephrine levels was found. Postoperative plasma metanephrine levels did not differ significantly from those taken at the one-year follow-up. In conclusion, we have shown that early postoperative diagnostic workup of subjects with pheochromocytoma is possible and may thus simplify early postoperative management of this clinical condition.

Prediction of adrenocortical insufficiency after pituitary adenoma surgery using postoperative basal cortisol levels.

Our aim was to analyze the correlation of early postoperative cortisol levels in patients after transsphenoidal pituitary adenoma surgery compared to the standard dose ACTH test and Insulin tolerance test (ITT) several months later. We retrospectively reviewed data from 94 patients operated for pituitary adenoma in years 2009-2012. The comparison of day 7 (median) postoperative basal cortisol levels and 3.6 months (median) after pituitary adenoma surgery stimulation test - standard dose 250 microg 1-24ACTH test in 83 patients or ITT in 11 patients were performed. All 16 patients with early postoperative cortisol levels >500 nmol/l proved a sufficient response in the stimulation tests. At basal cortisol levels of 370-500 nmol/l the sufficient response was found in 96 % (27/28) of patients. In the postoperative basal cortisol levels 200-370 nmol/l we found a preserved corticotroph axis later on in 88 % (28/32) of cases. Patients with basal cortisol levels 100-200 nmol/l had a maintained corticotroph axis function in 8/11 cases - 73 %. All patients with an early postoperative basal cortisol level above 500 nmol/l proved in the stimulation tests a preserved corticotroph axis function. The interval 370-500 nmol/l showed a minimal risk of postoperative adrenal insufficiency.

Serum cortisol seems to be a more appropriate marker for adrenocortical reserve evaluation in ACTH test in comparison to salivary cortisol.

Salivary cortisol reflects the free fraction of serum cortisol. Monitoring salivary cortisol may be a promising alternative method for assessing serum cortisol in some clinical situations. We aimed to compare the reliability of salivary vs. serum cortisol during ACTH test. 84 subjects (mean age 63.2; 24-89 years; n=66 males) suspected for adrenocortical insufficiency underwent an ACTH test. Patients were divided based on peak serum cortisol into hypocortical group with cortisol <500 nmol/l and to reference group cortisol >500 nmol/l. Median serum cortisol levels in reference group were 445, 766, and 902 nmol/l at 0, 30, and 60 minutes, respectively, and in hypocortical group were 256, 394, and 453 nmol/l. Median salivary cortisol levels were 19.02, 40.02, and 62.1 nmol/l in reference group, and 9.60, 14.08, and 13.28 nmol/l in hypocortical group. Obtained values showed good correlation between serum and salivary cortisol (p<0.0001). The percentage of explained variability R(2) (coefficient of determination for linear model) representing a measure of agreement between experimental values and predictions for repeated measures ANOVA, was significantly higher (p=0.021) for serum cortisol (R2=93.4 %) when compared to the salivary cortisol (R2=89.3 %). A stronger discriminating power of serum versus salivary cortisol suggests that it seems to be slightly, but statistically significantly more appropriate marker of adrenocortical reserve in ACTH test.

[Recommendation of the Czech Society of Endocrinology for the treatment of Cushing's syndrome in adults]. / Doporucení Ceské endokrinologické spolecnosti pro lécbu Cushingova syndromu v dospelosti.

Cushing's syndrome is a rare disorder with variable aetiology which is connected with significantly increased morbidity and mortality. Therefore, early determination of correct aetiology and early treatment are essential for a decrease of morbidity and mortality of patients. Present article introduces review and current recommendation of Czech Society of Endocrinology for the treatment of Cushings syndrome.

High incidence of cardiovascular complications in pheochromocytoma.

Excess of catecholamines in pheochromocytoma is usually accompanied with classical symptoms and signs. In some cases, severe cardiovascular complications (e. g., heart failure, myocardial infarction) may occur. We performed a retrospective analysis focused on the incidence of cardiovascular complications (classified as follows: arrhythmias, myocardial involvement or ischemia and atherosclerosis, cerebrovascular impairment) before the establishment of diagnosis of pheochromocytoma among 145 subjects treated in our hospital. Cardiovascular complications occurred in 28 subjects, but these subjects did not differ significantly from subjects without complications in age, gender, body mass index, paroxysmal symptoms, symptom duration, tumor dimension, catecholamine secretory phenotype, and incidence of hypertension or diabetes mellitus. Arrhythmias occurred in 15 subjects (2 arrhythmia types in 2 subjects): atrial fibrillation in 9 subjects, supraventricular tachycardia in 3 cases, and ventricular tachycardia in 2 patients. Significant bradycardia was noted in 3 cases. Five subjects presented with heart failure with decreased systolic function (takotsubo-like cardiomyopathy found in 2 cases). One subject suffered from hypertrophic obstructive cardiomyopathy. Seven subjects presented with non-ST-segment elevation myocardial infarction, 2 patients with ST-segment myocardial infarction, and 1 subject underwent coronary artery bypass grafting. Two subjects suffered from significant peripheral atherosclerosis. Among cerebrovascular complications, transient ischemic attack was found in 3 cases, 2 subjects suffered from stroke, and subarachnoidal bleeding occurred in 1 patient. One subject suffered from diffuse neurological impairment due to multiple ischemic white matter lesions. These data show relatively high incidence of cardiovascular complications (19.3%) in subjects with pheochromocytoma. Early diagnosis is mandatory to prevent severe complications in pheochromocytoma.

Hypothalamo-pituitary dysfunction in patients with chronic subdural hematoma.

Relatively frequent pituitary hormone deficiencies are observed after traumatic brain injury (TBI) and subarachnoid hemorrhage (SAH) and according to the published studies the neuroendocrine consequenses of traumatic brain injury are underdiagnosed. In a cohort of 59 patients (49 males, mean age 68.3 years, 36-88 years) after evacuation of subdural hematoma (SDH) were evaluated hypothalamo-pituitary functions one week after surgery, after three months and after one year. Hypogonadism was present in 26 % of patients in an acute phase, but in the majority had a transient character. Less than half of patients was GH deficient (GHD) according to the GHRH+arginine test. We did not find any serious case of hypocortisolism, hypothyroidism, diabetes insipidus centralis nor syndrome of inappropriate secretion of ADH (SIADH). Transient partial hypocortisolism was present in two cases, but resolved. We did not find relation between extension of SDH or clinical severity and development of hypopituitarism. In conclusion, in some patients with SDH growth hormone deficiency or hypogonadism was present. No serious hypocortisolism, hypothyroidism, diabetes insipidus nor SIADH was observed. The possibility of neuroendocrine dysfunction should be considered in patients with SDH, although the deficits are less frequent than in patients after TBI or SAH.

Plasma concentrations of adipocyte fatty acid binding protein in patients with Cushing's syndrome.

Serum adipocyte fatty acid-binding protein (FABP-4) concentrations are linked to human obesity and other features of metabolic syndrome. Patients with Cushing´s syndrome (CS) develop numerous features of metabolic syndrome due to chronic cortisol excess. Here we tested the hypothesis that chronically increased cortisol levels in CS patients may alter circulating levels of FABP-4. Fourteen patients with CS, 19 patients with simple obesity (OB) and 36 healthy control subjects (C) were included in the study. Serum FABP-4 concentrations were significantly higher in both CS and OB patients relative to C group, but they did not differ between CS and OB groups. In a combined population of all groups, serum FABP-4 levels correlated positively with BMI, body fat content, serum glucose, triglycerides, HbA1c and HOMA index and were inversely related to HDL-cholesterol, resting energy expenditure and freeT3 levels. We conclude that FABP-4 levels are significantly increased in both patients with simple obesity and obese patients with Cushing´s syndrome. We suggest that increased FABP-4 concentrations in CS patients are rather due to their excessive fat accumulation and related metabolic abnormalities than due to a direct effect of cortisol on FABP-4 production.

Plasma concentrations of fibroblast growth factors 21 and 19 in patients with Cushing's syndrome.

The objective of this study was to measure plasma fibroblast growth factor 21 and 19 (FGF21 and FGF19) levels in patients with Cushing's syndrome (CS) and to compare it with those of lean control subjects (C) and patients with obesity (OB). Fourteen untreated patients with CS, 19 patients with OB and 36 controls were included in the study. Plasma FGF21 and FGF19 levels were measured by ELISA kits, other hormonal and biochemical parameters were measured by standard laboratory methods. Plasma FGF19 did not significantly differ among the studied groups. Plasma FGF21 levels were significantly higher in both CS and OB groups relative to C group but they did not differ between CS and OB groups. In a combined population of all three groups FGF21 levels positively correlated with BMI, waist circumference and percentage of total and truncal fat mass. Less prominent inverse relationship with these parameters was found for FGF19. Neither FGF21 nor FGF19 were significantly related to cortisol concentrations. Increased FGF21 concentrations in both patients with CS and OB relative to lean subjects suggest that excessive body fat and/or related metabolic abnormalities rather than direct effects of cortisol are responsible. In contrast neither obesity nor hypercortisolism significantly affected FGF19 concentrations.