Vitamin D deficiency (serum 25-hydroxyvitamin D (25(OH)D) < 50 nmol/l or 20 ng/ml), is common in Europe and the Middle East. It occurs in < 20 % of the population in Northern Europe, in 30-60% in Western, Southern and Eastern Europe and up to 80 % in Middle East countries. Severe deficiency (serum 25(OH)D < 30 nmol/l or 12 ng/ml) is found in > 10 % of Europeans. The ECTS advises that the measurement of serum 25(OH)D be standardized e.g. by the Vitamin D Standardization Program. Risk groups include young children, adolescents, pregnant women, older people, especially the institutionalized, and non-western immigrants. Consequences of vitamin D deficiency include mineralization defects and lower bone mineral density causing fractures. Extra-skeletal consequences may be muscle weakness, falls and acute respiratory infection, and are the subject of large ongoing clinical trials. The ECTS advises to improve vitamin D status by food fortification and the use of vitamin D supplements in risk groups. Fortification of foods by adding vitamin D to dairy products, bread and cereals can improve the vitamin D status of the whole population, but quality assurance monitoring is needed to prevent intoxication. Specific risk groups such as infants and children up to 3 years, pregnant women, older persons and non-western immigrants should routinely receive vitamin D supplements. Future research should include genetic studies to better define individual vulnerability for vitamin D deficiency, and Mendelian randomization studies to address the effect of vitamin D deficiency on long term non-skeletal outcomes such as cancer.
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Paul Lips, Kevin D Cashman, Cje Lamberg-Allardt, Heike Annette Bischoff-Ferrari, Barbara R Obermayer-Pietsch, Ml Bianchi, Jan Stepan, Ghada El-Hajj Fuleihan and Roger Bouillon
Aliya A Khan, Bart Clarke, Lars Rejnmark and Maria Luisa Brandi
Review calcium homeostasis in pregnancy and provide evidence-based best practice recommendations for the management of hypoparathyroidism in pregnancy.
We searched MEDLINE, EMBASE and Cochrane databases from January 2000 to April 1, 2018. A total of 65 articles were included in the final review.
During pregnancy, calcitriol levels increase by two- to—three-fold resulting in enhanced intestinal calcium absorption. The renal filtered calcium load increases leading to hypercalciuria. PTHrP production by the placenta and breasts increases by three-fold, and this may lower the doses of calcium and calcitriol required during pregnancy in mothers with hypoparathyroidism. The literature however describes a wide variation in the required doses of calcium and calcitriol during pregnancy in hypoparathyroid mothers, with some women requiring higher doses of calcitriol, whereas others require lower doses. Close monitoring is necessary as hypercalcemia in the mother may suppress the fetal parathyroid gland development. Also hypocalcemia in the mother is harmful as it may result in secondary hyperparathyroidism in the fetus. This may be associated with demineralization of the fetal skeleton and the development of intrauterine fractures. Inadequate treatment of hypoparathyroidism may also result in uterine contractions and an increased risk of miscarriage. Treatment targets during pregnancy are to maintain a low normal serum calcium. Calcium, calcitriol and vitamin D supplements are safe during pregnancy. Close monitoring of the mother with a multidisciplinary team is advised for optimal care. If calcium homeostasis is well controlled during pregnancy, most women with hypoparathyroidism have an uncomplicated pregnancy and give birth to healthy babies.
Julia Morera and Yves Reznik
The strategy for diagnosis of primary aldosteronism (PA) in the hypertensive population includes firstly a screening step, based on the measurement of plasma aldosterone-to-renin ratio (ARR), a test which must have high sensitivity, and secondly a confirmatory step based on the demonstration of excessive aldosterone production independent of the renin-angiotensin-aldosterone system (RAAS) activity. The high proportion of false-positive ARR results and conversely of actual PA without a persistent elevation in baseline plasma aldosterone concentration necessitates the addition of a confirmatory step in the work-up of PA diagnosis. The present review focuses on the description of the different dynamic tests available for demonstrating autonomy of aldosterone secretion, on the performance and limitations of confirmatory tests and on possible strategies for PA diagnosis which may either include or avoid the confirmatory step for PA diagnosis. Large prospective studies comparing different strategies with and without dynamic testing are mandatory to delineate clearly the role and limits of confirmatory tests in the work-up of PA.
Konstantinos Kalafatakis, Georgina M Russell and Stafford L Lightman
Glucocorticoids are a class of systematically secreted hormones, vital for mammalian life, which are intensively investigated for more than 80 years. They regulate multiple body processes like metabolism, fluid homeostasis, immune and stress system responsivity, as well as brain function. Glucocorticoids have a complex rhythm by which they are released to circulation from the adrenal cortex. The hormone exhibits a circadian variation, with high hormonal levels being secreted just prior and during the active part of the day, and progressively lower and lower amounts being released during the inactive part of it. Underlying this diurnal variation there is a more dynamic, ultradian rhythm composed of frequent episodes of glucocorticoid secretion (hormonal pulses). Accumulating evidence from observational, in silico, in vitro and in vivo, preclinical and clinical studies suggest that both aspects of glucocorticoid rhythmicity are preserved among mammalian species and are important for brain function. The central nervous system is exposed to both aspects of the hormonal rhythm and has developed mechanisms able to perceive them and translate them to differential cellular events, genomic and non-genomic. Thus, glucocorticoid rhythmicity regulates various physiological neural and glial processes, under baseline and stressful conditions, and hormonal dysrhythmicity has been associated with cognitive and behavioural defects. This raises a number of clinical implications concerning (i) glucocorticoid involvement in neuropsychiatric disease and (ii) improving the therapeutic efficacy or expanding the role of glucocorticoid-based treatments in such conditions.
Sophie Schweitzer, Meik Kunz, Max Kurlbaum, Johannes Vey, Sabine Kendl, Timo Deutschbein, Stefanie Hahner, Martin Fassnacht, Thomas Dandekar and Matthias Kroiss
Current workup for the pre-operative distinction between frequent adrenocortical adenomas (ACAs) and rare but aggressive adrenocortical carcinomas (ACCs) combines imaging and biochemical testing. We here investigated the potential of plasma steroid hormone profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS) for the diagnosis of malignancy in adrenocortical tumors.
Retrospective cohort study of prospectively collected EDTA-plasma samples in a single tertiary reference center.
Steroid hormone profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS) in random plasma samples and logistic regression modeling.
Fifteen steroid hormones were quantified in 66 ACAs (29 males; M) and 42 ACC (15 M) plasma samples. Significantly higher abundances in ACC vs ACA were observed for 11-deoxycorticosterone, progesterone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, DHEAS and estradiol (all P < 0.05). Maximal areas under the curve (AUC) for discrimination between ACA and ACC for single analytes were only 0.76 (estradiol) and 0.77 (progesterone), respectively. Logistic regression modeling enabled the discovery of diagnostic signatures composed of six specific steroids for male and female patients with AUC of 0.95 and 0.94, respectively. Positive predictive values in males and females were 92 and 96%, negative predictive values 90 and 86%, respectively.
This study in a large adrenal tumor patient cohort demonstrates the value of plasma steroid hormone profiling for diagnosis of ACC. Application of LC-MS/MS analysis and of our model may facilitate diagnosis of malignancy in non-expert centers. We propose to continuously evaluate and improve diagnostic accuracy of LC-MS/MS profiling by applying machine-learning algorithms to prospectively obtained steroid hormone profiles.
Paloma Almeda-Valdes, Donaji V Gómez Velasco, Olimpia Arellano Campos, Omar Yaxmehen Bello-Chavolla, Magdalena del Rocío Sevilla-González, Tannia Viveros Ruiz, Alexandro J Martagón Rosado, Claudia J Bautista, Liliana Muñoz Hernandez, Ivette Cruz-Bautista, Hortensia Moreno-Macias, Alicia Huerta-Chagoya, Karen Guadalupe Rodríguez-Álvarez, Geoffrey A Walford, Suzanne B R Jacobs, Luz E Guillen Pineda, Ma Luisa Ordoñez-Sánchez, Ernesto Roldan-Valadez, Joaquín Azpiroz, Jannette Furuzawa-Carballeda, Patricia Clark, Miguel F Herrera-Hernández, Elena Zambrano, Jose C Florez, María Teresa Tusié Luna and Carlos A Aguilar-Salinas
A haplotype at chromosome 17p13 that reduces expression and function of the solute carrier transporter SLC16A11 is associated with increased risk for type 2 diabetes in Mexicans. We aim to investigate the detailed metabolic profile of SLC16A11 risk haplotype carriers to identify potential physiological mechanisms explaining the increased type 2 diabetes risk.
We evaluated carriers (n = 72) and non-carriers (n = 75) of the SLC16A11 risk haplotype, with or without type 2 diabetes. An independent sample of 1069 subjects was used to replicate biochemical findings. The evaluation included euglycemic–hyperinsulinemic clamp, frequently sampled intravenous glucose tolerance test (FSIVGTT), dual-energy X-ray absorptiometry (DXA), MRI and spectroscopy and subcutaneous abdominal adipose tissue biopsies.
Fat-free mass (FFM)-adjusted M value was lower in carriers of the SLC16A11 risk haplotype after adjusting for age and type 2 diabetes status (β = −0.164, P = 0.04). Subjects with type 2 diabetes and the risk haplotype demonstrated an increase of 8.76 U/L in alanine aminotransferase (ALT) (P = 0.02) and of 7.34 U/L in gamma-glutamyltransferase (GGT) (P = 0.05) compared with non-carriers and after adjusting for gender, age and ancestry. Among women with the risk haplotype and normal BMI, the adipocyte size was higher (P < 0.001).
Individuals carrying the SLC16A11 risk haplotype exhibited decreased insulin action. Higher serum ALT and GGT levels were found in carriers with type 2 diabetes, and larger adipocytes in subcutaneous fat in the size distribution in carrier women with normal weight.
S Asioli, A Righi, M Iommi, C Baldovini, F Ambrosi, F Guaraldi, M Zoli, D Mazzatenta, M Faustini-Fustini, P Rucci, C Giannini and M P Foschini
Objective and design
A clinicopathological score has been proposed by Trouillas et al. to predict the evolution of pituitary adenomas. Aim of our study was to perform an independent external validation of this score and identify other potential predictor of post-surgical outcome.
The study sample included 566 patients with pituitary adenomas, specifically 253 FSH/LH-secreting, 147 GH-secreting, 85 PRL-secreting, 72 ACTH-secreting and 9 TSH-secreting tumours with at least 3-year post-surgical follow-up.
In 437 cases, pituitary adenomas were non-invasive, with low (grade 1a: 378 cases) or high (grade 1b: 59 cases) proliferative activity. In 129 cases, tumours were invasive, with low (grade 2a: 87 cases) or high (grade 2b: 42 cases) proliferative activity. During the follow-up (mean: 5.8 years), 60 patients developed disease recurrence or progression, with a total of 130 patients with pituitary disease at last follow-up. Univariate analysis demonstrated a significantly higher risk of disease persistence and recurrence/progression in patients with PRL-, ACTH- and FSH/LH-secreting tumours as compared to those with somatotroph tumours, and in those with high proliferative activity (grade 1b and 2b) or >1 cm diameter. Multivariate analysis confirmed tumour type and grade to be independent predictors of disease-free-survival. Tumour invasion, Ki-67 and tumour type were the only independent prognostic factors of disease-free survival.
Our data confirmed the validity of Trouillas’ score, being tumour type and grade independent predictors of disease evolution. Therefore, we recommend to always consider both features, together with tumour histological subtype, in the clinical setting to early identify patients at higher risk of recurrence.
S R Ali, J Bryce, M Cools, M Korbonits, J G Beun, D Taruscio, T Danne, M Dattani, O M Dekkers, A Linglart, I Netchine, A Nordenstrom, A Patocs, L Persani, N Reisch, A Smyth, Z Sumnik, W E Visser, O Hiort, A M Pereira, S F Ahmed and on behalf of Endo-ERN
To identify cross-border international registries for rare endocrine conditions that are led from Europe and to understand the extent of engagement with these registries within a network of reference centres (RCs) for rare endocrine conditions.
Database search of international registries and a survey of RCs in the European Reference Network for rare endocrine conditions (Endo-ERN) with an overall response rate of 82%.
Of the 42 conditions with orphacodes currently covered within Endo-ERN, international registries exist for 32 (76%). Of 27 registries identified in the Orphanet and RD-Connect databases, Endo-ERN RCs were aware of 11 (41%). Of 21 registries identified by the RC, RD-Connect and Orphanet did not have a record of 10 (48%). Of the 29 glucose RCs, the awareness and participation rate in an international registry was highest for rare diabetes at 75 and 56% respectively. Of the 37 sex development RCs, the corresponding rates were highest for disorders of sex development at 70 and 52%. Of the 33 adrenal RCs, the rates were highest for adrenocortical tumours at 68 and 43%. Of the 43 pituitary RCs, the rates were highest for pituitary adenomas at 43 and 29%. Of the 31 genetic tumour RCs, the rates were highest for MEN1 at 26 and 9%. For the remaining conditions, awareness and participation in registries was less than 25%.
Although there is a need to develop new registries for rare endocrine conditions, there is a more immediate need to improve the awareness and participation in existing registries.
Panagiotis Anagnostis, Konstantinos Christou, Aikaterini-Maria Artzouchaltzi, Nifon K Gkekas, Nikoletta Kosmidou, Pavlos Siolos, Stavroula A Paschou, Michael Potoupnis, Eustathios Kenanidis, Eleftherios Tsiridis, Irene Lambrinoudaki, John C Stevenson and Dimitrios G Goulis
Menopausal transition has been associated with a derangement of glucose metabolism. However, it is not known if early menopause (EM, defined as age at menopause <45 years) or premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with increased risk of type 2 diabetes mellitus (T2DM). To systematically investigate and meta-analyze the best evidence regarding the association of age at menopause with the risk of T2DM.
A comprehensive search was conducted in PubMed, CENTRAL and Scopus, up to January 31, 2018. Data are expressed as odds ratio (OR) with 95% confidence intervals (CI). The I 2 index was employed for heterogeneity.
Thirteen studies were included in the qualitative and quantitative analysis (191 762 postmenopausal women, 21 664 cases with T2DM). Both women with EM and POI were at higher risk of T2DM compared with those of age at menopause of 45–55 years (OR: 1.15, 95% CI: 1.04–1.26, P = 0.003; I 2: 61%, P < 0.002 and OR: 1.50, 95% CI: 1.03–2.19, P = 0.033; I 2: 75.2%, P < 0.003), respectively). Similar associations emerged when women with EM and POI were compared with those of age at menopause >45 years (OR: 1.12, 95% CI: 1.01–1.20, P < 0.02; I 2: 78%, P < 0.001 and OR: 1.53, 95% CI: 1.03–2.27, P = 0.035; I 2: 78%, P < 0.001), respectively).
Both EM and POI are associated with increased risk of T2DM.
Antiopi Ntouva, Konstantinos A Toulis, Deepikshana Keerthy, Nicola J Adderley, Wasim Hanif, Rasiah Thayakaran, Krishna Gokhale, G Neil Thomas, Kamlesh Khunti, Abd A Tahrani and Krishnarajah Nirantharakumar
Type 2 diabetes is associated with an increased risk of fracture. Any factor that incrementally increases this risk should be taken into account when individualising treatment. Hypoglycaemia is a common complication of antidiabetes medications and suggested as a risk factor for fractures; yet, its real-life clinical impact is unclear.
A population-based, retrospective open cohort study using routinely collected data between 1st of January 1995 and 1st of May 2016 in The Health Improvement Network (THIN) database.
Patients with type 2 diabetes mellitus with documented hypoglycaemic events were compared to randomly matched patients with type 2 diabetes mellitus without documented hypoglycaemic events matched to exposed patients on age, sex, duration of diabetes and BMI. The primary outcome was any incident fracture. Secondary outcome was incident fragility (osteoporotic) fracture.
A total of 41 163 patients with type 2 diabetes were included: 14 147 patients in the exposed cohort and 27 016 patients in the unexposed cohort. Patients with a documented hypoglycaemic event were significantly more likely to sustain any fracture compared to patients with no record of hypoglycaemic events: adjusted IRR = 1.20 (95% CI: 1.12–1.30; P < 0.0001). Patients who had a documented hypoglycaemic event were significantly more likely to suffer a fragility fracture compared to controls: adjusted IRR = 1.24 (95% CI: 1.13–1.37; P < 0.0001).
Hypoglycaemic events are a significant risk factor for fractures in patients with diabetes mellitus. This observation is clinically relevant when individualising targets for glycaemic control and selecting antidiabetic agents.