The ESPE Annual Meeting is nearly here. Its topical theme is ‘Narrative and precision medicine in paediatric endocrinology’, and the exciting programme is sure to stimulate discussion amongst delegates across the breadth of our discipline.You have until 10 August to take advantage of the standard registration rate, so hurry now to reserve your place in Athens. This issue of ESPE News takes the ESPE Meeting as its theme. We are delighted to have an interview with ESPE President, George Chrousos.
We wish them, you, and all your families and friends, health and peace in the coming months.
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The following consensus statement and clinical guideline have been developed with ESPE’s support: Diagnosis and management of pseudohypoparathyroidism and related disorders: first international consensus statement Mantovani et al. 2018 Nature Reviews Endocrinology 14 476–500 Endocrine treatment of gender-dysphoric/gender-incongruent persons: an Endocrine Society Clinical Practice Guideline Hembree et al. 2017 Journal of Clinical Endocrinology & Metabolism 102 3869–3903 Remember, if you’d like ESPE to develop or endorse a new guideline, a member of our Clinical Practice Committee must be involved throughout the development process. More guidance for consensus meetings and guideline development is available on our website. See www.eurospe.org/clinical-practice/consensus-meeting-and-guideline-development
The 2018 Yearbook of Pediatric Endocrinology, edited by Ken Ong and Ze’ev Hochberg, is being published online for the first time. This valuable reference tool provides a collection of abstracts summarising the highlights of publications from the past year. Online access will be available to all ESPE members and ESPE 2018 delegates. Details will be made available at ESPE 2018 in September and in the ESPE online members’ area
New interactive case presentations have been added to the ‘Obesity’ and ‘Pituitary’ chapters within ‘General content’. The Online Learning Committee has also developed a separate e-learning module containing teaching material intended for the three levels of healthcare (primary, secondary, tertiary) within ‘Resource limited countries’ (RLC). The RLC content is currently available in French, Spanish, Swahili and Chinese, and was developed in collaboration with the International Consortium of Paediatric Endocrinology (ICPE), whose societies are represented on the e-Learning Editorial Board. ESPE is currently reviewing its e-learning provision to ensure we are maximising its benefit within our wider education and training strategy. Registration for access to all of ESPE’s e-learning content
Bringing you recent highlights from the world of research
Kühtreiber et al. studied 49 adults with established type 1 diabetes and an average disease duration of 19 years. Nine received two doses of the BCG vaccine 4 weeks apart, and three received a placebo. Of these, three patients in each group were followed up to 8 years, when the mean HbA1c (glycated haemoglobin) of the BCG vaccine group was 6.65% compared with 7.22% in those who had placebo. This improvement was without any increase in C peptide, and so not due to increased endogenous insulin production. This contrasts with results in NOD (non-obese diabetic) mice, where BCG vaccine is associated with increased C peptide and pancreatic regeneration is hypothesised. The researchers investigated epigenetic effects of the repeat BCG vaccine on the immune system. They hypothesise a metabolic shift from oxidative phosphorylation to early aerobic glycolysis, which may affect blood glucose levels. Whilst the proposed mechanisms are fascinating, the small number of patients in the final analysis means the results must be interpreted with caution, and may not be generalisable to the wider population with type 1 diabetes
In a single-blind randomised controlled study of 89 adults with adrenal insufficiency (AI), Isidori et al. found that switching from twice- or thrice-daily standard hydrocortisone to an equivalent dose of once-daily modified-release hydrocortisone markedly reduced body weight and improved glucose metabolism. Notably, restoring a more physiological profile with the once daily treatment improved the immune cell profile and reduced infections, compared with the standard therapy. Regular twice- or thrice-daily standard hydrocortisone replacement therapy is well known to be non-physiological. After oral intake of hydrocortisone tablets, serum cortisol often peaks above the corticosteroid-binding globulin binding capacity. Human monocytes, macrophages, T lymphocytes and natural killer cells are influenced by glucocorticoids, suggesting that high levels of unbound cortisol directly affect immune cells. Modified-release hydrocortisone might thus help prevent life-threatening adrenal crises as a result of infections in AI. In the absence of objective indicators to assess the appropriateness of glucocorticoid replacement therapy, these results also support the use of leucocyte profiling as a novel tool to monitor AI.
In a multicentre randomised controlled trial, Kuppermann et al. evaluated 1255 children and 1389 episodes of diabetic ketoacidosis (DKA). Children were randomly assigned to receive 0.9% or 0.45% sodium chloride and a rapid or slow rate of administration. There were no significant differences in the percentage of episodes in which the Glasgow Coma Scale (GCS) score was below 14, or in the magnitude of the decline or in the duration of time for which the GCS score was below 14. The results of short term memory tests and the incidence of clinically apparent brain injury were not significantly different amongst treatment groups, and nor were the memory or IQ scores obtained after the children’s recovery. Neither intravenous fluid administration rate nor sodium chloride content affected the neurologic outcomes in children with DKA in this trial, suggesting that other mechanisms such as cerebral hypoperfusion, the effects of reperfusion or neuroinflammation could have a potential role in DKA-associated brain injury
X-linked hypophosphataemia is characterised by increased secretion of fibroblast growth factor 23 (FGF-23). Carpenter et al. investigated the efficacy and safety of burosumab, a monoclonal antibody targeting FGF-23, given subcutaneously every 2 or 4 weeks in 52 children with X-linked hypophosphataemia. The primary end-point was a change in Thacher rickets severity total score and additional end-points included changes in pharmacodynamic markers and linear growth from baseline to weeks 40 and 64. Physical ability, patient-reported outcomes and adverse events were also recorded. Mean Thacher rickets severity total score decreased and the improvement persisted at week 64. Renal tubular phosphate reabsorption and mean serum phosphorus level increased, while mean serum alkaline phosphatase level decreased in both groups. Mean standing-height z score increased in both groups, with greater improvement seen at all time points with dosing every 2 weeks rather than every 4 weeks. Physical ability improved and pain decreased. Nearly all adverse events were mildly or moderately severe. Burosumab was found to have a beneficial effect on phosphate homeostasis, linear growth, physical function pain and severity of rickets
ESPE President George Chrousos tells us about his career in paediatric endocrinology, and what you can look forward to at the forthcoming ESPE Meeting in his home city of Athens
How did you come to choose a career in medicine? I was born and raised in the beautiful Greek seaside town of Patras, the capital of the southern peninsula of Peloponnesus. I was impressed by and idolised my family physician, and read inspiring books by AJ Cronin, but I also had a talent for painting. I chose to pursue medicine rather than art when I was 17. I was accepted at the Medical School of the National and Kapodistrian University of Athens, and graduated 6 years later as the valedictorian of my class. Who or what inspired you to become a paediatric endocrinologist? I decided to enter paediatrics after a 1-year residency in internal medicine. I enjoy interacting with children, and the dynamic developmental dimension of paediatrics appeals to me as a scientist. After my paediatric residency at New York University Medical School, I went into endocrinology at the National Institutes of Health (NIH), because of its integrative nature and strong scientific basis. I have been lucky to have great mentors throughout my career. Gordon B Cutler, D Lynn Loriaux and Mortimer B Lipsett, all outstanding endocrinologists and role model physician-scientists, had a powerful effect on me. I would not have been who I am if my path had not crossed theirs. What have been the highlights of your career and why? I would count among these the honour of working with unique individuals at the NIH, and other fantastic collaborators, fellows and friends, as well as caring for complex patients referred to NIH by colleagues around the world. Over 60 young endocrine investigators from all over the world spent formative years in my department. Many of them now hold major academic and industry posts all over the world. My career at the NIH included establishing an accredited Fellowship Training Program in Pediatric Endocrinology in the 1980s, which thrives and still produces paediatric endocrinologists who take key academic positions internationally After a long career at the NIH I moved back to my alma mater to become Chairman of the First Department of Pediatrics, the oldest, largest and most prestigious department in Greece. My role changed, but what I learned in Bethesda came to be of great use in Athens. What has been your most satisfying discovery? Amongst many examples was having the good fortune to study the first cases of primary generalised, familial or sporadic glucocorticoid resistance, a hereditary disease of the glucocorticoid signalling system with a very broad clinical spectrum. Figuring out its pathophysiologic mechanisms, its therapy and, lastly, its molecular aetiology was a thrilling experience. Theorising on the extensive pervasiveness of target tissue glucocorticoid sensitivity changes in human nosology has provided a transformative concept in medicine and paediatrics. What role has ESPE played for you? I have been an ESPE member since I finished my endocrine training. I have always been impressed by the scope of ESPE’s work and support, its many schools, scholarships, prizes and awards, its contributions to young people, and its commitment to the spread of paediatric endocrine knowledge to other continents, where such knowledge is sparse and greatly needed. What have you most enjoyed about organising ESPE 2018? It has been a pleasure to work with the ESPE Programme Organising Committee to create a cutting-edge science programme, featuring fantastic plenaries and many clinically useful sessions for all the participants. It has also been a great opportunity to work with Bioscientifica (the meeting organiser) and its wonderful, experienced staff on the many practical aspects and details of this large and complex meeting. What will ESPE members most enjoy about ESPE 2018 in Athens? The amazing scientific programme of course! We should also mention the historic city where western civilisation was born, the calm Cerulean Sea and the countryside, set off by the deep blue sky of Greece’s Attic region, and the traditional hospitality of the country and its people. Finally, what is your message to current young paediatric endocrinologists? Follow the Hippocratic exhortation ‘Give your assistance to all for the love of man and for the love of the art’ and through this find ‘εuδαιμονία’– eudaimonia.*
In the first of two articles written by speakers at the forthcoming ESPE Meeting, plenary
lecturer Eran Segal (Rehovot, Israel) looks to the microbiome to personalise treatment.
Accumulating evidence supports a causal role for the human gut microbiome in obesity, diabetes, metabolic disorders, cardiovascular disease, and numerous other conditions. At ESPE 2018, I am delighted to be presenting our research on the role of the human microbiome in health and disease, aimed at developing approaches to personalised medicine that combine human genetics, the microbiome and nutrition. The personal nature of blood glucose responses We conducted a study to tackle the subject of personalisation of human nutrition, using a cohort of over 1000 people in whom we measured blood glucose responses to more than 50 000 meals, and undertook lifestyle, medical and food frequency questionnaires, blood tests, and genetics and gut microbiome analyses.1 Blood glucose responses to meals were found to vary greatly between people, even when consuming identical foods. We then devised the first algorithm for accurately predicting personalised glucose responses to food based on clinical and microbiome data, and showed that personalised diets based on our algorithm successfully balanced blood glucose levels in prediabetic individuals. Microbiome and environment Using the same cohort, we studied the relative contribution of host genetics and environmental factors in shaping human gut microbiome composition.2 Notably, although our cohort consisted of individuals from several distinct ancestral origins who shared a relatively common environment, we found no association between microbiome and genetic ancestry. In contrast, we showed that over 20% of the gut microbiome variance can be explained by environmental factors related to diet, drugs and anthropometric measurements. In addition, we found that 24–36% of the variance of several human traits and disease risk factors can be explained by the microbiome, even after accounting for the contribution of human genetics. These results suggest that the composition of the human microbiome is dominated by environmental factors rather than by host genetics. Microbial subgenomic variations In my talk, I will also present an algorithm that we devised for identifying variability in microbial subgenomic regions. We have found that such subgenomic variations (SGVs) are prevalent in the microbiome across multiple microbial phyla, and that they are associated with bacterial fitness. Their member genes are enriched for CRISPR-associated and antibiotic-producing functions and depleted from housekeeping genes. We have found over 100 novel associations between SGVs and host disease risk factors and have uncovered possible mechanistic links between the microbiome and its host, demonstrating that SGVs constitute a new layer of metagenomic information
In this second article by invited speakers at the
forthcoming ESPE Meeting, Maria Klapa (Patras, Greece)
examines the developing role of metabolomics.
High-throughput biomolecular (‘omic’) analyses in the systems biology era have revolutionised the way in which biological problems are now approached. They have achieved this by enabling the simultaneous quantification of hundreds or thousands of transcripts, proteins or metabolites in a biological system (cell culture, tissue or biological fluid). ‘Omic’ analyses contribute to the identification of characteristically discriminatory multi-component molecular profiles of a disease, transforming studies in molecular medicine from uni- or oligovariate (in the search for one or few specific biomarkers), to multivariate, thus enhancing precision and personalisation.1 We can now view molecular physiology as a dynamic arrangement of interacting biomolecular networks and interpret the molecular mechanisms underlying a disease as disruptions in this network’s connectivity and dynamics (network biology and medicine). Molecular quantities being interconnected, even subtle differences in one component can carry significance, if viewed in the context of the observed changes in the rest of the molecules. Thus, there is a higher probability of identifying considerable variations in molecular profiles in complex medical cases, when conventional analyses fail to provide statistically significant results. In this context, ‘omic’ analyses pave the way for in-depth systemic studies of human (patho)physiology.2 The emergence of metabolomics Metabolomics is the most recently introduced, but very fast-growing, ‘omic’ analysis. It refers to the analysis of the (relative) concentration profile of the free small metabolite pools of a biological system. This metabolic profile provides a comprehensive metabolic signature and a direct link to the phenotype.3 Since the concentrations of the free small molecules affect and are affected by the in vivo metabolic activity, the metabolic profile is a significant component of the epigenetic fingerprint of an individual,4 providing information about the molecular physiology, which is not directly available from the profiling of transcripts or proteins. In this context, metabolomics of biological fluids or tissues (when available) can be crucial in disease diagnosis and appropriate design of therapeutic treatments, either as singly applied or as part of integrated multi-omic studies. In endocrinology in particular, metabolomics can be an integral component of both research and practice. In the investigation of diagnostic profiles, untargeted blood metabolomics has mainly been used, as it is least invasive and directly mirrors the metabolic physiology of an individual (e.g. in a study of predisposition to latent insulin resistance).5 Excretome (urine and stool) analysis using metabolomics has also been applied, especially in pharmacometabolomic research, and lately as an integral part of the gut microbiome analysis and its connection to disease.6 More specific analyses of cerebrospinal fluid have been carried out to assess the molecular mechanisms of neurological diseases.1,7 Metabolomics has also been considered as part of personalised nutrition research and practice in the context of disease prevention and treatment.8 A tool of great potential Metabolomics can and should be part of clinical practice, as a major component of the clinical chemistry laboratory. It has numerous advantages over the other ‘omic’ analyses, including its lower cost and the absence of a need for special technological platforms. Metabolomics uses classical analytical chemistry equipment, most of which is part of a clinical chemistry laboratory: nuclear magnetic resonance (NMR) spectroscopy and/or mass spectrometry (MS), integrated with gas or liquid chromatography (GC or LC). However, the broad deployment of the metabolomic analytical platform to systems and precision medicine research and practice requires its standardisation for accurate, reproducible and validated performance. There have been international efforts to harmonise experimental and computational analysis protocols among laboratories. This would ensure comparable results and enable appropriate deposition of the acquired data into standardised repositories, facilitating their integrated use and meta-analysis. Moreover, the development of software that can help the clinician to correctly interpret the acquired data in the context of the available knowledge is important. In the near future, as metabolomics becomes established as an essential tool of medical research, and accurate in silico models of the human metabolic physiology are developed, we foresee that the acquisition of a metabolic profile will complement the classical biochemical tests, and provide doctors with direct assistance in accurately diagnosing and designing a personalised therapy
With the 57th ESPE Annual Meeting fast approaching, remember that the deadline for
standard registration is 10 August. You can register online at www.espe2018.org.
This year’s topic is ‘Narrative and precision medicine in paediatric endocrinology’, and we are delighted to include insights into two of the many exciting lectures on pages 6 and 7 of this issue of ESPE News. In addition to the plenary sessions, the symposia and meet the expert sessions will provide you with the opportunity to exchange high quality clinical information and basic science with international experts. Free communications and poster sessions will allow delegates from around the world to present and discuss their latest findings in an interactive environment and to promote international collaboration in research and clinical practice. Other highlights include special sessions devoted to Novel Advances, Controversies, How do I...? and Yearbook of Pediatric Endocrinology, as well as our new Young Investigators session. This will include novel data from several ESPE award winners and grant recipients. The Greek capital, Athens, hosts this year’s ESPE annual meeting, and the venue is conveniently located in the city centre. This means you will be well-positioned to enjoy the sights and sounds of this lively metropolis alongside the excellent scientific programme. You are sure to enjoy the delicious Greek cuisine during your stay, and perhaps see one or more of the famous ancient archaeological sites. The meeting’s many networking opportunities include the chance for you to meet with colleagues at our informal welcome event on the first day of the meeting. After the meeting closes, our ESPE Evening will provide you with a final, very enjoyable, networking event to discuss the event’s highlights with your fellow endocrinologists before you return home. Tickets can be purchased online when you register. We look forward to welcoming you all to Athens for ESPE 2018.
ESPE has developed this new postgraduate course jointly with the European Association for the Study of Diabetes (EASD) and the International Society for Pediatric and Adolescent Diabetes (ISPAD). It will cover essential topics within type 1 diabetes, and participants will be able to listen to and interact with experts and researchers in the field of diabetes from all over Europe in an informal setting. During lectures and workshops, faculty members will share their knowledge and clinical experiences and participants will gain new insights into the treatment of type 1 diabetes and its complications. Registration is free for successful applicants and the deadline for applications is 31 August 2018. Further details and the preliminaryprogramme are available at www.easd.org/easd-ispad espe-course-t1d.htm
ESPE Winter School February 2019, Azerbaijan If you are completing or have finished your basic paediatric training and are interested in endocrinology and diabetes, the ESPE Winter School could be for you! You can expect: • Interactive lectures from the teaching faculty • Case presentations by each student • Presentation of student research projects • Critical evaluation of selected publications • Small group teaching: student and teacher clinical case and research project presentations Details will be available shortly at www.eurospe.org/education/ winter-school. Supported by an educational grant from Ferring Pharmaceuticals A/S
You can now register for paid-for places at the 2018 Science Symposium on ‘the Science of Gender’, as the application deadline for free places has passed. This 2-day symposium will look at: • The evidence for what influences gender development and gender dysphoria and the respective impact of nature and nurture • The potential psychological–psychosocial impacts of endocrine treatment for gender dysphoria and the relevant science This, the first of ESPE’s Science Symposia, is brought to you by ESPE’s Working Group on Gender Dysphoria together with the UK Gender Identity Development Service, and is supported by by an educational grant from Pfizer
Symposium speakers Sarah-Jayne Blakemore, London, UK Gary Butler, London, UK Polly Carmichael, London, UK Martine Cools, Ghent, Belgium Sarah Davidson, London, UK Neil Evans, Glasgow, UK Alessandra Fisher, Florence, Italy Vibe Frokjaer, Copenhagen, Denmark Riittakerttu Kaltiala-Heino, Tampere, Finland Baudewijntje Kreukels, Amsterdam, The Netherlands Leighton Seal, London, UK Nicos Skordis, Nicosia, Cyprus Annelou de Vries, Amsterdam, The Netherlands