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Open access

Marloes Nies, Bernadette L Dekker, Esther Sulkers, Gea A Huizinga, Mariëlle S Klein Hesselink, Heleen Maurice-Stam, Martha A Grootenhuis, Adrienne H Brouwers, Johannes G M Burgerhof, Eveline W C M van Dam, Bas Havekes, Marry M van den Heuvel-Eibrink, Eleonora P M Corssmit, Leontien C M Kremer, Romana T Netea-Maier, Heleen J H van der Pal, Robin P Peeters, John T M Plukker, Cécile M Ronckers, Hanneke M van Santen, Anouk N A van der Horst-Schrivers, Wim J E Tissing, Gianni Bocca and Thera P Links

Objective

The impact of childhood differentiated thyroid carcinoma (DTC) on psychosocial development has not yet been studied. The aim of this study was to evaluate the achievement of psychosocial developmental milestones in long-term survivors of childhood DTC.

Design and methods

Survivors of childhood DTC diagnosed between 1970 and 2013 were included. Reasons for exclusion were age <18 or >35 years at follow-up, a follow-up period <5 years or diagnosis with DTC as a second malignant neoplasm. Survivors gathered peer controls of similar age and sex (n = 30). A comparison group non-affected with cancer (n = 508) and other childhood cancer survivors (CCS) were also used to compare psychosocial development. To assess the achievement of psychosocial milestones (social, autonomy and psychosexual development), the course of life questionnaire (CoLQ) was used.

Results

We included 39 survivors of childhood DTC (response rate 83.0%, mean age at diagnosis 15.6 years, and mean age at evaluation 26.1 years). CoLQ scores did not significantly differ between survivors of childhood DTC and the two non-affected groups. CoLQ scores of childhood DTC survivors were compared to scores of other CCS diagnosed at similar ages (n = 76). DTC survivors scored significantly higher on social development than other CCS, but scores were similar on autonomy and psychosexual developmental scales.

Conclusions

Survivors of childhood DTC showed similar development on social, autonomy, and psychosexual domains compared to non-affected individuals. Social development was slightly more favorable in DTC survivors than in other CCS, but was similar on autonomy and psychosexual domains.

Open access

Felix Haglund, Björn M Hallström, Inga-Lena Nilsson, Anders Höög, C Christofer Juhlin and Catharina Larsson

Context

Inflammatory infiltrates are sometimes present in solid tumors and may be coupled to clinical behavior or etiology. Infectious viruses contribute to tumorigenesis in a significant fraction of human neoplasias.

Objective

Characterize inflammatory infiltrates and possible viral transcription in primary hyperparathyroidism.

Design

From the period 2007 to 2016, a total of 55 parathyroid tumors (51 adenomas and 4 hyperplasias) with prominent inflammatory infiltrates were identified from more than 2000 parathyroid tumors in the pathology archives, and investigated by immunohistochemistry for CD4, CD8, CD20 and CD45 and scored as +0, +1 or +2. Clinicopathological data were compared to 142 parathyroid adenomas without histological evidence of inflammation. Transcriptome sequencing was performed for 13 parathyroid tumors (four inflammatory, 9 non-inflammatory) to identify potential viral transcripts.

Results

Tumors had prominent germinal center-like nodular (+2) lymphocytic infiltrates consisting of T and B lymphocytes (31%) and/or diffuse (+1–2) infiltrates of predominantly CD8+ T lymphocytes (84%). In the majority of cases with adjacent normal parathyroid tissue, the normal rim was unaffected by the inflammatory infiltrates (96%). Presence of inflammatory infiltrates was associated with higher levels of serum-PTH (P = 0.007) and oxyphilic differentiation (P = 0.002). Co-existent autoimmune disease was observed in 27% of patients with inflammatory infiltrates, which in turn was associated with oxyphilic differentiation (P = 0.041). Additionally, prescription of anti-inflammatory drugs was associated with lower serum ionized calcium (P = 0.037).

Conclusions

No evidence of virus-like sequences in the parathyroid tumors could be found by transcriptome sequencing, suggesting that other factors may contribute to attract the immune system to the parathyroid tumor tissue.

Open access

George Tharakan, Preeshila Behary, Nicolai J Wewer Albrechtsen, Harvinder Chahal, Julia Kenkre, Alexander D Miras, Ahmed R Ahmed, Jens J Holst, Stephen R Bloom and Tricia Tan

Objective

Roux-en-Y gastric bypass (RYGB) surgery is currently the most effective treatment for diabetes and obesity. An increasingly recognized and highly disabling complication of RYGB is postprandial hypoglycaemia (PPH). The pathophysiology of PPH remains unclear with multiple mechanisms suggested including nesidioblastosis, altered insulin clearance and increased glucagon-like peptide-1 (GLP-1) secretion. Whilst many PPH patients respond to dietary modification, some have severely disabling symptoms. Multiple treatments are proposed, including dietary modification, GLP-1 antagonism, GLP-1 analogues and even surgical reversal, with none showing a more decided advantage over the others. A greater understanding of the pathophysiology of PPH could guide the development of new therapeutic strategies.

Methods

We studied a cohort of PPH patients at the Imperial Weight Center. We performed continuous glucose monitoring to characterize their altered glycaemic variability. We also performed a mixed meal test (MMT) and measured gut hormone concentrations.

Results

We found increased glycaemic variability in our cohort of PPH patients, specifically a higher mean amplitude glucose excursion (MAGE) score of 4.9. We observed significantly greater and earlier increases in insulin, GLP-1 and glucagon in patients who had hypoglycaemia in response to an MMT (MMT Hypo) relative to those that did not (MMT Non-Hypo). No significant differences in oxyntomodulin, GIP or peptide YY secretion were seen between these two groups.

Conclusion

An early peak in GLP-1 and glucagon may together trigger an exaggerated insulinotropic response to eating and consequent hypoglycaemia in patients with PPH.

Open access

Michel Polak, Jo Blair, Primoz Kotnik, Effie Pournara, Birgitte Tønnes Pedersen and Tilman R Rohrer

Objective

To investigate the effect of age at growth hormone (GH) treatment start on near adult height (NAH) in children with isolated GH deficiency (GHD).

Design

NordiNet® International Outcome Study (IOS) (Nbib960128), a non-interventional, multicentre study, evaluates the long-term effectiveness and safety of Norditropin® (somatropin) (Novo Nordisk A/S) in the real-life clinical setting.

Methods

Patients (n = 172) treated to NAH (height at ≥18 years, or height velocity <2 cm/year at ≥16 (boys) or ≥15 (girls) years) were grouped by age (years) at treatment start (early (girls, <8; boys, <9), intermediate (girls, 8–10; boys, 9–11) or late (girls, >10; boys, >11)) and GHD severity (<3 ng/mL or 3 to ≤10 ng/mL). Multiple regression analysis was used to evaluate the effect of age at treatment start (as a categorical and continuous variable) on NAH standard deviation score (SDS).

Results

Age at treatment start had a marked effect on NAH SDS; NAH SDS achieved by patients starting treatment early (n = 40 (boys, 70.0%); least squares mean (standard error) −0.76 (0.14)) exceeded that achieved by those starting later (intermediate, n = 42 (boys, 57.1%); −1.14 (0.15); late, n = 90 (boys, 68.9%); −1.21 (0.10)). Multiple regression analysis showed a significant association between NAH SDS and age at treatment start (P < 0.0242), baseline height SDS (HSDS) (P < 0.0001), target HSDS (P < 0.0001), and GHD severity (P = 0.0012). Most (78.5%) patients achieved a normal NAH irrespective of age at treatment start.

Conclusions

Early initiation of GH treatment in children with isolated GHD improves their chance of achieving their genetic height potential.

Open access

M E Rodie, M A V Mudaliar, P Herzyk, M McMillan, M Boroujerdi, S Chudleigh, E S Tobias and S F Ahmed

Background

It is unclear whether a short-term change in circulating androgens is associated with changes in the transcriptome of the peripheral blood mononuclear cells (PBMC).

Aims and methods

To explore the effect of hCG stimulation on the PBMC transcriptome, 12 boys with a median age (range) of 0.7 years (0.3, 11.2) who received intramuscular hCG 1500u on 3 consecutive days as part of their investigations underwent transcriptomic array analysis on RNA extracted from peripheral blood mononuclear cells before and after hCG stimulation.

Results

Median pre- and post-hCG testosterone for the overall group was 0.7 nmol/L (<0.5, 6) and 7.9 nmol/L (<0.5, 31.5), respectively. Of the 12 boys, 3 (25%) did not respond to hCG stimulation with a pre and post median serum testosterone of <0.5 nmol/L and <0.5 nmol/L, respectively. When corrected for gene expression changes in the non-responders to exclude hCG effects, all 9 of the hCG responders consistently demonstrated a 20% or greater increase in the expression of piR-37153 and piR-39248, non-coding PIWI-interacting RNAs (piRNAs). In addition, of the 9 responders, 8, 6 and 4 demonstrated a 30, 40 and 50% rise, respectively, in a total of 2 further piRNAs. In addition, 3 of the responders showed a 50% or greater rise in the expression of another small RNA, SNORD5. On comparing fold-change in serum testosterone with fold-change in the above transcripts, a positive correlation was detected for SNORD5 (P = 0.01).

Conclusions

The identification of a dynamic and androgen-responsive PBMC transcriptome extends the potential value of the hCG test for the assessment of androgen sufficiency.

Open access

Theodora Kunovac Kallak, Charlotte Hellgren, Alkistis Skalkidou, Lotta Sandelin-Francke, Kumari Ubhayasekhera, Jonas Bergquist, Ove Axelsson, Erika Comasco, Rebecca E Campbell and Inger Sundström Poromaa

Objective

Prenatal androgen exposure has been suggested to play a role in polycystic ovary syndrome. Given the limited information on what maternal characteristics influence maternal testosterone levels, and the even less explored routes by which female fetus androgen exposure would occur, the aim of this study was to investigate the impact of maternal age, BMI, weight gain, depressed mood and aromatase SNPs on testosterone levels in maternal serum and amniotic fluid of female fetuses.

Methods

Blood samples from pregnant women (n = 216) obtained in gestational weeks 35–39, and pre-labor amniotic fluid samples from female fetuses (n = 56), taken at planned Caesarean section or in conjunction with amniotomy for induction of labor, were analyzed. Maternal serum testosterone and amniotic fluid testosterone and cortisol were measured by tandem mass spectrometry.

Results

Multiparity (β = −0.28, P < 0.001), self-rated depression (β = 0.26, P < 0.001) and weight gain (β = 0.18, P < 0.05) were independent explanatory factors for the maternal total testosterone levels. Maternal age (β = −0.34, P < 0.001), weight gain (β = 0.19, P < 0.05) and amniotic fluid cortisol levels (β = 0.44, P < 0.001) were independent explanatory factors of amniotic fluid testosterone in female fetuses, explaining 64.3% of the variability in amniotic fluid testosterone.

Wider implications of the findings

Young maternal age and excessive maternal weight gain may increase the prenatal androgen exposure of female fetuses. Further studies are needed to explore this finding.

Open access

Roberto Salvatori, Serban Radian, Yoan Diekmann, Donato Iacovazzo, Alessia David, Plamena Gabrovska, Giorgia Grassi, Anna-Marie Bussell, Karen Stals, Astrid Weber, Richard Quinton, Elizabeth C Crowne, Valentina Corazzini, Lou Metherell, Tara Kearney, Daniel Du Plessis, Ajay Kumar Sinha, Atik Baborie, Anne-Lise Lecoq, Philippe Chanson, Olaf Ansorge, Sian Ellard, Peter J Trainer, David Balding, Mark G Thomas and Márta Korbonits

Objective

Mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are associated with pituitary adenoma, acromegaly and gigantism. Identical alleles in unrelated pedigrees could be inherited from a common ancestor or result from recurrent mutation events.

Design and methods

Observational, inferential and experimental study, including: AIP mutation testing; reconstruction of 14 AIP-region (8.3 Mbp) haplotypes; coalescent-based approximate Bayesian estimation of the time to most recent common ancestor (tMRCA) of the derived allele; forward population simulations to estimate current number of allele carriers; proposal of mutation mechanism; protein structure predictions; co-immunoprecipitation and cycloheximide chase experiments.

Results

Nine European-origin, unrelated c.805_825dup-positive pedigrees (four familial, five sporadic from the UK, USA and France) included 16 affected (nine gigantism/four acromegaly/two non-functioning pituitary adenoma patients and one prospectively diagnosed acromegaly patient) and nine unaffected carriers. All pedigrees shared a 2.79 Mbp haploblock around AIP with additional haploblocks privately shared between subsets of the pedigrees, indicating the existence of an evolutionarily recent common ancestor, the ‘English founder’, with an estimated median tMRCA of 47 generations (corresponding to 1175 years) with a confidence interval (9–113 generations, equivalent to 225–2825 years). The mutation occurred in a small tandem repeat region predisposed to slipped strand mispairing. The resulting seven amino-acid duplication disrupts interaction with HSP90 and leads to a marked reduction in protein stability.

Conclusions

The c.805_825dup allele, originating from a common ancestor, associates with a severe clinical phenotype and a high frequency of gigantism. The mutation is likely to be the result of slipped strand mispairing and affects protein–protein interactions and AIP protein stability.

Open access

Lina Schiffer, Punith Kempegowda, Wiebke Arlt and Michael W O’Reilly

Female androgen excess and male androgen deficiency manifest with an overlapping adverse metabolic phenotype, including abdominal obesity, insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease and an increased risk of cardiovascular disease. Here, we review the impact of androgens on metabolic target tissues in an attempt to unravel the complex mechanistic links with metabolic dysfunction; we also evaluate clinical studies examining the associations between metabolic disease and disorders of androgen metabolism in men and women. We conceptualise that an equilibrium between androgen effects on adipose tissue and skeletal muscle underpins the metabolic phenotype observed in female androgen excess and male androgen deficiency. Androgens induce adipose tissue dysfunction, with effects on lipid metabolism, insulin resistance and fat mass expansion, while anabolic effects on skeletal muscle may confer metabolic benefits. We hypothesise that serum androgen concentrations observed in female androgen excess and male hypogonadism are metabolically disadvantageous, promoting adipose and liver lipid accumulation, central fat mass expansion and insulin resistance.

Open access

Sarah M Leiter, Victoria E R Parker, Alena Welters, Rachel Knox, Nuno Rocha, Graeme Clark, Felicity Payne, Luca Lotta, Julie Harris, Julio Guerrero-Fernández, Isabel González-Casado, Sixto García-Miñaur, Gema Gordo, Nick Wareham, Víctor Martínez-Glez, Michael Allison, Stephen O’Rahilly, Inês Barroso, Thomas Meissner, Susan Davies, Khalid Hussain, Karen Temple, Ana-Coral Barreda-Bonis, Sebastian Kummer and Robert K Semple

Objective

Genetic activation of the insulin signal-transducing kinase AKT2 causes syndromic hypoketotic hypoglycaemia without elevated insulin. Mosaic activating mutations in class 1A phospatidylinositol-3-kinase (PI3K), upstream from AKT2 in insulin signalling, are known to cause segmental overgrowth, but the metabolic consequences have not been systematically reported. We assess the metabolic phenotype of 22 patients with mosaic activating mutations affecting PI3K, thereby providing new insight into the metabolic function of this complex node in insulin signal transduction.

Methods

Three patients with megalencephaly, diffuse asymmetric overgrowth, hypoketotic, hypoinsulinaemic hypoglycaemia and no AKT2 mutation underwent further genetic, clinical and metabolic investigation. Signalling in dermal fibroblasts from one patient and efficacy of the mTOR inhibitor Sirolimus on pathway activation were examined. Finally, the metabolic profile of a cohort of 19 further patients with mosaic activating mutations in PI3K was assessed.

Results

In the first three patients, mosaic mutations in PIK3CA (p.Gly118Asp or p.Glu726Lys) or PIK3R2 (p.Gly373Arg) were found. In different tissue samples available from one patient, the PIK3CA p.Glu726Lys mutation was present at burdens from 24% to 42%, with the highest level in the liver. Dermal fibroblasts showed increased basal AKT phosphorylation which was potently suppressed by Sirolimus. Nineteen further patients with mosaic mutations in PIK3CA had neither clinical nor biochemical evidence of hypoglycaemia.

Conclusions

Mosaic mutations activating class 1A PI3K cause severe non-ketotic hypoglycaemia in a subset of patients, with the metabolic phenotype presumably related to the extent of mosaicism within the liver. mTOR or PI3K inhibitors offer the prospect for future therapy.

Open access

Mark Hamer, William Johnson and Joshua A Bell

Objective

We aimed to re-examine mortality risk estimates for metabolically healthy obesity by using a ‘stable’ healthy non-obese referent group.

Design

Prospective cohort study.

Methods

Participants were 5427 men and women (aged 65.9 ± 9.4 years, 45.9% men) from the English Longitudinal Study of Ageing. Obesity was defined as body mass index ≥30 kg/m2 (vs non-obese as below this threshold). Based on blood pressure, HDL cholesterol, triglycerides, glycated hemoglobin and C-reactive protein, participants were classified as ‘healthy’ (0 or 1 metabolic abnormality) or ‘unhealthy’ (≥2 metabolic abnormalities).

Results

Totally, 671 deaths were observed over an average follow-up of 8 years. When defining the referent group based on 1 clinical assessment, the unhealthy non-obese (hazard ratio (HR) = 1.22; 95% CI: 1.01, 1.45) and unhealthy obese (HR = 1.29; CI: 1.05, 1.60) were at greater risk of all-cause mortality compared to the healthy non-obese, yet no excess risk was seen in the healthy obese (HR = 1.14; CI: 0.83, 1.52). When we re-defined the referent group based on 2 clinical assessments, effect estimates were accentuated and healthy obesity was at increased risk of mortality (HR = 2.67; CI: 1.64, 4.34).

Conclusion

An unstable healthy referent group may make ‘healthy obesity’ appear less harmful by obscuring the benefits of remaining never obese without metabolic dysfunction.