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Open access

Anna Olsson-Brown, Rosemary Lord, Joseph Sacco, Jonathan Wagg, Mark Coles and Munir Pirmohamed

Introduction

Immune checkpoint inhibitors can lead to thyroid dysfunction. However, the understanding of the clinical phenotype of ICI-induced thyroid dysfunction in the real-world population is limited. The purpose of this study was to characterise the clinical patterns of dysfunction and evaluate the demographic, biochemical and immunological features associated with this patient cohort.

Materials and methods

To characterise the longitudinal clinical course of thyroid dysfunction in patients from a single, UK regional cancer centre, a retrospective review of patients was conducted. Inclusion criteria included all patients treated with antiPD-1 checkpoint inhibitors (ICI), either as monotherapy (pembrolizumab/nivolumab) or in combination with a CTLA-4 inhibitor (ipilimumab). Patterns of toxicity were evaluated together with assessment of antibody titres.

Results

Over 16 months, thyroid dysfunction was seen in 13/90 and 3/13 patients treated with anti-PD1 monotherapy and in combination with ipilimumab, respectively. Patients either developed hyperthyroidism followed by hypothyroidism (12/16) or de novo hypothyroidism (4/16). Most patients were female (n = 11). All patients required thyroid replacement therapy. There was no relationship between clinical pattern of dysfunction and the presence of thyroid autoantibodies.

Conclusions

There are two distinct patterns of thyroid dysfunction in ICI-treated patients. Patients with thyroiditis develop subsequent hypothyroidism in the vast majority of cases. The potential benefit from steroids or other therapy to manage the hyperthyroid phase remains unclear. Early detection of these patients through appropriate monitoring will improve clinical management and early hormone replacement, reducing the symptomatic burden of hypothyroidism.

Open access

Willem de Ronde and Diederik L Smit

This review summarizes ten years experience with male abusers of anabolic androgenic steroids (AAS). The typical user of AAS is male, aged between 20 and 40 and lifting weights. Illegal AAS are cheap and easily obtained via internet or local suppliers. AAS are mostly used in cycles with a duration between 6 and 18 weeks. Most AAS cycles contain multiple agents, used simultaneously in a dose vastly exceeding a substitution dose. A variety of other performance and image-enhancing drugs are commonly used, including human growth hormone, thyroid hormone, tamoxifen, clomiphene citrate and human chorionic gonadotrophin. Short term clinical and biochemical side effects are well established. Long term side effects are uncertain, but may include heart failure, mood-and anxiety disorders, hypogonadism and subfertility. We share our views on the management of common health problems associated with AAS abuse.

Open access

Kaiyu Pan, Chengyue Zhang, Xiaocong Yao and Zhongxin Zhu

Aim

Ensuring adequate calcium (Ca) intake during childhood and adolescence is critical to acquire good peak bone mass to prevent osteoporosis during older age. As one of the primary strategies to build and maintain healthy bones, we aimed to determine whether dietary Ca intake has an influence on bone mineral density (BMD) in children and adolescents.

Methods

We conducted a cross-sectional study composed of 10,092 individuals from the National Health and Nutrition Examination Survey (NHANES). Dietary Ca intake and total BMD were taken as independent and dependent variables, respectively. To evaluate the association between them, we conducted weighted multivariate linear regression models and smooth curve fittings.

Results

There was a significantly positive association between dietary Ca intake and total BMD. The strongest association was observed in 12–15 year old whites, 8–11 year old and 16–19 year old Mexican Americans, and 16–19 year old individuals from other race/ethnicity, in whom each quintile of Ca intake was increased. We also found that there were significant inflection points in females, blacks, and 12–15 year old adolescents group, which means that their total BMD would decrease when the dietary Ca intake was more than 2.6–2.8 g/d.

Conclusions

This cross-sectional study indicated that a considerable proportion of children and adolescents aged 8–19 years would attain greater total BMD if they increased their dietary Ca intake. However, higher dietary Ca intake (more than 2.6–2.8 g/d) is associated with lower total BMD in females, blacks, and 12–15 year old adolescents group.

Open access

Martine Cohen-Solal, Thomas Funch-Brentano and Pablo Urena

Mineral and bone diseases (MBD) are predominant in patients with chronic kidney disease (CKD) and leads to several bone manifestations, from pain to skeletal fractures. Cumulative traditional clinical risk factors, such as age and gender, in addition to those related to CKD, enhances the risk of comorbidity and mortality related to fractures. Despite great advances in understanding MBD in CKD, clinical and biological targets are lacking, which leads to under-management of fractures. Optimal PTH control results in a net improvement in defining the levels of bone remodeling. In addition, circulating biomarkers such as bone-specific alkaline phosphatase and cross-linked collagen type I peptide will also additional information about bone mineralization and evaluation of fracture risk. Imaging techniques will facilitate to characterize the patient at risk by the use of the measurement of bone mineral density by DEXA or by high peripheral computed tomography which allow the discrimination of trabecular and cortical bone. We here reviewed the literature related to the epidemiology and pathophysiological role of mineral and biochemical factors involved in CKD-MBD with a special focus in fracture risk. We also provide an algorithm that could be used for the management of bone diseases and the treatment decision. Finally, the combined expertise of clinicians from various disciplines is crucial for the best prevention of fractures.

Open access

Aleksandra Krygier, Ewelina Szczepanek-Parulska, Dorota Filipowicz and Marek Ruchała

Introduction

Hepcidin is an acute-phase protein and a key regulator of iron homeostasis. Anaemia frequently occurs in patients with thyroid dysfunction, and hepcidin may be a potential link.

Objectives

Prospective assessment of hepcidin serum concentration and other parameters related to Fe homeostasis in hyperthyroid patients in the course of GD at diagnosis and during remission.

Patients and Methods

Out of the 70 patients recruited, 42 (32 women, 10 men), aged 42.5 ± 15.1 years, met the inclusion criteria. Clinical and biochemical assessment, including hepcidin measurement by ELISA, was performed at baseline (T0) and after restoration of euthyroidism (T1).

Results

Hepcidin concentration at T0 in the 24 patients who completed the study was significantly higher than the value during euthyroidism (28.7 (8.1–39.4) ng/mL vs 7.9 (4.3–12.9) ng/mL, P < 0.001). Hepcidin level was most significantly correlated with ferritin (rho = 0.723) in women at T0. In both men (377 (171–411) vs 165 (84–237) ng/mL, P = 0.001) and women (84 (23–104) vs 35 (16–64) ng/mL, P = 0.001), a significant decrease in ferritin level was demonstrated following therapy. A significant (P < 0.001) increase in mean corpuscular volume (MCV) (83.5 (82.5–87.1) vs 89.5 (88.8–90.0) fL) and mean concentration of haemoglobin (MCH) (29.0 (28.0–29.4) vs 30.4 (29.5–31.1) pg) was observed.

Conclusions

Hepcidin and ferritin decrease significantly during the transition from a hyperthyroid state to euthyroidism in patients with GD. The observed changes occur in parallel to iron homeostasis fluctuations. During the transition from the hyperthyroid state to euthyroidism, the improvement of haematological status is reflected mainly by the increase in MCV and MCH.

Open access

Trevor Lewis, Eva Zeisig and Jamie E Gaida

Background

While metabolic health is acknowledged to affect connective tissue structure and function, the mechanisms are unclear. Glucocorticoids are present in almost every cell type throughout the body and control key physiological processes such as energy homeostasis, stress response, inflammatory and immune processes, and cardiovascular function. Glucocorticoid excess manifests as visceral adiposity, dyslipidemia, insulin resistance, and type 2 diabetes. As these metabolic states are also associated with tendinopathy and tendon rupture, it may be that glucocorticoids excess is the link between metabolic health and tendinopathy.

Objective

To synthesise current knowledge linking glucocorticoid exposure to tendon structure and function.

Methods

Narrative literature review.

Results

We provide an overview of endogenous glucocorticoid production, regulation, and signalling. Next we review the impact that oral glucocorticoid has on risk of tendon rupture and the effect that injected glucocorticoid has on resolution of symptoms. Then we highlight the clinical and mechanistic overlap between tendinopathy and glucocorticoid excess in the areas of visceral adiposity, dyslipidemia, insulin resistance and type 2 diabetes. In these areas, we highlight the role of glucocorticoids and how these hormones might underpin the connection between metabolic health and tendon dysfunction.

Conclusions

There are several plausible pathways through which glucocorticoids might mediate the connection between metabolic health and tendinopathy.

Open access

Nk Stepto, D Hiam, M Gibson-Helm, S Cassar, C L Harrison, S K Hutchison, A E Joham, Benedit Canny, A Moreno-Asso, B J Strauss, N Hatzirodos, R J Rodgers and H J Teede

Objective: Mechanisms of insulin resistance in polycystic ovary syndrome (PCOS) remain ill-defined, contributing to sub-optimal therapies. Recognising skeletal muscle plays a key role in glucose homeostasis we investigated early insulin signalling, its association with aberrant transforming growth factor β (TGFβ) regulated tissue fibrosis. We also explored the impact of aerobic exercise on these molecular pathways.

Methods: A secondary analysis from a cross-sectional study was undertaken in women with (n=30) or without (n=29) PCOS across lean and overweight BMIs. A subset of participants with (n=8) or without (n=8) PCOS who were overweight completed 12-weeks of aerobic exercise training. Muscle was sampled before and 30 min into a euglycaemic-hyperinsulinaemic clamp pre- and post-training.

Results: We found reduced signalling in PCOS of mechanistic target of rapamycin (mTOR). Exercise training augmented but did not completely rescue this signalling defect in women with PCOS. Genes in the TGFβ signalling network were upregulated in skeletal muscle in the overweight women with PCOS but were unresponsive to exercise training except for genes encoding LOX, collagen 1 and 3.

Conclusions: We provide new insights into defects in early insulin signalling, tissue fibrosis, and hyperandrogenism in PCOS-specific insulin resistance in lean and overweight women. PCOS-specific insulin-signalling defects were isolated to mTOR, while gene expression implicated TGFβ ligand regulating a fibrosis in the PCOS-obesity synergy in insulin resistance and altered responses to exercise. Interestingly, there was little evidence for hyperandrogenism as a mechanism for insulin resistance.

Open access

Sumana Chatterjee, Emily Cottrell, Stephen J Rose, Talat Mushtaq, Avinaash V Maharaj, Jack Williams, Martin O Savage, Louise A Metherell and Helen L Storr

Objectives

The homozygous GH receptor (GHR) pseudoexon (6Ψ) mutation leads to growth hormone insensitivity (GHI) with clinical and biochemical heterogeneity. We investigated whether transcript heterogeneity (6Ψ-GHR to WT-GHR transcript ratio) and/or concurrent defects in other short stature (SS) genes contribute to this.

Methods

6Ψ-GHR and WT-GHR mRNA transcripts of four 6Ψ patients (height SDS −4.2 to −3.1) and one control fibroblast were investigated by RT-PCR. Transcripts were quantified by qRT-PCR and delta delta CT analysis and compared using ANOVA with Bonferroni correction. In eleven 6Ψ patients, 40 genes known to cause GHI/SS were analysed by targeted next generation sequencing.

Results

RT-PCR confirmed 6Ψ-GHR transcript in the 6Ψ patients but not in the control. 6Ψ-GHR transcript levels were comparable in patients 1 and 3 but significantly different among all other patients. The mean 6Ψ:WT transcript ratios ranged from 29–71:1 for patients 1–4 and correlated negatively with height SDS (R = −0.85; P < 0.001). Eight deleterious variants in six genes were detected, but the number of gene hits did not correlate with the degree of SS in individual 6Ψ patients.

Conclusion

Variable amounts of 6Ψ- and WT-GHR transcripts were identified in 6Ψ patients but no 6Ψ transcript was present in the control. Higher 6Ψ:WT-GHR transcript ratio correlated with SS severity and may explain the phenotypic variability. Analysis of known SS genes suggested that phenotypic variation is independent of the genetic background. This is the first report of transcript heterogeneity producing a spectrum of clinical phenotypes in different individuals harbouring an identical homozygous genetic mutation.

Open access

Jintao Hu, Qingbo Chen, Xiao Ding, Xin Zheng, Xuefeng Tang, Song Li and Hui Yang

Objective

Many cancer cells cannot survive without exogenous glutamine (Gln); however, cancer cells expressing glutamine synthetase (GS) do not have this restriction. Previous metabolomics studies have indicated that glutamine metabolism is altered during pituitary tumorigenesis. However, the main role of Gln in pituitary adenoma (PA) pathophysiology remains unknown. The aim of this study was to evaluate the expression of GS and the main role of Gln in human PAs.

Methods

We used cell proliferation assay and flow cytometry to assess the effect of Gln depletion on three different pituitary cell lines and human primary PA cells. We then investigated the expression level of Gln synthetase (GS) in 24 human PA samples. At last, we used LC-MS/MS to identify the differences in metabolites of PA cells after the blockage of both endogenous and exogenous Gln.

Results

PA cell lines showed different sensitivities to Gln starvation, and the sensitivity is correlated with GS expression level. GS expressed in 21 out of the 24 human PA samples. Furthermore, a positive p53 and ki-67 index was correlated with a higher GS expression level (P < 0.05). Removal of both endogenous and exogenous Gln from GS-expressing PA cells resulted in blockage of nucleotide metabolism and cell cycle arrest.

Conclusions

Our data indicate that GS is needed for PA cells to undergo proliferation during Gln deprivation, and most human PA cells express GS and might have a negative response to exogenous Gln depletion. Moreover, Gln is mainly responsible for nucleotide metabolism in the proliferation of GS-expressing pituitary tumor cells.

Open access

M L M Barreto-Chaves, N Senger, M R Fevereiro, A C Parletta and A P C Takano

The cardiac growth process (hypertrophy) is a crucial phenomenon conserved across a wide array of species and is critically involved in the maintenance of cardiac homeostasis. This process enables an organism to adapt to changes in systemic demand and occurs due to a plethora of responses, depending on the type of signal or stimuli received. The growth of cardiac muscle cells in response to environmental conditions depends on the type, strength and duration of stimuli, and results in adaptive physiological responses or non-adaptive pathological responses. Thyroid hormones (TH) have a direct effect on the heart and induce a cardiac hypertrophy phenotype, which may evolve to heart failure. In this review, we summarize the literature on TH function in the heart by presenting results from experimental studies. We discuss the mechanistic aspects of TH associated with cardiac myocyte hypertrophy, increased cardiac myocyte contractility and electrical remodeling, as well as the associated signaling pathways. In addition to classical crosstalk with the sympathetic nervous system (SNS), emerging work pointing to the new endocrine interaction between TH and the renin-angiotensin system (RAS) is also explored. Given the inflammatory potential of the angiotensin II peptide, this new interaction may open the door for new therapeutic approaches which target the key mechanisms responsible for TH-induced cardiac hypertrophy.