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Jasna Aleksova, Peter R Ebeling, Frances Milat, and Grahame J Elder

Objective

Patients with end-stage kidney disease (ESKD) caused by type 1 diabetes mellitus (T1DM) have a heightened fracture risk. Bone mineral density (BMD) may predict fracture less accurately in ESKD than in patients with chronic kidney disease (CKD) stages 1–3b or the general population. Alternate, readily available imaging modalities are needed to improve ESKD fracture risk assessment. This study aimed to assess dual-energy X-ray absorptiometry (DXA)-derived BMD, the trabecular bone score (TBS) and advanced hip analysis parameters in patients with ESKD due to T1DM and to compare their results with those of patients with ESKD from other causes.

Methods

We compared the DXA-derived TBS, hip cortical thickness (CT) and femoral neck (FN) buckling ratio (BR), an index of FN stability, of patients with T1DM and ESKD undergoing simultaneous pancreas kidney transplantation, patients with ESKD from other causes receiving kidney transplants and population reference ranges.

Results

Of 227 patients with ESKD, 28% had T1DM and 65% were male. Compared with other ESKD patients, patients with T1DM were younger (42 ± 7.7 vs 51 ± 13.8 years), had shorter dialysis duration (24.4 ± 21 vs 42.6 ± 40 months), had higher HbA1c (7.9 ± 1.57% vs 5.4 ± 0.95%) and had lower BMI (25 ± 6 vs 27 ± 5 kg/m2). They had lower spine, hip and UD radius BMD Z-scores (all P ≤ 0.001), TBS (1.33 ± 0.12 vs 1.36 ± 0.12; P = 0.05), CT at the FN (P = 0.03), calcar (P = 0.006) and shaft (P < 0.001) and higher BR (10.1±7.1 vs 7.7±4; P = 0.006). All ESKD parameters were lower than population-based reference ranges (P <  0.001). Adjusting for age, sex, dialysis vintage and weight, prevalent vertebral fractures in patients with T1DM and ESKD were associated with higher BR (odds ratio (OR): 3.27 (95% CI: 1.19–8.92), P = 0.002) and lower FN CT (OR: 3.70 (95% CI: 1.13–12.50)).

Conclusion

Patients with ESKD and T1DM have reduced TBS, reduced CT and increased BR compared with other ESKD patients. Prospective study of these parameters is warranted to determine their utility in fracture risk prediction and management.

Significance statement

Patients with ESKD and T1DM have an elevated fracture risk due to decreased bone strength. As an adjunct to BMD, evaluating dual-energy X-ray absorptiometry parameters that incorporate structural change may have greater value in patients with ESKD and T1DM than in the general population. In this study, patients with ESKD due to T1DM had lower BMD, lower trabecular bone scores, more severe loss of CT and higher BR than other patients with ESKD and people from the general population. Both lower CT and higher BR were associated with prevalent vertebral fractures in patients with T1DM and ESKD. Changes to these parameters should be evaluated for incident fracture prediction.

Open access

Eystein S Husebye, Frederik Castinetti, Sherwin Criseno, Giuseppe Curigliano, Brigitte Decallonne, Maria Fleseriu, Claire E Higham, Isabella Lupi, Stavroula A Paschou, Miklos Toth, Monique van der Kooij, and Olaf M Dekkers

Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment but are associated with significant autoimmune endocrinopathies that pose both diagnostic and treatment challenges. The aim of this guideline is to provide clinicians with the best possible evidence-based recommendations for treatment and follow-up of patients with ICI-induced endocrine side-effects based on the Grading of Recommendations Assessment, Development, and Evaluation system. As these drugs have been used for a relatively short time, large systematic investigations are scarce. A systematic approach to diagnosis, treatment, and follow-up is needed, including baseline tests of endocrine function before each treatment cycle. We conclude that there is no clear evidence for the benefit of high-dose glucocorticoids to treat endocrine toxicities with the possible exceptions of severe thyroid eye disease and hypophysitis affecting the visual apparatus. With the exception of thyroiditis, most endocrine dysfunctions appear to be permanent regardless of ICI discontinuation. Thus, the development of endocrinopathies does not dictate a need to stop ICI treatment.

Open access

T Vilaca, A Evans, F Gossiel, M Paggiosi, R Eastell, and J S Walsh

Context

Obese (OB) adults (BMI ≥ 30) have a higher bone mineral density (BMD) and more favourable bone microarchitecture than normal-weight (NW) adults (BMI 18.5–24.9).

Objective

The objective of this study was to identify which fat compartments have the strongest association with bone density and bone turnover and whether biochemical factors (adipokines, hormones and bone regulators) are likely to be important mediators of the effect of obesity on bone.

Design

This was a cross-sectional, observational, matched case-control study.

Setting

Participants were recruited from the local community.

Participants

Two hundred healthy men and women aged 25–40 or 55–75 were recruited in individually matched OB and NW pairs. Body composition, BMD and bone microarchitecture were determined by dual-energy X-ray absorptiometry (DXA), computed tomography (CT) and high-resolution peripheral CT (HR-pQCT). Bone turnover and potential regulators such as C-terminal cross-linking telopeptide (CTX), type 1 procollagen N-terminal peptide (PINP), sclerostin, periostin, parathyroid hormone (PTH), 25-hydroxyvitamin D (25OHD), insulin-like growth factor 1 (IGF1), adiponectin, leptin and insulin were assessed.

Main outcome

Planned exploratory analysis of the relationships between fat compartments, areal and volumetric BMD, bone microarchitecture, bone turnover markers and bone regulators.

Results

Compared with NW, OB had lower CTX, PINP, adiponectin, IGF1, and 25OHD and higher leptin, PTH and insulin (all P < 0.05). CTX and subcutaneous adipose tissue (SAT) were the bone marker and fat compartment most consistently associated with areal and volumetric BMD. In regression models, SAT was negatively associated with CTX (P < 0.001). When leptin was added to the model, SAT was no longer associated with CTX, but leptin (P < 0.05) was negatively associated with CTX.

Conclusions

SAT is associated with lower bone resorption and properties favourable for bone strength in obesity. Leptin may be an important mediator of the effects of SAT on the skeleton.

Open access

Rosario Pivonello, Renata Simona Auriemma, Alessandra Delli Veneri, Francesca Dassie, Riccardina Lorusso, Marta Ragonese, Marco Liotta, Elisa Sala, Barbara Zarino, Elisa Lai, Claudio Urbani, Fausto Bogazzi, Giovanna Mantovani, Salvatore Cannavò, Pietro Maffei, Paolo Chiodini, and Annamaria Colao

Objective

Acromegaly is associated with somatic disfigurements which impair self-perception of well-being and quality of life. Nowadays, limited data are available on the interplay between hormonal excess and psychological discomfort. The study aimed at investigating the psychological profile, sleep quality, sexual function, cognitive functions, and quality of life in patients with acromegaly.

Methods

In 223 acromegaly patients from 5 referral centres, global psychological profile, sleep quality, sexual function, cognitive function, and quality of life were investigated.

Results

Depression was found in ~30% of patients, and anxiety in two-thirds, together with severe discomfort in body image mainly in women. Obstructive sleep apnoea syndrome risk and sleep disorders were found in >50% of patients and daily sleepiness in ~20%. Sexual dysfunction was reported in most of the patients, with the most severe impairment in women. Cognitive functions were compromised in ~10% of cases. Disease duration and patient’s age and gender were the main determinants of these psychopathological conditions. Depression (P = 0.047), somatic-affective mood lowering (P = 0.021), state (P < 0.001) and trait (P = 0.013) anxiety, and body image distortion in body uneasiness test A (P < 0.001) and B (P = 0.006) were significantly worsened in patients <45 years and slightly worsened in those with disease duration less than 2 years. Male (P < 0.001) and female (P < 0.001) sexual function scores were significantly worsened in patients aged >64 years and slightly worsened in those with disease duration for more than 10 years, particularly in presence of cardiometabolic and respiratory complications. Cognitive symptoms were slightly worsened in older patients and in those with long disease duration.

Conclusions

Acromegaly is associated with a relevant impairment of psychological profile persisting despite remission and long-term medical treatment.

Restricted access

Rachel Fourneaux, Rachel Reynaud, Gregory Mougel, Sarah Castets, Patricia Bretones, Benjamin Dauriat, Thomas Edouard, Gerald Raverot, Anne Barlier, Thierry Brue, Frederic Castinetti, and Alexandru Saveanu

Design

Thyroid-stimulating hormone deficiency (TSHD) is a rare disease. It may be isolated, secondary to abnormalities of genes involved in TSH biosynthesis, or associated with other pituitary deficits or abnormalities of genes involved in pituitary ontogenesis. Several genes are involved in thyrotroph development and function.

Objective

Our aim was to determine the genetic causes of TSHD, either isolated (ITSHD) or associated with somatotroph deficiency (TSHD-GHD), in the cohort of patients from the GENHYPOPIT network.

Methods

Next-generation sequencing (NGS) analyses were performed as a panel of genes on a cohort of patients with non-syndromic ITSHD or TSHGHD. The variants were classified according to the American College of Medical Genetics classification reviewed by the NGS-Diag network and correlated with the phenotype. Class 3, 4, and 5 single-nucleotide variants were checked by Sanger sequencing and copy number variants by multiplex ligation-dependent probe amplification (MLPA).

Results

A total of 64 index cases (22 ITSHD and 42 TSHD-GHD) were included in this cohort. A genetic cause was identified in 26.5% of patients, with 36.3% in the ITSHD group (variants in TSHβ and IGSF1) and 21.4% in TSHD-GHD (variants in IGSF1, TSHβ, TRHR, GH1, POU1F1, and PROP1). Among the pathogenic and likely pathogenic variants identified, 42% were in IGSF1, including six not previously reported.

Conclusion

Our results show that IGSF1 variants represent the most frequent aetiology of TSH deficiency. Despite a systematic NGS approach and the identification of new variants, most patients remain without a molecular diagnosis. Larger scale studies, such as exome or genome studies, should be considered in the future.

Open access

Maria Fleseriu, Richard J Auchus, Yona Greenman, Sabina Zacharieva, Eliza B Geer, Roberto Salvatori, Rosario Pivonello, Ulla Feldt-Rasmussen, Laurence Kennedy, Michael Buchfelder, Beverly MK Biller, Fredric Cohen, and Anthony P Heaney

Objective

This extended evaluation (EE) of the SONICS study assessed the effects of levoketoconazole for an additional 6 months following open-label, 6-month maintenance treatment in endogenous Cushing’s syndrome.

Design/Methods

SONICS included dose-titration (150–600 mg BID), 6-month maintenance, and 6-month EE phases. Exploratory efficacy assessments were performed at months 9 and 12 (relative to the start of maintenance). For pituitary MRI in patients with Cushing’s disease, a threshold of ≥2 mm denoted change from baseline in the largest tumor diameter.

Results

Sixty patients entered EE at month 6; 61% (33/54 with data) exhibited normal mean urinary free cortisol (mUFC). At months 9 and 12, respectively, 55% (27/49) and 41% (18/44) of patients with data had normal mUFC. Mean fasting glucose, total and LDL-cholesterol, body weight, BMI, abdominal girth, hirsutism, CushingQoL, and Beck Depression Inventory-II scores improved from the study baseline at months 9 and 12. Forty-six patients completed month 12; four (6.7%) discontinued during EE due to adverse events. The most common adverse events in EE were arthralgia, headache, hypokalemia, and QT prolongation (6.7% each). No patient experienced alanine aminotransferase or aspartate aminotransferase >3× upper limit of normal, Fridericia-corrected QT interval >460 ms, or adrenal insufficiency during EE. Of 31 patients with tumor measurements at baseline and month 12 or follow-up, the largest tumor diameter was stable in 27 (87%) patients, decreased in one, and increased in three (largest increase 4 mm).

Conclusion

In the first long-term levoketoconazole study, continued treatment through a 12-month maintenance period sustained the early clinical and biochemical benefits in most patients completing EE, without new adverse effects.

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Uri Nahum, Julie Refardt, Irina Chifu, Wiebke K Fenske, Martin Fassnacht, Gabor Szinnai, Mirjam Christ-Crain, and Marc Pfister

Objective

Differentiation between central diabetes insipidus (cDI) and primary polydipsia (PP) remains challenging in clinical practice. Although the hypertonic saline infusion test led to high diagnostic accuracy, it is a laborious test requiring close monitoring of plasma sodium levels. As such, we leverage machine learning (ML) to facilitate differential diagnosis of cDI.

Design

We analyzed data of 59 patients with cDI and 81 patients with PP from a prospective multicenter study evaluating the hypertonic saline test as new test approach to diagnose cDI. Our primary outcome was the diagnostic accuracy of the ML-based algorithm in differentiating cDI from PP patients.

Methods

The data set used included 56 clinical, biochemical, and radiological covariates. We identified a set of five covariates which were crucial for differentiating cDI from PP patients utilizing standard ML methods. We developed ML-based algorithms on the data and validated them with an unseen test data set.

Results

Urine osmolality, plasma sodium and glucose, known transsphenoidal surgery, or anterior pituitary deficiencies were selected as input parameters for the basic ML-based algorithm. Testing it on an unseen test data set resulted in a high area under the curve (AUC) score of 0.87. A further improvement of the ML-based algorithm was reached with the addition of MRI characteristics and the results of the hypertonic saline infusion test (AUC: 0.93 and 0.98, respectively).

Conclusion

The developed ML-based algorithm facilitated differentiation between cDI and PP patients with high accuracy even if only clinical information and laboratory data were available, thereby possibly avoiding cumbersome clinical tests in the future.

Restricted access

Sinéad M McGlacken-Byrne, Ashraf Abdelmaksoud, Mohammad Haini, Liina Palm, Michael Ashworth, Juan Li, Wei Wang, Xiumin Wang, Jian Wang, Bridget Callaghan, Veronica A. Kinsler, Francesca Faravelli, and Mehul T Dattani

Genetic alterations within the cAMP/protein kinase A (PKA) pathway result in a spectrum of adrenocortical disorders. Implicated genes include GNAS, PDE8B, PDE11A, PRKAR1A/B, and PRKACA. To date, pathogenic somatic PRKACA variants and germline PRKACA copy number gain have been associated with the development of cortisol-secreting adrenocortical adenomas and bilateral adrenal hyperplasia, respectively. While perturbations within the PRKAR1A gene are known to cause Carney complex, PKRACA mutations are rarely associated with an extra-adrenal phenotype. We describe a mosaic PRKACA duplication in an infant who presented with a Carney-like complex at the age of 3 months with bilateral non-pigmented micronodular adrenal hyperplasia, severe early-onset Cushing’s syndrome, and distinct acral soft tissue overgrowth due to cutaneous mucinosis. This represents a novel manifestation of PRKACA disruption and broadens its extra-adrenal phenotype. It suggests that the Cushing’s syndrome phenotypes arising from somatic and germline PRKACA abnormalities likely exist on a spectrum. We emphasise the importance of ascertaining a genetic diagnosis for PRKACA-mediated disease.

Significance statement

We describe a mosaic PRKACA duplication in a young infant who presented with a Carney-like complex: bilateral non-pigmented micronodular adrenal hyperplasia, severe early-onset Cushing’s syndrome, and distinct acral soft tissue overgrowth due to cutaneous mucinosis. This represents a novel manifestation of PRKACA disruption and broadens the extra-adrenal phenotype of PRKACA-associated Cushing’s syndrome. Our data suggest that Cushing’s syndrome phenotypes arising from somatic and germline PRKACA abnormalities can exist on a spectrum. We emphasise the value of ascertaining a genetic diagnosis for PRKACA-mediated adrenal and extra-adrenal disease to guide individualised and targeted care.