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Open access

Cheng Han Ng, Yip Han Chin, Marcus Hon Qin Tan, Jun Xuan Ng, Samantha Peiling Yang, Jolene Jiayu Kiew and Chin Meng Khoo

Purpose: Primary hyperparathyroidism (PHPT) is common condition, affecting people of all ages and is mainly treated with parathyroidectomy. Cinacalcet has been widely used in secondary or tertiary hyperparathyroidism, but the use of cinacalcet in PHPT is less clear.

Methods: Searches were conducted in Medline and Embase for cinacalcet use in PHPT from induction to 10th April 2020. Articles and conferences abstracts describing the use of cinacalcet for PHPT in prospective or retrospective cohorts and randomized controlled trials restricted to English Language only. We initially identified 1301 abstracts. Each article went extraction by two blinded authors on a structured proforma. Continuous outcomes were pooled with weight mean difference (WMD). Quality of included articles was assessed with Newcastle Ottwa Scale and Cochrane risk of Bias 2.0.

Results: 28 articles were included. Normalization rate of serum calcium levels was reported at 90% (CI: 0.82 to 0.96). Serum levels of calcium and PTH levels were significantly reduced (calcium, WMD: 1.647 (CI: -1.922 to -1.371; PTH, WMD: -31.218, CI: -41.671 to -20.765) and phosphate levels significantly increased (WMD: 0.498, CI: 0.400 to 0.596) after cinacalcet therapy The higher the baseline calcium levels, the greater calcium reduction with cinacalcet treatment. Age and gender did not modify the effect of cinacalcet on serum calcium levels.

Conclusion: The results from the meta-analysis support the use of cinacalcet as an alternative or bridging therapy to treat hypercalcemia in people with PHPT.

Open access

David Koeckerling, Jeremy W Tomlinson and Jeremy Cobbold

Non-alcoholic fatty liver disease is a chronic liver disease which is closely associated with components of the metabolic syndrome. Its high clinical burden results from the growing prevalence, inherent cardiometabolic risk and potential of progressing to cirrhosis. Patients with non-alcoholic fatty liver disease show variable rates of disease progression through a histological spectrum ranging from steatosis to steatohepatitis with or without fibrosis. The presence and severity of fibrosis are the most important prognostic factors in non-alcoholic fatty liver disease. This necessitates risk stratification of patients by fibrosis stage using combinations of non-invasive methods such as composite scoring systems and/or transient elastography. A multidisciplinary approach to treatment is advised, centred on amelioration of cardiometabolic risk through lifestyle and pharmacological interventions. Despite the current lack of licensed, liver-targeted pharmacotherapy, several promising agents are undergoing late-phase clinical trials to complement standard management in patients with advanced disease. This review summarises the current concepts in diagnosis and disease progression of non-alcoholic liver disease, focusing on pragmatic approaches to risk assessment and management in both primary and secondary care settings.

Open access

Chunliang Yang, Junyi Li, Fei Sun, Haifeng Zhou, Jia Yang and Chao Yang

Hyperglycemia is the consequence of blood glucose dysregulation and a driving force of diabetic complications including retinopathy, nephropathy and cardiovascular diseases. The serum and glucocorticoid inducible kinase-1 (SGK1) has been suggested in the modulation of various pathophysiological activities. However, the role of SGK1 in blood glucose homeostasis remains less appreciated. In this review, we intend to summarize the function of SGK1 in glucose level regulation and to examine the evidence supporting the therapeutic potential of SGK1 inhibitors in hyperglycemia. Ample evidence points to the controversial roles of SGK1 in pancreatic insulin secretion and peripheral insulin sensitivity, which reflects the complex interplay between SGK1 activation and blood glucose fluctuation. Furthermore, SGK1 is engaged in glucose absorption and excretion in intestine and kidney, and participates in the progression of hyperglycemia induced secondary organ damage. As a net effect, blockage of SGK1 activation via either pharmacological inhibition or genetic manipulation seems to be helpful in glucose control at varying diabetic stages.

Open access

Anne Jouinot, Juliane Lippert, Martin Fassnacht, Bruno De La Villeon, Amandine Septier, Mario Neou, Karine Perlemoine, Silke Appenzeller, Mathilde Sibony, Sebastien Gaujoux, Bertrand Dousset, Rosella Libe, Lionel Groussin, Cristina L Ronchi, Guillaume Assie and Jerome Bertherat

Background: The prognosis of adrenocortical carcinoma (ACC) is heterogeneous. Genomic studies have identified ACC subgroups characterized by specific molecular alterations, including features measured at DNA level (somatic mutations, chromosome alterations, DNA methylation), which are closely associated with outcome. The aim of this study was to evaluate intratumor heterogeneity of prognostic molecular markers at the DNA level.

Methods: Two different tissue samples (primary tumor, local recurrence or metastasis) were analyzed in 26 patients who underwent surgery for primary or recurrent ACC. DNA-related biomarkers with prognostic role were investigated in frozen and paraffin-embedded samples. Somatic mutations of p53/Rb and Wnt/β-catenin pathways were assessed using next-generation sequencing (n=26), chromosome alteration profiles were determined using SNP arrays (n=14) and methylation profiles were determined using 4-gene bisulfite pyrosequencing (n=12).

Results: Somatic mutations for ZNRF3, TP53, CTNN1B and CDKN2A were found in 7, 6, 6 and 4 patients respectively, with intratumor heterogeneity in 8/26 patients (31%). Chromosome alteration profiles were 'Noisy' (numerous and anarchic alterations) in 8/14 and 'Chromosomal' (extended patterns of loss of heterozygosity) in 5/14 of the study samples. For these profiles, no intratumor heterogeneity was observed. Methylation profiles were hypermethylated in 5/12 and non-hypermethylated in 7/12 of the study samples. Intratumor heterogeneity of methylation profiles was observed in 2/12 patients (17%).

Conclusions: Intratumor heterogeneity impacts DNA-related molecular markers. While somatic mutation can differ, prognostic DNA methylation and chromosome alteration profile seem rather stable, and might be more robust for the prognostic assessment.

Open access

Milica Popovic, Fahim Ebrahimi, Sandrine Andrea Urwyler, Marc Yves Donath and Mirjam Christ-Crain

Arginine vasopressin (AVP) was suggested to contribute to cardiovascular risk and type 2 diabetes in patients with metabolic syndrome. The proinflammatory cytokine interleukin-(IL)-1 is able to induce AVP secretion and plays a causal role in cardiovascular mortality and type 2 diabetes. We investigated in two studies whether copeptin levels – the surrogate marker for AVP – are regulated by IL-1-mediated chronic inflammation in patients with metabolic syndrome. Study A was a prospective, interventional, single-arm study (2014-2016). Study B was a randomized, placebo-controlled, double-blind study (2016-2017). n=73 (Study A) and n=66 (Study B) adult patients with metabolic syndrome were treated with 100 mg anakinra or placebo (only in study B) twice daily for 1 day (study A), and 28 days (study B). Fasting blood samples were drawn at day 1, 7, and 28 of treatment for measurement of serum copeptin. Patients with chronic low-grade inflammation (C-reactive protein levels ≥2 mg/l) and BMI >35 kg/m2 had higher baseline copeptin levels (7.7 [IQR 4.9-11.9] vs. 5.8 [IQR 3.9-9.3] pmol/l, pinflamm=0.009; 7.8 [IQR 5.4-11.7] vs. 4.9 [IQR 3.7-9.8] pmol/l, pBMI=0.008). Copeptin levels did not change neither in the anakinra nor in the placebo group and remained stable throughout the treatment (p=0.44). Subgroup analyses did not reveal effect modifications. Therefore, we conclude that although IL-1-mediated inflammation is associated with increased circulating copeptin levels, antagonizing IL-1 does not significantly alter copeptin levels in patients with metabolic syndrome.

Open access

Marie Reeberg Sass, Nicolai Jacob Wewer Albrechtsen, Jens Pedersen, Kristine Juul Hare, Nis Borbye Pedersen, Katalin Kiss, Tina Vilsbøll, Filip Krag Knop, Steen S. Poulsen, Niklas Rye Jørgensen, Jens Juul Holst, Cathrine Ørskov and Bolette Hartmann

Objective: Parathyroid hormone (PTH) is a key hormone in regulation of calcium homeostasis and its secretion is regulated by calcium. Secretion of PTH is attenuated during intake of nutrients, but the underlying mechanism(s) are unknown. We hypothesized that insulin acts as an acute regulator of PTH secretion.

Methods: Intact PTH was measured in plasma from patients with T1D and matched healthy individuals employing 4-hour oral glucose tolerance test (OGTT) and isoglycemic intravenous glucose infusion on two separate experimental. In addition, expression of insulin receptors on archived, surgical specimens of parathyroid glands were assessed by immunochemistry (IHC) and quantitative polymerase chain reaction (qPCR).

Results: The inhibition of PTH secretion was more pronounced in healthy individuals compared to patients with T1D during an OGTT (decrementalAUC0-240min: -5256 ± 3954 min×ng/L and -2408 ± 1435 min×ng/L, P=0.030). Insulin levels correlated significantly and inversely with PTH levels, also after adjusting for levels of several gut hormones and BMI (P=0.002). Expression of insulin receptors in human parathyroid gland were detected by IHC and qPCR.

Conclusion: Our study suggests that insulin may act as an acute regulator of PTH secretion in humans.

Open access

Qing Zhu, Jianbin Su, Xueqin Wang, Mengjie Tang, Yingying Gao and Dongmei Zhang

Graves' disease (GD), an organ-specific autoimmune disease, is the most common cause of hyperthyroidism. Tumour necrosis factor-alpha (TNF-α) exhibits immunological and metabolic activities involved in the induction and maintenance of immune responses. We attempted to evaluate the relationship between GD and serum TNF-α and its soluble receptors (sTNFRs), soluble tumour necrosis factor receptor 1 and 2 (sTNF-R1 and sTNF-R2). A total of 72 GD patients and 72 matched healthy individuals were recruited for this study. Serum TNF-α and sTNFRs were measured by sandwich ELISA. In our study, no significant difference was observed in TNF-α, but sTNFRs were found to be significantly elevated in GD patients compared to healthy individuals. Serum sTNFR levels were positively correlated with free triiodothyronine (FT3) and free thyroxine (FT4), and TNF-α was negatively correlated with thyroid-stimulating hormone (TSH) in the GD group. It was also shown that thyrotropin receptor antibody (TRAb) was positively correlated with TNF-α and sTNFRs. Spearman’s correlation analysis showed that only sTNF-R1 was positively correlated with complement C3. Multiple linear regression analysis suggests that serum levels of sTNF-R1 and FT4 may play an important role in the serum level of FT3. According to the median value of FT3 level, GD patients were further divided into a high FT3 group and a low FT3 group. The serum levels of sTNF-R1 in the high FT3 GD group were significantly higher than those in the low FT3 GD group. In conclusion, sTNFRs may play an important role in anti-inflammatory and immune response in GD.

Open access

Jana Ernst, Katharina Gert, Frank Bernhard Kraus, Ulrike Elisabeth Rolle-Kampczyk, Martin Wabitsch, Faramarz Dehghani and Kristina Schaedlich

The rapid increase of obesity during the last few decades and its future prospects are alarming. Besides the generally discussed causes of obesity, the 'Developmental Origins of Health and Disease' (DOHaD) hypothesis has received more attention in recent years. This hypothesis postulates an adverse influence during early development that programs the unborn child for metabolic dysfunctions later in life. Childhood obesity – an as much increasing problem – can be predisposed by maternal overweight and diabetes. Both, obesity and hyperinsulinemia are major causes of female hyperandrogenemia. As predicted by the DOHaD hypothesis and shown in animal models, developmental androgen excess can lead to metabolic abnormalities in offspring. In this study, we investigated, if androgen-exposure adversely affects the adipogenic differentiation of preadipocytes and the endocrine function of adult adipocytes. The human SGBS preadipocyte model was used to affirm the de-novo biosynthesis of steroid hormones under normal adipogenesis conditions. Normal adipogenesis was paralleled by an increase of corticosteroids and androgens, whereas estrogen remained at a steady level. Treatment with androstenedione had no effect on SGBS proliferation and differentiation, but adult adipocytes exhibited a significant higher accumulation of triglycerides. Progesterone (up to 2-fold), testosterone (up to 38-fold) and cortisone (up to 1.4-fold) – but not cortisol – were elevated by androstenedione-administration in adult adipocytes. Estrogen was not altered. Data suggest that androgen does not negatively influence adipogenic differentiation but steroidogenic function of SGBS adipocytes.

Open access

Mojca Zerjav Tansek, Ana Bertoncel, Brina Sebez, Janez Zibert, Urh Groselj, Tadej Battelino and Magdalena Avbelj Stefanija

Despite recent improvements in the composition of the diet, lower mineral bone density and overweight tendencies are incoherently described in patients with phenylketonuria (PKU). The impact of dietary factors and plasma phenylalanine levels on growth, body mass index, body composition, and bone mineral density was investigated in our cohort of patients with hyperphenylalaninemia (HPA) with or without dietary treatment. The anthropometric, metabolic, body mass index and other nutritional indicators and bone mineral density were compared between the group of 96 treated patients with PKU (58 classic PKU (cPKU) and 38 patients with moderate-mild PKU defined as non-classic PKU (non-cPKU)) and the untreated group of 62 patients with benign HPA. Having compared the treated and untreated groups, there were normal outcomes and no statistically significant differences in body mass index, body composition, and bone mineral density. Lower body height standard deviation scores were observed in the treated as compared to the untreated group (p <0.001), but the difference was not significant when analyzing patients older than 18 years; however, cPKU adults were shorter compared to non-cPKU treated adults (p=0.012). Interestingly, the whole-body fat was statistically higher in non-cPKU as compared to cPKU patients. In conclusion, the dietary treatment ensures adequate nutrition without significant consequences in body mass index, body composition, and bone mineral density. A low protein diet may delay the growth in childhood, but the treated patients gain a normal final height. Mild untreated hyperphenylalaninemia characteristic for benign HPA has no negative physiological effect on bone mineral density.

Open access

Tomás P Griffin, Caroline M Joyce, Sumaya Alkanderi, Liam M Blake, Derek T O’Keeffe, Delia Bogdanet, Md Nahidul Islam, Michael C Dennedy, John E Gillan, John J Morrison, Timothy O’Brien, John A Sayer, Marcia Bell and Paula M O’Shea

Introduction

Inactivating mutations in CYP24A1, encoding vitamin D-24-hydroxylase, can lead to an accumulation of active vitamin D metabolites and consequent hypercalcaemia. Patient (infantile and adult) presentation is varied and includes mild-severe hypercalcaemia, hypercalciuria, nephrocalcinosis and nephrolithiasis. This study aimed to characterize the clinical and biochemical phenotypes of a family with two CYP24A1 missense variants.

Methods

The proband and seven family members underwent detailed clinical and biochemical evaluation. Laboratory measurements included serum calcium, intact parathyroid hormone (iPTH), vitamin D metabolites and urine calcium and creatinine.

Results

The proband presented during the second trimester of a planned pregnancy with flu-like symptoms. Laboratory tests showed elevated adjusted calcium of 3.27 (upper reference limit (URL: 2.30) mmol/L), suppressed iPTH (<6 ng/L), elevated 25(OH)D (264 (URL: 55) nmol/L) and elevated 1,25(OH)D (293 (URL: <280) pmol/L). Ionized calcium was 1.55 (URL: 1.28) mmol/L. Sanger sequencing revealed two heterozygous missense variants in the CYP24A1: p.(Arg439Cys), R439C and p.(Trp275Arg), W275R. The proband’s brother and sister had the same genotype. The brother had intermittent hypercalcaemia and hypervitaminosis D. Only the sister had a history of nephrolithiasis. The proband’s daughter and two nephews were heterozygous for the R439C variant. The proband and her brother frequently had elevated 25(OH)D:24,25(OH)2D ratios (>50) during follow-up.

Conclusions

W275R is a new pathogenic CYP24A1 mutation in compound heterozygotic form with R439C in this family.