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Daniele Cappellani, Alessandro Brancatella, Riccardo Morganti, Simona Borsari, Fulvia Baldinotti, Maria Adelaide Caligo, Martin Kaufmann, Glenville Jones, Claudio Marcocci, and Filomena Cetani

Background and objectives

CYP24A1 encodes a 24-hydroxylase involved in vitamin D catabolism, whose loss-of-function results in vitamin D-dependent hypercalcemia. Since the identification of CYP24A1 variants as a cause of idiopathic infantile hypercalcemia, a large body of literature has emerged indicating heterogeneity in penetrance, symptoms, biochemistry, and treatments. The objectives of the present research work were to investigate the clinical heterogeneity of the disease, the possibility of a relevant phenotype for monoallelic carriers, and to compare the hypocalcemic effect of the available therapies.

Methods

Two reviewers searched different databases for studies published between the identification of CYP24A1 variants and December 31, 2020. Eligible studies included clinical trials and reports describing carriers of CYP24A1 variants.

Results

Fifty eligible studies were identified, accounting for 221 patients. Genetic data were retrieved and allele frequencies were calculated. Acute hypercalcemia was the typical presentation during the first year of life (76%, P = 0.0005), and nephrocalcinosis was more frequent in infancy (P < 0.0001). Pregnancy was associated with symptomatic hypercalcemia in 81.8% and high rates of obstetric complications. Monoallelic carriers displayed significant rates of nephrolithiasis (19.4%), nephrocalcinosis (4.9%), and symptomatic hypercalcemia (5.6%).

Conclusions

CYP24A1 loss-of-function results in an age-dependent phenotype, which can be exacerbated by triggering factors, such as pregnancy. Although biallelic carriers present more significant clinical and biochemical features, monoallelic carriers have an increased risk of calcium-related conditions. The highly variable tested therapeutic approaches did not allow to draw conclusions on preferable therapeutic regime.

Open access

Roberta Armignacco, Anne Jouinot, Lucas Bouys, Amandine Septier, Thomas Lartigue, Mario Neou, Cassandra Gaspar, Karine Perlemoine, Leah Braun, Anna Riester, Fidéline Bonnet-Serrano, Anne Blanchard, Laurence Amar, Carla Scaroni, Filippo Ceccato, Gian Paolo Rossi, Tracy Ann Williams, Casper K Larsen, Stéphanie Allassonnière, Maria-Christina Zennaro, Felix Beuschlein, Martin Reincke, Jérôme Bertherat, and Guillaume Assié

Objective

Cushing’s syndrome represents a state of excessive glucocorticoids related to glucocorticoid treatments or to endogenous hypercortisolism. Cushing’s syndrome is associated with high morbidity, with significant inter-individual variability. Likewise, adrenal insufficiency is a life-threatening condition of cortisol deprivation. Currently, hormone assays contribute to identify Cushing’s syndrome or adrenal insufficiency. However, no biomarker directly quantifies the biological glucocorticoid action. The aim of this study was to identify such markers.

Design

We evaluated whole blood DNA methylome in 94 samples obtained from patients with different glucocorticoid states (Cushing’s syndrome, eucortisolism, adrenal insufficiency). We used an independent cohort of 91 samples for validation.

Methods

Leukocyte DNA was obtained from whole blood samples. Methylome was determined using the Illumina methylation chip array (~850 000 CpG sites). Both unsupervised (principal component analysis) and supervised (Limma) methods were used to explore methylome profiles. A Lasso-penalized regression was used to select optimal discriminating features.

Results

Whole blood methylation profile was able to discriminate samples by their glucocorticoid status: glucocorticoid excess was associated with DNA hypomethylation, recovering within months after Cushing’s syndrome correction. In Cushing’s syndrome, an enrichment in hypomethylated CpG sites was observed in the region of FKBP5 gene locus. A methylation predictor of glucocorticoid excess was built on a training cohort and validated on two independent cohorts. Potential CpG sites associated with the risk for specific complications, such as glucocorticoid-related hypertension or osteoporosis, were identified, needing now to be confirmed on independent cohorts.

Conclusions

Whole blood DNA methylome is dynamically impacted by glucocorticoids. This biomarker could contribute to better assessment of glucocorticoid action beyond hormone assays.

Open access

Sara Santini, Nathalie Vionnet, Jérôme Pasquier, Michel Suter, Didier Hans, Elena Gonzalez-Rodriguez, Nelly Pitteloud, and Lucie Favre

Objective

Bariatric surgery (BS) induces loss of body fat mass (FM) with an inexorable loss of lean mass (LM). Menopause leads to deleterious changes in body composition (BC) related to estrogen deficiency including LM loss and increase in total and visceral adipose tissue (VAT). This study aims to describe the long-term weight evolution of post-menopausal women after Roux-en-Y gastric bypass (RYGB) and to compare the BC between BS patients vs post-menopausal non-operated women.

Design

Cross-sectional study of 60 post-menopausal women who underwent RYGB ≥2 years prior to the study with nested case–control design.

Methods

Post-menopausal BS women were matched for age and BMI with controls. Both groups underwent DXA scan, lipids and glucose metabolism markers assessment.

Results

Median follow-up was 7.5 (2–18) years. Percentage of total weight loss (TWL%) was 28.5 ± 10%. After RYGB, LM percentage of body weight (LM%) was positively associated with TWL% and negatively associated with nadir weight. Forty-one post-BS women were age- and BMI-matched with controls. Post-BS patients showed higher LM% (57.7% (±8%) vs 52.5% (±5%), P  = 0.001), reduced FM% (39.4% (±8.4%) vs 45.9% (±5.4%), P  < 0.01) and lower VAT (750.6 g (±496) vs 1295.3 g (±688), P  < 0.01) with no difference in absolute LM compared to controls. While post-BS women showed a better lipid profile compared to controls, no difference was found in glucose markers.

Conclusions

Post-menopausal women after RYGB have a lower FM and VAT, preserved LM and a better lipid profile compared to controls. Weight loss after RYGB seems to have a persistent positive impact on metabolic health.

Restricted access

Vin-Cent Wu, Shuo-Meng Wang, Kuo-How Huang, Yao Chou Tsai, Chieh-Kai Chan, Shao-Yu Yang, Lian-Yu Lin, Chin-Chen Chang, Ching-Chu Lu, Yen-Hung Lin, Yung-Ming Chen, and Jeff S Chueh

Objective

Long-term outcomes (especially mortality and/or major cardiovascular events (MACE)) of the unilateral primary aldosteronism (uPA) patients who underwent medical or surgery-targeted treatment, relative to those with essential hypertension (EH), have been scarcely reported.

Design and settings

Using the prospectively designed observational Taiwan Primary Aldosteronism Investigation cohort, we identified 858 uPA cases among 1220 primary aldosteronism patients and another 1210 EH controls.

Exposures

Operated uPA patients were grouped via their 1-year post-therapy statuses.

Results

Primary Aldosteronism Surgical Outcome clinical complete success (hypertension remission) was achieved in 272 (49.9%) of 545 surgically treated uPA patients. After follow-up for 6.3 ± 4.0 years, both hypertension-remissive (hazard ratio (HR): 0.54; P  < 0.001) and not-cured (HR: 0.61; P  < 0.001) uPA patients showed a lower risk of all-cause mortality than that of EH controls; whereas the not-cured group had a higher risk of incident MACE (sub-hazard ratio (sHR), 1.41; P = 0.037) but similar atrial fibrillation (Af) and congestive heart failure (CHF). Mineralocorticoid receptor antagonist (MRA)-treated uPA patients had higher risks of MACE (sHR: 1.38; P = 0.033), Af (sHR:1.62, P = 0.049), and CHF (sHR: 1.44; P = 0.048) than those of EH controls, with mortality as a competing risk. Using inverse probability of treatment-weighted matching and counting adrenalectomy as a time-varying factor, treatment with adrenalectomy was associated with lower risks of all-cause mortality (HR: 0.57; P = 0.035), MACE (HR: 0.67; P = 0.037), and CHF (HR: 0.49; P = 0.005) compared to those of MRA therapy.

Conclusions

Adrenalectomy, independent of post-surgical hypertension remission, was associated with lower all-cause mortality of uPA patients, compared to that of EH patients. We further documented a more beneficial effect of adrenalectomy over MRA treatment on long-term mortality, MACE, and CHF in uPA patients.

Open access

Zimin Song, Meng Gao, Jun Lv, Canqing Yu, Yu Guo, Zheng Bian, Yuxia Wei, Ling Yang, Huaidong Du, Yiping Chen, Jianqiang Zhang, Jvying Yao, Junshi Chen, Zhengming Chen, Tao Huang, Liming Li, and the China Kadoorie Biobank (CKB) Collaborative Group

Objectives

To prospectively assess the association of metabolic health status and its transition with incident diabetes risk across BMI categories.

Design

Cohort study based on the China Kadoorie Biobank (CKB).

Methods

The CKB study enrolled 512 715 adults aged 30–79 years from ten diverse areas in China during 2004–2008. After exclusion, 432 763 participants were cross-classified by BMI categories and the metabolic status was followed up for incident diabetes disease. The changes in BMI and metabolic health status were defined from baseline to the second resurvey.

Results

Type 2 diabetes risk is higher for metabolically healthy obese (MHO) subjects than metabolically healthy normal weight (MHN) individuals (HR: 3.97, 95% CI: 3.64–3.66), and it is highest for those affected by metabolically unhealthy obese (MUO) (HR: 6.47, 95% CI: 6.17–6.79). About 15.26% of participants with MHN converted to metabolically healthy overweight or obesity (MHOO), whereas 48.40% of MHOO remained unconverted throughout the follow-up. In obese or overweight people, the conversion from metabolically healthy to unhealthy might increase the chances of developing diabetes as compared to those with a stable metabolic healthy state (HR: 3.70, 95% CI: 2.99–4.59), while those with persistent metabolic disorders are most likely to have diabetes (HR: 8.32, 95% CI: 7.08–9.78).

Conclusions

Metabolic healthy is a transient state, and individuals converted from metabolically healthy status to unhealthy phenotypes across all BMI categories might raise the risk of diabetes.

Restricted access

Sailimai Man, Yongxiang Gao, Jun Lv, Mingkun Tong, Jianchun Yin, Bo Wang, Yi Ning, and Liming Li

Objective

The risk of gallstones among metabolically healthy obesity (MHO) individuals is largely unexplored. Therefore, the present study investigated the association between MHO and gallstones in a health check-up cohort of Chinese adults.

Design

A prospective cohort study.

Methods

Participants included 58 862 individuals from the MJ health check-up cohort aged ≥ 18 years without a history of gallstones at baseline. Gallstones were diagnosed using abdominal B-type ultrasound. Metabolically healthy was defined as not having any one of the components of metabolic syndrome. Obesity was identified by BMI and waist circumference (WC). Participants were cross-classified at baseline by metabolic health and obesity. Adjusted hazard ratios (HRs) and 95% CIs of gallstones across BMI or WC categories were estimated with Cox proportional hazard regression models.

Results

During a median follow-up of 3.0 years (interquartile range, 1.6–6.1), 1269 participants developed gallstones. Individuals with MHO (HR: 1.95, 95% CI: 1.23, 3.09 for BMI criteria; HR: 1.74, 95% CI: 1.37, 2.21 for WC criteria) had a significantly higher risk of gallstones than those with metabolically healthy normal weight. In metabolically healthy individuals, BMI and WC both displayed linear dose–response relationships with gallstones (P for non-linearity >0.05). The association between MHO and gallstones remained unchanged when using different criteria for metabolic health and obesity.

Conclusions

MHO was significantly associated with gallstones, suggesting that obesity can independently contribute to gallstones development, even among metabolically healthy individuals. These findings emphasize that metabolically healthy individuals may still benefit from maintaining normal body weight to prevent gallstones.

Restricted access

Ranyao Yang, Yue Hu, Chi Ho Lee, Yan Liu, Candela Diaz-Canestro, Carol Ho Yi Fong, Huige Lin, Kenneth K Y Cheng, Aparna Padmanabhan Pravelil, Erfei Song, Karen S L Lam, and Aimin Xu

Objective

Peptidase M20 domain containing 1 (PM20D1), a secreted enzyme catalysing condensation of fatty acids and amino acids into the bioactive lipids N-acyl amino acids (NAAA), induces uncoupling protein 1 (UCP1)-independent adaptive thermogenesis in brown/beige adipocytes in mice. This study aimed to explore the associations of the circulating levels of PM20D1 and major NAAA with obesity-related metabolic complications in humans.

Design and methods

Serum concentrations of PM20D1 and NAAA (C18:1-Leu and C18:1-Phe) in 256 Chinese subjects, including 78 lean and 178 overweight/obese individuals with or without diabetes, were measured with immunoassays and liquid chromatography–mass spectrometry, respectively. The impact of sulfonylurea and rosiglitazone on their circulating levels was examined in 62 patients with type 2 diabetes.

Results

Serum PM20D1 level was significantly elevated in overweight/obese individuals and was closely associated with circulating levels of C18:1-Leu and C18:1-Phe. Furthermore, serum PM20D1, C18:1-Leu and C18:1-Phe concentrations correlated positively with several parameters of adiposity as well as fasting and 2 h postprandial glucose, HbA1c, fasting insulin and HOMA-IR independent of BMI and age. Moreover, a significant elevation in PM20D1, C18:1-Leu and C18:1-Phe concentrations corresponding with increases in the number of components of the metabolic syndrome (MetS) was observed. Treatment with sulfonylurea significantly decreased circulating PM20D1, C18:1-Leu and C18:1-Phe in patients with type 2 diabetes.

Conclusions

Increased serum levels of PM20D1 and its catalytic products NAAA are closely associated with obesity-related glucose dysregulation, insulin resistance and MetS and can be potentially used as clinical biomarkers for diagnosing and monitoring these disorders.

Restricted access

Theresia Weber, Alicia Poplawski, Christian Vorländer, Cornelia Dotzenrath, Rolf Ringelband, Jochen Schabram, Christian Passler, Andreas Zielke, Nicolas Schlegel, Christoph Nies, Detlef Krenz, Joachim Jähne, Robert Schwab, Detlef K Bartsch, Marcel Binnebösel, Matthias Kemen, Carsten Klinger, Heinz Buhr, and Kerstin Lorenz

Aim

Calcitonin (Ctn) measurement in patients with thyroid disease could potentially increase the detection rates of medullary thyroid carcinoma (MTC) but remains a controversial issue. The aim of this study was to evaluate routine preoperative Ctn measurements.

Methods

All patients with thyroid surgery documented in the prospective StuDoQ|Thyroid registry between March 2017 and September 2020 were included. Cutoff levels for Ctn were determined with receiver-operating characteristic analyses to assess the preoperative diagnosis of MTC in subgroups for females and males.

Findings

In 29 590 of 39 679 patients (75%) participating in the registry, routine preoperative Ctn testing was performed. In 357 patients (227 females and 130 males), histopathology confirmed MTC with a mean tumor size of 14.7 mm (±12.43). Biochemical cure was achieved in 71.4% of the patients. Ctn levels between 11 and 20 pg/mL were seen in 2.6% of the patients, and only 0.7% of the patients had Ctn levels above 21 pg/mL. Cutoff levels for the diagnosis of MTC were 7.9 pg/mL for females and 15 pg/mL for males (P  < 0.001). The sensitivity and specificity for females were 95 and 98%, and 96 and 97% for males, respectively.

Conclusion

Routine Ctn testing is a reliable predictor for MTC and provides the opportunity for earlier thyroidectomy before lymph node metastases occur, resulting in a better prognosis. Females with Ctn levels >7.9 pg/mL and males >15 pg/mL without any other extrathyroidal sources for an elevated Ctn should be monitored. Thyroid surgery should be considered if Ctn levels are increasing or ultrasound detects suspicious thyroid lesions.

Restricted access

Mingqiang Zhu, Yangxi Li, Guanping Dong, Xuefeng Chen, Ke Huang, Wei Wu, Yangli Dai, Li Zhang, Hu Lin, Sihua Wang, Constantin Polychronakos, and Junfen Fu

Objective

Recessive WFS1 mutations are known to cause Wolfram syndrome, a very rare systemic disorder. However, they were also found in non-syndromic diabetes in Han Chinese misdiagnosed with type 1 diabetes (T1D), a molecular cause that appears to be considerably more common than the fully expressed syndrome. We aimed to better define the incidence and clinical features of non-syndromic diabetes due to recessive WFS1 mutation.

Design

We analyzed the genotype and phenotype of 320 consecutive incident Chinese pediatric diabetic patients diagnosed from 2016 to 2019 to search for non-syndromic diabetic cases due to recessive WFS1 mutation.

Methods

A cohort of 105 pancreatic autoantibody-negative patients were recruited for exome sequencing. All patients tested positive for pathogenic diallelic WFS1 mutations were examined for phenotypic features (fundoscopy, audiogram, and urine density).

Results

We found three cases of non-syndromic diabetes due to recessive WFS1 mutations (incidence = 0.94% (95% CI: 0.25–2.7%)). All three cases only had mild diabetes when diagnosed. All patients had well-conserved fasting C-peptide when diagnosed but one of them progressed to T1D-like insulin deficiency. In addition, we found a fourth case with previously undetected features of Wolfram syndrome.

Conclusions

Non-syndromic diabetes due to WFS1 mutation may be common among Chinese pediatric patients with diabetes. It is important to differentiate it from other maturity-onset diabetes in the young subtypes with similar phenotype by molecular diagnosis because of different prognosis and, potentially, therapy.

Open access

Fengjiao Peng, Paul Palazzi, Sakina Mezzache, Nasrine Bourokba, Jeremie Soeur, and Brice M.R. Appenzeller

Objective: Endogenous hormones regulate numerous physiological processes in humans. Some of them are routinely measured in blood, saliva and/or urine for the diagnosis of disorders. The analysis of fluids may however require multiple samples collected at different time points to avoid the high variability in the concentration of some hormones. In contrast, hair analysis has been proposed as an interesting alternative to reveal average hormone levels over longer period. In this work, we developed and validated an analytical method for analyzing 36 endogenous steroid and thyroid hormones and one pineal hormone in human hair using ultra-performance liquid chromatography (UPLC)-tandem mass spectrometry (MS/MS).

Methods: Sample preparation involved hair decontamination, pulverization, methanol extraction, and purification with C18-solid phase extraction. Extracts were then divided into two portions, respectively injected into an UPLC-MS/MS system, and analyzed using two different instrumental methods. The method was applied to a healthy female population aged 25-45 years.

Results: The method was validated on supplemented hair samples for the 37 targeted hormones, and its application to the population under study allowed to detect 32 compounds in 2 to 100% of the samples. Complete reference intervals (2.5th-97.5th percentiles) were established for estrone, 17β-estradiol, androstenedione, dehydroepiandrosterone, progesterone, 17α-hydroxyprogesterone, cortisone, cortisol and 3,3’,5-triiodo-L-thyronine. Hair cortisone, cortisol, tetrahydrocortisone and tetrahydrocortisol concentrations were highly correlated with each other, with Kendall's τ correlation coefficients ranging from 0.52 to 0.68.

Conclusion: Allowing the detection of 32 hormones from different chemical classes, the present method will allow to broaden hormonal profiling for better identifying endocrine disorders.