Journal of Clinical Endocrinology & Metabolism最新文献

Objective: To develop and validate a radiomics-clinical combined model combining preoperative computed tomography (CT) and clinical data from patients with papillary thyroid carcinoma (PTC) to predict the efficacy of initial postoperative 131I treatment.

Methods: A total of 181 patients with PTC who received total thyroidectomy and initial 131I treatment were divided into training and testing sets (7:3 ratio). Univariate analysis and multivariate logistic regression were used to screen clinical factors affecting the therapeutic response to 131I treatment and construct a clinical model. Radiomics features extracted from preoperative CT images of PTCs were dimensionally reduced through recursive feature elimination and least absolute shrinkage and selection operator. Logistic regression was used to establish a radiomics model, and a radiomics-clinical combined model was developed by integrating the clinical model. The area under the curve (AUC), sensitivity, and specificity were used to evaluate the prediction performance of each model.

Results: Multivariate analysis revealed that pre-131I treatment serum thyroglobulin was an independent clinical risk factor affecting the efficacy of initial 131I treatment (P = .002), and the AUC, sensitivity, and specificity for predicting the efficacy of initial 131I treatment were 0.895, 0.899, and 0.816, respectively. After dimensionality reduction, 14 key CT radiomics features of PTCs were included. The established radiomics model predicted the efficacy of 131I treatment in the training and testing sets with AUCs of 0.825 and 0.809, sensitivities of 0.828 and 0.636, and specificities of 0.745 and 0.944, respectively. The combined model improved the AUC, sensitivity, and specificity in both sets.

Conclusion: The preoperative CT-based radiomics model can effectively predict the efficacy of initial postoperative 131I treatment in patients with intermediate- or high-risk PTC, and the radiomics-clinical combined model exhibits better predictive performance.

Aims: In the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study, an intervention trial followed by an observational phase, half the participants reached the primary outcome [hemoglobin A1c (HbA1c) ≥ 8% for at least 6 months] within 4 years, which was associated with a decrease in C-peptide oral disposition index (oDI). We aimed to identify circulating microRNA (miRNA) species associated with a decline in beta cell function.

Methods: Following a preliminary survey of select participants using nCounter Human v3 miRNA Panel (NanoString Technologies), polymerase chain reaction analyses were carried out for 17 miRNAs from 365 participants from samples at baseline, 24, 60, 96, and 120 months.

Results: Using a backward selection approach, 4 baseline miRNA log2 fold-changes independently predicted treatment failure; however, baseline HbA1c was higher in those with treatment failure. Three baseline miRNA log2 fold-changes remained significant predictors of this C-peptide oDI decline ≥20% (P < .05). Increased levels of miRNA-155 [odds ratio (OR): 1.2, 95% confidence interval (CI): 1.1-1.4] and miRNA-130b (OR:1.3, 95% CI: 1.0-1.7) were associated with oDI decline, while decreased levels of miRNA-126 (OR: 0.6, 95% CI: .4-.8) were associated with oDI decline. miRNA-122 was negatively correlated with C-peptide oDI at baseline and 24 months (R = 0.22, P < .01 and R = 0.19, P < .01, respectively) and positively correlated with proinsulin at baseline, 24, and 60 months (R = 0.26, P < 0.01, R = 0.26, P < .01, R = 0.18, P < .01, respectively).

Conclusion: The miRNA species associated with beta cell function are associated with alterations in cellular metabolism and apoptosis, suggesting that differences in baseline abundance may serve as circulating markers of beta cell dysfunction and provide potential mechanistic insights into the aggressive nature of youth-onset type 2 diabetes.

Objective: The aim of this study is to evaluate performance of aldosterone-to-renin ratio (ARR) before washout of antihypertensive drugs as a screening test for primary aldosteronism (PA).

Methods: This retrospective analysis included consecutive patients screening for secondary hypertension during a period from January 2017 to May 2022 at the authors' institute. For inclusion in the final analysis, ARR had to be available prior to as well as after discontinuation of antihypertensives. Patients with ARR ≥2.4(ng/dL)/(μIU/mL) after washout proceeded to confirmatory tests. Diagnosis of PA was established based on a positive result of the confirmatory test. The diagnostic accuracy of ARR prior to the washout in predicting PA is shown as sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV).

Results: The analysis included a total of 1306 patients [median age of 50.2 (41.0-59.0) years, 64.0% male]. Confirmatory tests showed PA in 215(16.5%) patients and essential hypertension (EH) in the remaining 1091(83.5%) patients. In comparison to the second screening test, the first screening test (before washout of antihypertensives) yielded lower plasma aldosterone and higher renin and consequently lower ARR in both the PA and EH groups. At a cutoff of .7(ng/dL)/(μIU/mL), ARR before washout had 96.3% sensitivity, 61.2% specificity, .33 PPV, and .99 NPV. At a lower cutoff of .5(ng/dL)/(μIU/mL), the sensitivity, specificity, PPV, and NPV were 97.7%, 52.0%, .29, and .99, respectively.

Conclusion: ARR prior to washout of antihypertensives is a sensitive screening test for PA. Washout of antihypertensives could be omitted and further investigation for PA is not warranted if ARR is ≤ .7(ng/dL)/(μIU/mL) before washout.

Context: A Body Shape Index (ABSI) has been reported to have associations with cardiovascular risk factors. However, there is no information on the association between ABSI and incidence of cardiovascular events.

Methods: We investigated the associations between ABSI and first major cardiovascular events (death from cardiovascular disease, nonfatal acute coronary syndrome, and nonfatal stroke) in 1857 subjects from the database of Flow-Mediated Dilation Japan registry and from Hiroshima University Vascular Function registry.

Results: The areas under the curves of ABSI to predict the first major cardiovascular events were superior to BMI (men: P = .032, women: P = .015) and waist circumference in women (men: P = .078, women: P = .002). The subjects were divided into 2 groups based on the cutoff value of ABSI for predicting first major cardiovascular events: a low ABSI group (<0.0822 in men and <0.0814 in women) and a high ABSI group (≥0.0822 in men and ≥0.0814 in women). During a median follow-up period of 41.6 months, 56 subjects died (23 from cardiovascular causes), 16 had nonfatal acute coronary syndrome, and 14 had nonfatal stroke. The Kaplan-Meier curves for first major cardiovascular events were significantly different between the 2 groups (men, P < .001; women, P < .001). Multivariate analysis revealed that high ABSI remained an independent predictor of first major cardiovascular events (men: hazard ratio, 2.33; 95% CI, 1.07 to 5.06; P = .033; women: hazard ratio, 8.33; 95% CI, 1.06 to 65.49; P = .044).

Conclusion: High ABSI is independently associated with incidence of cardiovascular events. ABSI calculation should be performed for evaluation of risk of cardiovascular events.

Context: Testosterone therapy has been variably associated with increased thrombotic risk but investigations of global coagulation in this setting are lacking.

Objective: This work aimed to compare global coagulation of hypogonadal men before (T0) and 6 months after (T1) starting testosterone replacement therapy (TRT), and healthy controls (HCs).

Methods: An observational prospective cohort study was conducted at 2 tertiary endocrinological ambulatory care centers. Patients included 38 men with hypogonadism (mean age 55 years, SD 13) and 38 age-matched HCs. Thrombin generation assay (TGA) was performed at T0 and T1 in hypogonadal men and in HCs. TGA is an in vitro procedure based on the continuous registration of thrombin generation and decay under conditions mimicking the process that occurs in vivo. The following TGA parameters were recorded: lag time; thrombin-peak concentration; time-to-reach peak, velocity index, and endogenous thrombin potential (ETP), the latter representing the total amount of thrombin generated under the driving forces of procoagulants opposed by the anticoagulants. Protein C, antithrombin, factor (F) VIII, and fibrinogen were assessed.

Results: No changes in TGA parameters were observed between T0 and T1. Hypogonadal men displayed significantly higher ETP, fibrinogen, and significantly lower antithrombin levels both at T0 and T1 compared to HCs. Thrombin peak of hypogonadal men was significantly higher than HCs at T0 but not at T1. ETP and antithrombin were correlated with testosterone levels.

Conclusion: Hypogonadal men display a procoagulant imbalance detected by increased thrombin generation. Short-term TRT does not worsen global coagulation, suggesting that the treatment can be safely prescribed to men diagnosed with hypogonadism.

Introduction: Heterogenous clinical manifestations, overlapping phenotypes, and complex genetic backgrounds are common in patients with endocrine tumors. There are no comprehensive recommendations for genetic testing and counseling of these patients compared to other hereditary cancer syndromes. The application of multigene panel testing is common in clinical genetic laboratories, but their performance for patients with endocrine tumors has not been assessed.

Methods: As a national reference center, we prospectively tested the diagnostic utility and cost-efficiency of a multigene panel covering 113 genes representing genetic susceptibility for solid tumors; 1279 patients (including 96 cases with endocrine tumors) were evaluated between October 2021 and December 2022 who were suspected to have hereditary tumor syndromes.

Results: The analytical performance of the hereditary cancer panel was suitable for diagnostic testing. Clinical diagnosis was confirmed in 24% (23/96); incidental findings in genes not associated with the patient's phenotype were identified in 5% (5/96). A further 7% of pathogenic/likely pathogenic variants were detected in genes with potential genetic susceptibility roles but currently no clear clinical consequence. Cost-benefit analysis showed that the application of a more comprehensive gene panel in a diagnostic laboratory yielded a shorter turnaround time and provided additional genetic results with the same cost and workload.

Discussion: Using comprehensive multigene panel results in faster turnaround time and cost-efficiently identifies genetic alterations in hereditary endocrine tumor syndromes. Incidentally identified variants in patients with poor prognoses may serve as a potential therapeutic target in tumors where therapeutic possibilities are limited.

Context: The pituitary gland is key for childhood growth, puberty, and metabolism. Pituitary dysfunction is associated with a spectrum of phenotypes, from mild to severe. Congenital hypopituitarism (CH) is the most commonly reported pediatric endocrine dysfunction, with an incidence of 1:4000, yet low rates of genetic diagnosis have been reported.

Objective: We aimed to unveil the genetic etiology of CH in a large cohort of patients from Argentina.

Methods: We performed whole exome sequencing of 137 unrelated cases of CH, the largest cohort examined with this method to date.

Results: Of the 137 cases, 19.1% and 16% carried pathogenic or likely pathogenic variants in known and new genes, respectively, while 28.2% carried variants of uncertain significance. This high yield was achieved through the integration of broad gene panels (genes described in animal models and/or other disorders), an unbiased candidate gene screen with a new bioinformatics pipeline (including genes with high loss-of-function intolerance), and analysis of copy number variants. Three novel findings emerged. First, the most prevalent affected gene encodes the cell adhesion factor ROBO1. Affected children had a spectrum of phenotypes, consistent with a role beyond pituitary stalk interruption syndrome. Second, we found that CHD7 mutations also produce a phenotypic spectrum, not always associated with full CHARGE syndrome. Third, we add new evidence of pathogenicity in the genes PIBF1 and TBC1D32, and report 13 novel candidate genes associated with CH (eg, PTPN6, ARID5B).

Conclusion: Overall, these results provide an unprecedented insight into the diverse genetic etiology of hypopituitarism.

Context: X-linked hypophosphatemia (XLH) is a rare metabolic bone disease caused by inactivation mutations in the PHEX gene. Despite the extensive number of reported PHEX variants, only a few cases of chromosomal abnormalities have been documented.

Objective: We aimed to identify the pathogenic variants in 6 unrelated families with a clinical diagnosis of XLH and to propose a genetic workflow for hypophosphatemia patients suspected of having XLH.

Methods: Multiple genetic testing assays were used to analyze the 6 families' genetic profiles, including whole exome sequencing, multiplex ligation-dependent probe amplification, whole genome sequencing, reverse transcript polymerase chain reaction, Sanger sequencing, and karyotyping.

Results: The study identified 6 novel pathogenic variants, including 1 mosaic variant (exon 16-22 deletion), 3 chromosomal abnormalities (46, XN, inv[X][pter→p22.11::q21.31→p22.11::q21.31 →qter], 46, XN, inv[X][p22.11p22.11], and XXY), a nonclassical intron variant (NM_000444.6, c.1701_31A > G), and a deletion variant (NM_000444.6, c.64_5464-186 del5215) of PHEX. Additionally, a genetic testing workflow was proposed to aid in diagnosing patients suspected of XLH.

Conclusion: Our research expands the mutation spectrum of PHEX and highlights the significance of using multiple genetic testing methods to diagnose XLH.