Journal of Clinical Endocrinology & Metabolism最新文献

Context: X-linked hypophosphatemia (XLH) is the most common form of heritable hypophosphatemic rickets. Previous studies have found deteriorated bone microarchitecture in the XLH adults. Detailed studies on the skeletal microarchitecture of XLH adolescent and pediatric patients are still lacking.

Objective: This study aimed to evaluate bone geometry, density, microarchitecture, stiffness in XLH adolescent and pediatric patients by using high-resolution peripheral quantitative computed tomography (HR-pQCT).Method: This study utilized HR-pQCT to assess bone geometry, density, microarchitecture, and stiffness in 106 Chinese adolescent and pediatric patients with XLH.

Result: Compared with the sex- and age-matched controls, XLH patients had significantly higher trabecular area (Tb.Ar), lower total volumetric bone mineral density (Tot.vBMD), lower cortical volumetric BMD (Ct.vBMD), and lower stiffness at both the distal radius and the tibia after adjusting for height and weight. Alkaline phosphatase Z score (ALP-Z), a marker to reflect the disease activity of rickets, was negatively correlated with Ct.vBMD and cortical thickness (Ct.Th) at the distal radius, and Ct.vBMD at the distal tibia, and positively correlated with cortical porosity (Ct.Po) at the distal tibia. We developed an online calculator to estimate Tb.Ar, Ct.vBMD, and stiffness of the distal tibia of XLH adolescent and pediatric patients based on clinical general characteristic and biochemical indicators.

Conclusion: The bone microarchitecture of XLH adolescent and pediatric patients was deteriorated, and ALP-Z was negatively correlated with the skeletal quality of XLH adolescent and pediatric patients, especially in the cortical bone. HR-pQCT parameters can be estimated using clinical characteristics and biochemical indicators, which may assist physicians to monitor the disease progression in areas without HR-pQCT access.

Context and objective: Identifying the risk of malignancy and genetic status in primary paraganglioma or pheochromocytoma (PPGL) is a key challenge. The aim was to assess the diagnostic accuracy of genomic, metabolomic and histopathological biomarkers for predicting metastatic and genetic status.

Design, setting, and patients: COMETE-TACTIC is a prospective study (NCT02672020) conducted from November 2015 to March 2019 across 16 referral centers. Tumor samples and liquid biopsies from 231 consecutive patients with PPGL were collected.

Main outcome measures: Germline and somatic genetic status were determined by NGS. SDHB, SDHA and CA9 immunohistochemistries were performed on tumor tissues. TERT promoter methylation was assessed by pyrosequencing. Metabolomic profile and circulating miRNAs were measured in liquid biopsies by gas chromatography MS/MS and TaqMan assay quantified by droplet digital PCR, respectively.

Results: Tumor analysis outperformed germline analysis for determining genetic status. Positive SDHA and SDHB staining combined with negative CA9 labeling indicated the absence of SDHx and VHL variants. Plasma succinate levels above 4.94µM identified SDHx mutation carriers with 65% sensitivity and 92% specificity (AUC-ROC 0.82, 95%CI 0.70-0.93). Among circulating miRNAs, miR-483-5p was the best classifier of metastatic status (AUC-ROC 0.64, 95%CI 0.52-0.77). A sum of dinucleotide methylation rate of TERT promoter CpGs above 42% predicted metastatic status (AUC-ROC 0.75, 95%CI 0.65-0.85). Multivariate analyses showed that biomarker combinations significantly predicted SDHx status (AUC-ROC 0.99, 95%CI 0.98-1.00) and metastatic potential (AUC-ROC 0.93, 95%CI 0.84-1).

Conclusions: Circulating miR-483-5p, plasma succinate, TERT promoter methylation, and SDHB immunostaining are valuable for PPGL risk stratification. Combining biomarkers with clinical data provides excellent diagnostic accuracy for metastatic patients (AUC-ROC 0.97, 95%CI 0.93-1).

Context: BRAF V600E mutation is the most common genetic driver of papillary thyroid cancer (PTC), where it is found with various allele frequency (AF), reflecting the proportion of cells carrying the mutant and wild-type gene alleles.

Objective: To determine whether BRAF V600E AF can improve prognostication and inform initial surgical management of PTC.

Design: Retrospective cohort study (2016-2019).

Setting: UCLA health.

Patients: Consecutive patients with Bethesda V/VI nodules and isolated BRAF V600E mutation who underwent surgery with histopathology showing PTC.

Interventions: Blinded ThyroSeq v3 molecular analysis after completion of initial management and follow-up.

Main outcomes measures: Aggressive histopathology and cancer persistence/recurrence.

Results: Of 73 patients, the median BRAF V600E AF was 25.5% (IQR, 16.7-34.3%). Higher median AF was seen in patients classified as American Thyroid Association (ATA) high-risk (37%) vs. intermediate-risk (25.3%, p<0.01) and low-risk (24.7%, p<0.01), largely attributed to higher AF in patients with gross extrathyroidal extension (ETE) (40.1% vs. 25.2% without gross ETE, p=0.02). No differences in AF were observed on the basis of lymph node positivity or presence of aggressive variants of PTC. A higher BRAF V600E AF was also found in patients with tumors ≥2cm vs. <2cm (median 32.0% vs. 24.4%, p<0.01). Over 4.1 years of follow-up, disease persistence/recurrence was found in 7 patients (9.4%) and was associated with higher median AF than those without recurrence (35.3% vs. 25.2%, p=0.02). Higher AF was associated with poorer recurrence-free survival (AF≥35%, HR 7.40, CI 1.4-38.1).

Conclusions: Higher AF was associated with gross ETE and increased recurrence risk. This may inform initial management in patients with PTC harboring an isolated BRAF V600E mutation.

Objective: To examine potential differences in glucose levels during and after exercise between sexes in adults with type 1 diabetes.

Methods: The T1DEXI study was a prospective, 4-week free-living observational study in adults with type 1 diabetes. Ninety-one females were matched on age and insulin-modality to 91 males. Participants completed exercise study videos and personal exercise sessions. Study-collected food, insulin, exercise, and glucose data surrounding exercise and on sedentary days were compared between sexes to examine how they impact glucose levels during and after exercise.

Results: Female participants had higher glucose levels than male participants when starting study exercise (8.5 ± 2.8 vs. 8.0 ± 2.8 mmol/L, p=0.01) and when starting personal exercise activities (8.4 ± 2.9 vs. 7.8 ± 2.7 mmol/L, p=0.05). Glucose declines during study exercise were comparable between female and male participants (adjusted mean: -0.8 vs. -1.0 mmol/L respectively, p=0.11), but smaller in female participants during personal exercise (adjusted mean: -0.9 vs. -1.4 mmol/L, p<0.001). 24-hour mean glucose levels were also higher in female participants on sedentary days (p=0.04). Daily macronutrient consumption was similar between sexes after adjusting for weight, as were food, exercise, and insulin habits surrounding exercise.

Conclusions: Female participants had higher pre-exercise glucose levels compared to male participants, and smaller glucose declines during personal exercise, but there were no observable differences in food, exercise, and insulin habits.

Context: Patients with diabetes are prone to acute kidney injury with the potential transition to chronic kidney disease. Few studies have investigated the role of thiazolidinedione (TZD) in these patients under acute kidney disease (AKD) phase.

Objective: We sought to examine whether using TZD during AKD could reduce the risk of future major adverse outcomes.

Design and methods: We employed the TriNetX platform before September 30, 2022, for TZD administration to patients with type 2 diabetes mellitus (T2DM) within 90 days of an AKD diagnosis. Clinical endpoints include the risk of all-cause mortality, major adverse cardiovascular events (MACE), and major adverse kidney events (MAKE). Hazard ratios (HRs) and 95% confidence intervals were calculated with 1:1 ratio propensity score matching (PSM).

Results: Among the cohort of 263,101 patients with AKD and T2DM, we identified 2,723 individuals (1.03%) who were TZD users during the AKD period. After PSM, the final cohort of TZD users included 2,555 individuals, with 53.82% being male and a mean age of 64.0 ± 13.5 years. Over a median follow-up period of 1.5 years, the TZD group exhibited a lower risk across various outcomes, with hazard ratios (HR) of 0.68 (95% CI, 0.57-0.81) for all-cause mortality, 0.68 (95% CI, 0.58-0.80) for MACE, and 0.75 (95% CI, 0.66-0.86) for MAKE.

Conclusion: TZD demonstrated a notable reduction in mortality, cardiovascular events, and kidney-related adverse events among T2DM patients with AKD. These findings suggest a potential benefit of TZD usage for managing cardiovascular events in T2DM patients with AKD.

Context: Obesity is associated with low vitamin D and recent studies have suggested a difference in vitamin D metabolism between females and males.

Objective: The aim of this study was to investigate the effects of weight loss on vitamin D status in individuals with obesity, and secondarily, whether vitamin D metabolism differs between women and men.

Methods: Secondary analysis from a randomized placebo-controlled trial, designed to investigate the efficacy of 52 weeks of treatment with either liraglutide, exercise or combined, compared with placebo on weight loss maintenance after an 8-week low-calorie diet-induced weight loss in 195 individuals with obesity (BMI 32-43 kg/m2).

Results: The low-calorie diet-induced weight loss resulted in an increase in serum 25(OH)D in both women and men (12 nmol/L (95%CI 9-15) and 13 nmol/L (95%CI 8-17); p < 0.001 for both). Women who experienced a further weight loss during the 52 weeks of intervention had an increase in serum 25(OH)D compared with women regaining weight (14 nmol/L (95%CI 6-22); p = 0.001). Interestingly, women experiencing further weight loss at week 52 had a lower serum 25(OH)D at baseline compared with women regaining weight (54 nmol/L (SD 19) vs. 70 nmol/L (SD 25); p < 0.001).

Conclusion: Weight loss induced by a low-calorie diet resulted in an increase in serum 25(OH)D in both women and men. Only in women, further weight loss had an additional beneficial impact on vitamin D. Additionally, initial low serum 25(OH)D was associated with successful weight loss maintenance in women, but not men.

Objectives: Studies on the relationship between serum sclerostin, a Wnt/β-catenin pathway inhibitor, and atherosclerosis have yielded inconsistent results. We aim to longitudinally investigate the relationship between serum sclerostin levels and the risk of increased arterial stiffness in Japanese community-dwelling women.

Methods: Of 1044 women aged ≥50 years whose brachial-ankle pulse wave velocity (baPWV) value was available in a baseline survey in 2011-2012, we excluded 374 whose baPWVs were ≥1800 cm/s, set as the cutoff for increased arterial stiffness, and eight with missing data. Of the remaining 662 women, we included in the analysis 556 followed in the 4- to 5-year follow-up study. The coefficient of variation of the sclerostin measurement was 3.45%. We obtained odds ratios (ORs) for sclerostin at baseline categorized by tertiles, with the high tertile as reference for increased arterial stiffness.

Results: Ninety-four women showed increased arterial stiffness during a mean follow-up of 4.0 years. The increased arterial stiffness rates in the low, medium, and high tertiles were 22.2%, 16.1%, and 12.4%, respectively (trend test p = 0.013). The ORs for the medium and low tertiles for increased arterial stiffness were 1.58 (p = 0.205) and 2.16 (p = 0.027), respectively, after adjusting for age and baseline baPWV. After further adjustment for baseline BMI, hypertension, hyperlipidemia, diabetes mellitus, eGFR, and BMC at whole body, the ORs for the medium and low tertiles were 1.65 (p = 0.181) and 2.50 (p = 0.014), respectively.

Conclusion: Lower serum sclerostin levels were associated with elevated risks for increased arterial stiffness in Japanese community-dwelling women.

Purpose: The effect of methimazole withdrawl period (MWP) on the estimation of 24 hour-radioiodine thyroid uptake (131IU24h) from 99mTc-pertechnetate thyroid uptake (99mTcTU) remains unclear for patients with Graves disease (GD) . This study aims to investigate the feasibility and reliability of 99mTcTU-based 131IU24h estimation with different MWPs.

Methods: We enrolled 116 GD patients scheduled for 131I therapy at our hospital between April 2022 and April 2023. Based on MWP, the patients were categorized: standard (no methimazole or MWP>1 month), MWP1 (MWP≤1 week), MWP2 (MWP>1 week to ≤2 weeks) and MWP3 groups (MWP>2 weeks to <1 month). Fisher's exact test, one-way ANOVA or Kruskal-Wallis test were used to compare variables. Fitted curves of 99mTcTU20min versus 131IU24h were plotted for the standard group. Linear relationships and Bland-Altman plots were used to illustrate the relationship and consistency between estimated and measured 131IU24h.

Results: 131IU24h was higher in MWP1 group compared to MWP2 (70.22±7.95% vs 61.92±9.84%, P = 0.001), and thyroid masswas greater in MWP1 group (36.15±22.38g) versus MWP3 (21.25±11.90g, P = 0.005). The relationship between131IU24h and 99mTcTU20min in the standard group is described by the algorithm: estimated 131IU24h=11.3ln (99mTcTU20min)+39.4 (R2=0.62). Based on it, the correlation between estimated and measured 131IU24h was weak in MWP1 and MWP2 groups (both P>0.05) but strong in MWP3 (r=0.66, P=0.002). Additionally, the agreement between estimated and measured 131IU24h was highest in the MWP3 group (95% CI, -15.86 to 15.52%), compared to the MWP1and MWP2 groups.

Conclusion: Estimated 131IU24h based on 99mTcTU is not suitable for GD patients with MWP less than 2 weeks at our institution, necessitating further prospective multi-center studies for validation.

Introduction: People with HIV (PWH) with poor immune response despite adequate antiretroviral treatment (ART) are susceptible to non-AIDS-related health issues. This study seeks to evaluate bone quality in Immunological Non-Responders (INRs) in comparison to those with proper immune response (IRs) using in vivo microindentation to quantify bone quality, in addition to conventional bone mineral density (BMD) evaluations.

Methods: A cross-sectional study was conducted at Hospital del Mar in Barcelona from January 2019 to June 2023. Participants were matched in a 1:2-ratio (INRs:IR) based on age, sex, body mass index (BMI), and ART. Participants underwent bone quality assessment using in vivo microindentation, BMD and analysis of bone turnover and inflammation markers. Statistical analyses involved multivariable regression to adjust for potential confounding variables.

Results: A total of 159 PWH were included, 53 INRs and 106 IRs. INRs had worse bone quality, with lower median Bone Material Strength index (BMSi) compared to IRs (79 (76-87) vs. 86 (82-89); p<0.001), and similar BMD. INRs shown increased high-sensitive C-Reactive Protein levels with lower 25-(OH)-Vitamin D3. A significant negative correlation between inflammation and bone quality was found, especially noticeable in INRs. Multivariable linear regression shown that INR status is a major predictor of decreased bone quality, regardless of conventional risk factors.

Conclusion: INRs condition is significantly associated with higher inflammatory levels, which may contribute to a deleterious effect on bone quality as measured by in vivo microindentation. Further studies are needed to confirm these results and to focus on non-AIDS comorbidities in this subgroup of PWH.

Objectives: To examine the relationship between kidney hyperfiltration during adolescence and subsequent changes in estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) in a young cohort of participants with type 1 diabetes. Additionally, to explore urinary mitochondrial DNA:nuclear DNA ratio (mtDNA:nDNA) as a marker of metabolic stress and its association with early changes in kidney function.

Methods: Eighty adolescents were studied at baseline [mean (SD) age 14.2 (1.5) years; mean diabetes duration 6.7 (3.0) years] and followed up 9.2 (1.3) years later. Blood pressure, HbA1c, lipids, eGFR, UACR and heart rate variability were assessed at each visit. Urinary mtDNA:nDNA was measured by quantitative PCR (qPCR).

Results: Overall, 4.2% of participants had diabetic kidney disease (DKD) at follow-up. Hyperfiltration at baseline (>135 mL/min/1.73m2) was seen in 31% of adolescents and was associated with a decline in eGFR at follow-up when adjusted for sex, diabetes duration and HbA1c [hyperfiltration -1.46 (3.07) mL/min/1.73 m2/year vs non-hyperfiltration -0.51 (2.48) mL/min/1.73m2/year, P=0.02]. Participants with hyperfiltration also had higher odds of undergoing rapid eGFR decline (>3 mL/min/1.73m2/year) compared to those without hyperfiltration [OR 14.11, 95% CI (2.30-86.60), P=0.004]. Baseline urinary mtDNA:nDNA was significantly associated with both greater annual rate of eGFR decline and rapid eGFR decline in univariable but not multivariable modelling.

Conclusion: Hyperfiltration during adolescence is significantly associated with greater reduction in eGFR and higher risk of rapid eGFR decline after ∼9 years, following transition into young adulthood in type 1 diabetes. Urinary mtDNA:nDNA measured during adolescence may be a novel predictor of early changes in kidney function.