Journal of the Endocrine Society最新文献

Introduction: Differentiating pheochromocytomas from other adrenal masses based on computed tomography (CT) characteristics remains challenging, particularly in lipid-poor lesions with variable washout patterns. This study evaluated CT features for distinguishing pheochromocytomas in good and poor washout subcohorts.

Methods: We prospectively analyzed 72 patients with unilateral lipid-poor adrenal masses. CT protocol included basal, bolus-tracked arterial, early venous (45 seconds postarterial), and delayed (15 minutes postarterial) phases. Masses were categorized into good and poor washout groups. Histopathology provided the final diagnosis. CT characteristics and calculated indices were compared between pheochromocytomas and other masses in each washout category.

Results: The cohort included pheochromocytomas (n = 35), adrenocortical carcinoma (ACC; n = 15), lipid-poor adenomas (n = 13), and metastatic infiltration/infection (n = 9). In the good washout group, pheochromocytomas (n = 15) showed larger diameters (6.00 vs 3.45 cm, P = .001), higher necrosis frequency (73.3% vs 30%, P = .049), and greater arterial attenuation (173.2 vs 74.5 HU, P < .001) compared to adenomas (n = 9). Arterial attenuation provided a high discriminatory value [area under the curve (AUC): 0.967], with 100% sensitivity at 87.6 Hounsfield unit (HU) and 100% specificity at 139.9 HU. In the poor washout group, pheochromocytomas (n = 20) exhibited higher arterial attenuation (99.2 vs 59.2 HU, P < .001; AUC: 0.844) compared to ACC (n = 14), metastatic infiltration (n = 9), and adenomas (n = 4), with 85% sensitivity and 78% specificity at 73.3 HU. Normetanephrine-secreting/nonsecretory pheochromocytomas showed higher arterial enhancement than metanephrine-secreting ones (132.0 vs 90.5 HU, P = .020) within the poor washout group.

Conclusion: Arterial phase attenuation on CT has good diagnostic accuracy for differentiating pheochromocytomas from other adrenal masses in both good and poor washout categories, potentially guiding hormonal workup.

Obesity poses a significant global health challenge, with an alarming rise in prevalence rates. Traditional interventions, including lifestyle modifications, often fall short of achieving sustainable weight loss, ultimately leading to surgical interventions, which carry a significant burden and side effects. This necessitates the exploration of effective and relatively tolerable pharmacological alternatives. Among emerging therapeutic avenues, glucagon-based treatments have garnered attention for their potential to modulate metabolic pathways and regulate appetite. This paper discusses current research on the physiological mechanisms underlying obesity and the role of glucagon in energy homeostasis. Glucagon, traditionally recognized for its glycemic control functions, has emerged as a promising target for obesity management due to its multifaceted effects on metabolism, appetite regulation, and energy expenditure. This review focuses on the pharmacological landscape, encompassing single and dual agonist therapies targeting glucagon receptors (GcgRs), glucagon-like peptide-1 receptors (GLP-1Rs), glucose-dependent insulinotropic polypeptide receptors (GIPRs), amylin, triiodothyronine, fibroblast growth factor 21, and peptide tyrosine tyrosine. Moreover, novel triple-agonist therapies that simultaneously target GLP-1R, GIPR, and GcgR show promise in augmenting further metabolic benefits. This review paper tries to summarize key findings from preclinical and clinical studies, elucidating the mechanisms of action, safety profiles, and therapeutic potential of glucagon-based therapies in combating obesity and its comorbidities. Additionally, it explores ongoing research endeavors, including phase III trials, aimed at further validating the efficacy and safety of these innovative treatment modalities.

Context: The efficacy of tocilizumab (TCZ) in treating Graves orbitopathy (GO) remains uncertain due to the small sample sizes of earlier studies, and there is a lack of research on the drug for juvenile GO.

Objective: To evaluate the effectiveness of TCZ in treating GO that is resistant to conventional therapy.

Design: This observational study at a tertiary care center included 79 Chinese GO patients, 15 of whom were pediatric patients, with 52 of these patients having moderate to severe active GO (all adult patients having steroid-resistant GO). Intravenous infusion of TCZ 8 mg/kg was given every 28 days for 4 months. Changes from baseline in visual acuity (VA), intraocular pressure (IOP), proptosis, clinical activity score (CAS), and thyrotropin receptor antibody (TRAb) levels throughout TCZ therapy were assessed at baseline (T0), the fifth month (T4), and follow-up (T5). Additionally, improvements in CAS by at least 2 points and CAS < 4 points at T4 and T5 were evaluated.

Results: Significant improvements were found in VA, IOP, proptosis, CAS, and TRAb levels in the adult group, and proptosis in the pediatric group at T5 (P < .05). Additionally, significant improvements were identified in TRAb levels and CAS (active GO at T0) in the pediatric group at T4 (P < .05). In the adult and pediatric group with active GO at T5, 71.4% and 60% experienced a decrease in CAS by ≥ 2 points, respectively; 89.3% and 60% achieved the response criterion of low activity disease (CAS < 4 points), respectively.

Conclusion: TCZ emerged as a valuable therapeutic option for Chinese patients with active, corticosteroid-resistant, moderate to severe GO.

Context: Although bone loss is a recognized consequence of premature ovarian insufficiency (POI), the impact on skeletal muscle health is less well-defined.

Objective: To compare muscle mass and function parameters between women with POI and controls.

Methods: Cross-sectional study from a tertiary health network and community between 2017 and 2023. Participants were women aged 20 to 40 years with POI associated with Turner syndrome (TS; n = 11) and spontaneous normal karyotype POI (s-POI; n = 7) compared with age- and body mass index (BMI)-matched controls (n = 45).

Results: All women with POI (mean age 28.70 ± 5.58) were using hormone therapy. Appendicular lean mass (ALM)/total fat mass and ALM/ BMI was lower in the POI group. Height-adjusted muscle mass parameters did not differ between groups. Compared with controls, women with TS and s-POI had lower muscle strength (TS 19.72 ± 4.89; s-POI 22.73 ± 5.35; controls 28.67 ± 5.65 kg; P < .001) and muscle quality (TS 11.09 ± 2.06; s-POI 10.89 ± 2.01; controls 14.10 ± 1.99 kg/kg; P < .001). Higher C-reactive protein levels, higher depression scores, and lower sex-steroid and physical activity levels were observed in women with POI (P < .05). Creatinine/cystatin C ratio, insulin-like growth factor-1, and transthyretin did not differ between groups.

Conclusion: Despite hormone therapy usage, women with POI exhibited compromised muscle parameters compared with age-matched controls. Potential contributory factors were identified. Further research is required to clarify pathophysiology and inform management strategies.

Context: Excessive eating and intake of a Western diet negatively affect the intestinal immune system, resulting in compromised glucose homeostasis and lower gut bacterial diversity. The G protein-coupled receptor GPR183 regulates immune cell migration and intestinal immune response and has been associated with tuberculosis, type 1 diabetes, and inflammatory bowel diseases.

Objective: We hypothesized that with these implications, GPR183 has an important immunometabolic role and investigated this using a global Gpr183 knockout mouse model.

Methods: Wild-type (WT) and Gpr183-deficient (Gpr183^-/-) mice were fed a high-fat, high-sucrose diet (HFSD) for 15 weeks. We investigated changes in weight, body composition, fecal immunoglobulin A (IgA) levels, fecal microbiome, and glucose tolerance before and after the diet. Macrophage infiltration into visceral fat was determined by flow cytometry, and hepatic gene expression was measured.

Results: A sexual dimorphism was discovered, whereby female Gpr183^-/- mice showed adverse metabolic outcomes compared to WT counterparts with inferior glucose tolerance, lower fecal IgA levels, and increased macrophage infiltration in visceral fat. In contrast, male Gpr183^-/- mice had significantly lower fasting blood glucose after diet than male WT mice. Liver gene expression showed reduced inflammation and macrophage markers in Gpr183^-/- livers, regardless of sex, while the pancreatic islet area did not differ between the groups. No conclusive differences were found after microbiome sequencing.

Conclusion: Gpr183 maintains metabolic homeostasis in female but not in male mice independent of diet. If confirmed in humans, future therapy targeting GPR183 should consider this sexual dimorphism.

Context: Phthalates are ubiquitous endocrine-disrupting chemicals and suspected obesogens. However, the associations with fat distribution and associated cardiometabolic complications remain unclear.

Objective: We examined the associations between phthalate exposure, body fat (total and distribution patterns), and metabolic syndrome (MetS) among US adolescents and adults.

Methods: We analyzed cross-sectional data from 829 adolescents and 3905 adults in the 2013 to 2018 National Health and Nutrition Examination Survey. Total percentage body fat (%BF), visceral adipose tissue (VAT) mass, and android to gynoid (A/G) ratio were determined using dual-energy x-ray absorptiometry. Associations between molar sums of low molecular weight (∑LMW), high molecular weight (∑HMW), and di(2-ethylhexyl) phthalate (∑DEHP) metabolites, and adiposity indicators and MetS were analyzed with multivariable linear and logistic regressions. Models included sex interaction terms, were stratified by age group, and adjusted for relevant covariates.

Results: ∑HMW and ∑DEHP exposures were positively associated with %BF in males, and all phthalate groups were associated with greater VAT mass and A/G ratio in adolescent males. Five-fold increases in ∑HMW and ∑DEHP metabolites were associated with 21.7% (95% CI, 10.5-33.9) and 18.0% (95% CI, 7.72-29.2) greater VAT mass among adolescent males, respectively. Sex modified the relationship between ∑HMW exposure and A/G ratio among adolescents (interaction P value = .0185). Phthalates were not associated with odds of MetS. When assessing individual MetS components, phthalates were associated with hyperglycemia in adult males.

Conclusion: Greater exposure to phthalates was associated with greater %BF in all males, and with fat distribution in adolescent males; however, phthalates were not linked to MetS.

Tributyltin (TBT) is a synthetic chemical widely used in industrial and commercial applications. TBT exposure has been proven to elicit obesogenic effects. Gestational exposure led to increased white adipose tissue depot size in exposed (F1, F2) animals and in unexposed generations (F3, F4), an example of transgenerational inheritance. TBT exerts these effects in part by increasing the number and size of white adipocytes, altering the fate of multipotent mesenchymal stromal stem cells to favor the adipocyte lineage, altering adipokine secretion, and modulating chromatin structure. Adipose tissue resident macrophages are critical regulators in adipose tissue; however, the effects of TBT on adipose tissue macrophages remained unclear. Here we investigated the effects of TBT on macrophages and consequent impacts on adipocyte function. TBT significantly enhanced palmitate-induced inflammatory gene expression in mouse bone marrow derived macrophages and this effect was attenuated by the antagonizing action of the nuclear receptor peroxisome proliferator activated receptor gamma. TBT-treated macrophages decreased lipid accumulation in white adipocytes differentiated from mesenchymal stromal stem cells accompanied by increased expression of lipolysis genes. Lastly, ancestral TBT exposure increased Tnf expression in adipose tissue resident macrophages in both exposed (F2) and unexposed (F3) generations, suggesting that TBT exposure led to an inherited predisposition toward inflammatory adipose tissue macrophages that can manipulate adipose tissue function. These findings provide new insights into the interplay between adipocytes and adipose tissue macrophages in obesity, further establishing a role for obesogens such as TBT in the development of obesity-related metabolic disorders.

Context: Patients with adrenal insufficiency (AI) have both increased risk of cardiovascular disease and adverse outcomes with many medical emergencies. However, limited data exist specifically regarding ST-segment elevation myocardial infarction (STEMI) in the context of AI.

Objective: To evaluate associations between AI and in-hospital outcomes of patients with STEMI.

Methods: Admissions for STEMI were identified in the 2016-2019 National Inpatient Sample. In-hospital outcomes were compared between patients with and without AI. The primary outcome was in-hospital mortality. Secondary outcomes included percutaneous coronary intervention (PCI), coronary artery bypass graft (CABG), intervention, acute kidney injury (AKI), vasopressor use, mechanical circulatory support (MCS), mechanical ventilation, ventricular tachycardia (VT), hospital length of stay (LOS), and total charges. Multivariable regression models were used to adjust for potential confounders.

Results: Among 690 430 STEMI hospitalizations, 1382 (0.2%) had a diagnosis of AI. AI was associated with higher odds of in-hospital mortality (adjusted OR [aOR] 1.51, 95% CI 1.03-2.2), lower odds of PCI (aOR 0.73, 95% CI 0.55-0.98), higher odds of CABG (aOR 2.8, 95% CI 1.89-4.2) and, AKI (aOR 2.38, 95% CI 1.72-3.3), VT (aOR 1.55, 95% CI 1.1-2.2), need for vasopressors (aOR 2.34, 95% CI 1.33-4.1), mechanical ventilation (aOR 2.11, 95% CI 1.54-2.89), and MCS (aOR 2.18, 95% CI 1.57-3.03). Patients with AI also had a longer LOS (10 days vs 4.2 days, P < .001) and higher charges ($258 475 vs $115 505, P < .001).

Conclusion: Patients with AI admitted for STEMI had higher in-hospital mortality, nonfatal adverse outcomes, and resource utilization than patients without AI.

Objective: To examine the real-world clinical and healthcare resource burden of familial hypophosphatemia (FH).

Methods: In a retrospective, observational cohort study using MarketScan claims data from 2017 to 2021, clinical characteristics and healthcare resource utilization (HCRU) and costs were compared between burosumab-naïve pediatric and adult patients with ≥ 1 FH diagnosis code and matched controls without FH. Patient characteristics were evaluated at baseline, and disease characteristics, HCRU, and costs were evaluated over a 12-month follow-up period. Outcomes were analyzed descriptively. Costs were additionally analyzed using multivariate regression models.

Results: Overall, 570 patients with FH and 1710 non-FH matched controls were included. Approximately 10% of study participants were aged < 18 years. Patients with FH had 7.8-fold higher mean baseline comorbidity (Charlson Comorbidity Index). The prevalence of morbidities over the 12-month follow-up period was higher in patients with FH than controls, including renal disease (33% vs 3%), arthralgia (25% vs 10%), osteoarthritis (17% vs 6%), and delayed growth/walking difficulty (16% vs 2%; all P < .001). All-cause HCRU was significantly greater for patients with FH than controls over follow-up, including the proportion of patients with at least one inpatient admission (60% vs 4%), outpatient emergency room visit (52% vs 16%), and outpatient pharmacy prescription (96% vs 71%; all P < .001). The mean annual total healthcare cost per patient was also 22.6-fold higher for patients with FH than controls (adjusted cost difference = $129 643; P < .001). Differences were apparent across all age groups.

Conclusion: Compared with non-FH matched controls, burosumab-naïve patients with FH experienced multiple morbidities and had substantially higher HCRU and costs.