Daily Endocrinology Research Analysis
Analyzed 82 papers and selected 3 impactful papers.
Summary
Analyzed 82 papers and selected 3 impactful articles.
Selected Articles
1. Accounting for Age-Related Increases in HbA1c More Accurately Quantifies Risk of Type 1 Diabetes Progression in Islet Autoantibody-Positive Adults.
Using TrialNet and population modeling, the study shows that age-related HbA1c increases bias dysglycemia classification in adults at risk for type 1 diabetes. Applying age-adjusted HbA1c or an adult threshold of ≥6.0% aligns adult progression risk with that of children across autoantibody strata, improving prevention trial stratification.
Impact: Proposes a practical, evidence-based adjustment to HbA1c thresholds that could immediately refine risk stratification and selection in type 1 diabetes prevention settings.
Clinical Implications: Consider age-adjusted HbA1c or ≥6.0% as a dysglycemia criterion in adults (especially ≥30 years) for counseling, monitoring, and prevention trial enrollment among autoantibody-positive individuals.
Key Findings
- Standard HbA1c ≥5.7% classified children with higher 1-year progression risk than adults across single (38% vs 13%) and multiple autoantibody strata (55% vs 38%; both P<0.001).
- Age-adjusted HbA1c reduced adult–child differences; risks became similar for single autoantibody-positive participants (38% vs 27%; P=0.32).
- An HbA1c threshold ≥6.0% yielded comparable progression risk between adults and children across autoantibody subgroups.
- Adults <30 years had progression risk similar to children in post hoc analyses (P=0.1).
Methodological Strengths
- Large prospective cohort (TrialNet; n=5,024) with external modeling using a population-based adult cohort (Exeter 10000; n=6,273).
- Direct comparison of multiple HbA1c strategies (standard, age-adjusted, ≥6.0%) with quantified 1-year progression risks.
Limitations
- Observational analysis without randomized intervention; thresholds require prospective validation for clinical endpoints.
- Post hoc subgroup observations (e.g., adults <30 years) may be hypothesis-generating.
Future Directions: Prospective validation of age-adjusted/≥6.0% HbA1c thresholds in prevention trials; integrate with C-peptide, CGM metrics, and autoantibody titers to build composite risk algorithms.
OBJECTIVE: HbA1c thresholds used to define dysglycemia in autoantibody-positive individuals at risk for type 1 diabetes do not account for age-related increases in HbA1c and may overestimate progression risk in adults. We evaluated whether age-adjusted HbA1c or a higher HbA1c threshold improves risk stratification across age-groups. RESEARCH DESIGN AND METHODS: We analyzed 5,024 autoantibody-positive relatives (3,720 children and 1,304 adults) participating in the TrialNet Pathway to Prevention study. Age-related HbA1c effects were modeled using 6,273 adults from the population-based Exeter 10000 cohort. Progression risk was compared using the standard dysglycemia threshold (HbA1c ≥5.7% [39 mmol/mol]), age-adjusted HbA1c, and an alternative threshold of HbA1c ≥6.0% (42 mmol/mol). RESULTS: Using HbA1c ≥5.7% (39 mmol/mol), children had higher 1-year progression risk than adults among single autoantibody-positive participants (38% [95% CI 28, 47] vs. 13% [7.2, 19]) and multiple autoantibody-positive participants (55% [49, 60] vs. 38% [27, 47]) (both P < 0.001). Age adjustment reduced these differences; progression risk was similar among single autoantibody-positive participants (38% [28, 47] vs. 27% [13, 39]; P = 0.32), with attenuated differences among multiple autoantibody-positive participants. An HbA1c threshold ≥6.0% (42 mmol/mol) yielded comparable progression risk between adults and children across autoantibody subgroups. In post hoc analyses, adults aged <30 years had progression risk similar to children (P = 0.1). CONCLUSIONS: Age-related variation in HbA1c influences dysglycemia classification in adults at risk for type 1 diabetes. Age-adjusted HbA1c or a higher HbA1c threshold (≥6.0% [42 mmol/mol]) in adults aged ≥30 years identifies individuals with progression risk comparable to children and may improve age-specific risk stratification in prevention settings.
2. Aldosterone Synthase Expression vs. Cross-Sectional Imaging in Lateralized Primary Aldosteronism.
In 173 surgically treated primary aldosteronism patients, CYP11B2 immunohistochemistry mapped aldosterone-producing sources that matched cross-sectional imaging in only about one-third of cases, with nearly half showing discordance. Findings support avoiding imaging-guided targeted therapy without functional localization such as adrenal vein sampling.
Impact: Provides pathology-anchored evidence that challenges routine reliance on CT/MRI to guide unilateral adrenalectomy in PA, reinforcing the need for functional localization.
Clinical Implications: Adopt adrenal vein sampling or other functional localization for surgical guidance in PA rather than cross-sectional imaging alone, especially when imaging shows multiple or discordant nodules.
Key Findings
- Only 53/173 (31%) had a single APA/APN that matched between CYP11B2 IHC and imaging.
- Discordance occurred in 82/173 (47.4%) patients, including imaging-only additional nodules or IHC-only discrete CYP11B2-positive foci.
- Multiple CYP11B2-positive foci were present in 26.0% of patients, suggesting multifocal aldosterone production.
- KCNJ5 mutations were enriched in concordant cases, while CACNA1D mutations predominated in discordant cases.
Methodological Strengths
- Blinded cross-sectional imaging interpretation with gold-standard CYP11B2 immunohistochemistry.
- Real-world surgical cohort across a 12-year interval with detailed lesion mapping.
Limitations
- Single-center retrospective design limits generalizability.
- Lack of systematic correlation with long-term clinical outcomes post-adrenalectomy.
Future Directions: Prospective multicenter studies integrating AVS, IHC, and outcomes; evaluate advanced functional imaging (e.g., 11C-metomidate PET) to reduce reliance on AVS where appropriate.
CONTEXT: Adrenal vein sampling (AVS) is the standard of care for guiding surgery in primary aldosteronism (PA). Because of its technical complexity and limited availability, however, many centers still use cross-sectional imaging for surgical guidance. DESIGN: Single referral-center retrospective cohort study of patients with PA who underwent unilateral adrenalectomy between 2012-2024. Blinded cross-sectional imaging interpretation was corroborated with CYP11B2 immunohistochemistry (IHC) of formalin-fixed paraffin-embedded adrenal tissue. RESULTS: Of 173 patients, age 52.6±11.8 years, 119 (68.8%) were men, 134 (77.5%) White, 30 (17.3%) Black, and 9 (5.2%) other races. CYP11B2 IHC identified a single aldosterone-producing adenoma (APA) or nodule (APN) in 87 (50.3%) and 38 (22.0%) patients, respectively; multiple CYP11B2-positive foci in 45 (26.0%) patients, and no CYP11B2-positive lesions in 3 patients. A single corresponding APA or APN on both IHC and imaging was found in only 53/173 (31%) patients, and an additional 38/173 (22%) patients also had adrenal thickening. Discrepant IHC-imaging findings were observed in 82 (47.4%) patients, including: 1) additional nodule(s) on imaging (ipsilateral non-functional adenoma, n=21; bilateral nodules, n=29; or contralateral nodule(s), n=6); 2) normal adrenals (n=2) or unilateral adrenal hyperplasia (n=4), but discrete CYP11B2-positive foci on IHC; and 3) corresponding APA/APN on imaging-IHC with additional CYP11B2-positive area(s) (n=20). Patients with IHC-imaging concordance had the highest proportion of women and KCNJ5 mutations, while CACNA1D mutations were most frequent in the discordant group. CONCLUSIONS: Even in patients with lateralized PA, IHC mapping of aldosterone sources corresponded with imaging findings in approximately half of the cases. These data caution against targeted therapy guided by cross-sectional imaging.
3. Risk Stratification Tools for Thyroid Cancer: A Systematic Review of Models Combining Ultrasound, Cytology, and Clinical Risk Factors.
Across seven studies of five multimodal risk tools, TiPS and CUT achieved AUCs >0.9, while TNAPP underperformed despite broad inputs. Given prevalent single-center, retrospective derivation and limited external validation, current tools should augment (not replace) clinical judgment, particularly for indeterminate cytology.
Impact: Synthesizes the emerging landscape of multimodal thyroid nodule risk tools, highlighting high-performing models and critical methodological gaps that must be addressed before widespread adoption.
Clinical Implications: Use multimodal RSTs as adjuncts to inform surgery and follow-up in indeterminate nodules, recognizing performance variability and the need for local validation before routine use.
Key Findings
- TiPS achieved sensitivity 96.2% and specificity 97.5% with AUC >0.9.
- CUT score showed AUC >0.9, particularly effective in low-to-intermediate risk nodules.
- TNAPP underperformed (accuracy 50.5%; specificity 27.5%) despite broad inputs.
- Most models were single-center, retrospective, with limited external validation; MTNS and MSKCC nomogram promising for indeterminate cytology but insufficiently validated.
Methodological Strengths
- Comprehensive database search with explicit inclusion criteria requiring histologic validation.
- Risk of bias formally assessed using PROBAST+AI tailored to prediction models.
Limitations
- Heterogeneous model development and validation; predominance of single-center retrospective cohorts.
- Limited external validation restricts generalizability and routine clinical adoption.
Future Directions: Prospective, multicenter external validation of top-performing models (e.g., TiPS, CUT); harmonize inputs and thresholds; evaluate AI-enhanced models and clinical impact in decision trials.
BACKGROUND: The rising incidence of thyroid cancer presents a growing diagnostic and therapeutic challenge. Various risk stratification systems have sought to integrate clinical, ultrasonographic, and, in some cases, cytological features to aid malignancy prognostication. This systematic review aims to critically evaluate risk stratification tools (RSTs) for patients with thyroid nodules, which incorporate multimodal inputs to assess their diagnostic performance and clinical utility in supporting surgical decision-making. METHODS: PubMed, Embase, and Cochrane databases were searched from inception to 04/13/2026, identifying studies evaluating multivariable risk prediction models for adult patients undergoing assessment of thyroid nodules. Studies were excluded if the proposed tool failed to incorporate clinical features, ultrasound findings, and cytology results or was not validated with histology. Data extraction encompassed methodology of model development, performance metrics, and approaches to validation. Risk of bias was assessed using the PROBAST+AI tool. RESULTS: Seven studies describing five distinct RSTs met inclusion criteria Thyroid Nodule App (TNAPP), the McGill Thyroid Nodule Score (MTNS), CUT Score, Memorial Sloan Kettering Cancer Centre (MSKCC) nomogram, and Thyroid Prediction Score (TiPS). TiPS demonstrated the highest sensitivity (96.2%) and specificity (97.5%) with area under the curve (AUC) >0.9. The CUT score also showed strong performance (AUC >0.9), particularly in low-to-intermediate risk nodules. TNAPP underperformed (accuracy 50.5%; specificity 27.5%) despite broad clinical inputs. The MTNS and MSKCC, although promising for indeterminate cytology, lacked robust validation. Most models were derived from single-center, retrospective cohorts, limiting generalizability. CONCLUSIONS: RSTs integrating multimodal data may improve thyroid nodule risk stratification, particularly in cases of indeterminate cytology. However, methodological limitations and lack of external validation currently restrict clinical utility. Prospective evaluation in diverse populations is required to identify the most effective and generalizable tools. Until then, RSTs should be used as adjuncts to, not replacements for, clinical judgment and shared decision-making in thyroid nodule assessment.