Thyroid Function Tests in Children and Adolescents With Trisomy 21

By longitudinally assessing TFT in a wide pediatric DS population, we outlined the syndrome-specific reference nomograms for TSH, FT3, and FT4 and demonstrated a persistent upward shift of TSH compared to non-syndromic children.

source: JCEM

Summary

Definition of Syndrome-Specific Reference Ranges.

[Posted 13/Nov/2023]

AUDIENCE: Endocrinology, Pediatric, Family Medicine

KEY FINDINGS: By longitudinally assessing TFT in a wide pediatric DS population, we outlined the syndrome-specific reference nomograms for TSH, FT3, and FT4 and demonstrated a persistent upward shift of TSH compared to non-syndromic children.

BACKGROUND: The lack of syndrome-specific reference ranges for thyroid function tests (TFT) among pediatric patients with Down syndrome (DS) results in an overestimation of the occurrence of hypothyroidism in this population. Aim of this study is to (a) outline the age-dependent distribution of TFT among pediatric patients with DS; (b) describe the intraindividual variability of TFT over time; and (c) assess the role of elevated thyrotropin (TSH) in predicting the future onset of overt hypothyroidism.

DETAILS: In this retrospective, monocentric, observational analysis, authors included 548 patients with DS (0-18 years) longitudinally assessed between 1992 and 2022. Exclusion criteria were abnormal thyroid anatomy, treatments affecting TFT, and positive thyroid autoantibodies. Authors determined the age-dependent distribution of TSH, FT3, and FT4 and outlined the relative nomograms for children with DS. Compared with non-syndromic patients, median TSH levels were statistically greater at any age (P < .001). Median FT3 and FT4 levels were statistically lower than controls (P < .001) only in specific age classes (0-11 for FT3, 11-18 years for FT4). TSH levels showed a remarkable fluctuation over time, with a poor (23%-53%) agreement between the TSH centile classes at 2 sequential assessments. Finally, the 75th centile was the threshold above which TSH values predicted future evolution into overt hypothyroidism with the best statistical accuracy, with a satisfactory negative predictive value (0.91), but poor positive predictive value (0.15).

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Copyright © The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.

Source: Cattoni, A., Molinari, S., Capitoli, G., et al. (2023). Thyroid Function Tests in Children and Adolescents With Trisomy 21: Definition of Syndrome-Specific Reference Ranges. JCEM. 2023; 108(11): 2779-2788. Published: November, 2023. DOI: 10.1210/clinem/dgad333.



Effect of SGLT2 Inhibitors on Heart Failure Outcomes and Cardiovascular Death Across the Cardiometabolic Disease Spectrum

SGLT2 inhibitors reduced heart failure events and cardiovascular death in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. These effects were consistent across a wide range of subgroups within these populations. This supports the eligibility of a large population with cardiorenal-metabolic diseases for treatment with SGLT2 inhibitors.

source: The Lancet

Summary

A Systematic Review and Meta-Analysis

[Posted 14/Jul/2024]

AUDIENCE: Endocrinology, Cardiology

KEY FINDINGS: SGLT2 inhibitors reduced heart failure events and cardiovascular death in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease. These effects were consistent across a wide range of subgroups within these populations. This supports the eligibility of a large population with cardiorenal-metabolic diseases for treatment with SGLT2 inhibitors.

BACKGROUND: Sodium-glucose co-transporter-2 (SGLT2) inhibitors have been studied in patients with heart failure, type 2 diabetes, chronic kidney disease, atherosclerotic cardiovascular disease, and acute myocardial infarction. Individual trials were powered to study composite outcomes in one disease state. We aimed to evaluate the treatment effect of SGLT2 inhibitors on specific clinical endpoints across multiple demographic and disease subgroups.

DETAILS: In this systematic review and meta-analysis, authors queried online databases (PubMed, Cochrane CENTRAL, and SCOPUS) up to Feb 10, 2024, for primary and secondary analyses of large trials (n>1000) of SGLT2 inhibitors in patients with heart failure, type 2 diabetes, chronic kidney disease, and atherosclerotic cardiovascular disease (including acute myocardial infarction). Outcomes studied included composite of first hospitalisation for heart failure or cardiovascular death, first hospitalisation for heart failure, cardiovascular death, total (first and recurrent) hospitalisation for heart failure, and all-cause mortality. Effect sizes were pooled using random-effects models. Authors included 15 trials (N=100,952). Compared with placebo, SGLT2 inhibitors reduced the risk of first hospitalisation for heart failure by 29% in patients with heart failure (hazard ratio [HR] 0.71 [95% CI 0.67-0.77]), 28% in patients with type 2 diabetes (0.72 [0.67-0.77]), 32% in patients with chronic kidney disease (0.68 [0.61-0.77]), and 28% in patients with atherosclerotic cardiovascular disease (0.72 [0.66-0.79]). SGLT2 inhibitors reduced cardiovascular death by 14% in patients with heart failure (HR 0.86 [95% CI 0.79-0.93]), 15% in patients with type 2 diabetes (0.85 [0.79-0.91]), 11% in patients with chronic kidney disease (0.89 [0.82-0.96]), and 13% in patients with atherosclerotic cardiovascular disease (0.87 [0.78-0.97]). The benefit of SGLT2 inhibitors on both first hospitalisation for heart failure and cardiovascular death was consistent across the majority of the 51 subgroups studied. Notable exceptions included acute myocardial infarction (22% reduction in first hospitalisation for heart failure; no effect on cardiovascular death) and heart failure with preserved ejection fraction (26% reduction in first hospitalisation for heart failure; no effect on cardiovascular death).

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Source: Usman, M. S., Bhatt, D. L., Hameed, I., et al. (2024). Effect of SGLT2 Inhibitors on Heart Failure Outcomes and Cardiovascular Death Across the Cardiometabolic Disease Spectrum: A Systematic Review and Meta-Analysis. The Lancet. 2024; Published: July, 2024. DOI: 10.1016/S2213-8587(24)00102-5.



MASLD and MASH At the Crossroads of Hepatology Trials and Cardiorenal Metabolic Trials

The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting.

source: JIM

Summary

[Posted 12/Jul/2024]

AUDIENCE: Internal Medicine

KEY FINDINGS: The challenge is defining the optimal combination of biomarkers, imaging and morbidity/mortality outcomes and ensuring that they are included in future trials while minimizing the burden on patients, trialists and trial sponsors. This paper provides an overview of some of the wide array of CV, liver and kidney measurements that were discussed at the MOSAIC meeting.

BACKGROUND: Steatotic liver disease (SLD) is a worldwide public health problem, causing considerable morbidity and mortality. Patients with SLD are at increased risk for major adverse cardiovascular (CV) events, type 2 diabetes mellitus and chronic kidney disease.

DETAILS: Conversely, patients with cardiometabolic conditions have a high prevalence of SLD. In addition to epidemiological evidence linking many of these conditions, there is evidence of shared pathophysiological processes. In December 2022, a unique multi-stakeholder, multi-specialty meeting, called MOSAIC (Metabolic multi Organ Science Accelerating Innovation in Clinical Trials) was convened to foster collaboration across metabolic, hepatology, nephrology and CV disorders. One of the goals of the meeting was to consider approaches to drug development that would speed regulatory approval of treatments for multiple disorders by combining liver and cardiorenal endpoints within a single study. Non-invasive tests, including biomarkers and imaging, are needed in hepatic and cardiorenal trials. They can be used as trial endpoints, to enrich trial populations, to diagnose and risk stratify patients and to assess treatment efficacy and safety. Although they are used in proof of concept and phase 2 trials, they are often not acceptable for regulatory approval of therapies.

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Copyright © John Wiley & Sons, Inc. All rights reserved

Source: Zannad, F., Sanyal, A. J., Butler, J., et al. (2024). MASLD and MASH At the Crossroads of Hepatology Trials and Cardiorenal Metabolic Trials. Journal of Internal Medicine. 2024; 296(1): 24-38. Published: July, 2024. DOI: 10.1111/joim.13793.



Left Main Coronary Artery Calcium and Diabetes Confer Very-High-Risk Equivalence in Coronary Artery Calcium More Than 1,000

Among asymptomatic patients with a CAC of more than 1,000 without a prior index event, diabetes, and severe LM CAC define very high risk ASCVD, identifying individuals who may benefit from more intensive prevention therapies across several domains, including low-density lipoprotein-cholesterol lowering.

source: J Am Coll Cardiol Img

Summary

[Posted 5/Jul/2024]

AUDIENCE: Cardiology, Endocrinology

KEY FINDINGS: Among asymptomatic patients with a CAC of >=1,000 without a prior index event, diabetes, and severe LM CAC define very high risk ASCVD, identifying individuals who may benefit from more intensive prevention therapies across several domains, including low-density lipoprotein-cholesterol lowering.

BACKGROUND: Although a coronary artery calcium (CAC) of >=1,000 is a subclinical atherosclerosis threshold to consider combination lipid-lowering therapy, differentiating very high from high atherosclerotic cardiovascular disease (ASCVD) risk in this patient population is not well-defined. Among persons with a CAC of >=1,000, the authors sought to identify risk factors equating with very high-risk ASCVD mortality rates.

DETAILS: The authors studied 2,246 asymptomatic patients with a CAC of >=1,000 from the CAC Consortium without a prior ASCVD event. Cox proportional hazards regression modelling was performed for ASCVD mortality during a median follow-up of 11.3 years. Crude ASCVD mortality rates were compared with those reported for secondary prevention trial patients classified as very high risk, defined by >=2 major ASCVD events or 1 major event and >=2 high-risk conditions (1.4 per 100 person-years). The mean age was 66.6 years, 14% were female, and 10% were non-White. The median CAC score was 1,592 and 6% had severe left main (LM) CAC (vessel-specific CAC >=300). Diabetes (HR: 2.04 [95% CI: 1.47-2.83]) and severe LM CAC (HR: 2.32 [95% CI: 1.51-3.55]) were associated with ASCVD mortality. The ASCVD mortality per 100 person-years for all patients was 0.8 (95% CI: 0.7-0.9), although higher rates were observed for diabetes (1.4 [95% CI: 0.8-1.9]), severe LM CAC (1.3 [95% CI: 0.6-2.0]), and both diabetes and severe LM CAC (7.1 [95% CI: 3.4-10.8]).

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Copyright © American College of Cardiology Foundation. All rights reserved.

Source: Razavi, A. C., Shaw, L. J., Berman, D. S., et al. (2024). Left Main Coronary Artery Calcium and Diabetes Confer Very-High-Risk Equivalence in Coronary Artery Calcium > 1,000. JACC: Cardiovascular Imaging. 2024; 17(7): 766-776. Published: July 1, 2024. DOI: 10.1016/j.jcmg.2023.12.006.



High Incidence of Diabetes Mellitus After Distal Pancreatectomy and Its Predictors

Impaired glucose tolerance and reduced early-phase insulin response to glucose are involved in the development of new-onset diabetes after DP (Distal Pancreatectomy); the latter is an additional factor in the development of diabetes and becomes apparent when pancreatic beta cell mass is reduced after DP.

source: JCEM

Summary

A Long-term Follow-up Study

[Posted 26/Feb/2024]

AUDIENCE: Endocrinology, Nephrology

KEY FINDINGS: Impaired glucose tolerance and reduced early-phase insulin response to glucose are involved in the development of new-onset diabetes after DP; the latter is an additional factor in the development of diabetes and becomes apparent when pancreatic beta cell mass is reduced after DP.

BACKGROUND: Aim of this study is to investigate the changes in diabetes-related traits before and after DP and to clarify the incidence of diabetes and its predictors.

DETAILS: Among 493 registered patients, 117 underwent DP. Among these, 56 patients without diabetes before surgery were included in the study. Glucose and endocrine function were prospectively assessed using a 75-g oral glucose tolerance test preoperatively, 1 month after DP, and every 6 months thereafter for up to 36 months. Pancreatic volumetry was performed using multidetector row computed tomography before and after surgery. Insulin secretion decreased and blood glucose levels worsened after DP. Residual pancreatic volume was significantly associated with the reserve capacity of insulin secretion but not with blood glucose levels or the development of diabetes. Among 56 patients, 33 developed diabetes mellitus. The cumulative incidence of diabetes at 36 months after DP was 74.1%. Multivariate Cox regression analysis showed that impaired glucose tolerance as a preoperative factor as well as a decreased insulinogenic index and impaired glucose tolerance at 1 month postoperatively were identified as risk factors for diabetes following DP.

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Copyright © The Author(s). Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved.

Source: Imamura, S., Niwano. F., Babaya, N., et al. (2024). High Incidence of Diabetes Mellitus After Distal Pancreatectomy and Its Predictors: A Long-term Follow-up Study. The Journal of Clinical Endocrinology & Metabolism. 2024; 109(3): 619-630. Published: March, 2024. DOI: 10.1210/clinem/dgad634.



Associations of Biomarkers of Tubular Injury and Inflammation with Biopsy Features in Type 1 Diabetes

Biomarkers of tubular injury and inflammation were associated with kidney structural parameters in early type 1 diabetes and may be indicators of kidney disease risk.

source: Clin J Am Soc Nephrol.

Summary

[Posted 22/Jan/2024]

AUDIENCE: Nephrology, Internal Medicine

KEY FINDINGS: Biomarkers of tubular injury and inflammation were associated with kidney structural parameters in early type 1 diabetes and may be indicators of kidney disease risk.

BACKGROUND: Whether biomarkers of tubular injury and inflammation indicate subclinical structural kidney pathology early in type 1 diabetes remains unknown.

DETAILS: Authors investigated associations of biomarkers of tubular injury and inflammation with kidney structural features in 244 adults with type 1 diabetes from the Renin-Angiotensin System Study, a randomized, placebo-controlled trial testing effects of enalapril or losartan on changes in glomerular, tubulointerstitial, and vascular parameters from baseline to 5-year kidney biopsies. Biosamples at biopsy were assessed for kidney injury molecule 1 (KIM-1), soluble TNF receptor 1 (sTNFR1), arginine-to-citrulline ratio in plasma, and uromodulin and epidermal growth factor (EGF) in urine. We examined cross-sectional correlations between biomarkers and biopsy features and baseline biomarker associations with 5-year changes in biopsy features. Participants' mean age was 30 years (SD 10) and diabetes duration 11 years (SD 5); 53% were women. The mean GFR measured by iohexol disappearance was 128 ml/min per 1.73 m2 (SD 19) and median urinary albumin excretion was 5 μg/min (interquartile range, 3–8). KIM-1 was associated with most biopsy features: higher mesangial fractional volume (0.5% [95% confidence interval (CI), 0.1 to 0.9] greater per SD KIM-1), glomerular basement membrane (GBM) width (14.2 nm [95% CI, 6.5 to 22.0] thicker), cortical interstitial fractional volume (1.1% [95% CI, 0.6 to 1.6] greater), fractional volume of cortical atrophic tubules (0.6% [95% CI, 0.2 to 0.9] greater), and arteriolar hyalinosis index (0.03 [95% CI, 0.1 to 0.05] higher). sTNFR1 was associated with higher mesangial fractional volume (0.9% [95% CI, 0.5 to 1.3] greater) and GBM width (12.5 nm [95% CI, 4.5 to 20.5] thicker) and lower GBM surface density (0.003 μm2/μm3 [95% CI, 0.005 to 0.001] lesser). EGF and arginine-to-citrulline ratio correlated with severity of glomerular and tubulointerstitial features. Baseline sTNFR1, uromodulin, and EGF concentrations were associated with 5-year glomerular and tubulointerstitial feature progression.

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Copyright © American Society of Nephrology. All rights reserved.

Source: Limonte, C., Prince, D., Hoofnagle, A. N., et al. (2023). Associations of Biomarkers of Tubular Injury and Inflammation with Biopsy Features in Type 1 Diabetes. Clinical Journal of the American Society of Nephrology. 2024; 19(1): 44-55, January 2024. Published: January, 2024. DOI: 10.2215/CJN.0000000000000333.



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