Daily Endocrinology Research Analysis
Analyzed 84 papers and selected 3 impactful papers.
Summary
Assay- and trimester-specific thresholds for maternal TSH receptor antibodies refined fetal/neonatal risk prediction in Graves’ disease pregnancies, challenging current one-size-fits-all cutoffs. In diabetes care, liver stiffness by transient elastography independently predicted all-cause mortality beyond FIB-4, arguing for broader fibrosis screening. A mechanistic study uncovered a bile acid–FXR–ACOX1–acetyl-CoA–mTORC1 pathway, with context-dependent miR-378 effects, identifying bile acids as inhibitors of hepatic autophagy in MASLD.
Research Themes
- Assay-specific endocrine biomarkers in pregnancy
- Noninvasive fibrosis risk stratification in diabetes
- Bile acid–autophagy crosstalk in MASLD pathophysiology
Selected Articles
1. Maternal TSH-receptor antibodies predict fetal/neonatal hyperthyroidism in pregnancies with a history of Graves' disease.
In a 44-center prospective cohort of 678 pregnancies with Graves’ disease history or activity, trimester- and assay-specific TRAb thresholds accurately stratified fetal/neonatal thyroid dysfunction risk. Thresholds (multiples of ULN) were higher than commonly used universal cutoffs and varied by gestational age and disease status, while some neonates developed hyperthyroidism despite low maternal TRAb under antithyroid therapy.
Impact: These findings provide validated, trimester- and platform-specific TRAb cutoffs that can immediately refine fetal surveillance strategies and prevent over-monitoring in Graves’ pregnancies.
Clinical Implications: Adopt trimester- and assay-specific TRAb thresholds (validated on BRAHMS Kryptor TRAK human) for risk stratification, rather than a single universal multiplier. Avoid unnecessary intensive fetal surveillance when below these thresholds, and maintain vigilance for neonatal hyperthyroidism even with low maternal TRAb under antithyroid therapy.
Key Findings
- In Graves’ history pregnancies (n=500), trimester-specific TRAb cutoffs at 25×, 19×, and 6× ULN achieved 100% negative predictive value.
- In active Graves’ pregnancies (n=178), cutoffs at 10×, 12×, and 10× ULN yielded sensitivities of 89%, 86%, and 83%, respectively.
- Universal ULN-based thresholds risk misclassification and overestimation of fetal/neonatal Graves’ disease across different assays.
- Neonatal hyperthyroidism occurred in some cases despite low/declining maternal TRAb under antithyroid drug treatment.
Methodological Strengths
- Prospective multicenter cohort across 44 centers with standardized TRAb measurement on a specified platform
- Clear, clinically relevant outcomes with performance metrics (NPV, sensitivity) by trimester and disease status
Limitations
- Findings directly validated only on the BRAHMS Kryptor TRAK human assay; generalizability requires platform-specific validation
- Observational design without randomized management allocation; antithyroid therapy may confound maternal–neonatal TRAb dynamics
Future Directions: Externally validate trimester-specific thresholds across major TRAb assay platforms and integrate into clinical pathways, including decision-analytic models to optimize fetal monitoring intensity.
CONTEXT: Transplacental transfer of Thyroid-Stimulating Hormone Receptor antibodies (TRAb) during pregnancy may cause fetal/neonatal thyroid dysfunction. Current guidelines recommend a universal TRAb titer threshold, irrespective of gestational age or assay platform. However, evidence supporting trimester-specific and assay-specific thresholds is lacking. OBJECTIVE: 1) To determine whether trimester-specific TRAb levels predict fetal/neonatal thyroid dysfunction. 2) to establish assay-specific cutoff values for clinical risk stratification. DESIGN: Prospective multicenter observational cohort study (2010-2023), in which maternal TRAb titers were measured using the TRAK human assay on the BRAHMS Kryptor Compact Plus analyzer. SETTING: Tertiary and secondary care centers (n=44) across the Netherlands. PATIENTS: Women with a history of (n=500) or active (n=178) Graves' disease. MAIN OUTCOME MEASURE(S): Biochemically confirmed fetal/neonatal hyperthyroidism or hypothyroidism. RESULTS: Trimester-specific TRAb titer thresholds predicted risk with high accuracy. In women with a history of Graves' disease (n=500), trimester-specific cut-offs of 25-, 19-, and 6-fold the upper limit of normal (ULN) showed a negative predictive value of 100%. In women with active Graves (n=178), cut-offs of 10-, 12-, and 10-fold the ULN showed sensitivities of 89%, 86%, and 83%. Neonatal hyperthyroidism occurred despite low or declining maternal TRAb levels in mothers treated with antithyroid drugs. CONCLUSIONS: Trimester-specific TRAb thresholds were higher than the universal ULN multipliers commonly applied in clinical practice, and differed by gestational age and disease status. Application of a single ULN-based threshold titer across different TRAb assays may result in misclassification (i.e. overestimation of fetal and neonatal Graves' disease) and consequently in unnecessary and resource-intensive fetal surveillance. This indicates that TRAb thresholds are assay-specific and require platform-specific clinical validation, even when assays are calibrated against a common international standard.
2. Aberrant miR-378 expression promotes hepatic lipid accumulation via hijacking the bile acid-regulated autophagy.
Bile acids emerged as inhibitors of hepatic autophagy via an FXR–ACOX1–acetyl-CoA–mTORC1 axis, linking elevated BA levels to steatosis in mice and humans. miR-378 showed context-dependent effects: pro-autophagic in short-term fasting but promoting lipid accumulation by amplifying BA signaling during HFD or prolonged fasting.
Impact: This study defines a previously unrecognized regulatory axis whereby bile acids suppress hepatic autophagy and drive steatosis, revealing actionable targets (FXR, ACOX1, miR-378) for MASLD.
Clinical Implications: Therapeutic strategies modulating bile acid signaling (e.g., FXR antagonism), acetyl-CoA production, or miR-378 may restore hepatic autophagy and reduce steatosis; caution is warranted with prolonged fasting in MASLD due to BA-induced autophagy suppression.
Key Findings
- Circulating bile acids were elevated in humans with steatosis and independently associated with hepatic steatosis risk.
- In mice, high-fat diet increased bile acids and reduced hepatic autophagic flux; pharmacologic FXR inhibition enhanced autophagy and alleviated steatosis.
- Mechanism: BA→FXR→ACOX1→acetyl-CoA→mTORC1 activation suppresses autophagy.
- miR-378 upregulated during prolonged fasting; while pro-autophagic in short fasting, it promoted lipid accumulation via the BA/FXR/ACOX1 axis under high BA conditions.
Methodological Strengths
- Integrated human association data with in vivo and in vitro mechanistic experiments
- Pharmacologic manipulation of FXR and pathway mapping to mTORC1 signaling
Limitations
- Preclinical nature limits immediate clinical translation; human interventional validation lacking
- Quantitative sample sizes and demographics for human datasets not detailed in the abstract
Future Directions: Test FXR antagonists, BA-modulating agents, and miR-378 targeting strategies in MASLD clinical trials; delineate context-specific autophagy modulation in human liver.
Dysregulated autophagy contributes to liver steatosis, yet its regulation under distinct metabolic contexts remains poorly defined. Here, we identify bile acids (BAs) as critical modulators of hepatic autophagy. Circulating BA levels are elevated in human subjects with liver steatosis and independently associated with increased hepatic steatosis risk. High-fat diet (HFD) feeding increases circulating BA levels, while simultaneously reducing hepatic autophagic flux in mice, whereas pharmacological inhibition of farnesoid X receptor (FXR) enhances autophagy and alleviates steatosis in the livers of HFD-fed mice. Mechanistically, circulating BAs promote hepatic acetyl-CoA production through FXR-induced acyl-CoA oxidase 1 (ACOX1), which in turn suppresses autophagy by increasing the mechanistic target of rapamycin complex 1 (mTORC1) signaling. Similar to HFD feeding, prolonged fasting elevates BA levels and hepatic lipid accumulation, while concurrently upregulating hepatic miR-378, a positive regulator of BA synthesis. Although miR-378 exerts a cell-autonomous pro-autophagic effect during short-term fasting, it paradoxically drives lipid accumulation by suppressing hepatic autophagy via BA/FXR/ACOX1/acetyl-CoA axis in a non-cell-autonomous manner during either HFD feeding or prolonged fasting when BA action becomes considerable. Together, our study uncovers BAs as a previously unrecognized class of inhibitors of hepatic autophagy during prolonged fasting and in metabolic dysfunction-associated steatotic liver disease (MASLD), providing novel insights into context-dependent autophagic regulation of hepatic lipid metabolism and potential therapeutic strategies for MASLD.
3. Liver Stiffness Measurement and All-Cause Mortality in Individuals With Diabetes.
In NHANES-linked data, liver stiffness by VCTE independently predicted all-cause mortality in individuals with diabetes, whereas FIB-4 did not after multivariable adjustment. Coexistence of diabetes with MASLD or advanced fibrosis markedly increased mortality risk.
Impact: Supports incorporating LSM into routine diabetes care for fibrosis screening and risk stratification, beyond current guidance that relies on FIB-4.
Clinical Implications: Consider routine VCTE-based LSM in adults with diabetes to identify advanced fibrosis and high-risk patients, even when FIB-4 is not elevated; integrate findings into cardiometabolic risk management.
Key Findings
- Among 4102 adults, diabetes with MASLD (CAP ≥274 dB/m) was associated with higher mortality (AHR 2.77, 95% CI 1.16–6.65).
- Diabetes with advanced fibrosis (LSM ≥9.7 kPa) conferred markedly increased mortality risk (AHR 6.41, 95% CI 1.03–39.85).
- In diabetics, continuous LSM (per 1 kPa) remained associated with all-cause mortality (AHR 1.06, 95% CI 1.04–1.09), whereas FIB-4 was not.
- Results were observed over a mean follow-up of ~24 months with survey-weighted analyses.
Methodological Strengths
- Population-based NHANES cohort with standardized VCTE/CAP and linkage to National Death Index
- Cox models adjusted for key covariates with complex survey weighting
Limitations
- Short follow-up and few deaths (1.4%), limiting precision, especially in subgroup estimates
- Observational design with potential residual confounding; cutoffs may vary by device/protocol
Future Directions: Prospective validation of LSM-based risk algorithms in diabetes clinics and evaluation of whether LSM-guided interventions improve outcomes.
IMPORTANCE: Current guidance from the American Diabetes Association recommends liver stiffness measurement (LSM) only when the Fibrosis-4 (FIB-4) index is elevated. However, LSM may provide additional valuable information compared with FIB-4, which is known to underperform in certain populations, such as individuals with type 2 diabetes. OBJECTIVE: To assess whether liver fibrosis evaluated by LSM is associated with increased mortality in individuals with and without diabetes. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included adult patients with complete vibration-controlled transient elastography (VCTE) and controlled attenuation parameter (CAP) data. Baseline data, including demographics and routine laboratory tests, were obtained from the 2017 to 2018 National Health and Nutrition Examination Survey and linked to data from the National Center for Health Statistics and National Death Index up to December 31, 2019. Patients with a history of liver disease other than metabolic dysfunction-associated steatotic liver disease were excluded. Data were analyzed from December 2024 to December 2025, accounting for the complex survey design using examination weights. EXPOSURES: Liver disease based on CAP results and LSM by VCTE. CAP results 274 dB/m or higher indicate a diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and LSM results 9.7 kPa or higher indicate advanced liver fibrosis. MAIN OUTCOMES AND MEASURES: All-cause mortality. Mortality risk was expressed as hazard ratios (HRs) with 95% CIs calculated using Cox proportional hazards regression models. RESULTS: A total of 4102 adult patients (mean [SEM] age, 47 [1] years; 50.7% female), were included in the study. The mean (SEM) body mass index (BMI), calculated as weight in kilograms divided by height in meters squared, was 29.5 (0.3). Diabetes was present in 14.5% of participants. After a mean (SEM) follow-up of 24 (2) months, 59 patients (1.4%) had died. Patients who died during follow-up vs those who did not were older (mean [SEM] age, 62 [3] years vs 47 [1] years; P < .001), had a higher prevalence of diabetes (35.7% vs 14.2%; P = .01), and were more likely to be of non-Hispanic White race (85.1% vs 62.7%, P = .002). Increased risk of all-cause mortality was associated with the coexistence of diabetes with MASLD (adjusted hazard ratio [AHR], 2.77; 95% CI, 1.16-6.65; P = .03) and diabetes with advanced liver fibrosis (AHR 6.41; 95% CI, 1.03-39.85; P = .047). In patients with diabetes, LSM (AHR, 1.06; 95% CI, 1.04-1.09; P < .001) but not FIB-4 index remained associated with all-cause mortality even after adjusting for other clinical variables, such as age, sex, BMI, and hemoglobin A1c. CONCLUSIONS AND RELEVANCE: In this cohort study, LSM was an independent risk factor for all-cause mortality in individuals with diabetes, even after a relatively short follow-up. Implementing LSM to screen for liver fibrosis as part of routine diabetes management could aid in early identification of patients with high mortality risk.