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ABSTRACT The syndrome of resistance to thyroid hormone beta (RTHβ) is characterized by impaired tissue responsiveness to thyroid hormone and manifests as non-suppressed thyrotropin despite elevated thyroid hormone levels. RTHβ is most often caused by missense mutations in the thyroid hormone receptor beta (THRB) gene and is typically inherited in an autosomal dominant manner. Autoimmune thyroid disease is the most common cause of primary hypothyroidism worldwide. Association of RTHβ with autoimmune hypothyroidism is extremely rare. We describe an Indian kindred with a similar association. The proband, a 49-year-old female, manifested elevated anti-thyroglobulin antibodies, with an unusual thyroid function test pattern, suggesting mid-normal to high-normal free thyroid hormone levels despite a significantly elevated thyrotropin (free T3 = 4.2 pg/mL; free T4 = 1.37 ng/dL; thyrotropin = 91.82 mIU/L). Family screening revealed a biochemical picture consistent with RTHβ in her elder sister, treated for hypothyroidism, and a daughter who is presently euthyroid with raised anti-thyroglobulin autoantibodies. Both the proband and her daughter harbored a missense mutation in exon 8 of the THRB gene (c. 728 G>A; p. Arg243Gln) that is known to impair TRβ function in experimental studies. Considering the hypothyroid state, the proband was started on levothyroxine, with a target to maintain thyrotropin in the normal range, while the daughter received beta-blocker therapy, which relieved her palpitations. To conclude, the coexistence of RTHβ and primary hypothyroidism can delay diagnosis as thyroid hormone levels appear deceptively normal. A discordance between thyrotropin and thyroid hormone, i.e., high thyrotropin with inappropriately normal or high-normal thyroid hormone levels, should prompt this association.

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Abstract Objective: To evaluate the effect of diabetes mellitus and its chronic complications on thiol/disulfide homeostasis. Methods: The study included 381 participants divided into six groups: healthy controls (Group 1; n = 91), patients with prediabetes (Group 2; n = 50), patients with diabetes mellitus without complications (Group 3; n = 70), patients with diabetic retinopathy (Group 4; n = 47), patients with diabetic nephropathy (Group 5; n = 70), and patients with diabetic foot (Group 6; n = 53). Thiol/disulfide homeostasis was determined by measuring the reduction reaction of oxidized thiols. Results: Native thiol levels were low in patients with diabetes mellitus complications (Group 4, 264.7 ± 58.5 µmol/L; Group 5, 246.6 ± 67.5 µmol/L; Group 6, 174.3 ± 65.9 µmol/L), as were total thiol levels. The highest and lowest disulfide levels were observed in Group 1 (controls; 20.4 ± 5.2 µmol/L) and Group 6 (16.2 ± 5.7 µmol/L), respectively. The disulfide/native thiol ratio was increased in Groups 4, 5, and 6 compared with Groups 1, 2, and 3. Conclusion: The presence of diabetes mellitus complications substantially decreased native thiol, total thiol, and disulfide levels.

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Abstract Objective: To investigate the association of copeptin levels in the postpartum period with previous gestational diabetes mellitus, as well as its cardiometabolic phenotypes and biomarkers. Methods: In this cross-sectional analysis, women followed at a specialized gestational diabetes mellitus outpatient clinic were studied. Eligibility criteria included age ≥ 18 years and body mass index > 25 kg/m2. Participants were divided into two groups: those with (n = 42) and without gestational diabetes mellitus (n = 43). In the postpartum period (2 to 6 months), between September 2018 and May 2020, blood samples were collected for measurement of copeptin and E-selectin (by enzyme-linked immunosorbent assay), adiponectin, blood glucose, insulin, glycated hemoglobin, lipid profile, thyroid stimulating hormone, and gamma-GT. Results: Eighty-five women were studied; 42 had previous gestational diabetes mellitus and 43 did not. There were no significant differences in copeptin levels between women with and without previous gestational diabetes mellitus (1.48 ± 0.66 versus 1.49 ± 0.68 pmol/L; p = 0.89). No associations were observed between copeptin levels and the other studied parameters. However, a positive association was found between copeptin and E-selectin levels in both groups (Kruskal-Wallis; p = 0.007). Conclusion: Circulating copeptin levels were not associated with previous gestational diabetes mellitus or other related phenotypes in the postpartum period. A positive association was observed between copeptin and plasma E-selectin levels in women with and without previous gestational diabetes mellitus, which warrants further investigation.

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Abstract Objective: To investigate the Mitochondrial Open Reading Frame of the 12S rRNA type-c (MOTS-c) peptide levels in individuals with obesity compared to those with a normal body mass index and to examine the association of MOTS-c levels with markers of insulin resistance, endothelial function, and inflammation. Methods: In this study 85 individuals were enrolled, including 48 with a body mass index ≥ 30 kg/m2 and 37 with a body mass index between 18.5 and 24.9 kg/m2. Individuals with smoking, pregnancy, type 2 diabetes mellitus and other chronic conditions were excluded. Blood samples were collected after at least 8 hours of fasting to measure serum MOTS-c, insulin, high-sensitivity C-reactive protein, and asymmetric dimethylarginine levels. Statistical analyses included t-tests, Mann-Whitney U tests, Chi-squared tests, correlation analyses, and multiple regression analyses. Results: We found no significant difference in serum MOTS-c levels between individuals with obesity and those with normal body mass index (14.33 ± 3.76 pg/mL versus 13.67 ± 3.44 pg/mL; p = 0.395). Serum MOTS-c levels showed a significant positive correlation with the HOMA-IR index (p < 0.05) but did not correlate with high-sensitivity C-reactive protein or asymmetric dimethylarginine levels. Multiple regression analysis indicated that age and HOMA-IR were significant predictors of MOTS-c levels, with MOTS-c decreasing with age and increasing with higher insulin resistance. Conclusion: Serum MOTS-c levels were similar in individuals with obesity and those with normal weight. The study highlighted age and insulin resistance as significant determinants of MOTS-c levels.

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Abstract Objective: This study investigated the clinical value of ultrasound-guided fine-needle aspiration biopsy (US-FNAB), computed tomography (CT) and BRAFV600E combination for papillary thyroid carcinoma (PTC) diagnosis. Subjects and methods: A total of 300 patients with thyroid nodules were assigned to the PTC group (n = 184) and the nodular goiter (NG) group (n = 116). The positive detection rates of US-FNAB, CT and BRAFV600E gene mutation and their relationship with tumor number, tumor diameter, lymphatic metastasis, capsule invasion and tumor-node-metastasis (TNM) staging were analyzed, with their diagnostic value for PTC analyzed by the receiver operating characteristic (ROC) curve. The area under multiple ROC curves (AUCs) were compared using MEDCALC software. Results: The positive detection rates of US-FNAB, CT and BRAFV600E gene mutation were 78.80%, 72.28% and 83.15% in the PTC group, and 30.17%, 27.59% and 9.48% in the NG group, while the negative detection rates were 21.20%, 27.72% and 16.85% in the PTC group, and 69.82%, 72.41% and 90.52% in the NG group. Positive US-FNAB and BRAFV600E gene mutation in PTC patients related to TNM staging. Positive CT and BRAFV600E gene mutation linked to lymphatic metastasis. US-FNAB (AUC: 0.743, sensitivity: 78.80%, specificity: 69.83%), CT (AUC: 0.723, sensitivity: 77.28%, specificity: 72.41%) and BRAFV600E (AUC: 0.868, sensitivity: 83.15%, specificity: 90.52%) gene detections helped PTC diagnosis, with their combined diagnostic value (AUC: 0.938, sensitivity: 78.26%, specificity: 96.55%) surpassing that of them alone. Conclusion: US-FNAB, CT and BRAFV600E gene tests helped PTC diagnosis, and their combined detection had higher diagnostic value for PTC than their single detection.

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Abstract Objective: The current study was conducted to investigate whether thyroid-stimulating hormone (TSH) and thyroid hormone sensitivity are associated with hyperuricemia probability in euthyroid population. Materials and methods: The observational analysis was based on a Chinese community-based cohort (n = 1,972). The prospective associations of TSH levels, TSH index (TSHI), thyrotrophic thyroxine resistance index (TT4RI), thyroid feedback quantile-based index (TFQI) and free triiodothyronine to free thyroxine (FT3/FT4) ratio with the risk of hyperuricemia were examined. Two-sample Mendelian randomization (MR) analysis was then used to test the causal effects of TSH on serum uric acid (SUA) levels and gout. Results: Among 1,972 participants with normal thyroid function, 244 new hyperuricemia cases were identified during follow-up. The results suggested that the higher levels of TSH (HR = 1.87, 95% CI: 1.28-2.73, p-value < 0.01), TSHI (HR = 2.02, 95% CI: 1.38-2.95, p-value < 0.01), TFQI (HR = 1.92, 95% CI: 1.33-2.76, p-value < 0.01) and TT4RI (HR = 1.93, 95% CI: 1.34-2.80, p-value < 0.01) were significantly associated with hyperuricemia incidence. The MR results further indicated causal effects of TSH on SUA levels (inverse variance weighting [IVW] β = 0.037, 95% CI: 0.017-0.057) and gout (IVW OR = 1.0018, 95% CI: 1.0004-1.0032). Conclusion: The higher levels of TSH, TSHI, TFQI and TT4RI are significantly associated with the risk of hyperuricemia in euthyroid population. The MR analysis supports the causal effects of TSH on SUA levels and gout.

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Abstract Objective: To identify cytologic characteristics in a suspicious for malignancy cohort that may help to recognize false positives in cytopathological tests of thyroid nodules in a “real world scenario”, with histopathological reports as the gold standard. Methods: Cytomorphologic features of suspicious for malignancy thyroid nodules in a 13-year retrospective database were reviewed. Therefore, we identified false positive cases, analyzed the possible causes of cytopathological diagnostic failure and calculated the frequency of false positive results and the risk of malignancy in the suspicious for malignancy cohort. Results: Among the 289 suspicious for malignancy type nodules, 283 were malignant, 5 were benign, and 1 was a noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). The most frequently reported cytology features were nuclear grooves and pseudoinclusions; however, they were present in malignant and benign specimens. Statistical analysis revealed that the presence of micronucleoli (p < 0.001) and/or irregular/oval nuclei (p = 0.05) were the characteristics most strongly associated with malignancy. The risk of malignancy was 98% in this study. Conclusion: The presence of micronucleoli and nuclear irregularity was highly predictive of malignancy according to suspicious for malignancy cytology and were not present in false positive patients. Hence, careful examination of nuclear characteristics can be helpful for identifying true malignancies via suspicious for malignancy cytology. This was significant even when only a qualitative analysis was taken into account.

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Abstract Objective: To determine the prevalence of protective sensory loss in patients with diabetes mellitus at a university hospital and to identify clinical and sociodemographic factors associated with this condition. Methods: This cross-sectional study was conducted with diabetic patients attending specialized outpatient clinics. Data were collected through patient interviews and medical record reviews, in conjunction with using the monofilament test to assess protective sensory loss in the feet. Statistical analyses included descriptive and exploratory tests, as well as bivariate and multivariate analyses to identify factors associated with sensory loss (p < 0.05). Results: A total of 184 patients were interviewed, but only 169 were included in the primary outcome analyses. The median age was 61 years, with the majority being female (72%), self-identifying as mixed-race (54%), and diagnosed with type 2 diabetes mellitus (87%). The prevalence of protective sensory loss was 20%. Factors such as a longer duration of diabetes mellitus (95%CI 1.01-1.09; p = 0.022), the presence of target organ damage (95%CI 1.25-6.84; p = 0.015), and increased body weight (OR = 1.04; 95%CI 1.01-1.07; p = 0.007) were significantly associated with sensory loss. Although systemic arterial hypertension was initially associated in the bivariate analysis, it did not remain an independent predictor. Conclusion: The significant prevalence of protective sensory loss and the lack of awareness about the monofilament test among many patients emphasize the need to expand neuropathy screening and health education in diabetes management.

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Abstract Objective: To evaluate muscle functionality, physical performance and body composition in young people living with human immunodeficiency virus (PLWH). Subjects and methods: Eighty-one HIV-infected and 54 uninfected (20 to 50 years) male and female subjects were enrolled to participate. Patient evaluation included body composition by DXA (dual energy X-rays), SARC-F questionnaire, hand grip and timed up & go (TUG) tests. Results: Fifty PLWH and 50 age-gender matched controls completed the study. The median age was 40 (25-49) vs. 36.5 (22-50) for the HIV and control groups, respectively (p 0.120). Race, gender, body mass index, phosphorus and 25-hydroxyvitamin D were similar between groups. HDL-c was significantly lower in HIV-infected (p 0.006). Groups had similar body composition parameters, although more PLWH presented appendicular lean mass (ALM) and ALM adjusted to height (ALM/h2) below reference values (18% vs 4%). SARC-F questionnaire and TUG were significantly compromised in HIV-infected when compared to controls (p 0.001 and 0.005, respectively). Hand grip test was slightly lower in PLWH than in control group (29.0 kg (9.3-56.0) vs. 32.8 kg (13.3-57.3); p 0.052). Conclusion: Our results suggest that there is loss of functionality, physical performance and muscle strength in young PLWH. Therefore, screening using SARC-F, hand grip and TUG test might be interesting in HIV-infected which are considered at high-risk for sarcopenia. With early diagnosis there is the possibility of decreasing muscle dysfunction, morbimortality, providing an increase in quality of life and working hours.

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Abstract Objective: This study aimed to evaluate the efficacy and safety of selective estrogen receptor modulators (SERMs), specifically clomiphene and enclomiphene, in treating men with functional hypogonadism. Materials and methods: A systematic search was conducted in PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov for randomized controlled trials comparing SERMs with placebo, testosterone (T) gel, or human chorionic gonadotropin (hCG), up to July 2024. The primary endpoints were total testosterone (TT), follicle-stimulating hormone (FSH), and luteinizing hormone (LH). Weighted mean differences (MDs) and risk ratios (RRs) were calculated for continuous and binary endpoints, respectively, with 95% confidence intervals (CIs). Results: SERM therapy significantly improved TT (MD: 273.76 ng/dL; 95% CI: 191.87-355.66 ng/dL; p < 0.01; I2 = 89%), LH (MD: 4.66 IU/L; 95% CI: 3.37-5.94 IU/L; p < 0.01; I2 = 55%), and FSH (MD: 4.59 IU/L; 95% CI: 2.88-6.30 IU/L; p < 0.01; I2 = 68%) compared to placebo. No significant difference in TT was observed between the SERM and T gel groups. TT levels were significantly higher with SERM therapy and the combined treatment of SERM and hCG compared to hCG alone (158 vs. 153 vs. 134 ng/dL, respectively; p < 0.002 for both comparisons). Conclusion: SERM therapy is associated with significantly improved levels of TT, LH, and FSH in hypogonadal men compared to placebo, and significantly enhanced levels of LH and FSH compared to T gel. The findings suggest that SERM therapy effectively increases TT levels in men with functional hypogonadism and should be considered as an alternative to T gel therapy.

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Abstract Objective: Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease, affects approximately 38% of the global population. MASLD’s strong association with obesity and type 2 diabetes positions it as an increasingly prevalent indication for liver transplantation. Hence, this study sought to assess the prevalence of MASLD as an indication for liver transplantation, to characterize the clinical and epidemiological profile of the affected population, and to investigate the rates of post-transplant recurrence and de novo occurrence. We also compared survival outcomes between recipients with MASLD and other etiologies. Materials and methods: We conducted a retrospective analysis of 610 patients listed for liver transplantation at Hospital das Clínicas (University of São Paulo) between 2005 and 2015. Data regarding demographics, comorbidities, and post-transplant outcomes were collected from medical records. The statistical analysis encompassed both descriptive and inferential methods. Results: Out of 610 patients, 61 (10%) were diagnosed with MASLD-related cirrhosis, presenting a waitlist mortality rate of 42.6%. Among the 264 who received transplants, 36 (13.6%) had MASLD as the primary diagnosis. Post-transplantation, 58 recipients developed steatosis, with 82.8% of these cases being de novo allograft steatosis. Pre-transplant obesity and hypertension were identified as significant risk factors. Importantly, patients undergoing transplantation for MASLD showed lower survival rates compared to those with other etiologies. Conclusion: MASLD patients who undergo liver transplantation exhibit distinctive clinical outcomes and reduced survival rates. These findings underscore the critical need for targeted risk assessments and developing long-term strategies to enhance the prognosis for this increasingly common patient demographic.

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ABSTRACT Objective: To evaluate the efficacy of radioactive iodine therapy and to identify determinants of treatment outcomes in young adults with Graves disease. Methods: This retrospective cohort study analyzed young adults with Graves disease who underwent radioactive iodine therapy at two tertiary medical centers in Southwest China. Patients were stratified into two groups based on therapy outcomes at 6 months post-radioactive iodine therapy: euthyroidism or hypothyroidism (therapy success) and persistent hyperthyroidism necessitating either a second radioactive iodine therapy or continuation of anti-thyroid drug therapy (therapy failure). Multivariate logistic regression and receiver operating characteristic curve analyses were employed to assess predictive factors for treatment outcome. Results: A cohort of 163 young adults with Graves disease, with a mean age of 18 years (range: 6 to 20 years) were included. The overall therapy success rate was 60.7%. Multivariate regression analysis identified that thyroid mass (OR 1.013, 95%CI 1.002 - 1.025; p-value = 0.022) and interval between diagnosis and radioactive iodine therapy (> 1 year; OR 2.471, 95%CI 1.128 - 5.415; p-value = 0.024) were risk factors associated with therapy failure. ROC curve analysis identified 38 g as the optimal thyroid mass cutoff for predicting treatment failure, demonstrating a sensitivity of 69% and specificity of 70%. The positive and negative predictive values were 60% and 78%, respectively. Conclusion: A therapy success rate of 60.7% was observed in radioactive iodine therapy in young adults with Graves disease. Larger thyroid volume and prolonged disease duration emerged as significant risk factor for therapy failure.

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Abstract Objective: This study aimed to investigate the presence of tertiary lymphoid structures (TLSs) and tumor-infiltrating B cells within the germinal centers of TLSs in the tumor microenvironment of thyroid cancer, utilizing a morphological approach. Materials and methods: Histological samples from patients with papillary thyroid carcinoma (PTC) (n = 112) stained with hematoxylin and eosin were examined. The presence of lymphoid neogenesis in PTC was determined based on morphological features and classified according to TLS location and maturation status. Immunofluorescence staining was performed on selected cases to identify B cells within mature TLSs. Additionally, 499 scanned slides from the PTC cohort in The Cancer Genome Atlas - Thyroid Carcinoma (TCGA-THCA) dataset were accessed via cBioPortal to assess the presence of TLSs and compare the clinical and molecular characteristics of PTC cases with and without TLSs. Results: Tertiary lymphoid structures, resembling ectopic lymph nodes, were identified in 41% (46/112) of the histological PTC samples. Among these, 63% (29/46) were located in peritumoral regions, while 13% (6/46) were found within the intratumoral area. Mature TLSs containing germinal centers, in which B cells were detected, were observed in 15% (7/46) of cases. Immature TLSs were detected in 52% (24/46) of PTC cases with TLSs. Analysis of PTC scanned images from cBioPortal revealed TLSs in 8.4% of cases, of which 62% harbored the BRAFV600E mutation, along with upregulation of immune cell markers and SLC5A5 (NIS) expression. Conclusion: The identification of TLSs across multiple malignancies underscores their functional significance in modulating tumor-immune interactions with clinical implications. Therefore, the identification and morphological characterization of TLSs in PTC may provide valuable insights into their potential as immunobiomarkers in thyroid cancer.

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Abstract Introduction: Familial chylomicronemia syndrome (FCS) is an autosomal recessive disorder that affects approximately 1 to 10 individuals per million and is caused by variants in the genes encoding for the lipoprotein lipase (LPL) enzyme. In addition to its heterogeneous clinical presentation, FCS is characterized by a higher risk of life-threatening, recurrent acute pancreatitis and type 3 diabetes. Since available evidence on FCS in Latin America is limited, there is a clear need for a consensus document that provides relevant recommendations to guide the management of suspected cases and optimize disease diagnosis across the region. Methods: A panel of specialists from Latin America with extensive experience in the diagnosis of chylomicronemia was invited to participate in the creation of this document. The modified Delphi technique was used to reach group consensus through multiple rounds of questionnaires using statistical techniques and controlled feedback. Results and discussion: Seventeen recommendations on diagnosis of FCS were generated. This consensus reflects the collaborative efforts of Latin American scientific societies and is essential to suspect and diagnose FCS. The organizations that support this document, including Sociedad Argentina de Lípidos, Federación Argentina de Sociedades de Endocrinología, Fundación Bioquímica Argentina, Corporación Grupo Chileno de Trabajo en Ateroesclerosis, Asociación Colombiana de Endocrinología, Diabetes y Metabolismo, Departamento de Aterosclerose da Sociedade Brasileira de Cardiología, and Sociedad Mexicana de Nutrición y Endocrinología, are a robust support network that might aid the adoption of these recommendations in local healthcare systems.