Comparison of pathophysiology in subclinical hyperthyroidism with different etiologies.

Subclinical hyperthyroidism (SHyper) is defined as normal levels of free thyroxine (fT4) and free triiodothyronine (fT3) with suppressed levels of TSH. Previous studies have reported the individual pathophysiology of endogenous SHyper patients and athyreotic patients receiving TSH suppression therapy with levothyroxine; however, apparently no studies have compared the two conditions. Five-hundred-forty untreated endogenous SHyper patients and 1,024 patients receiving TSH suppression therapy who underwent total thyroidectomy for papillary thyroid carcinoma were sampled. Thyroid hormone profiles and peripheral indices related to thyrotoxicosis were investigated in endogenous SHyper patients, athyreotic patients receiving TSH suppression therapy, and healthy participants. Endogenous SHyper patients showed significantly higher thyroid hormone levels (fT4 [p < 0.001] and fT3 [p < 0.001]), and peripheral indices showed a significant tendency towards thyrotoxicosis (strong TSH suppression: alkaline phosphatase [ALP, p < 0.001], creatinine [Cre, p < 0.001], pulse rate [p < 0.05]; and mild TSH suppression: Cre [p < 0.05]) than healthy participants. In contrast, athyreotic patients receiving TSH suppression therapy showed a significant tendency towards thyrotoxicosis than healthy participants only when TSH was strongly suppressed (fT3 [p < 0.001] and Cre [p < 0.001]). Endogenous SHyper patients showed significantly higher fT3 levels (p < 0.001) than athyreotic patients receiving TSH suppression therapy; however, there was a significant tendency towards thyrotoxicosis only when TSH was strongly suppressed (ALP [p < 0.05] and pulse rate [p < 0.05]). The effects of endogenous SHyper and TSH suppression therapy on target organ function are different. Although the serum thyroid hormone profile is similar to that of the thyrotoxic state, athyreotic patients receiving TSH suppression therapy with mildly suppressed serum TSH levels are not thyrotoxic.

Gestational trimester-specific reference ranges for serum thyrotropin and free thyroxine in Japanese.

Thyroid diseases in pregnant and lactating women may result in adverse outcomes for both mothers and infants. A reference range for thyroid function is required in different areas; however, few studies on the gestational change or reference ranges of thyrotropin (TSH) and free thyroxine (FT4) concentrations for Japanese pregnant women have been reported. To establish the gestational trimester-specific reference ranges of serum TSH and FT4 concentrations, our previously published data on 481 pregnant women with the mean age of 30.8 years who provided serum samples as early as gestational week (GW) 6 was compiled by using their percentile values. The overall median urinary iodine concentration (UIC) during pregnancy was 201 µg/L suggesting adequate iodine intake. The prevalence of positive serum thyroid autoantibody (ThAb), i.e., antithyroid peroxidase antibody (TPOAb) and antithyroglobulin antibody (TgAb), was 11.4%. The reference ranges (2.5-97.5th percentile) of serum TSH and FT4 concentration calculated for samples with negative TgAb and TPOAb were 0.04-6.06 mIU/L in the first trimester (T1), 0.31-3.11 mIU/L in the second trimester (T2) and 0.48-3.93 mIU/L in the third trimester (T3) for TSH, and 1.10-1.87 ng/dL (T1), 0.76-1.56 ng/dL (T2) and 0.76-1.14 ng/dL (T3) for FT4. Compared to published data around the world in the 2017 American Thyroid Association (ATA) guideline, both the upper and lower limits of our TSH and FT4 reference ranges in the first trimester were higher than those in other countries. Further research is necessary in larger samples.

Toward a science-based testing strategy to identify maternal thyroid hormone imbalance and neurodevelopmental effects in the progeny - part I: which parameters from human studies are most relevant for toxicological assessments?

The 2018 European Food Safety Authority/European Chemicals Agency Guidance on the Identification of Endocrine Disruptors lacks clarity on how the presence or absence of substance-induced maternal thyroid hormone imbalance, or the potential for subsequent deleterious consequences in child neurodevelopment, should be established by toxicological assessments. To address these uncertainties, this narrative review evaluates human evidence on how altered maternal thyroid function may be associated with child neurodevelopmental outcomes; and seeks to identify parameters in human studies that appear most relevant for toxicological assessments. Serum levels of free thyroxine (fT4) and thyroid stimulating hormone (TSH) are most frequently measured when assessing thyroid function in pregnant women, whereas a broad spectrum of neurodevelopmental parameters is used to evaluate child neurodevelopment. The human data confirms an association between altered maternal serum fT4 and/or TSH and increased risk for child neurodevelopmental impairment. Quantitative boundaries of effects indicative of increased risks need to be established. Moreover, it is unknown if altered serum levels of total T4, free or total triiodothyronine, or parameters unrelated to serum thyroid hormones might be more relevant indicators of such effects. None of the human studies established a link between substance-mediated liver enzyme induction and increased serum thyroid hormone clearance, let alone further to child neurodevelopmental impairment. This review identifies research needs to contribute to the development of toxicity testing strategies, to reliably predict whether substances have the potential to impair child neurodevelopment via maternal thyroid hormone imbalance.

Reference intervals for thyroid stimulating hormone and free thyroxine derived from neonates undergoing routine screening for congenital hypothyroidism at a university teaching hospital in Nairobi, Kenya: a cross sectional study.

BACKGROUND: In order to accurately interpret neonatal thyroid function tests (TFTs), it is necessary to have population specific reference intervals (RIs) as there is significant variation across different populations possibly due to genetic, environmental or analytical issues. Despite the importance of RIs, globally there are very few publications on RIs for neonatal TFTs primarily due to ethical and technical issues surrounding recruitment of neonates for a prospective study. To the best of our knowledge, this is the first report from Africa on neonatal RIs for TFTs. METHODS: We used hospital based data largely derived from neonates attending the wellness clinic at the Aga Khan University Hospital Nairobi (AKUHN) where screening for congenital hypothyroidism is routinely done. Specifically we derived age and gender stratified RIs for free thyroxine (fT4) and thyroid stimulating hormone (TSH) which had been analyzed on a Roche e601 analyzer from 2011 to 2013. Determination of reference intervals was done using a non-parametric method. RESULTS: A total of 1639 and 1329 non duplicate TSH and fT4 values respectively were used to derive RIs. There was a decline in TSH and fT4 levels with increase in age. Compared to the Roche RIs, the derived RIs for TSH in neonates aged 0-6 days and those aged 7-30 days had lower upper limits and narrower RIs. The fT4 lower limits for neonates less than 7 days and those aged 7-30 days were higher than those proposed by Roche. There was a significant difference in TSH RIs between male and female neonates aged less than 15 days. No gender differences were seen for all other age stratifications for both TSH and fT4. Appropriate age and gender specific RIs were subsequently determined. CONCLUSION: The AKUHN derived RIs for fT4 and TSH revealed similar age related trends to what has been published. However, the differences seen in upper and lower limits across different age stratifications when compared to the Roche RIs highlight the need for population specific RIs for TFTs especially when setting up a screening programme for congenital hypothyroidism. We subsequently recommend the adoption of the derived RIs by the AKUHN laboratory and hope that the RIs obtained can serve as a reference for the African population.

The predictive value of free thyroxine combined with tubular atrophy/interstitial fibrosis for poor prognosis in patients with IgA nephropathy.

Background: IgA nephropathy (IgAN), the most common type of glomerulonephritis, has great individual differences in prognosis. Many studies showed the relationship between thyroid hormones and chronic kidney disease. However, the relationship between free thyroxine (FT4), as a thyroid hormone, and IgAN is still unclear. This study aimed to evaluate the impact of FT4 on IgAN prognosis. Methods: This retrospective study involved 223 patients with biopsy-proven IgAN. The renal composite outcomes were defined as: (1) ESRD, defined as eGFR < 15 ml/(min·1.73 m2) or initiation of renal replacement therapy (hemodialysis, peritoneal dialysis, renal transplantation); (2) serum creatinine doubled from baseline; (3) eGFR decreased by more than 50% from baseline. The predictive value was determined by the area under the curve (AUC). Kaplan-Meier and Cox proportional hazards analyses assessed renal progression and prognosis. Results: After 38 (26-54) months of follow-up, 23 patients (10.3%) experienced renal composite outcomes. Kaplan-Meier survival curve analysis showed that the renal survival rate of the IgAN patients with FT4<15.18pmol/L was lower than that with FT4≥15.18pmol/L (P < 0. 001). Multivariate Cox regression model analysis showed that FT4 was a protective factor for poor prognosis of IgAN patients, whether as a continuous variable or a categorical variable (HR 0.68, 95%CI 0.51-0.90, P =0.007; HR 0.04, 95%CI 0.01-0.20, P <0.001). ROC curve analysis showed that FT4 combined with t score had a high predictive value for poor prognosis of IgAN patients (AUC=0.881, P<0.001). Conclusion: FT4 was a protective factor for IgAN. In addition, FT4 combined with tubular atrophy/interstitial fibrosis had a high predictive value for poor prognosis of IgAN.

Changes in Central Sensitivity to Thyroid Hormones vs. Urine Iodine during Pregnancy.

INTRODUCTION/AIM: Central sensitivity to thyroid hormones refers to the responsiveness of the hypothalamic-pituitary-thyroid (HPT) axis to changes in circulating free thyroxine (fT4). Although dose-response relationships between thyroid hormones per se and urinary iodine (UI) levels have been observed, central sensitivity to thyroid hormones in relation to UI remains unexplored. The aim of the present study was to evaluate central sensitivity to thyroid hormones (by means of the Thyroid Feedback Quantile-based Index [TFQI], which is a calculated measure, based on TSH and fT4, that estimates central sensitivity to thyroid hormones) in pregnancy and to assess whether it differs according to gestational age and/or iodine intake. MATERIALS AND METHODS: One thousand, one hundred and two blood and urine samples were collected from pregnant women (with a mean age ± SD of 30.4 ± 4.6 years) during singleton pregnancies; women with known/diagnosed thyroid disease were excluded. Specifically, TSH and fT4, anti-thyroid peroxidase antibodies and UI were measured in each trimester and at two months postpartum, while the TFQI was calculated for all the study samples. After the elimination of outliers, statistical analysis was conducted with analysis of variance (ANOVA) for the variables versus time period, while Pearson's correlation was used to assess the TFQI versus UI. RESULTS: The mean TFQI index ranged from -0.060 (second trimester) to -0.053 (two months postpartum), while the corresponding UI was 137 and 165 µg/L, respectively. The TFQI-UI correlation was marginally negative (Pearson r: -0.323, p: 0.04) and significantly positive (r: +0.368, p: 0.050) for UI values over 250 µg/L, in the first and the second trimesters of pregnancy, respectively. DISCUSSION: The TFQI is a new index reflecting central sensitivity to thyroid hormones. A lower TFQI indicates higher sensitivity to thyroid hormones. In our sample, the TFQI was mainly positively related to iodine intake in the second trimester of pregnancy (following the critical period of organogenesis). Thus, the observed changes in the TFQI may reflect the different ways of the central action of thyroid hormones, according to the phase of pregnancy. These results have the potential to enhance our comprehension of the changes in the HPT axis' function via variations in central sensitivity to thyroid hormones and its interplay with nutritional iodine status during pregnancy.

Thyroxine changes in COVID-19 pandemic: A systematic review and meta-analysis.

Objective: COVID-19 infection may affect thyroid function. However, changes in thyroid function in COVID-19 patients have not been well described. This systematic review and meta-analysis assess thyroxine levels in COVID-19 patients, compared with non-COVID-19 pneumonia and healthy cohorts during the COVID-19 epidemic. Methods: A search was performed in English and Chinese databases from inception to August 1, 2022. The primary analysis assessed thyroid function in COVID-19 patients, comparing non-COVID-19 pneumonia and healthy cohorts. Secondary outcomes included different severity and prognoses of COVID-19 patients. Results: A total of 5873 patients were enrolled in the study. The pooled estimates of TSH and FT3 were significantly lower in patients with COVID-19 and non-COVID-19 pneumonia than in the healthy cohort (P < 0.001), whereas FT4 were significantly higher (P < 0.001). Patients with the non-severe COVID-19 showed significant higher in TSH levels than the severe (I2 = 89.9%, P = 0.002) and FT3 (I2 = 91.9%, P < 0.001). Standard mean differences (SMD) of TSH, FT3, and FT4 levels of survivors and non-survivors were 0.29 (P= 0.006), 1.11 (P < 0.001), and 0.22 (P < 0.001). For ICU patients, the survivors had significantly higher FT4 (SMD=0.47, P=0.003) and FT3 (SMD=0.51, P=0.001) than non-survivors. Conclusions: Compared with the healthy cohort, COVID-19 patients showed decreased TSH and FT3 and increased FT4, similar to non-COVID-19 pneumonia. Thyroid function changes were related to the severity of COVID-19. Thyroxine levels have clinical significance for prognosis evaluation, especially FT3.

TSH and FT4 Reference Intervals in Pregnancy: A Systematic Review and Individual Participant Data Meta-Analysis.

CONTEXT: Interpretation of thyroid function tests during pregnancy is limited by the generalizability of reference intervals between cohorts due to inconsistent methodology. OBJECTIVE: (1) To provide an overview of published reference intervals for thyrotropin (TSH) and free thyroxine (FT4) in pregnancy, (2) to assess the consequences of common methodological between-study differences by combining raw data from different cohorts. METHODS: (1) Ovid MEDLINE, EMBASE, and Web of Science were searched until December 12, 2021. Studies were assessed in duplicate. (2) The individual participant data (IPD) meta-analysis was performed in participating cohorts in the Consortium on Thyroid and Pregnancy. RESULTS: (1) Large between-study methodological differences were identified, 11 of 102 included studies were in accordance with current guidelines; (2) 22 cohorts involving 63 198 participants were included in the meta-analysis. Not excluding thyroid peroxidase antibody-positive participants led to a rise in the upper limits of TSH in all cohorts, especially in the first (mean +17.4%; range +1.6 to +30.3%) and second trimester (mean +9.8%; range +0.6 to +32.3%). The use of the 95th percentile led to considerable changes in upper limits, varying from -10.8% to -21.8% for TSH and -1.2% to -13.2% for FT4. All other additional exclusion criteria changed reference interval cut-offs by a maximum of 3.5%. Applying these findings to the 102 studies included in the systematic review, 48 studies could be used in a clinical setting. CONCLUSION: We provide an overview of clinically relevant reference intervals for TSH and FT4 in pregnancy. The results of the meta-analysis indicate that future studies can adopt a simplified study setup without additional exclusion criteria.

Comparison on the consistency of Mindray and Siemens chemiluminescence analyzers for detecting FT3, FT4 and TSH in patients with hyper- and hypothyroidism.

Background: To examine the consistency of the Mindray and Siemens full-automatic chemiluminescence analyzers in detecting serum free triiodothyronine (FT3), free thyroxine (FT4) and thyroid stimulating hormone (TSH) in patients with hyper- or hypothyroidism. Methods: Included in this study were 164 new patients with abnormal thyroid function assessed at Nan Fang Hospital of Southern Medical University in 2021: 107 patients with hyperthyroidism and 57 with hypothyroidism. Additional 100 healthy individuals comprised the control group. Consistency of the FT3, FT4 and TSH results from the two systems in the different groups was analyzed by Kappa, linear correlation, regression, Bland-Altman and area under the receiver operating characteristic curve (AUC). Results: Compared with the control group, FT3 and FT4 levels were increased and TSH level was decreased in the hyperthyroid group (both P<0.05), whereas FT3 and FT4 levels were decreased and TSH level was increased in the hypothyroidism group (both P<0.05), suggesting that both test systems could provide references for relevant clinical evaluation. Kappa analysis showed high consistency of the two systems in detecting FT3, FT4 and TSH in both hyper- and hypothyroidism patients (mean Kappa value >0.7). In addition, there was a good linear correlation between the test results of the two systems (R2>0.90). Bland-Altman consistency analysis showed that most mean difference values were within the consistency limit (x±1.96s), indicating that the difference between the two systems was acceptable. AUC of FT3, FT4 and TSH detected by the two systems was higher than 0.80 in each group, showing no significant difference between them (both P>0.05), and the difference in sensitivity and specificity was within the acceptable range. Conclusions: Mindray and Siemens chemiluminescence analyzers are highly consistent in detecting FT3, FT4 and TSH in both hyper- and hypothyroidism patients.

Contribution of Obstructive Sleep Apnoea to Cognitive Functioning of Males With Coronary Artery Disease: A Relationship With Endocrine and Inflammatory Biomarkers.

Introduction: Our exploratory study aimed to determine whether obstructive sleep apnoea (OSA) could affect cognitive functioning in males with coronary artery disease (CAD), and whether such impact could be associated with changes in thyroid hormones and inflammatory marker regulation on cognitive functioning. Method: We evaluated different endocrine and inflammatory biomarkers, including free triiodothyronine [fT3], free tetraiodothyronine [fT4], N-terminal pro-B-type natriuretic peptide [NT-pro-BNP], and high-sensitivity C-reactive protein [hs-CRP] serum levels in 328 males ( x ¯ = 57 ± 10 years), undergoing cardiac rehabilitation after an acute coronary event. Participants underwent full-night polysomnography and were classified in mild/non-OSA (n = 253) and OSA (n = 75) according to an apnoea-hypopnoea index ≥ 15 event/h. Cognitive functioning testing included the Digit Span Test, Digit Symbol Test (DSST), and Trail Making Test. Analyses of variance assessed the impact of OSA on cognitive functioning and possible relationships of fT3/fT4, NT-pro-BNP and with hs-CRP on cognitive measures. Results: Significant group (OSA, mild/non-OSA) × NT-pro-BNP (<157.0 vs. ≥157.0, ng/L) interactions were found for the DSST raw score (F (2,324) = 3.58, p = 0.014). Decomposition of interactions showed that the DSST scores of the OSA group with NT-pro-BNP ≥ 157.0 ng/L (M = 33.2; SD = 8.1) were significantly lower, p = 0.031, than those of the mild/non-OSA with NT-pro-BNP < 157.0 ng/L (M = 37.7; SD = 8.9). Conclusion: These findings indicate that males with OSA and clinically elevated NT-pro-BNP levels experienced inferior psychomotor performance compared to those without OSA and reduced NT-pro-BNP levels.

The potential association of polybrominated diphenyl ether concentrations in serum to thyroid function in patients with abnormal thyroids: a pilot study.

BACKGROUND: To explore possible associations between polybrominated diphenyl ether (PBDE) exposure and patients with abnormal thyroid hormone levels whose thyroid function parameters are above normal ranges. METHODS: The serum of 40 patients with thyroid hormone abnormalities was collected in Kunming. triiodothyronine (T3), thyroxine (T4), free triiodothyronine (FT3), free thyroxine (FT4), and thyroid-stimulating hormone (TSH) were detected in serum using chemiluminescence. The PBDE homologs in the patients' serum were quantitatively analyzed by gas chromatography-mass spectrometry. If the detection frequency of the compound exceeded 50%, it was included in the analysis. Spearman's rank correlation coefficient and multiple linear regression were used to evaluate the correlation between PBDE homologs and five thyroid function parameters. RESULTS: A total of 33 PBDE homologs were detected, 7 of which had a more than 50% detection rate. BDE-47 was the main homolog detected. Spearman's correlation showed that no relationship was found between PBDE homologs and thyroid hormones. Multiple linear regression showed that BDE-153 was positively correlated with T4, negatively correlated with T3, while BDE-47 was negatively correlated with FT4 (P<0.05). The correlation between other PBDE homologs and thyroid function parameters was weak (P>0.05). The ß coefficient showed that the increase in the logarithmic unit of ∑7PBDEs was related to an increase in FT4 and T4 levels and decreased TSH, T3, and FT3 levels. CONCLUSIONS: There is a significant correlation between exposure to PBDE and thyroid dysfunction. The increase of total PBDEs was significantly correlated with the increase of FT4 and T4 levels and decreased TSH, T3, and FT3 levels.