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1.
Artigo em Inglês | MEDLINE | ID: mdl-39083675

RESUMO

BACKGROUND: Establishing local trimester-specific reference intervals for gestational TSH and FT4 is often not feasible, necessitating alternative strategies. We aimed to systematically quantify the diagnostic performance of standardized modifications of center-specific non-pregnancy reference intervals as compared to trimester-specific reference intervals. METHODS: We included prospective cohorts participating in the Consortium on Thyroid and Pregnancy. After relevant exclusions, reference intervals were calculated per cohort in thyroperoxidase antibody-negative women. Modifications to the non-pregnancy reference intervals included an absolute modification (per 0.1 mU/L TSH or 1 pmol/L FT4), relative modification (in steps of 5%) and fixed limits (upper TSH limit between 3.0 to 4.5 mU/L and lower FT4 limit 5-15 pmol/L). We compared (sub)clinical hypothyroidism prevalence, sensitivity and positive predictive value (PPV) of aforementioned methodologies with population-based trimester-specific reference intervals. RESULTS: The final study population comprised 52,496 participants in 18 cohorts. Optimal modifications of standard reference intervals to diagnose gestational overt hypothyroidism were -5% for the upper limit of TSH and +5% for the lower limit of FT4 (sensitivity 0.70, confidence interval [CI] 0.47-0.86; PPV 0.64, CI 0.54-0.74). For subclinical hypothyroidism, these were -20% for the upper limit of TSH and -15% for the lower limit of FT4 (sensitivity 0.91, CI 0.67-0.98; PPV 0.71, CI 0.58-0.80). Absolute and fixed modifications yielded similar results. Confidence intervals were wide, limiting generalizability. CONCLUSION: We could not identify modifications of non-pregnancy TSH and FT4 reference intervals that would enable centers to adequately approximate trimester-specific reference intervals. Future efforts should be turned towards studying the meaningfulness of trimester-specific reference intervals and risk-based decision limits.

2.
Thyroid ; 34(5): 646-658, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38546971

RESUMO

Background: International guidelines recommend targeted screening to identify gestational thyroid dysfunction. However, currently used risk factors have questionable discriminative ability. We quantified the risk for thyroid function test abnormalities for a subset of risk factors currently used in international guidelines. Methods: We included prospective cohort studies with data on gestational maternal thyroid function and potential risk factors (maternal age, body mass index [BMI], parity, smoking status, pregnancy through in vitro fertilization, twin pregnancy, gestational age, maternal education, and thyroid peroxidase antibody [TPOAb] or thyroglobulin antibody [TgAb] positivity). Exclusion criteria were pre-existing thyroid disease and use of thyroid interfering medication. We analyzed individual participant data using mixed-effects regression models. Primary outcomes were overt and subclinical hypothyroidism and a treatment indication (defined as overt hypothyroidism, subclinical hypothyroidism with thyrotropin >10 mU/L, or subclinical hypothyroidism with TPOAb positivity). Results: The study population comprised 65,559 participants in 25 cohorts. The screening rate in cohorts using risk factors currently recommended (age >30 years, parity ≥2, BMI ≥40) was 58%, with a detection rate for overt and subclinical hypothyroidism of 59%. The absolute risk for overt or subclinical hypothyroidism varied <2% over the full range of age and BMI and for any parity. Receiver operating characteristic curves, fitted using maternal age, BMI, smoking status, parity, and gestational age at blood sampling as explanatory variables, yielded areas under the curve ranging from 0.58 to 0.63 for the primary outcomes. TPOAbs/TgAbs positivity was associated with overt hypothyroidism (approximate risk for antibody negativity 0.1%, isolated TgAb positivity 2.4%, isolated TPOAb positivity 3.8%, combined antibody positivity 7.0%; p < 0.001), subclinical hypothyroidism (risk for antibody negativity 2.2%, isolated TgAb positivity 8.1%, isolated TPOAb positivity 14.2%, combined antibody positivity 20.0%; p < 0.001) and a treatment indication (risk for antibody negativity 0.2%, isolated TgAb positivity 2.2%, isolated TPOAb positivity 3.0%, and combined antibody positivity 5.1%; p < 0.001). Twin pregnancy was associated with a higher risk of overt hyperthyroidism (5.6% vs. 0.7%; p < 0.001). Conclusions: The risk factors assessed in this study had poor predictive ability for detecting thyroid function test abnormalities, questioning their clinical usability for targeted screening. As expected, TPOAb positivity (used as a benchmark) was a relevant risk factor for (subclinical) hypothyroidism. These results provide insights into different risk factors for gestational thyroid dysfunction.


Assuntos
Hipotireoidismo , Complicações na Gravidez , Testes de Função Tireóidea , Humanos , Gravidez , Feminino , Fatores de Risco , Hipotireoidismo/epidemiologia , Hipotireoidismo/complicações , Hipotireoidismo/diagnóstico , Adulto , Autoanticorpos/sangue , Índice de Massa Corporal , Iodeto Peroxidase/imunologia , Estudos Prospectivos , Idade Materna , Tireotropina/sangue
3.
J Clin Endocrinol Metab ; 109(3): 868-878, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-37740543

RESUMO

CONTEXT: Guidelines recommend use of population- and trimester-specific thyroid-stimulating hormone (TSH) and free thyroxine (FT4) reference intervals (RIs) in pregnancy. Since these are often unavailable, clinicians frequently rely on alternative diagnostic strategies. We sought to quantify the diagnostic consequences of current recommendations. METHODS: We included cohorts participating in the Consortium on Thyroid and Pregnancy. Different approaches were used to define RIs: a TSH fixed upper limit of 4.0 mU/L (fixed limit approach), a fixed subtraction from the upper limit for TSH of 0.5 mU/L (subtraction approach) and using nonpregnancy RIs. Outcome measures were sensitivity and false discovery rate (FDR) of women for whom levothyroxine treatment was indicated and those for whom treatment would be considered according to international guidelines. RESULTS: The study population comprised 52 496 participants from 18 cohorts. Compared with the use of trimester-specific RIs, alternative approaches had a low sensitivity (0.63-0.82) and high FDR (0.11-0.35) to detect women with a treatment indication or consideration. Sensitivity and FDR to detect a treatment indication in the first trimester were similar between the fixed limit, subtraction, and nonpregnancy approach (0.77-0.11 vs 0.74-0.16 vs 0.60-0.11). The diagnostic performance to detect overt hypothyroidism, isolated hypothyroxinemia, and (sub)clinical hyperthyroidism mainly varied between FT4 RI approaches, while the diagnostic performance to detect subclinical hypothyroidism varied between the applied TSH RI approaches. CONCLUSION: Alternative approaches to define RIs for TSH and FT4 in pregnancy result in considerable overdiagnosis and underdiagnosis compared with population- and trimester-specific RIs. Additional strategies need to be explored to optimize identification of thyroid dysfunction during pregnancy.


Assuntos
Hipotireoidismo , Testes de Função Tireóidea , Gravidez , Humanos , Feminino , Prevalência , Hipotireoidismo/diagnóstico , Hipotireoidismo/epidemiologia , Tiroxina , Tireotropina , Valores de Referência
4.
J Clin Endocrinol Metab ; 109(3): e1290-e1298, 2024 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-37878891

RESUMO

CONTEXT: Triiodothyronine (T3) is the bioactive form of thyroid hormone. In contrast to thyroid-stimulating hormone and free thyroxine, we lack knowledge on the association of gestational T3 with adverse obstetric outcomes. OBJECTIVE: To investigate the associaiton of gestational free or total T3 (FT3 or TT3) with adverse obstetric outcomes. METHODS: We collected individual participant data from prospective cohort studies on gestational FT3 or TT3, adverse obstetric outcomes (preeclampsia, gestational hypertension, preterm birth and very preterm birth, small for gestational age [SGA], and large for gestational age [LGA]), and potential confounders. We used mixed-effects regression models adjusting for potential confounders. RESULTS: The final study population comprised 33 118 mother-child pairs of which 27 331 had data on FT3 and 16 164 on TT3. There was a U-shaped association of FT3 with preeclampsia (P = .0069) and a J-shaped association with the risk of gestational hypertension (P = .029). Higher TT3 was associated with a higher risk of gestational hypertension (OR per SD of TT3 1.20, 95% CI 1.08 to 1.33; P = .0007). A lower TT3 but not FT3 was associated with a higher risk of very preterm birth (OR 0.72, 95% CI 0.55 to 0.94; P = .018). TT3 but not FT3 was positively associated with birth weight (mean difference per 1 SD increase in TT3 12.8, 95% CI 6.5 to 19.1 g, P < .0001) but there was no association with SGA or LGA. CONCLUSION: This study provides new insights on the association of gestational FT3 and TT3 with major adverse pregnancy outcomes that form the basis for future studies required to elucidate the effects of thyroid function on pregnancy outcomes. Based on the current study, routine FT3 or TT3 measurements for the assessment of thyroid function during pregnancy do not seem to be of added value in the risk assessment for adverse outcomes.


Assuntos
Hipertensão Induzida pela Gravidez , Pré-Eclâmpsia , Nascimento Prematuro , Gravidez , Feminino , Humanos , Recém-Nascido , Tri-Iodotironina , Peso ao Nascer , Hipertensão Induzida pela Gravidez/epidemiologia , Hipertensão Induzida pela Gravidez/etiologia , Pré-Eclâmpsia/epidemiologia , Pré-Eclâmpsia/etiologia , Nascimento Prematuro/epidemiologia , Nascimento Prematuro/etiologia , Estudos Prospectivos , Hormônios Tireóideos , Tireotropina , Tiroxina
5.
Front Endocrinol (Lausanne) ; 14: 1285504, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-38047117

RESUMO

Background: Autoimmune thyroid disease is a prevalent condition affecting women of reproductive age, leading to thyroid dysfunction and impacting pregnancy outcomes. While the critical role of thyroid hormone in pregnancy outcomes is well-established, the potential association between positive anti-thyroid peroxidase antibodies (TPOAb) and adverse pregnancy outcomes in pregnant women with normal thyroid function remains unclear. Objective: This study aims to investigate the relationship between maternal TPOAb positivity and adverse pregnancy outcomes with normal thyroid function. Methods: We collected baseline information from pregnant women who visited our hospital between February 2009 and June 2012. Blood samples were taken to measure thyroid stimulating hormone (TSH), free thyroxine (FT4), TPOAb, and anti-thyroglobulin antibodies (TGAb). The incidence of adverse pregnancy outcomes was compared between TPOAb-positive and TPOAb-negative groups among participants with normal thyroid function. Results: A total of 7,046 pregnant women with normal thyroid function were included, comprising 6,700 with negative TPOAb and 346 with positive TPOAb. The TPOAb-positive group exhibited a higher age (26.0 vs. 27.0 years, p = 0.02) and greater serum TSH levels (1.72 vs. 1.94 mIU/L, p = 0.029), while the gestational week of blood collection was lower (31.9 vs. 26.5 weeks, p = 0.001). Univariate analysis revealed a higher incidence of low birth weight (LBW) in offspring of TPOAb-positive women compared to the TPOAb-negative group (3.5% vs. 1.9%, p = 0.035). After adjusting for confounding factors such as age, gestational week of blood collection, menstrual history, education level, gestational diabetes, gestational hypertension, TGAb, TSH, and FT4, TPOAb positivity emerged as an independent risk factor for LBW infants (OR: 2.317, 95% CI: 1.057-5.076, p = 0.036), while other adverse pregnancy outcomes did not show a significant correlation with TPOAb positivity. Conclusion: Our findings suggest that TPOAb-positive pregnant women with normal thyroid function are more likely to deliver LBW infants. Regular monitoring of TPOAb-positive pregnancies and timely interventions throughout all stages of pregnancy are crucial.


Assuntos
Iodeto Peroxidase , Tiroxina , Recém-Nascido , Feminino , Gravidez , Humanos , Lactente , Incidência , Hormônios Tireóideos , Tireotropina , Recém-Nascido de Baixo Peso
6.
BMC Nephrol ; 24(1): 154, 2023 05 31.
Artigo em Inglês | MEDLINE | ID: mdl-37259071

RESUMO

OBJECTIVE: Thrombospondin-2 (TSP-2) is a multifunctional matricellular glycoprotein correlated with glucose homeostasis, insulin sensitivity, and estimated glomerular filtration rate. Investigation of the association of TSP-2 with type 2 diabetes mellitus (T2DM) and the potential diagnostic value of serum TSP-2 for detecting early diabetic kidney disease (DKD) is needed. RESEARCH DESIGN AND METHODS: An enzyme-linked immunosorbent assay was used for detection serum TSP-2 levels in 494 Chinese T2DM subjects. The protein expression of TSP-2 in the kidney and other tissues were tested by western blotting. RESULTS: Serum TSP-2 levels in T2DM subjects were significantly higher than in healthy individuals. Serum TSP-2 correlated positively with triglycerides, serum uric acid, creatinine, platelets, and urinary albumin-to-creatinine ratio (UACR), but negatively with estimated glomerular filtration rate, after adjusting for age, sex, and T2DM duration. Logistic regression analysis demonstrated an independent association between serum TSP-2 and early DKD. Furthermore, the high UACR identified at risk of early DKD increased significantly from 0.78 (95%CI 0.73-0.83) to 0.82 (95%CI 0.77-0.86, p < 0.001) when added to a clinical model consisting of TSP-2 and age. In db/db mice, serum TSP-2 levels were elevated. TSP-2 expression was markedly increased in the kidney tissue compared with that in db/m and m/m mice. Furthermore, serum TSP-2 expression correlated well with UACR in mice. CONCLUSIONS: TSP-2 is a novel glycoprotein associated with early DKD in patients with T2DM. The paradoxical increase of serum TSP-2 in T2DM individuals may be due to a compensatory response to chronic inflammatory and renal vascular endothelial growth, warranting further investigation.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Trombospondinas , Animais , Camundongos , Biomarcadores , Creatinina/sangue , Creatinina/urina , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/diagnóstico , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/etiologia , Trombospondinas/sangue , Ácido Úrico/sangue , Humanos
7.
Endocr J ; 70(6): 611-618, 2023 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-37032065

RESUMO

To study the effects of third trimester maternal isolated hypothyroxinemia (serum low free thyroxine and normal thyroid stimulating hormone level) on pregnancy outcomes, we performed a retrospective cohort study in women with singleton pregnancy between February 2009 and June 2012. Pregnant women were assigned to two groups, a hypothyroxinemia group (with maternal isolated hypothyroxinemia in the third trimester and normal thyroid function in the first and second trimesters) and a control group (with normal serum thyroid functions). The pregnancy outcomes, including preterm birth, fetal distress, birth weight, premature rupture of membranes, and Apgar score at one minute after the birth, were recorded and compared between the two groups. A total of 3,945 pregnant women (median age 26 year old) were included in the study, with 195 women in the hypothyroxinemia group and 3,750 women in the control group. Compared with the women in the control group, women in the hypothyroxinemia group had higher incidences of premature rupture of membranes and low Apgar score at one minute after the birth. The multivariate logistic regression analysis showed that the low third trimester serum thyroxine level was the independent risk factor for the premature rupture of membranes and low Apgar score. There were no statistically significant differences in preterm birth, macrosomia, and intrauterine fetal distress between two groups. Third trimester maternal isolated hypothyroxinemia was associated with adverse pregnancy outcomes. The maternal serum thyroxine level should be monitored during late pregnancy and necessary management should be applied to improve the pregnancy outcomes.


Assuntos
Complicações na Gravidez , Nascimento Prematuro , Gravidez , Feminino , Recém-Nascido , Humanos , Adulto , Resultado da Gravidez , Terceiro Trimestre da Gravidez , Tiroxina , Estudos Retrospectivos , Sofrimento Fetal , Complicações na Gravidez/epidemiologia
8.
Front Microbiol ; 13: 1099592, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36583050

RESUMO

Introduction: Endophytic fungi associated with medicinal plants have proven to possess a high potential to produce structurally diverse metabolites, some of which are valuable for medicinal applications. In this study, Penicillium sp. YT2019-3321, an endophytic fungus derived from traditional Chinese medicine Lonicera japonica, was chemically studied. Methods: The chemical structures of the isolated compounds were established by a correlative interpretation of HRESIMS and NMR spectroscopic data. The optical resolution of (±)-1 by chiral HPLC yielded individual enantiomers (+)-1 and (-)-1, and their stereochemistry were solved by X-ray diffraction crystallography, respectively. Results and discussion: Eight structurally diversified secondary metabolites, including two previously unreported polyketides, named (±)-chrysoalide B (1) and penicidone E (2), were isolated and identified from Penicillium sp. YT2019-3321. Compound 2 possessed the γ-pyridone nucleus, which is rarely found in natural products. Cytotoxic assay revealed that the new compound 2 demonstrated a dose-dependent cytotoxicity against the human pancreatic tumor cells PATU8988T with the IC50 value of 11.4 µM. Further studies indicated that 2 significantly induced apoptosis of PATU8988T cell lines, characterized by the morphologies abnormity, the reduction of cell number, the upregulation of proportion of apoptotic cells, and the ratio of Bcl-2 to Bax. Our study demonstrates that fungal secondary metabolites may have important significance in the discovery of drug leads.

9.
Front Microbiol ; 13: 1033823, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36225350

RESUMO

Fungal secondary metabolites are inherently considered valuable resources for new drugs discovery. To search for novel fungal secondary metabolites with lead compounds potential, a fungal strain Penicillium oxalicum 2021CDF-3, an endophyte of the marine red algae Rhodomela confervoides, was chemically studied. Cultivation of this fungus on solid rice medium yielded 10 structurally diverse metabolites (1-10), including two new polyketides, namely oxalichroman A (1) and oxalihexane A (2). Their structures were determined by detailed analysis of NMR and HRESIMS spectroscopic data. Oxalihexane A (2) was elucidated as a novel polyketide formed by a cyclohexane and cyclohexanone moiety via an ether bond. The stereochemistry of 2 was successfully assigned by NMR and ECD calculations. In the cytotoxic assay, the new compound 2 showed remarkable inhibitory effect on the human pancreatic cancer PATU8988T cell line. Further pharmacological study demonstrated that the expression level of Cyclin D1 was down-regulated by the treatment with 2, which suggested that cell cyclin abnormity was involved in pancreatic tumor cell apoptosis. Moreover, the activation of Wnt5a/Cyclin D1 signaling pathway might be involved in the mechanism of panreatic tumor cell apoptosis induced by 2.

10.
J Clin Endocrinol Metab ; 107(10): 2925-2933, 2022 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-35861700

RESUMO

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.


Assuntos
Iodeto Peroxidase , Tiroxina , Feminino , Humanos , Gravidez , Valores de Referência , Testes de Função Tireóidea , Glândula Tireoide , Tireotropina
11.
Thyroid ; 32(7): 828-840, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35596568

RESUMO

Objectives: Thyroid autoimmunity is common in pregnant women and associated with thyroid dysfunction and adverse obstetric outcomes. Most studies focus on thyroid peroxidase antibodies (TPOAbs) assessed by a negative-positive dichotomy and rarely take into account thyroglobulin antibodies (TgAbs). This study aimed at determining the association of TPOAbs and TgAbs, respectively, and interdependently, with maternal thyroid function. Methods: This was a meta-analysis of individual participant cross-sectional data from 20 cohorts in the Consortium on Thyroid and Pregnancy. Women with multiple pregnancy, pregnancy by assisted reproductive technology, history of thyroid disease, or use of thyroid interfering medication were excluded. Associations of (log2) TPOAbs and TgAbs (with/without mutual adjustment) with cohort-specific z-scores of (log2) thyrotropin (TSH), free triiodothyronine (fT3), total triiodothyronine (TT3), free thyroxine (fT4), total thyroxine (TT4), or triiodothyronine:thyroxine (T3:T4) ratio were evaluated in a linear mixed model. Results: In total, 51,138 women participated (51,094 had TPOAb-data and 27,874 had TgAb-data). Isolated TPOAb positivity was present in 4.1% [95% confidence interval, CI: 3.0 to 5.2], isolated TgAb positivity in 4.8% [CI: 2.9 to 6.6], and positivity for both antibodies in 4.7% [CI: 3.1 to 6.3]. Compared with antibody-negative women, TSH was higher in women with isolated TPOAb positivity (z-score increment 0.40, CI: 0.16 to 0.64) and TgAb positivity (0.21, CI: 0.10 to 0.32), but highest in those positive for both antibodies (0.54, CI: 0.36 to 0.71). There was a dose-response effect of higher TPOAb and TgAb concentrations with higher TSH (TSH z-score increment for TPOAbs 0.12, CI: 0.09 to 0.15, TgAbs 0.08, CI: 0.02 to 0.15). When adjusting analyses for the other antibody, only the association of TPOAbs remained statistically significant. A higher TPOAb concentration was associated with lower fT4 (p < 0.001) and higher T3:T4 ratio (0.09, CI: 0.03 to 0.14), however, the association with fT4 was not significant when adjusting for TgAbs (p = 0.16). Conclusions: This individual participant data meta-analysis demonstrated an increase in TSH with isolated TPOAb positivity and TgAb positivity, respectively, which was amplified for individuals positive for both antibodies. There was a dose-dependent association of TPOAbs, but not TgAbs, with TSH when adjusting for the other antibody. This supports current practice of using TPOAbs in initial laboratory testing of pregnant women suspected of autoimmune thyroid disease. However, studies on the differences between TPOAb- and TgAb-positive women are needed to fully understand the spectrum of phenotypes.


Assuntos
Doenças da Glândula Tireoide , Tiroxina , Autoanticorpos , Estudos Transversais , Feminino , Humanos , Iodeto Peroxidase , Gravidez , Tireoglobulina , Tireotropina , Tri-Iodotironina
12.
Lancet Diabetes Endocrinol ; 10(4): 243-252, 2022 04.
Artigo em Inglês | MEDLINE | ID: mdl-35255260

RESUMO

BACKGROUND: Adequate maternal thyroid function is important for an uncomplicated pregnancy. Although multiple observational studies have evaluated the association between thyroid dysfunction and hypertensive disorders of pregnancy, the methods and definitions of abnormalities in thyroid function tests were heterogeneous, and the results were conflicting. We aimed to examine the association between abnormalities in thyroid function tests and risk of gestational hypertension and pre-eclampsia. METHODS: In this systematic review and meta-analysis of individual-participant data, we searched MEDLINE (Ovid), Embase, Scopus, and the Cochrane Database of Systematic Reviews from date of inception to Dec 27, 2019, for prospective cohort studies with data on maternal concentrations of thyroid-stimulating hormone (TSH), free thyroxine (FT4), thyroid peroxidase (TPO) antibodies, individually or in combination, as well as on gestational hypertension, pre-eclampsia, or both. We issued open invitations to study authors to participate in the Consortium on Thyroid and Pregnancy and to share the individual-participant data. We excluded participants who had pre-existing thyroid disease or multifetal pregnancy, or were taking medications that affect thyroid function. The primary outcomes were documented gestational hypertension and pre-eclampsia. Individual-participant data were analysed using logistic mixed-effects regression models adjusting for maternal age, BMI, smoking, parity, ethnicity, and gestational age at blood sampling. The study protocol was registered with PROSPERO, CRD42019128585. FINDINGS: We identified 1539 published studies, of which 33 cohorts met the inclusion criteria and 19 cohorts were included after the authors agreed to participate. Our study population comprised 46 528 pregnant women, of whom 39 826 (85·6%) women had sufficient data (TSH and FT4 concentrations and TPO antibody status) to be classified according to their thyroid function status. Of these women, 1275 (3·2%) had subclinical hypothyroidism, 933 (2·3%) had isolated hypothyroxinaemia, 619 (1·6%) had subclinical hyperthyroidism, and 337 (0·8%) had overt hyperthyroidism. Compared with euthyroidism, subclinical hypothyroidism was associated with a higher risk of pre-eclampsia (2·1% vs 3·6%; OR 1·53 [95% CI 1·09-2·15]). Subclinical hyperthyroidism, isolated hypothyroxinaemia, or TPO antibody positivity were not associated with gestational hypertension or pre-eclampsia. In continuous analyses, both a higher and a lower TSH concentration were associated with a higher risk of pre-eclampsia (p=0·0001). FT4 concentrations were not associated with the outcomes measured. INTERPRETATION: Compared with euthyroidism, subclinical hypothyroidism during pregnancy was associated with a higher risk of pre-eclampsia. There was a U-shaped association of TSH with pre-eclampsia. These results quantify the risks of gestational hypertension or pre-eclampsia in women with thyroid function test abnormalities, adding to the total body of evidence on the risk of adverse maternal and fetal outcomes of thyroid dysfunction during pregnancy. These findings have potential implications for defining the optimal treatment target in women treated with levothyroxine during pregnancy, which needs to be assessed in future interventional studies. FUNDING: Arkansas Biosciences Institute and Netherlands Organization for Scientific Research.


Assuntos
Hipertensão Induzida pela Gravidez , Hipertireoidismo , Hipotireoidismo , Pré-Eclâmpsia , Complicações na Gravidez , Doenças da Glândula Tireoide , Feminino , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Hipotireoidismo/epidemiologia , Masculino , Pré-Eclâmpsia/epidemiologia , Gravidez , Estudos Prospectivos , Doenças da Glândula Tireoide/complicações , Doenças da Glândula Tireoide/epidemiologia , Tireotropina , Tiroxina
13.
J Diabetes Res ; 2021: 6662418, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34307690

RESUMO

Zinc is an essential trace element that is often reduced under the type 1 diabetic condition. Previous studies demonstrated that zinc deficiency enhanced type 1 diabetes-induced liver injury and that zinc supplementation significantly helped to prevent this. Due to the differences in pathogenesis between type 1 and type 2 diabetes, it is unknown whether zinc supplementation can induce a beneficial effect on type 2 diabetes-induced liver injury. This possible protective mechanism was investigated in the present study. A high-fat diet, along with a one-time dose of streptozotocin, was applied to metallothionein (MT) knockout mice, nuclear factor-erythroid 2-related factor (Nrf) 2 knockout mice, and age-matched wild-type (WT) control mice, in order to induce type 2 diabetes. This was followed by zinc treatment at 5 mg/kg body weight given every other day for 3 months. Global metabolic disorders of both glucose and lipids were unaffected by zinc supplementation. This induced preventive effects on conditions caused by type 2 diabetes like oxidative stress, apoptosis, the subsequent hepatic inflammatory response, fibrosis, hypertrophy, and hepatic dysfunction. Additionally, we also observed that type 2 diabetes reduced hepatic MT expression, while zinc supplementation induced hepatic MT expression. This is a crucial antioxidant. A mechanistic study showed that MT deficiency blocked zinc supplementation-induced hepatic protection under the condition of type 2 diabetes. This suggested that endogenous MT is involved in the hepatic protection of zinc supplementation in type 2 diabetic mice. Furthermore, zinc supplementation-induced hepatic MT increase was unobserved once Nrf2 was deficient, indicating that Nrf2 mediated the upregulation of hepatic MT in response to zinc supplementation. Results of this study indicated that zinc supplementation prevented type 2 diabetes-induced liver injury through the activation of the Nrf2-MT-mediated antioxidative pathway.


Assuntos
Complicações do Diabetes/prevenção & controle , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Tipo 2/complicações , Hepatopatias/prevenção & controle , Metalotioneína/fisiologia , Fator 2 Relacionado a NF-E2/fisiologia , Zinco/administração & dosagem , Animais , Suplementos Nutricionais , Estresse do Retículo Endoplasmático , Metabolismo dos Lipídeos , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Estreptozocina
14.
Toxicol Appl Pharmacol ; 412: 115378, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33352188

RESUMO

Chronic excessive ethanol consumption is associated with a high incidence of mortality due to ethanol-induced dilated cardiomyopathy, known as alcoholic cardiomyopathy (ACM). Mechanistic studies have demonstrated that apoptosis is key to the pathogenesis of ACM, and endoplasmic reticulum (ER) stress-associated apoptosis contributes to various ethanol-related diseases. Astaxanthin (AST) is a natural carotenoid that exerts an anti-ER stress effect. Importantly, strong evidence has shown that AST induces beneficial effects in various cardiovascular diseases. The present study aimed to investigate whether AST induces beneficial effects on ACM by suppressing cardiac apoptosis mediated by ER stress. We showed that after 2 months of chronic excessive ethanol consumption, mice displayed obvious cardiac dysfunction and morphological changes associated with increased fibrosis, oxidative stress, ER stress and apoptosis. However, cardiac damage above was attenuated in response to AST treatment. The cardioprotective effect of AST against ethanol toxicity was also confirmed in both H9c2 cells and primary cardiomyocytes, indicating that AST-induced protection directly targets cardiomyocytes. Both in vivo and in vitro studies showed that AST inhibited all three ER stress signaling pathways activated by ethanol. Furthermore, administration of the ER stress inhibitor sodium 4-phenylbutyrate (4-PBA) strongly suppressed ethanol-induced cardiomyocyte damage. Interestingly, AST induced further anti-apoptotic effects once co-treated with 4-PBA, indicating that AST protects the heart from ACM partially by attenuating ER stress, but other mechanisms still exist. This study highlights that administration of AST ablated chronic excessive ethanol consumption-induced cardiomyopathy by suppressing cardiac ER stress and subsequent apoptosis.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Cardiomiopatia Alcoólica/prevenção & controle , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Miócitos Cardíacos/efeitos dos fármacos , Animais , Proteínas Reguladoras de Apoptose/metabolismo , Cardiomiopatia Alcoólica/etiologia , Cardiomiopatia Alcoólica/metabolismo , Cardiomiopatia Alcoólica/fisiopatologia , Linhagem Celular , Modelos Animais de Doenças , Etanol , Fibrose , Masculino , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Transdução de Sinais , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Xantofilas/farmacologia
15.
Front Endocrinol (Lausanne) ; 11: 528146, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33178133

RESUMO

Objective: Adverse maternal outcomes and perinatal complications are associated with overt and subclinical maternal hypothyroidism. It is not clear whether these complications also occur in women with isolated hypothyroxinemia during pregnancy. The aim of this study was to evaluate the effects of isolated hypothyroxinemia on maternal and perinatal outcomes during pregnancy. Methods: This study included data from 2,864 pregnant women in the first trimester (67 women with isolated hypothyroxinemia, 784 euthyroid women) and the second trimester (70 women with isolated hypothyroxinemia, 1,943 euthyroid women) of pregnancy. Maternal serum samples were collected in the first and second trimesters to examine thyroid hormone concentration. Hypothyroxinemia was defined as a normal maternal thyroid-stimulating hormone concentration with a low maternal free thyroxine concentration and negative thyroid autoantibodies. The following maternal outcomes were recorded: gestational hypertension, gestational diabetes mellitus, placenta previa, placental abruption, prelabor rupture of membranes, and premature delivery. Perinatal outcomes, including fetal growth restriction, fetal distress, low birth weight, intrauterine fetal death, and malformation. The incidence of adverse pregnancy outcomes and perinatal complications was compared between women in the first trimester and second trimester with isolated hypothyroxinemia. Results: There were no significant differences in the incidence rates of adverse maternal outcomes and perinatal complications between patients in the first and second trimesters with isolated hypothyroxinemia. Conclusion: The results of this study indicate that isolated hypothyroidism does not increase the incidence of adverse maternal outcomes and perinatal complications.


Assuntos
Hipotireoidismo/sangue , Complicações na Gravidez/sangue , Primeiro Trimestre da Gravidez/sangue , Segundo Trimestre da Gravidez/sangue , Tiroxina/sangue , Adulto , Feminino , Humanos , Recém-Nascido de Baixo Peso/fisiologia , Recém-Nascido , Gravidez , Resultado da Gravidez , Testes de Função Tireóidea , Adulto Jovem
16.
Lancet Diabetes Endocrinol ; 8(6): 501-510, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32445737

RESUMO

BACKGROUND: Adequate transplacental passage of maternal thyroid hormone is important for normal fetal growth and development. Maternal overt hypothyroidism and hyperthyroidism are associated with low birthweight, but important knowledge gaps remain regarding the effect of subclinical thyroid function test abnormalities on birthweight-both in general and during the late second and third trimester of pregnancy. The aim of this study was to examine associations of maternal thyroid function with birthweight. METHODS: In this systematic review and individual-participant data meta-analysis, we searched MEDLINE (Ovid), Embase, Web of Science, the Cochrane Central Register of Controlled Trials, and Google Scholar from inception to Oct 15, 2019, for prospective cohort studies with data on maternal thyroid function during pregnancy and birthweight, and we issued open invitations to identify study authors to join the Consortium on Thyroid and Pregnancy. We excluded participants with multiple pregnancies, in-vitro fertilisation, pre-existing thyroid disease or thyroid medication usage, miscarriages, and stillbirths. The main outcomes assessed were small for gestational age (SGA) neonates, large for gestational age neonates, and newborn birthweight. We analysed individual-participant data using mixed-effects regression models adjusting for maternal age, BMI, ethnicity, smoking, parity, gestational age at blood sampling, fetal sex, and gestational age at birth. The study protocol was pre-registered at the International Prospective Register of Systematic Reviews, CRD42016043496. FINDINGS: We identified 2526 published reports, from which 36 cohorts met the inclusion criteria. The study authors for 15 of these cohorts agreed to participate, and five more unpublished datasets were added, giving a study population of 48 145 mother-child pairs after exclusions, of whom 1275 (3·1%) had subclinical hypothyroidism (increased thyroid stimulating hormone [TSH] with normal free thyroxine [FT4]) and 929 (2·2%) had isolated hypothyroxinaemia (decreased FT4 with normal TSH). Maternal subclinical hypothyroidism was associated with a higher risk of SGA than was euthyroidism (11·8% vs 10·0%; adjusted risk difference 2·43%, 95% CI 0·43 to 4·81; odds ratio [OR] 1·24, 1·04 to 1·48; p=0·015) and lower mean birthweight (mean difference -38 g, -61 to -15; p=0·0015), with a higher effect estimate for measurement in the third trimester than in the first or second. Isolated hypothyroxinaemia was associated with a lower risk of SGA than was euthyroidism (7·3% vs 10·0%, adjusted risk difference -2·91, -4·49 to -0·88; OR 0·70, 0·55 to 0·91; p=0·0073) and higher mean birthweight (mean difference 45 g, 18 to 73; p=0·0012). Each 1 SD increase in maternal TSH concentration was associated with a 6 g lower birthweight (-10 to -2; p=0·0030), with higher effect estimates in women who were thyroid peroxidase antibody positive than for women who were negative (pinteraction=0·10). Each 1 SD increase in FT4 concentration was associated with a 21 g lower birthweight (-25 to -17; p<0·0001), with a higher effect estimate for measurement in the third trimester than the first or second. INTERPRETATION: Maternal subclinical hypothyroidism in pregnancy is associated with a higher risk of SGA and lower birthweight, whereas isolated hypothyroxinaemia is associated with lower risk of SGA and higher birthweight. There was an inverse, dose-response association of maternal TSH and FT4 (even within the normal range) with birthweight. These results advance our understanding of the complex relationships between maternal thyroid function and fetal outcomes, and they should prompt careful consideration of potential risks and benefits of levothyroxine therapy during pregnancy. FUNDING: Netherlands Organization for Scientific Research (grant 401.16.020).


Assuntos
Peso ao Nascer/fisiologia , Hipotireoidismo/fisiopatologia , Complicações na Gravidez/fisiopatologia , Glândula Tireoide/fisiologia , Glândula Tireoide/fisiopatologia , Feminino , Idade Gestacional , Humanos , Hipotireoidismo/complicações , Recém-Nascido de Baixo Peso/fisiologia , Recém-Nascido , Gravidez , Testes de Função Tireóidea/tendências
17.
Diabetes Metab J ; 44(4): 566-580, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32431116

RESUMO

BACKGROUND: Fibroblast growth factor 21 (FGF21) has been only reported to prevent type 1 diabetic nephropathy (DN) in the streptozotocin-induced type 1 diabetes mellitus (T1DM) mouse model. However, the FVB (Cg)-Tg (Cryaa-Tag, Ins2-CALM1) 26OVE/PneJ (OVE26) transgenic mouse is a widely recommended mouse model to recapture the most important features of T1DM nephropathy that often occurs in diabetic patients. In addition, most previous studies focused on exploring the preventive effect of FGF21 on the development of DN. However, in clinic, development of therapeutic strategy has much more realistic value compared with preventive strategy since the onset time of DN is difficult to be accurately predicted. Therefore, in the present study OVE26 mice were used to investigate the potential therapeutic effects of FGF21 on DN. METHODS: Four-month-old female OVE26 mice were intraperitoneally treated with recombinant FGF21 at a dose of 100 µg/kg/day for 3 months. The diabetic and non-diabetic control mice were treated with phosphate-buffered saline at the same volume. Renal functions, pathological changes, inflammation, apoptosis, oxidative stress and fibrosis were examined in mice of all groups. RESULTS: The results showed that severe renal dysfunction, morphological changes, inflammation, apoptosis, and fibrosis were observed in OVE26 mice. However, all the renal abnormalities above in OVE26 mice were significantly attenuated by 3-month FGF21 treatment associated with improvement of renal adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) activity and sirtuin 1 (SIRT1) expression. CONCLUSION: Therefore, this study demonstrated that FGF21 might exert therapeutic effects on DN through AMPK-SIRT1 pathway.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1 , Nefropatias Diabéticas , Animais , Diabetes Mellitus Tipo 1/tratamento farmacológico , Nefropatias Diabéticas/tratamento farmacológico , Feminino , Fatores de Crescimento de Fibroblastos , Masculino , Camundongos
18.
Diabetes Metab J ; 44(1): 158-172, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31701691

RESUMO

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is required for renal fibrosis, which is a characteristic of diabetic nephropathy (DN). Our previous study demonstrated that fibroblast growth factor 21 (FGF21) prevented DN associated with the suppressing renal connective tissue growth factor expression, a key marker of renal fibrosis. Therefore, the effects of FGF21 on renal fibrosis in a DN mouse model and the underlying mechanisms were investigated in this study. METHODS: Type 1 diabetes mellitus was induced in C57BL/6J mice by intraperitoneal injections of multiple low doses of streptozotocin. Then, diabetic and non-diabetic mice were treated with or without FGF21 in the presence of pifithrin-α (p53 inhibitor) or 10-[4'-(N,N-Diethylamino)butyl]-2-chlorophenoxazine hydrochloride (10-DEBC) hydrochloride (Akt inhibitor) for 4 months. RESULTS: DN was diagnosed by renal dysfunction, hypertrophy, tubulointerstitial lesions, and glomerulosclerosis associated with severe fibrosis, all of which were prevented by FGF21. FGF21 also suppressed the diabetes-induced renal EMT in DN mice by negatively regulating transforming growth factor beta (TGF-ß)-induced nuclear translocation of Smad2/3, which is required for the transcription of multiple fibrotic genes. The mechanistic studies showed that FGF21 attenuated nuclear translocation of Smad2/3 by inhibiting renal activity of its conjugated protein p53, which carries Smad2/3 into the nucleus. Moreover pifithrin-α inhibited the FGF21-induced preventive effects on the renal EMT and subsequent renal fibrosis in DN mice. In addition, 10-DEBC also blocked FGF21-induced inhibition of renal p53 activity by phosphorylation of mouse double minute-2 homolog (MDM2). CONCLUSION: FGF21 prevents renal fibrosis via negative regulation of the TGF-ß/Smad2/3-mediated EMT process by activation of the Akt/MDM2/p53 signaling pathway.


Assuntos
Diabetes Mellitus Experimental/patologia , Nefropatias Diabéticas/patologia , Transição Epitelial-Mesenquimal , Fatores de Crescimento de Fibroblastos/metabolismo , Túbulos Renais/patologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Animais , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 1/complicações , Nefropatias Diabéticas/metabolismo , Fibrose , Túbulos Renais/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Transdução de Sinais , Proteína Smad2/metabolismo , Estreptozocina , Fator de Crescimento Transformador beta/metabolismo , Proteína Supressora de Tumor p53/metabolismo
19.
Int J Biol Sci ; 15(1): 239-252, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30662363

RESUMO

Hyperglycemia-induced renal fibrosis causes end-stage renal disease. Clopidogrel, a platelet inhibitor, is often administered to decrease cardiovascular events in diabetic patients. We investigated whether clopidogrel can reduce diabetes-induced renal fibrosis in a streptozotocin-induced type 1 diabetes murine model and fibronectin involvement in this protective response. Diabetic and age-matched controls were sacrificed three months after the onset of diabetes, and additional controls and diabetic animals were further treated with clopidogrel or vehicle for three months. Diabetes induced renal morphological changes and fibrosis after three months. Clopidogrel, administered during the last three months, significantly decreased blood glucose, collagen and fibronectin expression compared to vehicle-treated diabetic mice. Diabetes increased TGF-ß expression, inducing fibrosis via Smad-independent pathways, MAP kinases, and Akt activation at three months but returned to baseline at six months, whereas the expression of fibronectin and collagen remained elevated. Our results suggest that activation of TGF-ß, CTGF, and MAP kinases are early profibrotic signaling events, resulting in significant fibronectin accumulation at the early time point and returning to baseline at a later time point. Akt activation at the three-month time point may serve as an adaptive response in T1D. Mechanisms of clopidogrel therapeutic effect on the diabetic kidney remain to be investigated as this clinically approved compound could provide novel approaches to prevent diabetes-induced renal disease, therefore improving patients' survival.


Assuntos
Clopidogrel/uso terapêutico , Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/tratamento farmacológico , Fibronectinas/metabolismo , Fibrose/tratamento farmacológico , Fibrose/etiologia , Nefropatias/tratamento farmacológico , Animais , Coagulação Sanguínea/efeitos dos fármacos , Western Blotting , Clopidogrel/farmacologia , Fibrose/metabolismo , Imuno-Histoquímica , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/etiologia , Nefropatias/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas do Receptor Purinérgico P2Y/farmacologia , Antagonistas do Receptor Purinérgico P2Y/uso terapêutico
20.
Int J Biol Sci ; 14(9): 1000-1011, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29989062

RESUMO

Data from the International Diabetes Federation show that 347 million people worldwide have diabetes, and the incidence is still rising. Although the treatment of diabetes has been advanced, the current therapeutic options and outcomes, e.g. complications, are yet far from ideal. Therefore, an urgent need exists for the development of more effective therapies. Numerous studies have been conducted to establish and confirm whether FGF21 exerts beneficial effects on obesity and diabetes along with its complications. However, most of the studies associated with FGF21 were conducted in the patients with type 2 diabetes. Subsequently, the effect of FGF21 in the prevention or treatment of type 1 diabetes and its complications were also increasingly reported. In this review, we summarize the findings available on the function of FGF21 and the status of FGF21's treatment for type 1 diabetes. Based on the available information, we found that FGF21 exerts a hypoglycemic effect, restores the function of brown fat, and inhibits various complications in type 1 diabetes patients. Although these features are predominantly similar to those observed in the studies that showed the beneficial impact of FGF21 on type 2 diabetes and its complications, there are also certain distinct features and findings that may be of provide important and instructive for us to understand mechanistic insights and further promote the prevention and treatment of type 1 diabetes.


Assuntos
Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/metabolismo , Fatores de Crescimento de Fibroblastos/uso terapêutico , Animais , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fatores de Crescimento de Fibroblastos/sangue , Humanos
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