Summary Hypothyroidism is a common condition of thyroid hormone deficiency, which is readily diagnosed and managed but potentially fatal in severe cases if untreated. The definition of hypothyroidism ...is based on statistical reference ranges of the relevant biochemical parameters and is increasingly a matter of debate. Clinical manifestations of hypothyroidism range from life threatening to no signs or symptoms. The most common symptoms in adults are fatigue, lethargy, cold intolerance, weight gain, constipation, change in voice, and dry skin, but clinical presentation can differ with age and sex, among other factors. The standard treatment is thyroid hormone replacement therapy with levothyroxine. However, a substantial proportion of patients who reach biochemical treatment targets have persistent complaints. In this Seminar, we discuss the epidemiology, causes, and symptoms of hypothyroidism; summarise evidence on diagnosis, long-term risk, treatment, and management; and highlight future directions for research.
Bisphenols and triclosan are considered as potential thyroid disruptors. While mild alterations in maternal thyroid function can result in adverse pregnancy and child developmental outcomes, there is ...still uncertainty whether bisphenols or triclosan can interfere with thyroid function during pregnancy.
We aimed to investigate the association of urinary bisphenol A (BPA), bisphenol S (BPS), bisphenol F (BPF) and triclosan with early pregnancy thyroid function.
This study was embedded in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study (SELMA), a population-based prospective pregnancy cohort. In total, 1996 participants were included in the current study. Maternal urinary concentrations of three bisphenols and triclosan, collected at median (95% range) 10 (6–14) weeks of pregnancy as well as serum concentrations of thyroid stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), total thyroxine (TT4), and total triiodothyronine (TT3) were measured.
Higher BPA levels were associated with lower TT4 concentrations (non-monotonic, P = 0.03), a lower FT4/FT3 ratio (β SE -0.02 0.01, P = 0.03) and a lower TT4/TT3 ratio (β SE -0.73 0.27, P = 0.008). Higher BPF levels were associated with a higher FT3 (β SE 0.01 0.007, P = 0.04). There were no associations between other bisphenols or triclosan and absolute TSH, (F)T4 or (F)T3 concentrations. The association of BPA with thyroid function differed with gestational age. The negative association of BPA with FT4/FT3 and TT4/TT3 ratios was only apparent in early but not late gestation (P for interaction: 0.003, 0.008, respectively).
These human data during pregnancy substantiate experimental findings suggesting that BPA could potentially affect thyroid function and deiodinase activities in early gestation.
•Bisphenol A (BPA) had a non-monotonic association with total T4 in pregnant women.•Higher BPA was associated with lower (F)T4/(F)T3 ratio in very early pregnancy.•Bisphenol F had a positive association with FT3.•Bisphenol S and triclosan were not associated with thyroid function.
Thyroid disease in pregnancy is a common clinical problem. Since the guidelines for the management of these disorders by the American Thyroid Association (ATA) were first published in 2011, ...significant clinical and scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid disease in women during pregnancy, preconception, and the postpartum period.
The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations. The guideline task force had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members.
The revised guidelines for the management of thyroid disease in pregnancy include recommendations regarding the interpretation of thyroid function tests in pregnancy, iodine nutrition, thyroid autoantibodies and pregnancy complications, thyroid considerations in infertile women, hypothyroidism in pregnancy, thyrotoxicosis in pregnancy, thyroid nodules and cancer in pregnant women, fetal and neonatal considerations, thyroid disease and lactation, screening for thyroid dysfunction in pregnancy, and directions for future research.
We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid disease in pregnant and postpartum women. While all care must be individualized, such recommendations provide, in our opinion, optimal care paradigms for patients with these disorders.
Thyroid Hormone Transporters Groeneweg, Stefan; van Geest, Ferdy S; Peeters, Robin P ...
Endocrine reviews,
04/2020, Letnik:
41, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Abstract
Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting ...polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease.
Graphical Abstract
Graphical Abstract
•Exposure to phthalates disrupt the maternal thyroid system.•Metabolites of DEHP can disrupt the maternal hypothalamic-pituitary-thyroid axis.•Several phthalates can increase the maternal T4 ...metabolism.•Phthalate substitutes such as DINCH are also capable of thyroid system disruption.
The extent of thyroid disruptive effects of phthalates during pregnancy remains unclear.
To investigate the association of maternal urinary phthalates with markers of the thyroid system during early pregnancy.
Urinary concentrations of phthalate metabolites and serum concentrations of thyroid stimulating hormone (TSH), free and total thyroxine (FT4 and TT4) and free and total triiodothyronine (FT3 and TT3) were measured in pregnant women in early pregnancy in the Swedish Environmental Longitudinal, Mother and child, Asthma and allergy study (2007-ongoing), a population-based prospective cohort.
In the 1,996 included women, higher di-ethyl-hexyl phthalate (DEHP) metabolites were associated with a lower FT4 (β SE for the molar sum: −0.13 0.06, P = 0.03) and a higher TSH/FT4 ratio (0.003 0.001, P = 0.03). Higher concentrations of di-iso-nonyl phthalate (DINP) metabolites were associated with a lower TT4 (β SE for the molar sum: 0.93 0.44, P = 0.03) as well as with lower TT4/FT4 and TT4/TT3 ratios. Higher metabolites of both dibutyl and butyl-benzyl phthalate (DBP and BBzP) were associated with lower T4/T3 ratio (free and total) and higher FT4/TT4 and FT3/TT3 ratios. A higher diisononyl cyclohexane dicarboxylate (DINCH) metabolite concentration was associated with a higher TT3.
These results translate results from experimental studies suggesting that exposure to phthalates may interfere with the thyroid system during pregnancy. This is also true for compounds that have been introduced to replace known disruptive phthalates. Further experimental studies should take into account the human evidence to better investigate the potential underlying mechanisms of thyroid disruption by phthalates.
Thyroid hormone is essential for fetal (brain) development. Plasma membrane transporters control the intracellular bioavailability of thyroid hormone. In the past few decades, 15 human thyroid ...hormone transporters have been identified, and among them, mutations in monocarboxylate transporter (MCT)8 and organic anion transporting peptide (OATP)1C1 are associated with clinical phenotypes. Different animal and human models have been employed to unravel the (patho)-physiological role of thyroid hormone transporters. However, most studies on thyroid hormone transporters focus on postnatal development. This review summarizes the research on the thyroid hormone transporters in pregnancy and fetal development, including their substrate preference, expression and tissue distribution, and physiological and pathophysiological role in thyroid homeostasis and clinical disorders. As the fetus depends on the maternal thyroid hormone supply, especially during the first half of pregnancy, the review also elaborates on thyroid hormone transport across the human placental barrier. Future studies may reveal how the different transporters contribute to thyroid hormone homeostasis in fetal tissues to properly facilitate development. Employing state-of-the-art human models will enable a better understanding of their roles in thyroid hormone homeostasis.
A number of recent advances in our understanding of thyroid physiology may shed light on why some patients feel unwell while taking levothyroxine monotherapy. The purpose of this task force was to ...review the goals of levothyroxine therapy, the optimal prescription of conventional levothyroxine therapy, the sources of dissatisfaction with levothyroxine therapy, the evidence on treatment alternatives, and the relevant knowledge gaps. We wished to determine whether there are sufficient new data generated by well-designed studies to provide reason to pursue such therapies and change the current standard of care. This document is intended to inform clinical decision-making on thyroid hormone replacement therapy; it is not a replacement for individualized clinical judgment.
Task force members identified 24 questions relevant to the treatment of hypothyroidism. The clinical literature relating to each question was then reviewed. Clinical reviews were supplemented, when relevant, with related mechanistic and bench research literature reviews, performed by our team of translational scientists. Ethics reviews were provided, when relevant, by a bioethicist. The responses to questions were formatted, when possible, in the form of a formal clinical recommendation statement. When responses were not suitable for a formal clinical recommendation, a summary response statement without a formal clinical recommendation was developed. For clinical recommendations, the supporting evidence was appraised, and the strength of each clinical recommendation was assessed, using the American College of Physicians system. The final document was organized so that each topic is introduced with a question, followed by a formal clinical recommendation. Stakeholder input was received at a national meeting, with some subsequent refinement of the clinical questions addressed in the document. Consensus was achieved for all recommendations by the task force.
We reviewed the following therapeutic categories: (i) levothyroxine therapy, (ii) non-levothyroxine-based thyroid hormone therapies, and (iii) use of thyroid hormone analogs. The second category included thyroid extracts, synthetic combination therapy, triiodothyronine therapy, and compounded thyroid hormones.
We concluded that levothyroxine should remain the standard of care for treating hypothyroidism. We found no consistently strong evidence for the superiority of alternative preparations (e.g., levothyroxine-liothyronine combination therapy, or thyroid extract therapy, or others) over monotherapy with levothyroxine, in improving health outcomes. Some examples of future research needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin measurements, mechanistic research on serum triiodothyronine levels (including effects of age and disease status, relationship with tissue concentrations, as well as potential therapeutic targeting), and long-term outcome clinical trials testing combination therapy or thyroid extracts (including subgroup effects). Additional research is also needed to develop thyroid hormone analogs with a favorable benefit to risk profile.
The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and ...potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.
Context:
Although thyroid function is associated with several risk factors of nonalcoholic fatty liver disease (NAFLD), its role in NAFLD development remains unclear.
Objective:
We aimed to ...prospectively investigate the association between variations in thyroid function and NAFLD.
Design and Setting:
The Rotterdam Study, a large population-based, prospective cohort study.
Participants and Main Outcome Measures:
Participants with thyroid function measurements at baseline and NAFLD data (ie, at baseline fatty liver index/at follow-up ultrasound) were eligible. Transient elastography was performed to assess the presence of fibrosis in patients with NAFLD, using the liver stiffness measurements more than or equal to 8 kPa as cutoff for clinically relevant fibrosis. The association between thyroid parameters and incident NAFLD was explored by using logistic regression models.
Results:
A total of 9419 participants (mean age, 64.75 y) were included. The median follow-up time was 10.04 years (interquartile range, 5.70–10.88 y). After adjusting for age, sex, cohort, follow-up time, use of hypolipidemic drugs, and cardiovascular risk factors, higher free T4 levels were associated with a decreased risk of NAFLD (odds ratio, 0.42; 95% confidence interval CI, 0.28–0.63). In line, higher TSH levels were associated with an increased risk of having clinically relevant fibrosis in NAFLD (odds ratio, 1.49; CI, 1.04–2.15). Compared with euthyroidism, hypothyroidism was associated with a 1.24-fold higher NAFLD risk (CI, 1.01–1.53). Moreover, NAFLD risk decreased gradually from hypothyroidism to hyperthyroidism (P for trend = .003).
Conclusion:
Lower thyroid function is associated with an increased NAFLD risk. These findings may lead to new avenues regarding NAFLD prevention and treatment.
This study evaluated the effect of thyroid function on the subsequent risk of NAFLD and presence of clinically relevant fibrosis. Lower thyroid function was associated with an increased NAFLD risk.
Maternal thyroid hormone insufficiency during pregnancy can affect children's cognitive development. Nevertheless, the behavioral outcomes of children exposed prenatally to mild thyroid hormone ...insufficiency are understudied.
To examine whether exposure to maternal mild thyroid hormone insufficiency in early pregnancy was related to symptoms of attention-deficit/hyperactivity disorder (ADHD) in children at 8 years of age.
The study was embedded within the Generation R, a population-based birth cohort in the Netherlands. Children in the Generation R Study are followed up from birth (April 1, 2002, through January 31, 2006) until young adulthood. Of the 4997 eligible mother-child pairs with data on maternal thyroid levels (excluding twins), 3873 pairs of children and caregivers (77.5%) visited the Generation R research center for in-depth assessments and were included in the main analyses. Data collection in Generation R started December 1, 2001 (enrollment of pregnant women), and is ongoing. For this study, we used the data that were collected until January 1, 2014. Data analyses started on January 31 and finished June 30, 2014.
Maternal hypothyroxinemia, characterized by low levels of free thyroxine coexisting with reference thyrotropin levels, and children's symptoms of ADHD. Maternal thyroid hormone levels (thyrotropin, free thyroxine, thyroid peroxidase antibodies) were measured at a mean (SD) of 13.6 (1.9) weeks of gestation. Children's ADHD symptoms were assessed at 8 years of age using the Conners' Parent Rating Scale-Revised Short Form; higher scores indicate more ADHD symptoms (possible range, 0-36).
Maternal hypothyroxinemia (n = 127) in early pregnancy was associated with higher scores for ADHD symptoms in children at 8 years of age after adjustments for child and maternal factors (ie, sex, ethnicity, maternal age, maternal educational level, and income) (increase in ADHD scores, 7% 95% CI, 0.3%-15%). The results remained essentially unchanged when women with elevated levels of thyroid peroxidase antibodies were excluded from the analyses (increase in ADHD scores, 8% 95% CI, 1%-16%). Additional adjustment for children's IQ or comorbid autistic symptoms attenuated the association (increase in ADHD scores adjusted for autistic symptoms, 7% 95% CI, 1%-15%; increase in ADHD scores adjusted for IQ, 6% 95% CI, 1%-14%).
Children exposed to maternal hypothyroxinemia in early pregnancy had more ADHD symptoms, independent of confounders. This finding suggests that intrauterine exposure to insufficient thyroid hormone levels influences neurodevelopment in offspring.
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