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The Journal of Clinical Endocrinology... Oct 2021Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either... (Comparative Study)
Comparative Study Randomized Controlled Trial
INTRODUCTION
Studies comparing levothyroxine (LT4) therapy with LT4 + liothyronine (LT3) or desiccated thyroid extract (DTE) did not detect consistent superiority of either treatment. Here, we investigated these therapies, focusing on the whole group of LT4-treated hypothyroid patients, while also exploring the most symptomatic patients.
METHODOLOGY
Prospective, randomized, double-blind, crossover study of 75 hypothyroid patients randomly allocated to 1 of 3 treatment arms, LT4, LT4 + LT3, and DTE, for 22 weeks. The primary outcomes were posttreatment scores on the 36-point thyroid symptom questionnaire (TSQ-36), 12-point quality of life general health questionnaire (GHQ-12), the Wechsler memory scale-version IV (VMS-IV), and the Beck Depression Inventory (BDI). Secondary endpoints included treatment preference, biochemical and metabolic parameters, etiology of hypothyroidism, and Thr92Ala-DIO2 gene polymorphism. Analyses were performed with a linear mixed model using subject as a random factor and group as a fixed effect.
RESULTS
Serum TSH remained within reference range across all treatment arms. There were no differences for primary and secondary outcomes, except for a minor increase in heart rate caused by DTE. Treatment preference was not different and there were no interferences of the etiology of hypothyroidism or Thr92Ala-DIO2 gene polymorphism in the outcomes. Subgroup analyses of the 1/3 most symptomatic patients on LT4 revealed strong preference for treatment containing T3, which improved performance on TSQ-36, GHQ-12, BDI, and visual memory index (VMS-IV component).
CONCLUSIONS
As a group, outcomes were similar among hypothyroid patients taking DTE vs LT4 + T3 vs LT4. However, those patients that were most symptomatic on LT4 preferred and responded positively to therapy with LT4 + LT3 or DTE.
Topics: Adult; Aged; Cross-Over Studies; Desiccation; Double-Blind Method; Female; Hormone Replacement Therapy; Humans; Hypothyroidism; Male; Middle Aged; Placebos; Prospective Studies; Quality of Life; Surveys and Questionnaires; Thyroid Gland; Thyroxine; Tissue Extracts; Treatment Outcome; Triiodothyronine
PubMed: 34185829
DOI: 10.1210/clinem/dgab478 -
The Journal of Clinical Endocrinology... Sep 2020It is well recognized that some hypothyroid patients on levothyroxine (LT4) remain symptomatic, but why patients are susceptible to this condition, why symptoms persist,... (Review)
Review
CONTEXT
It is well recognized that some hypothyroid patients on levothyroxine (LT4) remain symptomatic, but why patients are susceptible to this condition, why symptoms persist, and what is the role of combination therapy with LT4 and liothyronine (LT3), are questions that remain unclear. Here we explore evidence of abnormal thyroid hormone (TH) metabolism in LT4-treated patients, and offer a rationale for why some patients perceive LT4 therapy as a failure.
EVIDENCE ACQUISITION
This review is based on a collection of primary and review literature gathered from a PubMed search of "hypothyroidism," "levothyroxine," "liothyronine," and "desiccated thyroid extract," among other keywords. PubMed searches were supplemented by Google Scholar and the authors' prior knowledge of the subject.
EVIDENCE SYNTHESIS
In most LT4-treated patients, normalization of serum thyrotropin levels results in decreased serum T3/T4 ratio, with relatively lower serum T3 levels; in at least 15% of the cases, serum T3 levels are below normal. These changes can lead to a reduction in TH action, which would explain the slower rate of metabolism and elevated serum cholesterol levels. A small percentage of patients might also experience persistent symptoms of hypothyroidism, with impaired cognition and tiredness. We propose that such patients carry a key clinical factor, for example, specific genetic and/or immunologic makeup, that is well compensated while the thyroid function is normal but might become apparent when compounded with relatively lower serum T3 levels.
CONCLUSIONS
After excluding other explanations, physicians should openly discuss and consider therapy with LT4 and LT3 with those hypothyroid patients who have persistent symptoms or metabolic abnormalities despite normalization of serum thyrotropin level. New clinical trials focused on symptomatic patients, genetic makeup, and comorbidities, with the statistical power to identify differences between monotherapy and combination therapy, are needed.
Topics: Drug Resistance; Drug Therapy, Combination; Hormone Replacement Therapy; Humans; Hypothyroidism; Practice Patterns, Physicians'; Precision Medicine; Thyroid Function Tests; Thyrotropin; Thyroxine; Treatment Failure; Triiodothyronine
PubMed: 32614450
DOI: 10.1210/clinem/dgaa430 -
Endocrine Oct 2019The purpose of this article will be to review the basics of thyroid hormone therapy, including various thyroid hormone formulations, the institution and monitoring of... (Review)
Review
The purpose of this article will be to review the basics of thyroid hormone therapy, including various thyroid hormone formulations, the institution and monitoring of thyroid hormone therapy, adverse effects of overtreatment, the management of patients with persistent symptoms despite normal thyroid function tests, and potential new innovations in thyroid hormone therapy. The conclusions support the necessity to personalize thyroid hormone replacement therapy in hypothyroid patients.
Topics: Hormone Replacement Therapy; Humans; Hypothyroidism; Thyroid Hormones; Thyrotropin; Treatment Failure
PubMed: 31372822
DOI: 10.1007/s12020-019-02023-7 -
Frontiers in Endocrinology 2022Preterm newborns are forced to adapt to harsh extrauterine conditions and endure numerous adversities despite their incomplete growth and maturity. The inadequate... (Review)
Review
Preterm newborns are forced to adapt to harsh extrauterine conditions and endure numerous adversities despite their incomplete growth and maturity. The inadequate thyroid hormones secretion as well as the impaired regulation of hypothalamus-pituitary-thyroid axis may lead to hypothyroxinemia. Two first weeks after birth are pivotal for brain neurons development, synaptogenesis and gliogenesis. The decreased level of thyroxine regardless of cause may lead to delayed mental development. Congenital hypothyroidism (CH) is a disorder highly prevalent in premature neonates and it originates from maternal factors, perinatal and labor complications, genetic abnormalities, thyroid malformations as well as side effects of medications and therapeutic actions. Because of that, the prevention is not fully attainable. CH manifests clinically in a few distinctive forms: primary, permanent or transient, and secondary. Their etiologies and implications bear little resemblance. Therefore, the exact diagnosis and differentiation between the subtypes of CH are crucial in order to plan an effective treatment. Hypothyroxinemia of prematurity indicates dynamic changes in thyroid hormone levels dependent on neonatal postmenstrual age, which directly affects patient's maintenance and wellbeing. The basis of a successful treatment relies on an early and accurate diagnosis. Neonatal screening is a recommended method of detecting CH in preterm newborns. The preferred approach involves testing serum TSH and fT4 concentrations and assessing their levels according to the cut-off values. The possible benefits also include the evaluation of CH subtype. Nevertheless, the reference range of thyroid hormones varies all around the world and impedes the introduction of universal testing recommendations. Unification of the methodology in neonatal screening would be advantageous for prevention and management of CH. Current guidelines recommend levothyroxine treatment of CH in preterm infants only when the diagnose is confirmed. Moreover, they underline the importance of the re-evaluation among preterm born infants due to the frequency of transient forms of hypothyroidism. However, results from multiple clinical trials are mixed and depend on the newborn's gestational age at birth. Some benefits of treatment are seen especially in the preterm infants born <29 weeks' gestation. The discrepancies among trials and guidelines create an urgent need to conduct more large sample size studies that could provide further analyses and consensus. This review summarizes the current state of knowledge on congenital hypothyroidism in preterm infants. We discuss screening and treatment options and demonstrate present challenges and controversies.
Topics: Congenital Hypothyroidism; Female; Humans; Infant; Infant, Newborn; Infant, Premature; Neonatal Screening; Pregnancy; Thyroid Dysgenesis; Thyroxine
PubMed: 35370986
DOI: 10.3389/fendo.2022.860862 -
Current Medical Research and Opinion Mar 2023Subclinical hypothyroidism (SCH) is diagnosed when serum thyroid stimulation hormone (thyrotropin; TSH) levels are above the reference range, accompanied by levels of... (Review)
Review
Subclinical hypothyroidism (SCH) is diagnosed when serum thyroid stimulation hormone (thyrotropin; TSH) levels are above the reference range, accompanied by levels of free thyroxine within its reference range. The management of SCH remains a diagnostic and therapeutic challenge despite many years of research relating to its epidemiology, aetiology, effectiveness of treatment and safety. European Thyroid Association (ETA) guidelines for the management of SCH were published almost a decade ago. This narrative review summarizes the clinical literature relating to SCH and outcomes since the publication of these guidelines. Clinical evidence emerging during the previous decade generally supports the view that SCH is associated with adverse outcomes to an extent that is intermediate between euthyroidism and overt hypothyroidism although evidence that treatment with thyroid hormone replacement is beneficial is lacking. Accordingly, the rationale for the recommendations for intervention in the ETA guidelines based on the age of the patient, level of serum TSH, symptoms and comorbidities remains valid today.
Topics: Humans; Thyroxine; Hypothyroidism; Thyroid Hormones; Thyrotropin; Hormone Replacement Therapy
PubMed: 36632720
DOI: 10.1080/03007995.2023.2165811 -
Frontiers in Endocrinology 2022Observational studies have reported an association between coronavirus disease 2019 (COVID-19) risk and thyroid dysfunction, but without a clear causal relationship. We... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Observational studies have reported an association between coronavirus disease 2019 (COVID-19) risk and thyroid dysfunction, but without a clear causal relationship. We attempted to evaluate the association between thyroid function and COVID-19 risk using a bidirectional two-sample Mendelian randomization (MR) analysis.
METHODS
Summary statistics on the characteristics of thyroid dysfunction (hypothyroidism and hyperthyroidism) were obtained from the ThyroidOmics Consortium. Genome-wide association study statistics for COVID-19 susceptibility and its severity were obtained from the COVID-19 Host Genetics Initiative, and severity phenotypes included hospitalization and very severe disease in COVID-19 participants. The inverse variance-weighted (IVW) method was used as the primary analysis method, supplemented by the weighted-median (WM), MR-Egger, and MR-PRESSO methods. Results were adjusted for Bonferroni correction thresholds.
RESULTS
The forward MR estimates show no effect of thyroid dysfunction on COVID-19 susceptibility and severity. The reverse MR found that COVID-19 susceptibility was the suggestive risk factor for hypothyroidism (IVW: OR = 1.577, 95% CI = 1.065-2.333, = 0.022; WM: OR = 1.527, 95% CI = 1.042-2.240, = 0.029), and there was lightly association between COVID-19 hospitalized and hypothyroidism (IVW: OR = 1.151, 95% CI = 1.004-1.319, = 0.042; WM: OR = 1.197, 95% CI = 1.023-1.401, = 0.023). There was no evidence supporting the association between any phenotype of COVID-19 and hyperthyroidism.
CONCLUSION
Our results identified that COVID-19 might be the potential risk factor for hypothyroidism. Therefore, patients infected with SARS-CoV-2 should strengthen the monitoring of thyroid function.
Topics: COVID-19; Genome-Wide Association Study; Humans; Hyperthyroidism; Hypothyroidism; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; SARS-CoV-2
PubMed: 36147565
DOI: 10.3389/fendo.2022.961717 -
Thyroid : Official Journal of the... Feb 2021Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these... (Review)
Review
Fourteen clinical trials have not shown a consistent benefit of combination therapy with levothyroxine (LT4) and liothyronine (LT3). Despite the publication of these trials, combination therapy is widely used and patients reporting benefit continue to generate patient and physician interest in this area. Recent scientific developments may provide insight into this inconsistency and guide future studies. The American Thyroid Association (ATA), British Thyroid Association (BTA), and European Thyroid Association (ETA) held a joint conference on November 3, 2019 (live-streamed between Chicago and London) to review new basic science and clinical evidence regarding combination therapy with presentations and input from 12 content experts. After the presentations, the material was synthesized and used to develop Summary Statements of the current state of knowledge. After review and revision of the material and Summary Statements, there was agreement that there was equipoise for a new clinical trial of combination therapy. Consensus Statements encapsulating the implications of the material discussed with respect to the design of future clinical trials of LT4/LT3 combination therapy were generated. Authors voted upon the Consensus Statements. Iterative changes were made in several rounds of voting and after comments from ATA/BTA/ETA members. Of 34 Consensus Statements available for voting, 28 received at least 75% agreement, with 13 receiving 100% agreement. Those with 100% agreement included studies being powered to study the effect of deiodinase and thyroid hormone transporter polymorphisms on study outcomes, inclusion of patients dissatisfied with their current therapy and requiring at least 1.2 μg/kg of LT4 daily, use of twice daily LT3 or preferably a slow-release preparation if available, use of patient-reported outcomes as a primary outcome (measured by a tool with both relevant content validity and responsiveness) and patient preference as a secondary outcome, and utilization of a randomized placebo-controlled adequately powered double-blinded parallel design. The remaining statements are presented as potential additional considerations. This article summarizes the areas discussed and presents Consensus Statements to guide development of future clinical trials of LT4/LT3 combination therapy. The results of such redesigned trials are expected to be of benefit to patients and of value to inform future thyroid hormone replacement clinical practice guidelines treatment recommendations.
Topics: Consensus; Drug Combinations; Evidence-Based Medicine; Humans; Hypothyroidism; Thyroxine; Treatment Outcome; Triiodothyronine
PubMed: 33276704
DOI: 10.1089/thy.2020.0720 -
Association of Thyroid Dysfunction With Cognitive Function: An Individual Participant Data Analysis.JAMA Internal Medicine Nov 2021In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature...
IMPORTANCE
In clinical guidelines, overt and subclinical thyroid dysfunction are mentioned as causal and treatable factors for cognitive decline. However, the scientific literature on these associations shows inconsistent findings.
OBJECTIVE
To assess cross-sectional and longitudinal associations of baseline thyroid dysfunction with cognitive function and dementia.
DESIGN, SETTING, AND PARTICIPANTS
This multicohort individual participant data analysis assessed 114 267 person-years (median, 1.7-11.3 years) of follow-up for cognitive function and 525 222 person-years (median, 3.8-15.3 years) for dementia between 1989 and 2017. Analyses on cognitive function included 21 cohorts comprising 38 144 participants. Analyses on dementia included eight cohorts with a total of 2033 cases with dementia and 44 573 controls. Data analysis was performed from December 2016 to January 2021.
EXPOSURES
Thyroid function was classified as overt hyperthyroidism, subclinical hyperthyroidism, euthyroidism, subclinical hypothyroidism, and overt hypothyroidism based on uniform thyrotropin cutoff values and study-specific free thyroxine values.
MAIN OUTCOMES AND MEASURES
The primary outcome was global cognitive function, mostly measured using the Mini-Mental State Examination. Executive function, memory, and dementia were secondary outcomes. Analyses were first performed at study level using multivariable linear regression and multivariable Cox regression, respectively. The studies were combined with restricted maximum likelihood meta-analysis. To overcome the use of different scales, results were transformed to standardized mean differences. For incident dementia, hazard ratios were calculated.
RESULTS
Among 74 565 total participants, 66 567 (89.3%) participants had normal thyroid function, 577 (0.8%) had overt hyperthyroidism, 2557 (3.4%) had subclinical hyperthyroidism, 4167 (5.6%) had subclinical hypothyroidism, and 697 (0.9%) had overt hypothyroidism. The study-specific median age at baseline varied from 57 to 93 years; 42 847 (57.5%) participants were women. Thyroid dysfunction was not associated with global cognitive function; the largest differences were observed between overt hypothyroidism and euthyroidism-cross-sectionally (-0.06 standardized mean difference in score; 95% CI, -0.20 to 0.08; P = .40) and longitudinally (0.11 standardized mean difference higher decline per year; 95% CI, -0.01 to 0.23; P = .09). No consistent associations were observed between thyroid dysfunction and executive function, memory, or risk of dementia.
CONCLUSIONS AND RELEVANCE
In this individual participant data analysis of more than 74 000 adults, subclinical hypothyroidism and hyperthyroidism were not associated with cognitive function, cognitive decline, or incident dementia. No rigorous conclusions can be drawn regarding the role of overt thyroid dysfunction in risk of dementia. These findings do not support the practice of screening for subclinical thyroid dysfunction in the context of cognitive decline in older adults as recommended in current guidelines.
Topics: Aged; Cognition; Cognitive Dysfunction; Correlation of Data; Data Analysis; Female; Humans; Hyperthyroidism; Hypothyroidism; Male; Mental Status and Dementia Tests; Risk Assessment; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyroxine
PubMed: 34491268
DOI: 10.1001/jamainternmed.2021.5078 -
Frontiers in Endocrinology 2022Observational studies suggest an association between hypothyroidism and the risk of hepatocellular carcinoma (HCC), but the causality and direction of these effects are...
OBJECTIVE
Observational studies suggest an association between hypothyroidism and the risk of hepatocellular carcinoma (HCC), but the causality and direction of these effects are still inconclusive. We aim to test whether hypothyroidism is causally associated with the risk of HCC by using Mendelian randomization (MR) analysis.
METHODS
Single-nucleotide polymorphisms (SNPs) associated with hypothyroidism were screened a genome-wide association study (GWAS) on 337,159 individuals of European descent (16,376 cases and 320,783 controls). The SNPs associated with thyroid-stimulating hormone (TSH) and free thyroxine (FT4) were selected from a GWAS of 72,167 individuals of European descent. Summary-level data for HCC (168 cases and 372,016 controls) were extracted from UK Biobank. An inverse-variance-weighted (IVW) method was used as the primary MR analysis. Sensitivity analyses were examined MR-Egger regression, heterogeneity test, pleiotropy test, and leave-one-out sensitivity test. The assumption that exposure causes outcome was verified using the MR Steiger test.
RESULTS
Two-Sample MR analysis showed inverse associations between genetically predicted hypothyroidism and HCC risk (OR = 0.997, 95% CI, 0.995-0.999; = 0.016). There were no statistical indications of heterogeneity among instruments (-het = 0.667). Across five MR methods, genetically predicted hypothyroidism shows a consistent correlation with HCC. The leave-one-out analysis indicated that no single SNP changed the overall estimate ( = 0.016). In addition, the MR Steiger test revealed that hypothyroidism was causal for HCC and not the opposite ( = 0.000). Finally, there was no evidence for a direct causal effect of TSH level and FT4 level on HCC risk.
CONCLUSION
Our results provide some that genetically determined hypothyroidism decreases the risk of HCC, although the size of the causal estimate is small. Further research is required to comprehend the mechanisms underlying this putative causative association, and follow-up clinical trials need to be conducted to establish whether inducing hypothyroidism could be beneficial for patients who are suffering from HCC. During future treatment of hypothyroidism, close attention to liver function may also be required to prevent a possible increased risk of HCC.
Topics: Humans; Carcinoma, Hepatocellular; Genome-Wide Association Study; Hypothyroidism; Liver Neoplasms; Mendelian Randomization Analysis; Thyrotropin; Thyroxine
PubMed: 36246884
DOI: 10.3389/fendo.2022.987401 -
EBioMedicine Nov 2021Although the association between hypothyroidism and idiopathic pulmonary fibrosis (IPF) is found in observational studies, it remains uncertain whether hypothyroidism...
BACKGROUND
Although the association between hypothyroidism and idiopathic pulmonary fibrosis (IPF) is found in observational studies, it remains uncertain whether hypothyroidism causally influences IPF.
METHODS
Two-sample Mendelian randomisation (MR) was conducted with hypothyroidism genome-wide association study (GWAS) data in the UK Biobank from 289,307 individuals (18,740 cases and 270,567 controls) and the largest GWAS summary statistics of IPF from 11,259 individuals (2,668 cases and 8,591 controls). Findings were verified using an independent validation dataset, as well as through different MR methods with different model assumptions. A multivariable MR based on Bayesian model averaging was further performed to evaluate whether hypothyroidism, even given several other comorbidities of IPF, remained to be the true causal one of IPF.
FINDINGS
A positive causal effect of hypothyroidism on IPF was revealed (MR inverse-variance weighted [MR-IVW], odds ratio [OR]=1.125, 95% confidence interval [CI] 1.028-1.231; P=0.011), which was further verified in an independent validation set (MR-IVW, OR=1.229, 95% CI 1.054-1.432; P=0.008). The results were consistent from a variety of MR methods. Bidirectional analyses also indicated no reverse causation. Multivariable MR analysis showed hypothyroidism had the strongest marginal evidence (marginal inclusion probability=0.397, false discovery rate=0.025) compared with other comorbidities of IPF.
INTERPRETATION
Our results illustrate the significant causal effect of hypothyroidism on IPF, which holds even given several other comorbidities of IPF. These findings may have an important insight into pathogenesis and possible future therapies of IPF.
FUNDING
National Natural Science Foundation of China, the Natural Science Foundation of Shandong Province and the Young Scholars Program of Shandong University.
Topics: Alleles; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Hypothyroidism; Idiopathic Pulmonary Fibrosis; Mendelian Randomization Analysis; Polymorphism, Single Nucleotide; Reproducibility of Results; Risk Factors
PubMed: 34749302
DOI: 10.1016/j.ebiom.2021.103669