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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 -
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 -
Revista Medica Del Instituto Mexicano... Apr 2020There are well-recognized relationships between thyroid hormones, heart and peripheral vascular system. Thyroid hormones have relevant actions on the heart and... (Review)
Review
BACKGROUND
There are well-recognized relationships between thyroid hormones, heart and peripheral vascular system. Thyroid hormones have relevant actions on the heart and circulation, generate multiple effects including hemodynamic changes and exert mediated effects on cardiac cells through gene expression.
CLINICAL CASE
We present a 64-year-old woman with diagnosis of dilated cardiomyopathy with reduced ejection fraction, in whom coronary disease was thought of as the most probable etiology by clinical antecedents but in the evolution, other possible etiologies were to appear.
CONCLUSIONS
Numerous complementary diagnostic studies were carried out, such as cinecoronariography, cardiac nuclear magnetic resonance imaging, laboratory analysis, to name a few, and it was concluded that the etiological cause was due to primary hypothyroidism.
Topics: Cardiomyopathy, Dilated; Female; Heart Failure; Humans; Hypothyroidism; Middle Aged; Thyroid Hormones
PubMed: 34101566
DOI: 10.24875/RMIMSS.M20000019 -
Deutsche Medizinische Wochenschrift... Oct 2021Autoimmune thyroiditis (AIT) is not only one of the most prevalent human autoimmune diseases, but also the most frequent cause of primary hypothyroidism. It is...
Autoimmune thyroiditis (AIT) is not only one of the most prevalent human autoimmune diseases, but also the most frequent cause of primary hypothyroidism. It is characterized by lymphocytic infiltration of the thyroid gland with subsequent gradual destruction and fibrous replacement of thyroid tissue. Genetic predisposition, epigenetic modifications and environmental factors are suspected as disease triggers. Signs and symptoms of hypothyroidism include fatigue, bradycardia, constipation and cold intolerance. In subclinical hypothyroidism, symptoms may be absent. The diagnosis of AIT is based on the presence of antibodies against thyroid specific antigens, primarily anti-thyroid peroxidase antibodies and on a sonographically proven reduced echogenicity of the thyroid parenchyma. The diagnosis of concomitant hypothyroidism is primarily based on clinical signs and symptoms as well as measurement of thyroid-stimulating hormone (TSH)-concentration. Subclinical hypothyroidism is characterized by elevated TSH with normal serum free thyroxine (fT) and triiodothyronine (fT) levels, while in manifest hypothyroidism serum fT and fT levels are reduced. Levothyroxine (LT) treatment in subclinical hypothyroidism is a controversy in the scientific literature and should be discussed individually. It not only depends on the level of TSH-elevation, but also on other factors, such as patient age, presence of comorbidities and clinical symptoms of hypothyroidism. In contrast, overt hypothyroidism and subclinical hypothyroidism with a TSH-level > 10 mIU/L is a strong indication for LT administration, aiming at rapid achievement of euthyroidism. In patients with dissatisfaction due to persistence of symptoms despite optimal LT-treatment LT/T-combination therapy should be considered, based on expert opinion.
Topics: Hashimoto Disease; Humans; Hypothyroidism; Thyrotropin; Thyroxine; Triiodothyronine
PubMed: 34644793
DOI: 10.1055/a-1258-5674 -
JAMA Oct 2018The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of... (Meta-Analysis)
Meta-Analysis Review
Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis.
IMPORTANCE
The benefit of thyroid hormone therapy for subclinical hypothyroidism is uncertain. New evidence from recent large randomized clinical trials warrants an update of previous meta-analyses.
OBJECTIVE
To conduct a meta-analysis of the association of thyroid hormone therapy with quality of life and thyroid-related symptoms in adults with subclinical hypothyroidism.
DATA SOURCES
PubMed, EMBASE, ClinicalTrials.gov, Web of Science, Cochrane Library, CENTRAL, Emcare, and Academic Search Premier from inception until July 4, 2018.
STUDY SELECTION
Randomized clinical trials that compared thyroid hormone therapy with placebo or no therapy in nonpregnant adults with subclinical hypothyroidism were eligible. Two reviewers independently evaluated eligibility based on titles and abstracts of all retrieved studies. Studies not excluded in this first step were independently assessed for inclusion after full-text evaluation by 2 reviewers.
DATA EXTRACTION AND SYNTHESIS
Two independent reviewers extracted data, assessed risk of bias (Cochrane risk-of-bias tool), and evaluated the quality of evidence (GRADE tool). For synthesis, differences in clinical scores were transformed (eg, quality of life) into standardized mean differences (SMDs; positive values indicate benefit of thyroid hormone therapy; 0.2, 0.5, and 0.8 correspond to small, moderate, and large effects, respectively). Random-effects models for meta-analyses were applied.
MAIN OUTCOMES AND MEASURES
General quality of life and thyroid-related symptoms after a minimum follow-up of 3 months.
RESULTS
Overall, 21 of 3088 initially identified publications met the inclusion criteria, with 2192 adults randomized. After treatment (range, 3-18 months), thyroid hormone therapy was associated with lowering the mean thyrotropin value into the normal reference range compared with placebo (range, 0.5-3.7 mIU/L vs 4.6 to 14.7 mIU/L) but was not associated with benefit regarding general quality of life (n = 796; SMD, -0.11; 95% CI, -0.25 to 0.03; I2=66.7%) or thyroid-related symptoms (n = 858; SMD, 0.01; 95% CI, -0.12 to 0.14; I2=0.0%). Overall, risk of bias was low and the quality of evidence assessed with the GRADE tool was judged moderate to high.
CONCLUSIONS AND RELEVANCE
Among nonpregnant adults with subclinical hypothyroidism, the use of thyroid hormone therapy was not associated with improvements in general quality of life or thyroid-related symptoms. These findings do not support the routine use of thyroid hormone therapy in adults with subclinical hypothyroidism.
Topics: Adult; Blood Pressure; Humans; Hypothyroidism; Practice Guidelines as Topic; Quality of Life; Thyrotropin; Thyroxine
PubMed: 30285179
DOI: 10.1001/jama.2018.13770 -
Reviews in Endocrine & Metabolic... Jun 2022Levothyroxine (LT4) is a safe, effective means of hormone replacement therapy for hypothyroidism. Here, we review the pharmaceutical, pathophysiological and behavioural... (Review)
Review
Levothyroxine (LT4) is a safe, effective means of hormone replacement therapy for hypothyroidism. Here, we review the pharmaceutical, pathophysiological and behavioural factors influencing the absorption, distribution, metabolism and excretion of LT4. Any factor that alters the state of the epithelium in the stomach or small intestine will reduce and/or slow absorption of LT4; these include ulcerative colitis, coeliac disease, bariatric surgery, Helicobacter pylori infection, food intolerance, gastritis, mineral supplements, dietary fibre, resins, and various drugs. Once in the circulation, LT4 is almost fully bound to plasma proteins. Although free T4 (FT4) and liothyronine concentrations are extensively buffered, it is possible that drug- or disorder-induced changes in plasma proteins levels can modify free hormone levels. The data on the clinical significance of genetic variants in deiodinase genes are contradictory, and wide-scale genotyping of hypothyroid patients is not currently justified. We developed a decision tree for the physician faced with an abnormally high thyroid-stimulating hormone (TSH) level in a patient reporting adequate compliance with the recommended LT4 dose. The physician should review medications, the medical history and the serum FT4 level and check for acute adrenal insufficiency, heterophilic anti-TSH antibodies, antibodies against gastric and intestinal components (gastric parietal cells, endomysium, and tissue transglutaminase 2), and Helicobacter pylori infection. The next step is an LT4 pharmacodynamic absorption test; poor LT4 absorption should prompt a consultation with a gastroenterologist and (depending on the findings) an increase in the LT4 dose level. An in-depth etiological investigation can reveal visceral disorders and, especially, digestive tract disorders.
Topics: Adult; Helicobacter Infections; Helicobacter pylori; Hormone Replacement Therapy; Humans; Hypothyroidism; Thyrotropin; Thyroxine
PubMed: 34671932
DOI: 10.1007/s11154-021-09691-9 -
The Journal of Clinical Endocrinology... Jan 2022Thyroid dysfunction is associated with higher anemia prevalence, although causality remains unclear. (Observational Study)
Observational Study
CONTEXT
Thyroid dysfunction is associated with higher anemia prevalence, although causality remains unclear.
OBJECTIVE
This study aimed to investigate the association between thyroid function and anemia.
METHODS
This cross-sectional and Mendelian randomization study included 445 482 European participants from the UK Biobank (mean age 56.77 years (SD 8.0); and 54.2% women). Self-reported clinical diagnosis of hypothyroidism was stated by 21 860 (4.9%); self-reported clinical diagnosis of hyperthyroidism by 3431 (0.8%). Anemia, defined as hemoglobin level of < 13 g/dL in men and < 12 g/dL in women, was present in 18 717 (4.2%) participants.
RESULTS
In cross-sectional logistic regression analyses, self-reported clinical diagnoses of hypo- and hyperthyroidism were associated with higher odds of anemia (OR 1.12; 95% CI, 1.05-1.19 and OR 1.09; 95% CI, 0.91-1.30), although with wide confidence intervals for hyperthyroidism. We did not observe an association of higher or lower genetically influenced thyrotropin (TSH) with anemia (vs middle tertile: OR for lowest tertile 0.98 [95% CI, 0.95-1.02]; highest tertile 1.02 [95% CI, 0.98-1.06]), nor of genetically influenced free thyroxine (fT4) with anemia. Individuals with genetic variants in the DIO3OS gene implicated in intracellular regulation of thyroid hormones had a higher anemia risk (OR 1.05; 95% CI, 1.02-1.10); no association was observed with variants in DIO1 or DIO2 genes.
CONCLUSION
While self-reported clinical diagnosis of hypothyroidism was associated with higher anemia risk, we did not find evidence supporting a causal association with variation of thyroid function within the euthyroid range. However, intracellular regulation of thyroid hormones might play a role in developing anemia.
Topics: Aged; Anemia; Biological Specimen Banks; Causality; Cohort Studies; Cross-Sectional Studies; Female; Genome-Wide Association Study; Humans; Hypothyroidism; Male; Mendelian Randomization Analysis; Middle Aged; Prevalence; Self Report; Thyroid Gland; Thyrotropin; United Kingdom
PubMed: 34514498
DOI: 10.1210/clinem/dgab674 -
Nature Reviews. Disease Primers May 2022
Topics: Humans; Hypothyroidism
PubMed: 35589732
DOI: 10.1038/s41572-022-00364-8