Selenium supplementation and placebo are equally effective in improving quality of life in patients with hypothyroidism.

PURPOSE: We investigated whether selenium supplementation improves quality-of-life (QoL) in patients with autoimmune thyroiditis (ID:NCT02013479). METHODS: We included 412 patients ≥18 years with serum thyroid peroxidase antibody (TPOAb) level ≥100 IU/mL in a multicentre double-blinded randomised clinical trial. The patients were allocated 1:1 to daily supplementation with either 200 µg selenium as selenium-enriched yeast or matching placebo tablets for 12 months, as add-on to levothyroxine (LT4) treatment. QoL, assessed by the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39), was measured at baseline, after six weeks, three, six, 12, and 18 months. RESULTS: In total, 332 patients (81%) completed the intervention period, of whom 82% were women. Although QoL improved during the trial, no difference in any of the ThyPRO-39 scales was found between the selenium group and the placebo group after 12 months of intervention. In addition, employing linear mixed model regression no difference between the two groups was observed in the ThyPRO-39 composite score (28.8 [95%CI:24.5-33.6] and 28.0 [24.5-33.1], respectively; P=0.602). Stratifying the patients according to duration of the disease at inclusion, ThyPRO-39 composite score, TPOAb level, or selenium status at baseline did not significantly change the results. TPOAb levels after 12 months of intervention were lower in the selenium group than in the placebo group (1995 [95%CI:1512-2512] vs. 2344 kIU/L [1862-2951]; P=0.016) but did not influence LT4 dosage or free triiodothyronine/free thyroxin ratio. CONCLUSION: In hypothyroid patients on LT4 therapy due to autoimmune thyroiditis, daily supplementation with 200 µg selenium or placebo for 12 months improved QoL to the same extent.

Hypothyroid women have persistently higher oxidative stress compared to healthy controls.

Objective: Some studies suggest that hypothyroidism is associated with increased oxidative stress. Urinary excretion of 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) represents whole-body RNA and DNA oxidation, respectively. These biomarkers have only been explored sparsely in patients with thyroid disorders. Methods: In 45 Danish women with newly diagnosed hypothyroidism, we compared 8-oxoGuo and 8-oxodG before or shortly after initiating levothyroxine with the excretion rates at euthyroidism. We also compared the excretion of 8-oxoGuo and 8-oxodG in the patients after restored euthyroidism with 18 healthy control subjects. Results: Compared with baseline, none of the biomarkers changed significantly in the patients after becoming euthyroid. The geometric mean of 8-oxoGuo was 1.63 (95% CI: 1.49-1.78) nmol/mmol creatinine at baseline and 1.67 nmol/mmol at euthyroidism (95% CI: 1.53-1.83) (P = 0.39), while that of 8-oxodG was 1.28 nmol/mmol creatinine at baseline (95% CI: 1.14-1.44) and 1.32 nmol/mmol at euthyroidism (95% CI: 1.18-1.48), respectively (P = 0.47). The relative mean differences were 0.97 (95% CI: 0.91-1.04) for 8-oxoGuo and 0.97 (95% CI: 0.88-1.06) for 8-oxodG. At baseline, multiple linear regression revealed a positive association between free thyroxine and both biomarkers (8-oxoGuo, P < 0.001; 8-oxodG, P = 0.04). Furthermore, 8-oxoGuo was positively associated with age (P = 0.04) and negatively associated with thyrotropin (P = 0.02). In the control group, the geometric mean of 8-oxoGuo was 1.23 nmol/mmol creatinine (95% CI: 1.07-1.42), while that of 8-oxodG was 1.04 nmol/mmol creatinine (95% CI: 0.88-1.23). Thus, compared with control subjects, euthyroid patients showed a significantly higher level of both 8-oxoGuo (P < 0.001) and 8-oxodG (P = 0.03). Conclusion: In hypothyroid women, no significant effect of levothyroxine treatment on the oxidative stress biomarkers 8-oxoGuo and 8-oxodG could be demonstrated. However, the excretion of these biomarkers was significantly higher than in healthy controls.

Severity of hypothyroidism is inversely associated with impaired quality of life in patients referred to an endocrine clinic.

PURPOSE: We investigated the association between health-related quality of life (HRQL) and the severity of hypothyroidism at diagnosis in patients referred to a secondary hospital clinic. METHODS: Sixty-seven adult patients referred from primary care were enrolled. All patients had newly diagnosed hypothyroidism due to autoimmune thyroiditis and were treated with levothyroxine (LT4). The dose was adjusted according to thyroid function tests aiming at a normal plasma thyrotropin. Patients were stratified according to the severity of hypothyroidism in two different ways: the conventional approach (subclinical or overt hypothyroidism) and a novel approach according to the change (decrease or increase) in plasma level of free triiodothyronine index (FT3I) following LT4 treatment. The ThyPRO-39 questionnaire was used for measurement of HRQL at referral to the Endocrine Outpatient Clinic (higher score corresponds to worse HRQL). RESULTS: Free thyroxine index (FT4I) at diagnosis correlated positively with the scores on the Hypothyroid Symptoms and Tiredness scales (p = 0.018 for both). In accordance, patients with subclinical hypothyroidism (n = 36) scored higher on Hypothyroid Symptoms (p = 0.029) than patients with overt hypothyroidism (n = 31). The difference in HRQL was more pronounced if patients were stratified according to the dynamics in FT3I following LT4 treatment. Thus, patients who showed a decrease in FT3I following treatment (n = 24) scored significantly worse for Anxiety (p = 0.032) and Emotional Susceptibility (p = 0.035) than patients with an increase in FT3I (n = 43). CONCLUSION: Patients referred to an endocrine clinic with mild hypothyroidism had an impaired HRQL, compared to patients with more severe hypothyroidism. The most likely explanation of this finding is a lower threshold for seeking medical consultation and secondary care referral if HRQL is deteriorated. The dynamics in plasma FT3I following treatment may be more sensitive for such a discrimination in HRQL than a stratification according to the thyroid function tests at diagnosis.

Intravenous vs. intraosseous vascular access during out-of-hospital cardiac arrest - protocol for a randomised clinical trial.

Objective: During cardiac arrest, current guidelines recommend attempting intravenous access first and to consider intraosseous access if intravenous access is unsuccessful or impossible. However, these recommendations are only based on very low-certainty evidence. Therefore, the "Intravenous vs Intraosseous Vascular Access During Out-of-Hospital Cardiac Arrest" (IVIO) trial aims to determine whether there is a difference in patient outcomes depending on the type of vascular access attempted during out-of-hospital cardiac arrest. This current article describes the clinical IVIO trial. Methods: The IVIO trial is an investigator-initiated, randomised trial of intravenous vs. intraosseous vascular access during adult non-traumatic out-of-hospital cardiac arrest in Denmark. The intervention will consist of minimum two attempts (if unsuccessful on the first attempt) to successfully establish intravenous or intraosseous vascular access during cardiac arrest. The intraosseous group will be further randomised to the humeral or tibial site. The primary outcome is sustained return of spontaneous circulation and key secondary outcomes include survival and survival with a favourable neurological outcome at 30 days. A total of 1,470 patients will be included. Results: The trial started in March 2022 and the last patient is anticipated to be included in the spring of 2024. The primary results will be reported after 90-day follow-up and are anticipated in mid-2024. Conclusion: The current article describes the design of the Danish IVIO trial. The findings of this trial will help inform future guidelines for selecting the optimal vascular access route during out-of-hospital cardiac arrest.

Long-Term Selenium-Yeast Supplementation Does Not Affect Bone Turnover Markers: A Randomized Placebo-Controlled Trial.

Higher selenium status has been associated with lower bone turnover markers (BTM) in epidemiological studies. However, the long-term impact of selenium supplementation on BTMs has not been studied. We investigated the effects of selenium supplementation on BTMs including osteocalcin (OC), procollagen type I N-terminal propeptide (PINP), collagen type I cross-linked C-telopeptide (CTX), and bone alkaline phosphatase (BALP) in the short (6 months) and long term (5 years). A total of 481 Danish men and women (60-74 years) were randomized to receive placebo-yeast versus 100, 200, or 300 µg selenium as selenium-enriched yeast daily for 5 years. Plasma selenium concentration was measured using inductively coupled plasma mass spectrometry, and BTMs were measured in nonfasted samples at baseline, 6 months, and 5 years. Data were analyzed by ANCOVA to investigate the shape of the dose-response relationships. Covariates included age, body mass index, baseline selenium status, baseline BTM, smoking, alcohol, supplement use, and medication. Plasma selenium concentration (mean 86.5 µg/d at baseline) increased significantly with increasing selenium supplementation to 152.6, 209.1, and 253.7 µg/L after 6 months and remained elevated at 5 years (158.4, 222.4, and 275.9 µg/L for 100, 200, and 300 µg supplemental selenium/d, respectively (p < 0.001)). There was no change in plasma selenium concentration in the placebo-treated group. There was no significant effect of selenium supplementation on OC (6 months p = 0.37; 5 years p = 0.63), PINP (6 months p = 0.37; 5 years p = 0.79), CTX (6 months p = 0.91; 5 years p = 0.58) or BALP (6 months p = 0.17; 5 years p = 0.53). The relatively replete baseline selenium status in the study participants may explain this lack of effect. Testing in more deficient populations may provide further insights into the impact of selenium supplementation on bone health. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Treatment of Hyperthyroidism Reduces Systemic Oxidative Stress, as Measured by Markers of RNA and DNA Damage.

BACKGROUND: Whole-body oxidative stress can be estimated by the urine excretion of oxidized guanosine species, 8-oxo-7,8-dihydroguanosine (8-oxoGuo) and 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), derived from RNA and DNA, respectively. These oxidative stress markers are not well explored in thyroid disorders. OBJECTIVE: We aimed to determine whether treatment of hyperthyroid patients affects the levels of these oxidative stress markers. METHODS: Urinary excretion of 8-oxoGuo and 8-oxodG was measured in 51 hyperthyroid patients (toxic nodular goiter [TNG], n = 30; Graves disease [GD], n = 21) before or shortly after initiation of therapy and when stable euthyroidism had been achieved for at least 12 months. RESULTS: Adjusting for age, the baseline urinary excretion of oxidative stress markers correlated positively with plasma thyroxine (8-oxoGuo, P = 0.002; 8-oxodG, P = 0.021) and was significantly higher in GD than in TNG patients (P = 0.001 for both oxidative stress markers). Restoration of euthyroidism significantly affected the excretion of the oxidative stress markers. In TNG, 8-oxoGuo decreased from geometric mean 2.11 nmol/mmol creatinine (95% CI, 1.85-2.39) to 1.91 nmol/mmol (95% CI, 1.67-2.19; P = 0.001), while 8-oxodG decreased from 1.65 nmol/mmol (95% CI, 1.41-1.93) to 1.48 nmol/mmol (95% CI, 1.27-1.74; P = 0.026). In GD, 8-oxoGuo decreased from 2.25 nmol/mmol (95% CI, 1.95-2.59) to 1.79 nmol/mmol (95% CI, 1.63-1.97; P = 0.0003), while 8-oxodG decreased from 2.02 nmol/mmol (95% CI, 1.73-2.38) to 1.54 nmol/mmol (95% CI, 1.31-1.81; P = 0.001). In the euthyroid state, there were no differences between groups. CONCLUSION: Restoration of euthyroidism in patients with hyperthyroidism significantly decreased the systemic oxidative stress load by 10% to 25%. Our findings may help to explain the higher morbidity and mortality linked to hyperthyroid diseases, as shown in observational studies.

Consequences of Hyperthyroidism and Its Treatment for Bone Microarchitecture Assessed by High-Resolution Peripheral Quantitative Computed Tomography.

Background: Hyperthyroidism is associated with bone mass reduction and increased fracture risk, but the effects on other important bone parameters have been sparsely examined. Therefore, we investigated bone microarchitecture and estimated bone strength by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hyperthyroid patients at diagnosis and after being euthyroid for at least one year. Methods: Two approaches were used: (A) a case-control study comparing 61 hyperthyroid women with 61 euthyroid women matched for age and menopause status; (B) a follow-up study, in which 46 of the 61 women were re-examined after having been euthyroid for one year. HR-pQCT of the distal radius and tibia, and dual-energy X-ray absorptiometry (DXA) of the lumbar spine and the hip were performed. Results: In analysis A: In the radius, compared with the healthy controls, hyperthyroid patients had higher total area (16.9% ± 29.5%; p < 0.001), trabecular area (28.6% ± 45.7%; p < 0.001), and lower cortical area (-11.7% ± 23.2%; p < 0.001). Total volumetric bone mineral density (vBMD) (-13.9% ± 26.5%; p < 0.001), cortical vBMD (-5.8% ± 7.9%; p < 0.001), cortical thickness (-16.7% ± 26.0%; p < 0.001), and estimated bone strength (-6.6% ± 19.5%; p < 0.01) were lower. No significant differences were found in the tibia or in the DXA parameters. In analysis B: In the radius, significant improvements were observed in the cortical area (2.1% ± 4.6%; p < 0.01), cortical thickness (2.5% ± 5.1%; p < 0.001), and total vBMD (0.8% ± 3.0%; p < 0.05). Trabecular area decreased (-0.5% ± 1.0%; p < 0.01) and trabecular separation increased (2.0% ± 8.3%; p < 0.05). In the tibia, cortical area (3.6% ± 7.3%; p < 0.01) and cortical thickness (3.8% ± 7.6%; p < 0.01) increased, and trabecular area decreased (-0.5% ± 1.1%; p < 0.01). Areal BMD, measured by DXA, increased in the spine (1.1% ± 3.4%; p < 0.05) and in the hip (2.0% ± 3.8%; p < 0.01). Conclusions: Compared with the healthy control group, hyperthyroid women had lower vBMD, lower estimated bone strength, and compromised cortical microarchitecture in the radius. After restoration of euthyroidism, significant improvements in vBMD and cortical microarchitecture were observed, highlighting the importance of achieving and maintaining euthyroidism.

Restoration of euthyroidism in women with Hashimoto's thyroiditis changes bone microarchitecture but not estimated bone strength.

PURPOSE: Fracture risk in hypothyroid patients is debated, and since the effects of hypothyroidism on bone microarchitecture and strength are unclarified, we investigated these characteristics by high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: Two approaches were used: a cross-sectional control study, comparing 32 hypothyroid women (mean age; 47 ± 12 years) suffering from Hashimoto's thyroiditis with 32 sex-, age-, and menopause-matched healthy controls; a prospective study, where 27 of the women were reexamined 1 year after restoration of euthyroidism. HR-pQCT of the distal radius and tibia, and dual-energy X-ray absorptiometry (DXA) of the spine and hip were performed. Bone strength was estimated using a finite element analysis (FEA). RESULTS: Cross-sectional control study: in the radius, total (mean 14.6 ± 29.3% (SD); p = 0.04) and trabecular bone areas (19.8 ± 37.1%, p = 0.04) were higher, and cortical volumetric bone mineral density (vBMD) lower (-2.2 ± 6.5%, p = 0.032) in hypothyroid patients than in controls. All indices of tibia cortical and trabecular vBMD, microarchitecture, and estimated bone strength were similar between groups, as was hip and spine areal BMD (aBMD). Prospective study: in the radius, mean cortical (-0.9 ± 1.8%, p = 0.02) and trabecular (-1.5 ± 4.6%, p = 0.02) vBMD decreased, and cortical porosity increased (18.9 ± 32.7%, p = 0.02). In the tibia, mean total vBMD (-1.1 ± 1.9%, p = 0.01) and cortical vBMD (-0.8 ± 1.4%, p = 0.01) decreased, while cortical porosity (8.2 ± 11.5%, p = 0.002) and trabecular area (0.2 ± 0.6%, p = 0.047) increased. No changes in FEA were detected. Lumbar spine aBMD decreased (-1.3 ± 3.0%, p = 0.04). CONCLUSIONS: Hypothyroidism was associated with an increased trabecular bone area and a lower mineral density of cortical bone in the radius, as assessed by HR-pQCT. Restoration of euthyroidism mainly increased cortical porosity, while estimated bone strength was unaffected.

Repurposing GLP1 agonists for neurodegenerative diseases.

There is a large unmet medical need to find disease modifying therapies against neurodegenerative diseases. This review summarizes data indicating that insulin resistance occurs in neurodegeneration and strategies to normalize insulin sensitivity in neurons may provide neuroprotective actions. In particular, recent preclinical and clinical studies in Parkinson's disease and Alzheimer's disease have indicated that glucagon-like peptide 1 (GLP1) agonism and dipeptidyl peptidase-4 inhibition may exert neuroprotection. Mechanistic insights from these studies and future directions for drug development against neurodegeneration based on GLP1 agonism are discussed.

A 2018 European Thyroid Association Survey on the Use of Selenium Supplementation in Hashimoto's Thyroiditis.

OBJECTIVE: To investigate clinical practice regarding the use of selenium supplementation in patients with Hashimoto's thyroiditis (HT) among members of the European Thyroid Association (ETA). METHODS: ETA members were invited to participate in an online survey investigating the use of selenium supplementation across the spectrum of benign thyroid diseases. Of 872 invited members, 242 (28%) completed the survey. After exclusion of basic scientists and non-European members, survey data from 212 respondents were eligible for further analyses. Responses from 65 (31%) individuals who did not at all recommend selenium, or only considered its use in the setting of a clinical trial, were not included in the final analysis of survey data from 147 respondents. RESULTS: While only a minority of respondents (29 of 147, 20%) stated that the available evidence warrants the use of Se in patients with HT, a statistically significant majority (95 of 147; 65%, p < 0.001) used Se occasionally or routinely. Se was predominantly recommended for patients with HT not receiving LT4 (102 of 147; 69%) to reduce circulating thyroid autoantibody levels. Very few respondents routinely recommended Se to pregnant patients with HT. CONCLUSIONS: A minority of responding ETA members stated that the available evidence warrants the use of Se in HT, but a majority recommended it to some extent, especially to patients not yet receiving LT4. This is questionable, and selenium is not recommended to patients with HT according to current ETA guidelines. Ongoing and future trials may lead to the reversal of current medical practice.

Selenium in thyroid disorders - essential knowledge for clinicians.

In the 1990s, selenium was identified as a component of an enzyme that activates thyroid hormone; since this discovery, the relevance of selenium to thyroid health has been widely studied. Selenium, known primarily for the antioxidant properties of selenoenzymes, is obtained mainly from meat, seafood and grains. Intake levels vary across the world owing largely to differences in soil content and factors affecting its bioavailability to plants. Adverse health effects have been observed at both extremes of intake, with a narrow optimum range. Epidemiological studies have linked an increased risk of autoimmune thyroiditis, Graves disease and goitre to low selenium status. Trials of selenium supplementation in patients with chronic autoimmune thyroiditis have generally resulted in reduced thyroid autoantibody titre without apparent improvements in the clinical course of the disease. In Graves disease, selenium supplementation might lead to faster remission of hyperthyroidism and improved quality of life and eye involvement in patients with mild thyroid eye disease. Despite recommendations only extending to patients with Graves ophthalmopathy, selenium supplementation is widely used by clinicians for other thyroid phenotypes. Ongoing and future trials might help identify individuals who can benefit from selenium supplementation, based, for instance, on individual selenium status or genetic profile.

A 2018 European Thyroid Association Survey on the Use of Selenium Supplementation in Graves' Hyperthyroidism and Graves' Orbitopathy.

OBJECTIVE: Selenium (Se) supplementation has been suggested in the treatment of Graves' disease (GD). We sought to investigate Se prescription patterns for GD across European countries. METHODS: Members of the European Thyroid Association were invited to participate in an online survey investigating the use of Se in GD either without or with orbitopathy (GO). Of 872 invited members, 244 (28%) completed the survey. After exclusion of basic scientists and non-European members, 197 responses were retrieved out of clinical trials (nearly half of clinician members), of whom 61 do not use Se. Thus, 136 respondents remained for further analyses. RESULTS: Among the 136 analyzed respondents, most (64.7%) were not aware of the Se status in their populations, did not assess Se levels (78.7%), nor considered iodine status (74.3%). In GD without GO, 38.2% recommend Se supplementation ("sometimes" [27.2%], "frequently" [5.9%] or "always" [5.1%]). When GO occurs, 94.1% recommend Se supplementation ("sometimes" [39%], "frequently" [30.1%] or "always" [25%]). Of these, 60.1% recommend Se as an alternative to watchful waiting in patients with mild ocular involvement and 44.9% as an adjuvant to the established treatment modalities in patients with moderate to severe ocular involvement. CONCLUSIONS: In Graves' hyperthyroidism without GO, 38.2% of ETA (European Thyroid Association) members recommend Se supplementation. Conversely, Se is recommended by the majority of respondents in GO, both in patients with mild and moderate to severe ocular involvement. This clinical practice is partially in disagreement with current European treatment guidelines that recommend Se as a 6-month treatment in mild GO only.

Effect of selenium supplementation on changes in HbA1c: Results from a multiple-dose, randomized controlled trial.

AIM: To investigate the effect of selenium supplementation at different dose levels on changes in HbA1c after 6 months and 2 years in a population of low selenium status. MATERIALS AND METHODS: The Denmark PRECISE study was a single-centre, randomized, double-blinded, placebo-controlled, multi-arm, parallel clinical trial with four groups. In total, 491 volunteers aged 60 to 74 years were randomly assigned to treatment with 100, 200 or 300 µg selenium/day as selenium-enriched yeast or placebo-yeast. HbA1c measurements were available for 489 participants at baseline, 435 at 6 months, and 369 after 2 years of selenium supplementation. Analyses were performed by intention to treat. RESULTS: The mean (SD) age, plasma-selenium concentration, and blood HbA1c at baseline were 66.1 (4.1) years, 86.5 (16.3) ng/g and 36.6 (7.0) mmol/mol, respectively. During the initial 6-month intervention period, mean HbA1c (95% CI) decreased by 1.5 (-2.8 to -0.2) mmol/mol for 100 µg/d of selenium supplementation and by 0.7 (-2.0 to 0.6) mmol/mol for the 200 and 300 µg/d groups compared with placebo (P = 0.16 for homogeneity of changes across the four groups). After 2 years of selenium supplementation, HbA1c had decreased significantly in all treatment groups, with no difference between active treatment and placebo. CONCLUSIONS: Selenium supplementation in an elderly European population of low selenium status did not significantly affect HbA1c levels after 2 years. Our findings corroborate a possible U-shaped response of selenium supplementation on glucose metabolism.

Association of apolipoprotein E gene polymorphisms with blood lipids and their interaction with dietary factors.

BACKGROUND: Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. METHODS: The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi-quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country. RESULTS: There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (P = 4 × 10- 4 and P = 0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54 ± 0.97 mmol/L) than those with the E3 (5.98 ± 1.05 mmol/L) (P = 0.001) and E4 (6.09 ± 1.06 mmol/L) (P = 2 × 10- 4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (P = 2 × 10- 6 and P = 3 × 10- 4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (P = 4 × 10- 4 and P = 0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes. CONCLUSION: In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene-diet interactions on lipids require further investigation in larger cohorts.

Effect of long-term selenium supplementation on mortality: Results from a multiple-dose, randomised controlled trial.

BACKGROUND: Selenium, an essential trace element, is incorporated into selenoproteins with a wide range of health effects. Selenoproteins may reach repletion at a plasma selenium concentration of ~ 125 µg/L, at which point the concentration of selenoprotein P reaches a plateau; whether sustained concentrations higher than this are beneficial, or indeed detrimental, is unknown. OBJECTIVE: In a population of relatively low selenium status, we aimed to determine the effect on mortality of long-term selenium supplementation at different dose levels. DESIGN: The Denmark PRECISE study was a single-centre, randomised, double-blinded, placebo-controlled, multi-arm, parallel clinical trial with four groups. Participants were 491 male and female volunteers aged 60-74 years, recruited at Odense University Hospital, Denmark. The trial was initially designed as a 6-month pilot study, but supplemental funding allowed for extension of the study and mortality assessment. Participants were randomly assigned to treatment with 100, 200, or 300 µg selenium/d as selenium-enriched-yeast or placebo-yeast for 5 years from randomization in 1998-1999 and were followed up for mortality for a further 10 years (through March 31, 2015). RESULTS: During 6871 person-years of follow-up, 158 deaths occurred. In an intention-to-treat analysis, the hazard ratio (95% confidence interval) for all-cause mortality comparing 300 µg selenium/d to placebo was 1.62 (0.66, 3.96) after 5 years of treatment and 1.59 (1.02, 2.46) over the entire follow-up period. The 100 and 200 µg/d doses showed non-significant decreases in mortality during the intervention period that disappeared after treatment cessation. Although we lacked power for endpoints other than all-cause mortality, the effects on cancer and cardiovascular mortality appeared similar. CONCLUSIONS: A 300 µg/d dose of selenium taken for 5 years in a country with moderately-low selenium status increased all-cause mortality 10 years later. While our study was not initially designed to evaluate mortality and the sample size was limited, our findings indicate that total selenium intake over 300 µg/d and high-dose selenium supplements should be avoided.

Is selenium supplementation in autoimmune thyroid diseases justified?

PURPOSE OF REVIEW: This review provides an appraisal of recent evidence for or against selenium supplementation in patients with autoimmune thyroid diseases, and discusses possible effect mechanisms. RECENT FINDINGS: Epidemiological data suggest an increased prevalence of autoimmune thyroid diseases under conditions of low dietary selenium intake. Two systematic reviews have evaluated controlled trials among patients with autoimmune thyroiditis and report that selenium supplementation decreases circulating thyroid autoantibodies. The immunomodulatory effects of selenium might involve reducing proinflammatory cytokine release. However, clinically relevant effects of selenium supplementation, including improvement in quality of life, are more elusive. In Graves' disease, some, but not all, trials indicate that adjuvant selenium supplementation enhances the restoration of biochemical euthyroidism, and might benefit patients with mild Graves' orbitopathy. SUMMARY: The use of selenium supplementation as adjuvant therapy to standard thyroid medication may be widespread, but a growing body of evidence yields equivocal results. The available evidence from trials does not support routine selenium supplementation in the standard treatment of patients with autoimmune thyroiditis or Graves' disease. However, correction of moderate to severe selenium deficiency may offer benefits in preventing, as well as treating, these disorders. Molecular mechanisms have been proposed, but further studies are needed.

Insufficient documentation for clinical efficacy of selenium supplementation in chronic autoimmune thyroiditis, based on a systematic review and meta-analysis.

By a systematic review and meta-analysis to investigate clinically relevant effects of selenium supplementation in patients with chronic autoimmune thyroiditis. Controlled trials in adults (≥18 years) with autoimmune thyroiditis, comparing selenium with or without levothyroxine substitution, versus placebo and/or levothyroxine substitution, were eligible for inclusion. Identified outcomes were serum thyrotropin (thyroid stimulating hormone) levels in LT4-untreated patients, thyroid ultrasound and health-related quality of life. Eleven publications, covering nine controlled trials, were included in the systematic review. Random effects model meta-analyses were performed in weighted mean difference for thyroid stimulating hormone, ultrasound and health-related quality of life. Quality of evidence was assessed per outcome, using GRADE. Meta-analyses showed no change in thyroid stimulating hormone, or improvements in health-related quality of life or thyroid echogenicity (ultrasound), between levothyroxine substitution-untreated patients assigned to selenium supplementation or placebo. Three trials found some improvement in wellbeing in patients receiving levothyroxine substitution, but could not be synthesized in a meta-analysis. The quality of evidence ranged from very low to low for thyroid stimulating hormone as well as ultrasound outcomes, and low to moderate for health-related quality of life, and was generally downgraded due to small sample sizes. We found no effect of selenium supplementation on thyroid stimulating hormone, health-related quality of life or thyroid ultrasound, in levothyroxine substitution-untreated individuals, and sporadic evaluation of clinically relevant outcomes in levothyroxine substitution-treated patients. Future well-powered RCTs, evaluating e.g. disease progression or health-related quality of life, are warranted before determining the relevance of selenium supplementation in autoimmune thyroiditis.

Selenium Supplementation Significantly Reduces Thyroid Autoantibody Levels in Patients with Chronic Autoimmune Thyroiditis: A Systematic Review and Meta-Analysis.

BACKGROUND: Selenium supplementation may decrease circulating thyroid autoantibodies in patients with chronic autoimmune thyroiditis (AIT), but the available trials are heterogenous. This study expands and critically reappraises the knowledge on this topic. METHODS: A literature search identified 3366 records. Controlled trials in adults (≥18 years of age) with AIT, comparing selenium with or without levothyroxine (LT4), versus placebo and/or LT4, were eligible. Assessed outcomes were serum thyroid peroxidase (TPOAb) and thyroglobulin (TgAb) autoantibody levels, and immunomodulatory effects. After screening and full-text assessment, 16 controlled trials were included in the systematic review. Random-effects meta-analyses in weighted mean difference (WMD) were performed for 3, 6, and 12 months of supplementation in two different populations: one receiving LT4 therapy and one newly diagnosed and LT4-untreated. Heterogeneity was estimated using I2, and quality of evidence was assessed per outcome, using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. RESULTS: In LT4-treated populations, the selenium group had significantly lower TPOAb levels after three months (seven studies: WMD = -271 [confidence interval (CI) -366 to -175]; p < 0.0001; I2 = 45.4%), which was consistent at six months (three studies) and 12 months (one study). TgAb decreased at 12 months, but not at three or six months. In LT4-untreated populations, the selenium group showed a decrease in TPOAb levels after three months (three studies: WMD = -512 [CI -626 to -398]; p < 0.0001, I2 = 0.0%), but not after 6 or 12 months. TgAb decreased at 3 months, but not at 6 or 12 months. Quality of evidence was generally assessed as low. Study participants receiving selenium had a significantly higher risk than controls of reporting adverse effects (p = 0.036). CONCLUSIONS: Selenium supplementation reduced serum TPOAb levels after 3, 6, and 12 months in an LT4-treated AIT population, and after three months in an untreated AIT population. Whether these effects correlate with clinically relevant measures remains to be demonstrated.

Respiratory Manifestations of Hypothyroidism: A Systematic Review.

BACKGROUND: Hypothyroidism has been associated with increased pulmonary morbidity and overall mortality. A systematic review was conducted to identify the prevalence and underlying mechanisms of respiratory problems among patients with thyroid insufficiency. METHODS: PubMed and EMBASE databases were searched for relevant literature from January 1950 through January 2015 with the following study eligibility criteria: English-language publications; adult subclinical or overt hypothyroid patients; intervention, observational, or retrospective studies; and respiratory manifestations. The Preferred Reporting Items for Systematic reviews and Meta-Analyses statement was followed, and Cochrane's risk of bias tool was used. RESULTS: A total of 1699 papers were screened by two independent authors for relevant titles. Of 109 relevant abstracts, 28 papers underwent full-text analyses, of which 22 were included in the review. Possible mechanisms explaining respiratory problems at multiple physiological levels were identified, such as the ventilator control system, diaphragmatic muscle function, pulmonary gas exchange, goiter caused upper airway obstruction, decreased capacity for energy transduction, and reduced glycolytic activity. Obstructive sleep apnea syndrome was found among 30% of newly diagnosed patients with overt hypothyroidism, and demonstrated reversibility following treatment. The evidence for or against a direct effect on pulmonary function was ambiguous. However, each of the above-mentioned areas was only dealt with in a limited number of studies. Therefore, it is not possible to draw any strong conclusions on any of these themes. Moreover, most studies were hampered by considerable risk of bias due for example to small numbers of patients, lack of control groups, randomization and blinding, and differences in body mass index, sex, and age between subjects and controls. CONCLUSION: Mechanistic data linking hypothyroidism and respiratory function are at best limited. This area of research is therefore open for retesting hypotheses, using appropriate study designs and methods.