Abstract
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 6 weeks, and after 3, 6, 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 thyroxine 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.
Introduction
Autoimmune thyroiditis (AIT) is the leading cause of hypothyroidism in iodine-sufficient countries (1). AIT is characterised by lymphocytic infiltration of the thyroid gland and the presence of autoantibodies against thyroid peroxidase (TPOAb) and/or thyroglobulin (2). The prevalence of overt hypothyroidism ranges between 0.2% and 5.3% in Europe, depending on geography, gender, age, and genetic factors (1). The standard treatment is lifelong levothyroxine (LT4) substitution with adjusted dosage to normalise circulating thyrotropin (TSH) levels (3). However, despite adequate treatment, quality of life (QoL) remains impaired in a subset of patients (4, 5, 6), and excess morbidity and mortality persist (7, 8). The fact that the aetiology of AIT is multifactorial, with complex interactions between genetic and environmental factors, as well as personality traits (9), further emphasises the need to search for ways of improving treatment (10).
Selenium is a metalloid and an essential micronutrient with fundamental importance to human health (11). The selenium concentration in the thyroid gland is higher than in most other organs. In addition, selenium has been identified in the active site of iodothyronine deiodinases type 1 and 2, which catalyse the conversion of thyroxin (T4) to triiodothyronine (T3), thus establishing the importance of selenium status for thyroid metabolism (11, 12). These findings have led to investigations into the clinical relevance of selenium status in thyroid diseases, and several selenium supplementation studies in patients with AIT have been carried out during the last 20 years. Meta-analyses have supported that supplementation with selenium, organic (13) as well as inorganic (14), leads to a reduction in TPOAb levels (15, 16). However, in a systematic review and meta-analysis, we concluded that there is no evidence of effects on clinically relevant outcomes such as disease remission, progression, lowered LT4 dose, or improved QoL (2, 17). In the current international guidelines, selenium supplementation is not recommended for the management of hypothyroidism (3, 18).
Information on the use of selenium supplementation in clinical practice has been investigated in survey studies. In a study on European Thyroid Association (ETA) members, 20% of the 147 respondents considered that current evidence warrants selenium supplementation in patients with AIT. If the patient was not receiving LT4, 65% of the respondents would occasionally recommend selenium supplementation (19). In a study among members of the Danish Endocrine Society, 37.5% indicated that supplementation with selenium or iodine could be used if requested by the patient (20).
The combination of gaps in current evidence regarding clinical efficacy and the apparent everyday use and recommendation of selenium supplements underlines the need for well-powered trials evaluating important clinical outcomes to help clinical decision-making. In ‘The chronic autoimmune thyroiditis quality of life selenium trial’ (CATALYST) (21), we aimed to investigate the effect of selenium supplementation on disease-specific QoL in patients with hypothyroidism due to AIT.
Methods
Study design and participants
CATALYST is a randomised placebo-controlled double-blinded multicentre trial, investigating the effect of 12 months selenium supplementation on disease-specific QoL in patients with AIT. The study protocol (21) was approved by the Regional Scientific Ethical Committees for Southern Denmark (project ID: S-20130123) and registered at ClinicalTrials.gov (ID: NCT02013479).
Participants were randomised 1:1 at the baseline visit to daily supplementation of either 200 μg selenium as selenium-enriched yeast or matching placebo tablets for 12 months. The patients attended four planned visits (V1–4): at baseline and after 3, 12, and 18 months. Anthropometric data, medical history, and current medication including LT4 dosage were recorded, and project pre-specified blood and urine samples were obtained and stored at −80°C in the research biobank at Odense University Hospital (OUH) until analysis after study completion.
The trial intervention was given in addition to the current LT4 treatment. The trial was conducted according to a pragmatic design, meaning that the participants were followed routinely at their local outpatient clinic and according to local clinical guidelines. Routine thyroid function tests were done on a regular basis to adjust the LT4 dose, aiming for a serum TSH level within the reference range.
Inclusion criteria
Inclusion criteria were age ≥18 years; diagnosis of AIT with serum TPOAb ≥100 kIU/L measured within the last 12 months; LT4 treatment based on an initial serum TSH ≥4.0 mIU/L; and written informed consent.
Exclusion criteria
Exclusion criteria were previous diagnosis of toxic nodular goitre; Graves’ hyperthyroidism or orbitopathy; postpartum thyroiditis; previous radioiodine therapy or thyroid surgery; antithyroid drug treatment; comorbidity rendering the participant unable to process patient-reported outcomes or receive intervention during the trial; immunomodulatory medication; other medications known to affect thyroid function; pregnancy, breastfeeding, or planned pregnancy within the next 18 months; allergy towards any component in the selenium or the placebo tablets; intake of selenium supplementation >55 μg/day; inability to read or understand Danish; or lack of informed consent.
Allocation and randomisation
From March 2014, participants were recruited from six clinical sites in Denmark (Odense University Hospital, Rigshospitalet, Bispebjerg Hospital, the Hospital of Southwest Jutland, Herlev/Gentofte Hospital, and the Hospital of Southern Jutland) and randomised 1:1 to daily supplementation with either 200 μg selenium as selenium-enriched yeast or matching placebo tablets for 12 months.
The allocation sequences were computer-generated by the central pharmacy at Odense University Hospital, with varying block size. Randomisation was stratified by clinical site and duration of LT4 treatment (less or more than three months) (Fig. 1). Blinding was maintained for both investigators and participants throughout all aspects of the trial, until all analyses were completed.
Primary and secondary outcomes
The primary outcome was health-related QoL after 12 months of intervention, as measured by the Composite score from the Thyroid-related Patient-Reported-Outcome questionnaire (ThyPRO-39) assessed at baseline, after 6 weeks, and after 3, 6, 12, and 18 months. Secondary outcomes were the LT4 dosage, serum TPOAb, and serum free T3 index (FT3I)/free T4 (FT4) ratio (22), assessed at each study visit (V1–4).
Thyroid status
Serum TSH (reference level: 0.3–4.0 mIU/L), FT4 (10.0-22.0 pmol/L), total T3 (1.3–2.2 nmol/L), and T3 uptake test (0.75–1.25) were determined at Gentofte Hospital, Copenhagen, by two-site chemiluminescent immunometric assay using Siemens Atellica® IM Analyser. Serum TPOAb (value <60 kIU/L is considered negative) was determined at Herlev Hospital, Copenhagen, by two-site chemiluminescent immunometric assay using Siemens Atellica® IM Analyser. The coefficient of variation (CV) was 2.5% and 5% at TSH levels of 1.04 and 10.7 mIU/L, respectively; CVs were 8.0% and 4.9% at total T3 levels of 1.4 and 4.4 nmol/L, respectively; CVs were 10% at T3-uptake test levels of 0.68 and 1.05, respectively; CVs were 7.7% and 8.0% at FT4 levels of 12.3 and 28.9 pmol/L, respectively, and CVs were 7.0% and 4.8% at TPOAb levels of 120 and 520 kIU/L, respectively.
Selenium status
Serum selenium was assessed at Charité Universitätsmedizin, Berlin, Germany. Serum samples were diluted 1:2 with a Gallium (Ga) containing buffer, which served as standard. Eight microliters of the diluted serum samples containing Ga were applied on quartz glass slides (Bruker Nano GmbH) and left to dry overnight in a 37°C incubator. Subsequently, total selenium was measured using a benchtop TXRF analyser (T-Star, Bruker Nano GmbH, Berlin, Germany) by examining the emission spectra (23). A standard serum was included in all sets of measurements to serve as control. The inter-assay CV was 7.3% and intra-assay CV was below 7.8%.
Health-related quality of life
QoL was measured by the validated short-form of the disease-specific questionnaire ThyPRO-39 consisting of 39 items (24, 25, 26, 27). Scales regarding hyperthyroidism (hyperthyroid symptoms, eye symptoms, and cosmetic complaints) were not included in this study. The items employ a recall period of 4 weeks and are summarised in ten multi-item scales as well as a single item scale measuring the overall impact of thyroid disease on QoL. The items are scored from 0 to 4, following a Likert scale (where ‘0’ is equivalent to ‘nothing at all’ and ‘4’ to ‘very much’). The average score of items in each scale is divided by four and multiplied by 100 to generate scores from 0 to 100, with higher scores indicating poorer health status. A ThyPRO-39 composite score, based on 21 items from the tiredness, cognition, anxiety, depressivity, emotional susceptibility, impaired social life, and impaired daily life scales, plus the overall QoL item, was also computed (23).
Sample size and power estimation
A sample size estimation was made based on the primary outcome (ThyPRO-39 Composite score). With a correlation between observations on the same participant of 0.50, and a type I error probability (two-sided α level) of 0.05 it was estimated that 236 participants in each intervention group were required to identify a difference between the two intervention groups of four points on the 0–100 ThyPRO-39 Composite scale with 80% power (21).
Based on the calculated sample size of 472 in total, a difference in serum TPOAb levels of 138 IU/mL between the two intervention groups could then be identified with 80% power. Likewise, the probability of finding a true difference in LT4 dosage of 25 μg/day between the two groups following intervention was calculated to be 92% (21).
Statistical analysis
Statistical analyses were performed with intact blinding, meaning that the experimental intervention and control intervention were randomly coded as ‘A’ and ‘B’. The blinding was broken after completion of all statistical analyses.
We assessed normality assumptions by quantile plots. Due to deviation from the normal distribution TPOAb were log-transformed before calculation. Groups were compared using chi-squared test or Student’s t-test for parametric data, and Mann–Whitney U-test for nonparametric data. Data are presented as n (%); means ± s.d. or medians and quartiles (25–75%).
We compared changes in health-related QoL (Composite score, Hypothyroid symptoms, and Goitre symptoms) between the two intervention groups from baseline to 6 weeks, and 3, 6, 12, and 18 months by linear mixed regression models for longitudinal data, a model which efficiently deals with missing data. The same method was also used to compare changes in serum selenium, serum TPOAb, serum FT3I/FT4 ratio, and LT4 dosage. For each of the dependent variables, we included a participant-specific random intercept as well as a random slope. Robust standard errors were used to compute confidence intervals (CIs) and P-values. Figures are showing plots with predicted mean values and 95% CI.
The analyses were performed using Stata software (V17.0; StataCorp, College Station, TX, USA). Statistical significance was defined as P < 0.05. All statistical tests were two sided.
Results
Study participants
The trial was terminated before the intended number of participants was achieved, because the expiry date of the trial medication was reached by January 2020. From March 2014 until that point, 412 patients were included. The mean age at baseline was 49 ± 14 years and women constituted 85% of the participants. In total, 332 (81%) completed 12 months of intervention of whom 82% were women, and 80 patients (19%) dropped out (Fig. 1). The reasons for leaving the study before completion were pregnancy (n = 6), change from LT4 to liothyronine + LT4 combination treatment (n = 14), great desire for selenium supplementation (n = 3), adverse effects attributed to the trial medication (n = 13), or withdrawn consent for unknown reason or absence from trial visits (n = 44). Differences between patients who completed the trial and those who dropped out are shown in Table 1. The non-completers were younger than the completers (45 ± 13 vs 40 ± 13 years; P = 0.002). No other differences were observed.
Baseline characteristics of patients completing the study (completers) vs those who dropped out in the intervention period (non-completers). Data are shown as mean ± s.d. or median and quartiles (25–75%).
| Completers | Non-completers | P | |
|---|---|---|---|
| n | 332 | 80 | |
| Age (years) | 50 ± 13 | 45 ± 13 | 0.002 |
| Gender, n (%) | 0.74 | ||
| Male | 60 (18) | 10 (12) | |
| Female | 272 (82) | 70 (88) | |
| Weight (kg) | 78.1 ± 16.9 | 75.1 ± 16.9 | 0.151 |
| Time from diagnosis to inclusion, n (%) | 0.289 | ||
| <3 months | 93 (28) | 25 (31) | |
| >3 months | 239 (72) | 55 (69) | |
| LT4 dosage (µg/day) | 103.2 ± 44.7 | 108.9 ± 45.2 | 0.296 |
| LT4 treatment (n) | 0.782 | ||
| Eltroxin® | 211 | 56 | |
| Euthyrox® | 93 | 22 | |
| Composite score, n | 0.256 | ||
| <30 | 167 | 34 | |
| >30 | 161 | 45 | |
| Randomisation, n (%) | |||
| Placebo | 168 (51) | 31 (39) | |
| Selenium | 164 (49) | 49 (61) | 0.071 |
| s-TSH (mlU/L) | 3.7 ± 8.3 | 3.2 ± 3.6 | 0.444 |
| s-FT4 (pmol/L) | 17.6 ± 3.3 | 17.3 ± 3.1 | 0.573 |
| s-FT3I (nmol/L) | 1.9 ± 0.5 | 1.8 ± 0.4 | 0.156 |
| s-FT3I/FT4 ratio | 0.11 ± 0.04 | 0.11 ± 0.03 | 0.253 |
| Log(s-TPOAb) | 3.5 (3.1–3.9) | 3.5 (3.0–3.9) | 0.459 |
| Antilog(TPOAb)(kIU/L) | 2884 (1175–7244) | 3236 (1071–9120) | |
| s-selenium (µg/L) | 85.9 ± 17.6 | 83.1 ± 18.7 | 0.219 |
Statistically significant difference (P < 0.05) is highlighted in bold.
FT3I, free T3 index; FT4, free thyroxine; LT4, levothyroxine; T3, triiodothyronine; TSH, thyrotropin; TPOAb, thyroid peroxidase antibodies.
Patient characteristics at baseline and after 12 months of intervention are shown in Table 2. No significant differences between the selenium group and the placebo group were observed. Further, no significant differences between the two groups were observed at three and at 18 months of follow-up (data not shown).
Characteristics of patients randomised to receive selenium or placebo for 12 months (end of intervention).
| Baseline | End of intervention | |||||
|---|---|---|---|---|---|---|
| Placebo | Selenium | P | Placebo | Selenium | P | |
| n | 201 | 211 | 170 | 162 | ||
| Age (years) | 48 ± 14 | 49 ± 13 | 0.56 | 49 ± 14 | 51 ± 13 | 0.334 |
| Gender, n (%) | 0.41 | 0.295 | ||||
| Male | 27 (13) | 35 (17) | 23 (14) | 29 (18) | ||
| Female | 174 (87) | 176 (83) | 147 (86) | 133 (82) | ||
| Weight (kg) | 78.1 ± 16.5 | 76.8 ± 17.7 | 0.449 | 78.1 ± 17.7 | 77.9 ± 17.1 | 0.949 |
| Time from diagnosis to inclusion, n (%) | 0.51 | 0.98 | ||||
| <3 months | 54 (27) | 63 (30) | 46 (27) | 43 (27) | ||
| >3 months | 147 (73) | 148 (70) | 124 (73) | 119 (73) | ||
| LT4 dosage (µg/day) | 101.7 ± 43.6 | 107.1 ± 45.9 | 0.22 | 117.3 ± 38.4 | 116.7 ± 42.1 | 0.89 |
| LT4 treatment (n) | 0.738 | 0.542 | ||||
| Eltroxin® | 134 | 133 | 116 | 106 | ||
| Euthyrox® | 55 | 60 | 46 | 50 | ||
| Smoking, n (%) | 0.997 | 0.963 | ||||
| Yes | 26 (13) | 28 (13) | 19 (11) | 15 (9) | ||
| No | 175 (87) | 183 (87) | 151 (89) | 147 (91) | ||
LT4, levothyroxine.
Biochemical results
At baseline, no significant treatment group differences were found for serum levels of TSH, FT4, FT3I, TPOAb, and selenium (Table 3). At 12 months, serum selenium was significantly higher in the selenium group than in the placebo group (140.4 ± 32.8 vs 84.1 ± 15.9 µg/L; P < 0.001), while the serum TPOAb level was lower (median and quartiles: 1862 (724–4365) vs 2455 kIU/L (977–6760); P = 0.032).
Biochemical variables at baseline and after end of intervention (12 months) with selenium supplementation or placebo. Data are shown as mean ± S.D. or median and quartiles (25-75%).
| Baseline | End of intervention | |||||
|---|---|---|---|---|---|---|
| Placebo | Selenium | P | Placebo | Selenium | P | |
| All patients, n | 189 | 203 | 165 | 162 | ||
| s-TSH (mU/L) | 3.2 ± 4.5 | 3.9 ± 9.5 | 0.293 | 2.2 ± 2.1 | 2.1 ± 2.0 | 0.688 |
| s-FT4 (pmol/L) | 17.5 ± 3.4 | 17.7 ± 3.2 | 0.487 | 18.2 ± 3.6 | 17.8 ± 2.8 | 0.339 |
| s-FT3I (nmol/L) | 1.9 ± 0.5 | 1.9 ± 0.5 | 0.443 | 1.8 ± 0.6 | 1.8 ± 0.5 | 0.786 |
| s-FT3I/FT4 ratio | 0.11 ± 0.04 | 0.11 ± 0.04 | 0.281 | 0.10 ± 0.04 | 0.10 ± 0.03 | 0.918 |
| Log(s-TPOAb) | 3.5 (3.1–3.9) | 3.4 (3.0–3.9) | 0.467 | 3.4 (2.9–3.8) | 3.3 (2.9–3.6) | 0.034 |
| AntiLog(s-TPOAb) (kIU/L) | 3011 (1202–7413) | 2630 (1096–8128) | 2455 (977–6760) | 1862 (724–4365) | ||
| s-selenium (µg/L) | 85.4 ± 17.9 | 85.4 ± 17.7 | 0.996 | 84.1 ± 15.9 | 140.4 ± 32.8 | <0.001 |
Statistically significant difference (P < 0.05) is highlighted in bold. Due to missing data the numbers of patients differ from those shown in Table 2.
FT3I, free T3 index; FT4, free thyroxine; T3, triiodothyronine; TSH, thyrotropin; TPOAb, thyroid peroxidase antibodies.
Similar results were found by linear mixed model regressions, shown in Fig. 2 (and in Supplementary Table 1, see the section on supplementary materials given at the end of this article). Serum selenium was significantly higher in the selenium group compared to the placebo group after 12 months of intervention (139.9 (95% CI: 133.2–146.4) vs 84.3 µg/L (79.9–88.6); P < 0.001; Fig. 2A), and the TPOAb level was lower (1995 (95% CI: 1512–2512) vs 2344 kIU/L (1862–2951); P = 0.016; Fig. 2B). No significant differences were found between the two groups regarding changes in the FT3I/FT4 ratio or the LT4 dosage (Fig. 2C and D). At 18 months of follow-up (6 months off intervention) the only difference between the two groups was that serum selenium was still significantly higher in patients initially randomised to receive selenium (P < 0.001; Fig. 2A).
Linear mixed model regressions showing changes in (A) serum selenium, (B) serum TPOAb, (C) serum FT3I/FT4 ratio, and (D) LT4 dose in patients randomised to daily supplementation with either 200 μg selenium or placebo. The intervention ended after 12 months, and the patients were followed for further 6 months. Data presented as predicted mean and 95% CI.
Citation: European Thyroid Journal 13, 1; 10.1530/ETJ-23-0175
Health-related quality of life
No group differences in QoL measured by ThyPRO-39 were found at baseline or after 12 months (Fig. 3). Similarly, in linear mixed model regressions no significant difference between the two groups was found at any time point in the ThyPRO-39 Composite score and in the Goitre symptoms score (Fig. 4A and B, Supplementary Table 1). At 12 months, participants in the placebo group had a lower score (better QoL) in the Hypothyroid symptoms scale compared to the selenium group (P = 0.016; Fig. 4C and Supplementary Table 1).
Radar plot showing mean ThyPRO-39 scale scores at baseline and after 12 months of intervention with either selenium supplementation or placebo. Scores in the general population are shown for comparison (from ref. 5). Each scale ranges 0–100, with higher scores indicating poorer quality of life.
Citation: European Thyroid Journal 13, 1; 10.1530/ETJ-23-0175
Linear mixed model regressions showing the difference in (A) composite score, (B) goitre symptoms score, and (C) hypothyroid symptoms score in patients randomised to daily supplementation with either 200 μg selenium or placebo. The intervention ended after 12 months, and the patients were followed for further 6 months.
Citation: European Thyroid Journal 13, 1; 10.1530/ETJ-23-0175
Subgroup analyses
Post hoc subgroup analyses stratifying the patients according to duration of the disease (LT4 treatment longer or shorter than 3 months, Fig. 5), median baseline QoL (ThyPRO-39 Composite score <30 or >30), median TPOAb level at baseline (<2950 or >2950 kIU/L), or median selenium status at baseline (<83.3 or >83.3 µg/L) did not significantly change the results, nor did we find any effect of selenium supplementation, according to these stratifications, on QoL, LT4 dosage, or the FT3I/FT4 ratio, as compared to placebo supplementation (data not shown).
Radar plots showing mean ThyPRO-39 scale scores at baseline and after 12 months of intervention with either selenium supplementation or placebo. Scores in the general population are shown for comparison (from ref. 5). (A) Patients who started treatment with levothyroxine less than 3 months prior to inclusion. (B) Patients who started treatment with levothyroxine more than 3 months prior to inclusion. Each scale ranges 0–100, with higher scores indicating poorer quality of life.
Citation: European Thyroid Journal 13, 1; 10.1530/ETJ-23-0175
Differentiated effects were seen on the serum TPOAb level (Supplementary Table 2). Stratifying the patients according to duration of the disease (as defined earlier), the effect of selenium on TPOAb after 12 months was only significant in those receiving LT4 for more than 3 months, and not among those with a shorter duration of the disease; P = 0.006 and P = 0.599, respectively. By stratification according to baseline QoL (as defined earlier), the effect of selenium on TPOAb after 12 months was only significant among those with baseline Composite score >30 (i.e. lowest QoL) and not among those with baseline Composite score <30; at 12 months: P = 0.001 vs P = 0.795; and 18 months: P = 0.017 vs P = 0.581, respectively. Similarly, the effect of selenium on TPOAb after 12 months of intervention was only significant in the ‘low level’ serum selenium group (as defined earlier); P = 0.048 vs P = 0.176, respectively. Finally, the effect of selenium supplementation on the TPOAb level was only significant in the ‘high level’ TPOAb group (as defined earlier) and not in the ‘low level’ TPOAb group; P = 0.019 vs P = 0.439, respectively.
Adverse events
No serious adverse events were observed during the trial. No significant differences were found in adverse effects between the selenium group and the placebo group (P = 0.261). Thirteen patients (nine in the selenium group and four in the placebo group) dropped out during the intervention period because of adverse effects, including skin rash and itching, stomach pain, coughing, or general discomfort and tiredness. In the group of participants who completed the study, 31 participants (14 in the placebo group and 17 in the selenium group, P = 0.712) had adverse effects like skin rash and itching, stomach pain, and tiredness.
Discussion
The present study is, to our knowledge, the largest randomised controlled trial of selenium supplementation in patients with hypothyroidism due to AIT, including more than 400 patients, and the first study using QoL as the primary outcome. The main finding of our study was that selenium supplementation had no effect on QoL in patients with hypothyroidism due to AIT, as compared to placebo supplementation. Both intervention groups showed a marked improvement in QoL, compared to baseline, which emphasises the placebo effect, as demonstrated in numerous trials in the past. This improvement persisted even after the trial medication was discontinued. Approximately 20% of patients dropped out, of which only a minority were due to adverse events, being almost equally distributed between the selenium group and the placebo group. No serious adverse events were observed.
The majority of previous selenium supplementation trials in patients with AIT have focused on circulating thyroid autoantibody levels, with only a few studies reporting the effect on clinically relevant outcomes such as QoL (14, 28, 29, 30, 31, 32). Three of these studies reported improved well-being with selenium supplementation (14, 28, 29) while the remaining studies showed no effects (30, 31, 32). Different generic questionnaires for measuring QoL have been used, hindering these data to be synthesised into a meta-analysis (33, 34). The composite score of ThyPRO-39 was chosen as the primary outcome in the present trial (21). This questionnaire is a well-validated tool specifically designed to explore and monitor QoL among patients with benign thyroid diseases (24, 25, 26, 27).
To optimise the concentration of selenoprotein P, considered one of the most valid biomarkers of the selenium status, serum selenium should be in the range 120–130 μg/L. To reach this level, the required selenium intake is at least 100 μg per day (2, 35). Further, the impact of selenium deficiency may be modified by autoantibodies to selenoprotein P (36). Marginal selenium deficiency in Europe as well as lower selenium status in patients with AIT compared with healthy controls has been reported (12, 35, 37). This is in line with the present study where we found a baseline median selenium level of 83.3 μg/L. Patients randomised to selenium supplementation showed an increase of approximately 70% in serum selenium (from 84 to 140 μg/L) during the intervention period of 12 months. Taking the relatively low s.d. (33 μg/L) of serum selenium into account this indicates a good adherence to the intervention in the majority of our participants.
As the conversion of T4 to T3 in the organism is mediated by iodothyronine deiodinases type 1 and 2, selenium supplementation might theoretically result in a higher conversion rate, in case of suboptimal selenium levels. We found no effect of selenium supplementation on the serum FT3I/FT4 ratio, or the LT4 dose needed to maintain serum TSH within the reference range. These results are not surprising since the deiodinases are prioritised over other selenoproteins in case of selenium deficiency. Thus, the thyroid hormone conversion was most likely unaffected in our patients at baseline, even though the selenium intake may have been in the lower range (2). The only significant finding in our trial was that the level of TPOAb decreased significantly more in patients randomised to selenium than in those receiving placebo. Although we found no effects on QoL, LT4 dosage, or the FT3I/FT4 ratio, compared to placebo, a significant decrease in the TPOAb level was indeed observed in the ‘low level’ selenium group. These results are consistent with previous studies which demonstrated that LT4-treated patients with high TPOAb or low selenium levels are those showing the most pronounced reduction of TPOAb level by selenium supplementation (2, 15, 17). Nevertheless, whether supplementing selenium deficiency can prevent the development of AIT remains to be shown in clinical trials.
In addition to the importance for thyroid hormone conversion, the biological effects of selenium are mediated by selenoproteins with antioxidant and immunoregulatory capacity. However, a deeper understanding of how thyroid autoimmunity is reduced by selenium supplementation is lacking. Likewise, the clinical implication of this effect is uncertain (17). As thyroid diseases seem to carry a risk of increased burden of oxidative stress (38, 39, 40), selenoproteins with antioxidant properties, like glutathione peroxidase and thioredoxin reductases, may be of particular importance. We have recently reported that treatment of hyperthyroidism caused by Graves’ disease or toxic nodular goitre reduces systemic oxidative stress load by 10–25% (41), and mostly among patients with the former condition. Oxidative stress is reported to be increased also in patients with AIT (42, 43), suggesting that thyroid autoimmunity per se may be the key driver. The effect of selenium may be mediated, at least in part, through inflammatory pathways. Thus, selenium supplementation seems to upregulate activated T cells (44) and to inhibit the release of several pro-inflammatory cytokines, including interleukin 2, interferon gamma (IFNγ), and tumor necrosis factor (2, 45). A recent study found that 100 μg daily selenium supplementation in 29 women with AIT reduced IFNγ and increased interleukin 1β concentrations (46). Although the present trial found no positive effects on clinical outcomes, such as QoL and the LT4 dosage, further research is needed to explore whether the potential effects of selenium on the immune system, the oxidative stress burden, and low-grade inflammation are of clinical significance in patients with thyroid diseases. In addition, future studies may reveal if specific gene variants predict increased responsiveness to selenium supplementation (47, 48, 49).
Besides being a risk factor for developing AIT (2, 50) selenium deficiency as well as low dietary selenium intake (51) have been linked to increased risk of prostate cancer, mortality, decreased immune function, and impaired fertility (2, 50). Importantly, overexposure to selenium can have unintended health effects in humans. A randomised controlled trial found that 300 μg/day selenium supplementation significantly increased all-cause mortality by 11.3% after 10 years (52). Further, a US study linked high selenium levels to an increased mortality rate (53). This suggests a high intake of selenium supplements should be avoided unless a solid clinical indication exits, and the treatment is based on evidence from clinical trials.
The major strength of this study is the randomised, controlled, and double-blinded design, and use of the extensively validated ThyPRO-39 for measuring patient-reported outcomes (2, 24). Both men and women across a wide age range were included, and only those with AIT and positive TPOAb above 100 kIU/L were eligible. The trial was conducted according to a pragmatic approach to mimic normal clinical practice, meaning that the patients were followed by their usual clinician in parallel with their study visits to the investigators. The study was well-powered with more than 400 patients, which makes it the largest trial of selenium supplementation in this patient population. The trial was terminated before the intended number of 472 included patients was reached. However, we believe that the risk of a type II error is very low, as no trends of differences between the two intervention groups were observed in any of the major outcomes. Moreover, the ThyPRO instrument has been further validated since the trial was launched in 2014, including studies to determine minimal important change (MIC) values (54). MIC is defined as the smallest change in score that patients perceive as important. For the ThyPRO composite score, MIC between groups is 9.1 (54). Using this figure in the sample size calculation for the present trial, only 75 patients in each group would be needed.
A few limitations to this study exist. We included patients from six different sites over a period of seven years. The total number of patients with hypothyroidism followed at the hospital units during this period was clearly higher than the number of patients enrolled in the trial. For practical reasons, we only obtained complete clinical data on patients assessed for eligibility at Odense University Hospital. We consider this subgroup as representative of the entire study population, as Odense University Hospital was the main site, including more than half of the participants. Restricting our analyses to patients recruited only at this site did not significantly change the results (data not shown).
Although QoL in our patients clearly was lower than in the background population it may be a point of criticism that QoL at baseline was not sufficiently impaired, thereby attenuating any positive effect of the intervention, if indeed present. We do not find this to be of any major concern as no differences between the intervention groups could be found even if we restricted the analyses to patients with the lowest QoL at baseline.
In conclusion, selenium supplementation for 12 months, compared to placebo, did not improve QoL, LT4 dosage, or FT3I/FT4 ratio in patients with hypothyroidism due to AIT. The results from this large randomised controlled trial do not justify the routine use of selenium supplementation in patients with AIT.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ETJ-23-0175.
Declaration of interest
LS holds shares of selenOmed GmbH, a company involved in selenium status assessment. No competing financial interests exist. The other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported. Steen Bonnema is on the editorial board of European Thyroid Journal. Steen was not involved in the review or editorial process for this paper, on which he is listed as an author.
Funding
The study received funding from The Danish Council for Strategic Research, the Region of Southern Denmark, University of Southern Denmark, The Nissenske Family Foundation, and the Danish Thyroid Patient Federation. The experimental intervention and placebo were kindly provided by Pharma Nord ApS, Vejle, Denmark. UFR’s research salary was sponsored by a grant from Kirsten and Freddy Johansen’s Fund. Analytical work in the lab of LS was supported by the German Research Foundation.
Statement of ethics
All procedures performed in this study were in accordance with the ethical standards of the Regional Research Ethics Committee of Southern Denmark (protocol no.: S-20130123) and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The patients gave written and informed consent.
Data availability statement
The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
Author contribution statement
CBL: Data collection and analyses, writing the first draft of the manuscript. KW, TW, PC: Conception and design of trial, data collection. LS, KD, TC: Analysis of samples for selenium status. JG, SGH, FB, NK, BN: Data collection. UFR, LH, JBB, ÅKR, SJB: Conception and design of trial. All authors contributed to critical revision of the draft and approved the final draft of the manuscript.
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