Article - Add-On Effect of Selenium and Vitamin D Combined Supplementation in Early Control of Graves' Disease Hyperthyroidism During Methimazole Treatment.

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Take home message

Testing for Se and VD levels and appropriate supplementation to achieve sufficiency in both is recommended for patients newly diagnosed with GD.

Evidence category

A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)

Summary review

Introduction

Observational studies have shown decreased levels of selenium and vitamin D in patients newly diagnosed with Graves’ Disease (GD), the most common cause of hyperthyroidism.
The aim of this study was to investigate the potential benefit of addition of selenium (Se) and vitamin D (VD) to treatment with methimazole (MMI) in GD patients with low levels of Se and VD.

Methods

Single-blind, randomised controlled trial of supplementation with Se (100 mcg/day for 180 days) and VD (bolus dose dependent on VD level, followed by 7000 IU per week for the duration of the study, 270 days), alongside treatment with MMI, compared to MMI monotherapy.
42 Caucasian adults newly diagnosed with GD but otherwise healthy and serum Se <120 mcg/l and plasma VD <30ng/ml.
Primary outcome: free thyroxine (T4).
Secondary outcome variables: triiodothyronine (T3), positive TSH receptor antibody (TRAb), handgrip strength performance, systolic blood pressure, heart rate and quality of life (QoL) questionnaires, assessed by an unblinded clinician at 45, 180 and 270 days.

Results

At baseline, significantly more patients in the intervention group had severe disease compared to controls. This was accounted for in the data analysis by comparing changes from baseline rather than absolute values.
In the intervention group only, both serum Se and plasma VD increased significantly, both relative to baseline and to control (Increase at 45 days: Se 49.9 mcg/l (40.2;59.5) (mean/confidence interval), VD 37.8 ng/ml (32.1; 43.4)). Mean Se and VD levels were in the normal range from day 45 until the end of the study and significantly higher than in the control group (p=0.001 at 45, 180 and 270 days).
T4 improved in both groups but significantly more so in the intervention group (p=0.002 at 180 days, thereafter T4 levels remained stable in both groups). QoL also improved more in the intervention group (p=0.007 at 45 days and p=0.03 at 270 days).
T3, TRAb, systolic blood pressure, heart rate and hand grip strength improved in both groups with no significant difference between groups.
No relevant adverse effects were observed, including no selenosis or hypercalcaemia.

Conclusion

The authors conclude that in newly diagnosed GD patients with low Se and VD levels, supplementation of Se and VD in addition to treatment with MMI supports the restoration of a euthyroid condition as well as improvement in QoL.

Clinical practice applications

Testing Se and VD levels in patients newly diagnosed with GD and supplementing to achieve sufficiency, where indicated, is recommended.
Supplementing Se and VD in newly diagnosed GD patients who are insufficient in these nutrients, alongside MMI, appears to be safe.

Considerations for future research

To establish whether Se and VD have a synergistic effect, larger studies with 4 groups would be of value (Se only, VD only, VD + Se, no supplementation, all in addition to standard treatment).
Larger studies that allow for stratification by Se/VD level and/or severity of disease at baseline.

Abstract

["Prompt and stable control of hyperthyroidism is fundamental to avoid the detrimental effects of thyroid hormone excess, and antithyroid drugs, mainly methimazole (MMI), represent the first-line treatment for Graves' disease (GD) hyperthyroidism. Decreased serum concentrations of selenium (Se) and calcifediol (25(OH)D, VitD) have been reported in newly diagnosed GD patients in observational studies. Low Se levels might exacerbate oxidative stress by compromising the antioxidant machinery's response to reactive oxygen species, and low VitD levels might hamper the anti-inflammatory immune response. We performed a randomized controlled clinical trial (EudraCT 2017-00505011) to investigate whether Se and cholecalciferol (VitD) addition to MMI is associated with a prompter control of hyperthyroidism. Forty-two consecutive patients with newly-onset GD and marginal\/insufficient Se and VitD levels were randomly assigned to treatment with either MMI monotherapy or MMI combined with Se and VitD. Se treatment was withdrawn after 180 days, while the other treatments were continued. Combination therapy resulted in a significantly greater reduction in serum FT4 concentration at 45 days (-37.9 pg\/ml, CI 95%, -43.7 to -32.2 pg\/ml) and 180 days (-36.5 pg\/ml, CI 95%, -42 to -30.9 pg\/ml) compared to MMI monotherapy (respectively: -25.7 pg\/ml, CI 95%, -31.6 to -19.7 pg\/ml and -22.9 pg\/ml, CI 95%, -28 to -17.3 pg\/ml, p 0.002). Data at 270 days confirmed this trend (-37.8 pg\/ml, CI 95%, -43.6 to -32.1 pg\/ml vs -24.4 pg\/ml, CI 95%, -30.3 to -18.4 pg\/ml). The quality of life (QoL) score was investigated by the validated \"Thyroid-related Patient-Reported Outcome\" questionnaire (ThyPRO). ThyPRO composite score showed a greater improvement in the intervention group at 45 days (-14.6, CI 95%, -18.8 to -10.4), 180 (-9, CI 95%, -13.9 to -4.2) and 270 days (-14.3, CI 95%, -19.5 to -9.1) compared to MMI group (respectively, -5.2, CI 95%, -9.5 to -1; -5.4, CI 95%, -10.6 to -0.2 and -3.5, CI 95%, -9 to -2.1, p 0-6 months and 6-9 months <0.05). Our results suggest that reaching optimal Se and VitD levels increases the early efficacy of MMI treatment when Se and VitD levels are suboptimal.",{"copyright":"Copyright \u00a9 2022 Gallo, Mortara, Veronesi, Cattaneo, Genoni, Gallazzi, Peruzzo, Lasalvia, Moretto, Bruno, Passi, Pini, Nauti, Lavizzari, Marin\u00f2, Lanzolla, Tanda, Bartalena and Piantanida."}]