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Vitamin C supplementation in patients with hypothyroidism requiring high-dose levothyroxine: a proof-of-concept pilot study.

  • 2025-10-23
  • Frontiers in endocrinology 16
    • Adnan Agha
    • Bachar Afandi
    • Javed Yasin
    • Charu Sharma
    • Mohammad Hamdan Alshaer
    • Mouza Ali Saif Alshamsi
    • Dana Ebraheim Yaaqeib
    • Bayena Khamis Eshaq Alblooshi
    • Juma AlKaabi

Study Design

Type
Randomized Controlled Trial (RCT)
Sample size
n = 6
Population
26 hypothyroid patients and 91 healthy controls; in RCT, 12 patients randomized, 11 completed (6 vitamin C, 5 placebo)
Methods
Two-phase study: phase one assessed vitamin C levels; phase two was a double-blind, randomized, placebo-controlled trial with 1g daily vitamin C or near-matched pH placebo for 16 weeks
Blinding
Double-blind
Duration
16 weeks

Background

Vitamin C supplementation may enhance the absorption of levothyroxine in patients with hypothyroidism. This proof-of-concept pilot study aimed to assess the frequency of vitamin C insufficiency and evaluate the feasibility and potential therapeutic signal of vitamin C supplementation in patients requiring high-dose levothyroxine.

Methods

This two-phase study initially assessed vitamin C levels in 26 hypothyroid patients and 91 healthy controls. In phase two, a double-blind, randomized, placebo-controlled trial was conducted. Twelve patients were randomized, and 11 completed the study. Participants received either 1g daily vitamin C (n=6) or a near-matched pH placebo (n=5) for 16 weeks. Primary outcomes were changes in the Zulewski clinical score and thyroid-stimulating hormone (TSH) levels.

Results

Vitamin C insufficiency was more frequent in hypothyroid patients (19.2%) versus controls (7.7%), though the difference in mean levels was not statistically significant (59.33 ± 24.62 µmol/L vs 73.12 ± 14.03 μmol/L in controls; p=0.21). In the RCT, the vitamin C group showed greater changes in Zulewski score (mean reduction 5.00 vs 1.40 points; difference 3.60, 95% CI: 1.88 to 5.32) and TSH levels (mean reduction 4.08 vs 2.35 mU/L; difference 1.73, 95% CI: -2.14 to 5.60) compared to placebo. However, the groups had significant baseline imbalances, notably in BMI (26.6 vs 43.4 kg/m²). After ANCOVA adjustment for baseline values, the between-group difference remained statistically significant for the Zulewski score (adjusted p=0.004) and marginally significant TSH (adjusted p=0.043). Primary biochemical outcome in this study was TSH rather than direct thyroid hormone measurement, as TSH represents the most sensitive biomarker for thyroid hormone adequacy in primary hypothyroidism and serves as the established therapeutic target in clinical guidelines.

Conclusions

This proof-of-concept study demonstrates the feasibility of studying vitamin C supplementation in patients on high-dose levothyroxine and detects a therapeutic signal, particularly in clinical symptoms. However, the findings are limited by the very small sample size and severe baseline imbalances, precluding any conclusions on efficacy. These preliminary data justify the need for larger, well-controlled trials with stratified randomization to determine if this intervention translates into a clinically meaningful effect.

Clinical trial registration

https://clinicaltrials.gov/study/NCT05733078, identifier NCT05733078.

Research Insights

  • Vitamin C→Increased Serum Free Thyroxine Levels

    the vitamin C group showed greater changes in ... TSH levels (mean reduction 4.08 vs 2.35 mU/L; difference 1.73, 95% CI: -2.14 to 5.60) ... After ANCOVA adjustment for baseline values, the between-group difference remained ... marginally significant TSH (adjusted p=0.043)

    Effect
    Beneficial
    Effect size
    Moderate
    Dose
    1g daily
  • Vitamin C→Reduced Hypothyroid Symptom Score

    the vitamin C group showed greater changes in Zulewski score (mean reduction 5.00 vs 1.40 points; difference 3.60, 95% CI: 1.88 to 5.32) ... After ANCOVA adjustment for baseline values, the between-group difference remained statistically significant for the Zulewski score (adjusted p=0.004)

    Effect
    Beneficial
    Effect size
    Moderate
    Dose
    1g daily
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