Highlights
- Adjunctive L-carnitine and selenium (LCT/Se) therapy significantly accelerates the time to TSH-receptor antibody (TRAb) negativity (HR = 2.35).
- Patients receiving the combined supplement required a significantly lower cumulative dose of methimazole (MMI) compared to those on monotherapy.
- The intervention group demonstrated a markedly higher rate of spontaneous remission (OR = 11.22) over a 24-month period.
- LCT/Se supplementation specifically mitigated symptoms of tremor, irritability, and exertional dyspnea, independent of thyroid hormone levels.
Background and Clinical Challenges in Graves’ Disease
Graves’ Disease (GD) remains a cornerstone of clinical endocrinology, characterized by hyperthyroidism resulting from circulating autoantibodies against the TSH receptor (TRAb). While methimazole (MMI) is the first-line pharmacotherapeutic approach globally, its clinical application is often fraught with challenges. The therapeutic response is frequently unpredictable, and many patients suffer from persistent thyrotoxic symptoms even after biochemical normalization of fT3 and fT4 levels. Furthermore, long-term MMI use carries risks of dose-dependent adverse effects, including hepatotoxicity and rare but severe agranulocytosis.
The quest for adjunctive therapies that can modulate the autoimmune process or mitigate the peripheral effects of thyroid hormones has led researchers to investigate micronutrients. Selenium (Se) is a critical trace element for thyroid function, serving as a cofactor for glutathione peroxidases and iodothyronine deiodinases, thereby exerting immunomodulatory and antioxidant effects. Concurrently, L-carnitine (LCT) has emerged as a peripheral antagonist of thyroid hormone action, specifically inhibiting the entry of triiodothyronine (T3) and thyroxine (T4) into the cell nucleus. The study by Rossi et al. (2025) explores whether the combination of these two agents can optimize the standard-of-care MMI therapy.
Study Design and Methodology
This multicenter prospective randomized trial enrolled 60 consecutive patients with newly diagnosed overt Graves’ Disease. The cohort was randomized into two arms: the Control Group, receiving standard methimazole titration, and the Intervention Group, receiving methimazole plus a combined supplement of L-carnitine and Selenium.
The primary objectives were to evaluate the biochemical profile—specifically TSH, fT3, fT4, and TRAb levels—every two months and to assess the impact on patient Quality of Life (QoL) through standardized symptom questionnaires. The study duration extended up to 24 months, or until the patient achieved spontaneous remission or required definitive therapy (radioactive iodine or surgery). This longitudinal design allowed for a robust assessment of both short-term symptomatic relief and long-term prognostic markers like TRAb seroconversion.
Key Findings: Biochemical Trends and MMI Sparing Effect
TRAb Kinetics and Remission Rates
Perhaps the most clinically significant finding was the impact on TRAb levels. While the normalization of fT3 and fT4 followed a similar trajectory in both groups, the Intervention Group reached TRAb negativity significantly faster than the Control Group (Hazard Ratio [HR] = 2.35; 95% CI, 1.14–4.81; p = 0.016). Given that persistent TRAb positivity is a major risk factor for relapse after drug withdrawal, this finding suggests a potential disease-modifying effect of the LCT/Se combination.
Furthermore, the rate of spontaneous remission was dramatically higher in the Intervention Group. The researchers reported an Odds Ratio (OR) of 11.22 (95% CI, 3.35–46.11; p < 0.001), indicating that the adjunctive therapy may fundamentally alter the immunological course of the disease, leading to a higher probability of successful MMI discontinuation.
Reduction in Drug Exposure
The study demonstrated a clear “MMI-sparing” effect. Patients in the Intervention Group required lower average daily doses of methimazole (p = 0.013) and, crucially, a significantly lower cumulative dose over the course of the study (p = 0.020). This reduction in cumulative exposure is vital for minimizing the risk of long-term antithyroid drug toxicity and may improve patient adherence to the treatment regimen.
Symptom Burden and Quality of Life
While the overall symptom score did not show a statistically significant difference across the entire cohort, a granular analysis of specific symptoms revealed clear benefits. The addition of LCT/Se exerted an independent effect in reducing the severity of several classic thyrotoxic manifestations, including tremor, irritability, mood lability, heat intolerance, and exertional dyspnea. This improvement in quality of life occurred even when adjusting for the rate of thyroid hormone normalization, suggesting that L-carnitine’s role as a nuclear antagonist helps mitigate the peripheral tissue response to excess thyroid hormone.
Mechanistic Insights: Why LCT and Se Work Together
The synergy between L-carnitine and Selenium appears to address Graves’ Disease at two distinct levels: the immunological trigger and the peripheral tissue response. Selenium’s role in GD is largely attributed to its concentration in the thyroid gland, where it helps reduce oxidative stress and modulates the cytokine profile, potentially dampening the autoimmune attack on the TSH receptor. This likely explains the accelerated decline in TRAb titers.
L-carnitine, on the other hand, functions as a peripheral antagonist. By inhibiting the transport of thyroid hormones into the cell nucleus, it reduces the genomic effects of T3, which is responsible for many of the cardiovascular and neurological symptoms of hyperthyroidism. This dual-action approach—targeting the source (autoimmunity) and the symptoms (peripheral action)—provides a more holistic management strategy than MMI alone.
Expert Commentary and Clinical Implications
The results of this trial are highly relevant for clinicians managing GD, particularly those seeking to improve the odds of long-term remission. Current guidelines emphasize the importance of TRAb monitoring to guide the duration of MMI therapy. The finding that LCT/Se supplementation leads to earlier TRAb negativity suggests that clinicians might be able to achieve treatment goals sooner and with greater confidence in the stability of the remission.
However, it is important to acknowledge the study’s limitations. With a sample size of 60 patients, larger multicenter trials are necessary to confirm these findings and to determine the optimal dosage and duration of supplementation. Furthermore, while the safety profile of LCT and Se is generally excellent, clinicians must ensure that selenium intake does not exceed the upper tolerable limits to avoid selenosis.
Conclusion
The integration of L-carnitine and Selenium into the standard methimazole treatment for overt Graves’ Disease represents a promising advancement in endocrine practice. By accelerating the normalization of TRAb, reducing the cumulative dose of methimazole, and providing targeted relief for debilitating symptoms like tremors and irritability, this combination therapy addresses several unmet needs in GD management. Future research should focus on whether these benefits translate into lower long-term relapse rates after the cessation of all therapies.
References
Rossi M, Meomartino L, Zavattaro M, Selvatico G, Rossetto Giaccherino R, Pagano L. Adding L-Carnitine and Selenium to Methimazole in Graves’ Disease: A Prospective Randomized Trial on Thyroid Markers and Quality of Life. Nutrients. 2025 Aug 20;17(16):2693. doi: 10.3390/nu17162693. PMID: 40871722; PMCID: PMC12389566.
