Beyond thyroid dysfunction: the systemic impact of iodine excess

Yet another paper which is highlighting the issues which can be caused by excess iodine intake.

In particular, read the Conclusion in the full paper.

Beyond thyroid dysfunction: the systemic impact of iodine excess
Aiman Khudair  1† Sara Anjum Niinuma 1† Haniya Habib 1† Butler 2*

    1 School of Medicine, Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, Bahrain
    2 Research Department, Royal College of Surgeons in Ireland - Medical University of Bahrain, Busaiteen, Bahrain

As an essential micronutrient, iodine plays a crucial role in several physiological systems, particularly in the production of thyroid hormone. While deficiency is widely recognized, the consequences of iodine excess (IE) are less studied. IE, which may be caused by iodine-rich diets, supplements, iodinated contrast media and salt iodization, has been implicated in a range of adverse outcomes on thyroid and systemic health. Examples include autoimmune thyroid diseases like Graves’ disease and Hashimoto’s thyroiditis, driven by immune cell polarization and gut microbiota alterations. Furthermore, excessive iodine intake is associated with increased risks of cardiovascular diseases, including hypertension and atherosclerosis, due to oxidative stress, inflammation, and endothelial dysfunction. It contributes to the development of thyroid cancer, particularly papillary thyroid cancer, through genetic mutations such as BRAF mutations and enhanced cancer cell proliferation. Excess iodine intake has been implicated to have neurotoxic effects, significantly impairing learning and memory, negatively impacting neonatal brain development, and potentially contributing to the progression of neurodegenerative conditions. It also has a potential role in renal dysfunction in vulnerable populations, due to overload from povidone-iodine in sterile equipment. This mini-review aims to collate the adverse effects of IE, beyond its effect on thyroid health, through investigation of the cardiovascular, nervous, and renal systems. Through our consolidation of the current literature, we hope to raise awareness and contribute to the understanding of the multifaceted impact of excessive iodine intake.

Open access:

https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2025.1568807/full

Identification and Characterization of Highly Potent and Isoenzyme-Selective Inhibitors of Deiodinase Type I via a Nonradioactive High-Throughput Screening Method

One of the many problems of hyperthyroidism is the limited number of medicines which act as anti-thyroid agents. The two groups that exist both have the potential for severe side effects/adverse reactions.

Any new agents have the potential for improving hyperthyroidism treatment. This is most especially true given that the accepted alternatives to the existing agents are radioactive iodine and thyroidectomy. Both of which are known to have the potential for numerous side effects and unintended consequences (e.g. damage to parathyroid glands, affecting the voice, salivary glands, etc.)

Even if these agents are not regarded as definitive, they might well allow safe long-term use.

Identification and Characterization of Highly Potent and Isoenzyme-Selective Inhibitors of Deiodinase Type I via a Nonradioactive High-Throughput Screening Method

Rajas Sane  1 , Carola Seyffarth  2 , Sabrina Kleissle  3 , Martin Neuenschwander  2 , Jens Peter von Kries  2 , Caroline Frädrich  1 , Kostja Renko  4 , Eva K Wirth  5   6 , Josef Köhrle  1

PMID: 40170637 DOI: 10.1089/thy.2025.0036 

Abstract

Objective:

Deiodinase type I (DIO1) is crucial in maintaining thyroid hormone (TH) balance. It converts the prohormone thyroxine (T4) to the active triiodothyronine (T3) and degrades T3 to inactive 3,3'-diiodothyronine (3,3'-T2). It also acts on reverse T3 (rT3) and sulfated TH metabolites, thus contributing to TH elimination. Upregulation of DIO1 is linked to hyperthyroid conditions such as Graves' disease and autonomous thyroid adenoma, making it a promising target for pharmacological intervention. The adverse side effects of the antithyroid drug propylthiouracil (PTU), used in clinics to treat hyperthyroidism due to its thyroid peroxidase- and DIO1-blocking action, highlight the need for novel and potent DIO1-selective inhibitors. 

Methods: 

Using a semiautomatic high-throughput screening (HTS) assay based on the Sandell-Kolthoff (SK) reaction in 384-well plates, we screened 69,344 low-molecular-weight compounds for DIO1-inhibitory effects. Shortlisted hits underwent detailed manual characterization, where we evaluated the potency and isoenzyme specificity by assessing their DIO-inhibitory effects on enzyme preparations from all three DIO isoenzymes, over a wide concentration range (5 nM-20 µM). To evaluate the DIO1 inhibitory effects in intact cells, we applied a novel protocol based on the SK reaction to cell culture supernatants and assessed the intracellular deiodinase activity in DIO1 overexpressing HEK293 cells.

Results: 

The robust HTS assay flagged 436 (<1%) of the screened compounds as hits, also including known DIO1 inhibitors such as PTU and genistein. Based on a validation screen of 298 compounds, we prioritized 26 compounds to comprehensively characterize their DIO1-selective inhibition. We identified 15 DIO1-selective compounds (IC50 < 1 µM), more potent than the bonafide DIO1-selective inhibitor PTU. Additionally, 8 of the 13 tested compounds were found capable of inhibiting DIO1 in intact cells.

Conclusions: 

With a successful SK-reaction-based HTS application, we identified novel, potent, and selective inhibitors of DIO1 with nanomolar IC50 values. Furthermore, we successfully showed that some of these compounds were also capable of inhibiting intracellular DIO1 in intact cells. These novel compounds hold immense potential in studying TH modulation, deciphering DIO1 enzyme structure, and developing structure-activity relationships. Furthermore, our novel inhibitors act as lead compounds in developing strategies to combat hyperthyroidism.

Keywords: DIO1; DIO1-inhibitors; deiodinases; high-throughput screening; thyroid hormones.