Introduction

Thyroid storm is a rare but very aggressive disease that occurs as an extreme complication of hyperthyroidism (thyrotoxicosis).¹ It results from a rapid increase in thyroid hormones, primarily thyroxine (T4) and triiodothyronine (T3), where T4 is the major circulating form, which converts into T3, the more biologically active hormone, causing a hypermetabolic status.² This condition, with mortality rates ranging from 8 to 25%, can be life-threatening, and if left untreated, can lead to further complications, such as multi-organ failure, including cardiac dysfunctions, neurological symptoms like delirium and seizures, metabolic issues, and others, which are the leading cause of death. An overactive cellular response to increased thyroid hormone levels during high-stress episodes or infections, with consequent changes in the immune system, is the possible mechanism of thyroid storm. In fact, it is very common for patients with mild hyperthyroidism to progress into thyroid storm due to certain precipitating events. 

The most common trigger factors include:

• Sudden withdrawal of antithyroid drugs
• Thyroid surgery and non-thyroid surgery
• Infections 
• Trauma
• Exposure to Iodinated contrast medium
• Parturition (childbirth)
• Stroke or brain injury
• Certain medications, like amiodarone, anesthetics, and salicylates, can also contribute¹

Identifying these precipitating factors is essential to prevent serious complications and improve patient' outcomes. 

Iodine exposure as a trigger

Role of iodine in thyroid hormone synthesis

Iodine is an essential component involved in the production of thyroid hormones T4 and T3, which are crucial for development, growth, metabolic regulation, and keeping the body’s internal systems balanced. It also has antioxidant, antimicrobial, and antitumor properties. Iodine is absorbed by the thyroid gland from the bloodstream, iodine is then incorporated into these hormones through a series of biochemical processes. It is important to have an adequate iodine intake for proper thyroid function, as deficiency can lead to hypothyroidism or goiter, especially in infants.³ In contrast, excessive iodine intake can also be pathological, as it can cause both hypothyroidism and hyperthyroidism.⁴

Jod-Basedow phenomenon and hyperthyroidism exacerbation

Iodine-induced hyperthyroidism, also known as the Jod-Basedow phenomenon, occurs when people living in low iodine areas take supplements. Considering that the thyroid gland has been under iodine deficiency for a long time, it adapts with a TSH hyperstimulation as a response. Therefore, introducing iodine exposure, such as iodized salt, leads to overproduction of thyroid hormone, causing hyperthyroidism. However, in these individuals, excessive iodine intake is not necessary, as even a small amount can trigger the phenomenon. 

Conversely, in iodine-sufficient areas, the multifactorial autoimmune disorder, Graves’ disease, is the most common cause of hyperthyroidism, particularly in young adults. In this case, there is no direct effect of excessive dietary iodine on Graves' disease onset, though it is still unclear if long-term iodine exposure may trigger the disease process.⁴

Sources of excess iodine 

1. Contrast Media: Iodinated contrast agents, used in computed tomography and interventional procedures, can induce acute reactions like allergies or chemotoxic responses, as well as kidney injury and severe thyrotoxicosis resulting in thyroid storm⁵
2. Medications: Amiodarone is a widely used antiarrhythmic drug historically implicated in thyroid disorders. In fact, it has a high concentration of iodine in its formulation, which over-stimulates thyroid follicles to produce excessive thyroid hormone, resulting in thyroid storm⁶
3. Dietary Intake: Iodine-rich foods include seaweed, dairy products, and certain animal milks like goat and camel. Excessive consumption of these foods can trigger thyroid disorders, especially in children and infants⁴

Stress and its impact on thyroid function

Stress, whether physical or psychological, has important effects on the endocrine, nervous, and immune systems. The primary activator of stress is the hypothalamic-pituitary-adrenal (HPA) axis, which develops throughout childhood and adolescence, becoming hyper-responsive during youth. Stress exposure during these sensitive periods results in prolonged glucocorticoid secretion with long-term effects.⁷ In patients with pre-existing hyperthyroidism, stress can act as a precipitating factor, exacerbating the condition,⁸ and potentially triggering a thyroid storm. 

Mechanisms of stress-induced thyroid hormone dysregulation

The hypothalamic-pituitary-thyroid (HPT) system is strictly regulated from birth to maintain thyroid hormone homeostasis. However, acute or chronic stress episodes can significantly alter the regulatory circuits of thyroid hormone production and metabolism. These are some mechanisms that stress exposure may induce, increasing the risk of thyroid storm:

• High cortisol levels: Chronic stress has important effects on the HPA axis, overstimulating it to release cortisol, also known as the stress hormone. High levels of cortisol have several negative effects on the body. Regarding individuals with hyperthyroidism, it dysregulates the thyroid hormone production with a rapid and dangerous increase of T4 and T3 release, therefore, triggering a potential thyroid storm. Moreover, in more serious cases, it compromises the inflammation status and the immune system, promoting increased oxidative stress, leading to damage to thyroid cells and increasing the susceptibility to thyroid cancer
• Prolonged inflammation: a long-term active inflammation status, induced by chronic stress, can severely impair thyroid function and interfere with hormone metabolism, leading to an uncontrolled production of T4 and T3⁹

Medical procedures as precipitating factors

Surgeries (thyroid and non-thyroid related)

A common trigger factor for a thyroid storm is thyroid surgery. For example, patients who undergo thyroidectomy (complete or partial removal of the thyroid), as a surgical treatment for cancer, experience the onset of thyroid storm. This is mainly due to metastatic thyroid carcinoma, which causes the overstimulation of autonomous thyroxine production, resulting in a potential thyroid storm.¹⁰

Similarly, non-thyroid surgeries can also exacerbate pre-existing hyperthyroidism, leading to thyroid storm. For instance, surgeries like coronary artery bypass graft (CABG) have been implicated in thyroid storm precipitation in undiagnosed or poorly controlled hyperthyroid patients who, after the intervention, have manifested the classic symptoms, such as extreme tachycardia, resulting in multiorgan failure and eventual death. This highlights the importance of treatment for hyperthyroidism before nonthyroidal surgeries.¹¹

Radioactive iodine therapy and its paradoxical effects

Radioactive iodine (RAI) therapy is an effective treatment modality for hyperthyroidism used in those cases where medical therapy is not sufficient. However, it can present serious side effects in these patients, including a transient rise of stored thyroid hormones after destroying the hyperactive thyroid cells, and consequently inducing thyroid storm. To avoid this complication, it is highly recommended that patients with hyperthyroidism undergo pre-treatment with Βeta-adrenergic blockers and antithyroid drugs (ATDs) to lower stored thyroid hormones before receiving RAI therapy.¹²

Infections as indirect procedural stressors

Infections, particularly certain viruses, are strongly linked with thyroid storm, as they interfere with proper thyroid function, forcing it to excessively release thyroid hormones. Common symptoms occur, such as fever, tachycardia, and other cardiac issues. For example, a recent case of COVID-19 demonstrated how the virus triggered a thyroid storm after causing an aggressive inflammatory response by binding to receptors in the thyroid.¹³

Diagnosis 

Thyroid storm can be identified by checking hormone levels in the blood, including TSH, T3 and T4. In particular, when a low TSH level is detected, it is usually indicative of thyroid disorders like hyperthyroidism. In such cases, doctors check if the reduced activation of TSH is combined with high concentrations of T3 and T4 to see if the hyperthyroidism is a mild or severe condition. For a diagnosis, doctors may also use tests like thyroid scans or ultrasounds.²

Management

Treatment for thyroid storm starts with supportive care, like IV fluids, oxygen, and cooling blankets. Also, specific medicines are prescribed to control thyroid function and manage the patient’s symptoms, including:

• Beta-blockers: to reduce symptoms like increased heart rate
• Thionamide: to decrease thyroid hormone production
• Iodine solution: to inhibit the release of thyroid hormones
• Iodinated radiocontrast agent, glucocorticoid, PTU, and propanol: to block the conversion of T4 into T3
• Bile acid sequestrant: to interfere with the recycling of thyroid hormones

After the patient improves, the use of methimazole is suggested as a long-term treatment. In some cases, iodine treatment or surgery may be required. The goal is to stabilise the patient and then treat the underlying thyroid problem with a permanent solution.¹

Summary

Thyroid storm is a critical condition that requires immediate recognition and management. It occurs as an aggressive complication of hyperthyroidism triggered by factors such as sudden withdrawal of antithyroid drugs, infections, thyroid and non-thyroid surgeries, high stress levels, excessive iodine exposure, and others.

Prompt identification of these well-known precipitating factors is fundamental to prevent this condition and potentially improve patients’ outcomes. Additionally, in patients with pre-existing hyperthyroidism, an early intervention with supportive care and specific medications is essential. Once the condition develops, treatment focuses on symptom control through beta-blockers, thionamides, iodine treatments, and more. 

Given that thyroid storm can lead to multi-organ failure and be fatal if left untreated, immediate medical intervention is imperative. Therefore, future research should focus on identifying better ways to manage and prevent precipitating factors, improve early detection, and refine treatment strategies.