Introduction

Definition of thyroid storm

Thyroid storm, or thyrotoxic crisis, is an acute, life-threatening condition resulting from hyperthyroidism with multi-system involvement.¹

Overview of thyroid hormones (T3 & T4)

The primary hormones secreted by the thyroid are thyroxine or tetraiodothyronine (T4) and triiodothyronine (T3). Thyrotropin-releasing hormone (TRH) from the hypothalamus, thyroid-stimulating hormone (TSH) from the anterior pituitary gland, and T4 function in coordinated harmony to regulate appropriate feedback mechanisms and homeostasis.²

Thyroid hormones: structure and function

Biosynthesis of T3 (Triiodothyronine) and T4 (Thyroxine)

T3 and T4 are produced in the thyroid gland from tyrosine residues and iodine. T4 is then converted to T3 in peripheral tissues, the active thyroid hormone.²

Role of the hypothalamic-pituitary-thyroid (HPT) axis

The HPT axis's role in the bone has also been profiled as a contentious skeletal science field. The prevailing thought that the effects of disruption of the axis in the skeleton come about as a result of the bone's changed response to T3 has been disputed by research studies that suggested that TSH serves as a suppressor of bone turnover.³

Normal physiological functions of T3 and T4

T3 and T4 control metabolism, affecting heart rate, body temperature, and energy use. They are crucial for development and growth, especially in babies.²

Pathophysiology of thyroid storm

Thyroid storm traditionally started several hours following thyroidectomy in a patient prepared for operation by potassium iodide only. Most such patients were not euthyroid and could not be said to be properly prepared for operation by today's standards. Worsening of the thyrotoxicosis continues to occur in patients referred to surgery before proper preparation, but this is rare in the anti-thyroid drug-treated patient. Thyroid storm is sometimes seen in patients who are operated on for some other disease but who are very thyrotoxic. Rarely does severe worsening of thyrotoxicosis happen after 131-I therapy for hyperthyroidism; however, a portion of such exacerbations may be classified as thyroid storm.

Thyroid storm most frequently develops after infection, which triggers an escape from the regulation of thyrotoxicosis. Pneumonia, infections of the upper respiratory tract, enteric infections, or any infection may precipitate it. Notably, serum free T4 levels were elevated among patients with thyroid storm compared to those with uncomplicated thyrotoxicosis, However,  serum total T4 was not different between the two groups, implying that occurrences such as infections might reduce serum binding of T4 and result in an increased rise in free T4 for causing storms. A further frequent cause of thyroid storm is a hyperthyroid patient abruptly discontinuing their anti-thyroid medications.⁴

Systemic impact of T3 and T4 during thyroid storm

Cardiovascular system

Free T3 also activates the renin angiotensin-aldosterone axis, stimulating systemic vascular resistance, increased diastolic blood pressure, cardiac chronotropy, and ionotropy, eventually leading to an increase in cardiac output.⁵

Metabolic system

Hypermetabolism and Enhanced Energy Expenditure: Elevated levels of T3 and T4 speed up metabolism, resulting in enhanced energy expenditure24.

Weight Loss and Muscle Atrophy: Despite enhanced appetite, weight loss and muscle atrophy result from an excessive metabolic rate.²

Clinical manifestations and diagnosis

Symptoms and signs of thyroid storm

Thyroid storm is an overexpression of hyperthyroidism, with the presence of an acute precipitating factor. Fever, cardiovascular involvement (including tachycardia, heart failure, arrhythmia), central nervous system (CNS) manifestations, and gastrointestinal symptoms are prevalent. Fever of 104°F to 106°F with diaphoresis is an important presenting feature. Cardiovascular manifestations are tachycardia greater than 140 beats/minute, heart failure with pulmonary and peripheral edema, hypotension, arrhythmia, and cardiac arrest. CNS manifestations are agitation, delirium, anxiety, psychosis, or coma. Gastrointestinal symptoms such as nausea, vomiting, diarrhoea, abdominal pain, intestinal obstruction, and acute hepatic failure. Japanese research demonstrated CNS involvement as a poor prognosis indicator of augmented mortality. Physical findings on examination could be elevated temperature, tachycardia, orbitopathy, goitre, tremors in hands, warm and wet skin, hyperreflexia, systolic hypertension, and jaundice.¹

Differential diagnosis

Diagnosis is made on clinical grounds and comprises the standard diagnostic tests for thyrotoxicosis. History of hyperthyroidism or physical examination signs of an enlarged thyroid or evidence of hyperthyroid eye changes is useful in making the diagnosis. Central features include thyrotoxicosis, abnormal CNS function, fever, tachycardia (most commonly >130bpm), symptoms of the GI tract, and signs of impending or overt CHF. No characteristic laboratory abnormalities exist. Free T4 and, where available, free T3 must be measured. Observe that T3 may be significantly decreased in proportion to the severity of the disease, as part of the related "non-thyroidal illness syndrome". Suppression of TSH levels is expected. Electrolytes, blood urea nitrogen (BUN), blood glucose, liver function tests, and plasma cortisol must be checked. Although the diagnosis of thyroid storm is still mostly a clinical judgment, there are two systems for measuring the severity of hyperthyroidism and the probability of thyroid storm (Figures 1 and 2). Appreciate that these scoring systems are guidelines only, and clinical judgement remains important. Comparison data for the two diagnostic systems indicate a general agreement, but underdiagnosis using the Japanese criteria. Unfortunately, no single laboratory abnormality that aids in diagnosing thyroid storm.⁴

Treatment strategies

Thyroid storm treatment involves supportive treatments such as intravenous fluids, oxygen, cooling blankets, acetaminophen, and definitive treatment to treat hyperthyroidism. Any precipitating factors, such as infection, must be treated. Patients with thyroid storm need admission into intensive care with tight cardiac monitoring and ventilatory assistance when required.^1,13

Strategic treatment steps in detail

• Increased adrenergic tone therapy: Beta-blocker
• Treatment to decrease thyroid hormone production: Thionamide
• Treatment to decrease the release of thyroid hormone: Iodine solution
• Treatment to inhibit peripheral conversion of T4 to T3: Iodinated radiocontrast agent, glucocorticoid, PTU, propranolol
• Therapy to reduce enterohepatic recycling of thyroid hormone: Bile acid sequestrant

After initial supportive treatment, a beta-blocker must be initiated for any instance of a suspected thyroid storm. Propranolol 40 mg to 80 mg is usually administered every 4 to 6 hours. A loading dose of propylthiouracil (PTU) 500 mg to 1000 mg with subsequent administration of 250 mg every 4 hours or Methimazole (MMI) 20 mg every 4 to 6 hours must be administered. Propylthiouracil is preferred since it has a minimal additional effect, inhibiting the peripheral conversion of T4 to T3. One hour after giving propylthiouracil or methimazole, administer 5 drops of SSKI (supersaturated potassium iodide) orally every 6 hours. Always give thionamide before initiating iodine solution (SSKI) therapy. This avoids the impending rise in thyroid hormone production due to augmented iodine load from supersaturated potassium iodide. Hydrocortisone 100 mg IV q8 h (or dexamethasone 2 mg q6 h) should be initiated as well. Oral cholestyramine 4 grams q.i.d. may be initiated in severe cases if available. The precipitating causes should be searched for and appropriately treated. Aspirin use is to be avoided because aspirin has been reported to be associated with the risk of free thyroid hormone rise through interference with thyroid-binding protein.

In the first 24 hours of treatment, propylthiouracil decreases the T3 level by 45%, but methimazole drops the T3 level by only 10 % to 15%. Methimazole causes more rapid normalisation of serum T3 levels after a few weeks of treatment, and it has less hepatotoxicity compared to propylthiouracil. Thus, after initial stabilisation, we need to treat with methimazole, and if propylthiouracil was initiated at the start, it should be switched to methimazole subsequently. For patients who are unable to tolerate oral antithyroid medication, a liquid formulation (pharmacist may need to compound) can be administered as enemas. Occasionally, pharmacists may be able to prepare an IV formulation of antithyroid medication by dissolving the tablet.

Esmolol, a beta-blocker with short action, may be administered in an ICU environment at a loading dose of 250 mcg/kg to 500 mcg/kg and then 50 mcg/kg to -100 mcg/kg/minute. Cardiovascular beta-blockers such as atenolol or metoprolol must be selected in patients with reactive airway disease. In case of a contraindication for beta-blocker use, diltiazem may be used. If thionamide therapy is not indicated due to an allergic reaction, thyroidectomy is required following treatment with a beta-blocker, hydrocortisone, cholestyramine, and iodine solution. Plasmapheresis is the final option if all else fails.

After patients' clinical conditions are stabilised, the iodine solution must be discontinued, glucocorticoids may be tapered and discontinued, and beta-blockers must be regulated. Thionamide therapy should be titrated, and if propylthiouracil is initiated first, it should be converted to methimazole. Patients must be referred for curative therapy with radioiodine (RAI) therapy or thyroidectomy. Surgery can be necessary in patients with Graves' disease for hyperthyroidism treatment. These patients need pretreatment with beta-blockers, glucocorticoids, and iodine preparations. Surgery is typically performed after 5 to 7 days. As has been recently described, therapeutic plasma exchange may be beneficial in treatment-resistant cases that are unresponsive to standard treatments.¹

Conclusion

Management of thyroid storm includes supportive care such as intravenous (IV) fluids, oxygen, cooling blankets, acetaminophen, and certain interventions for the treatment of hyperthyroidism. Any precipitating causes, such as infection, should be addressed first. Thyroid storm patients need to be hospitalised in the intensive care unit with close cardiac monitoring and ventilatory support as indicated.

The pharmacist might have to compound a special solution of iodine that can be given intravenously. Radiocontrast dyes can be beneficial for some patients. Plasmapheresis can be life-saving in some instances. The nephrologist/haematologist should be consulted early in the management of these patients and be prepared for plasmapheresis. The team needs to communicate to prevent the high mortality of thyroid storms. The prognosis for patients with thyroid storm is guarded. It is based on the age of the patient, the number of organs, comorbidities, requirement of mechanical ventilation, renal failure, and response to treatment.¹