Thyroid Storm

Etiology

Superimposed precipitating factors cause thyroid storms in patients with diagnosed or undiagnosed hyperthyroidism. It is more common with Graves disease but can occur with other etiologies of hyperthyroidism, such as toxic multinodular goiter and toxic thyroid adenoma.[2] The precipitating factors are:

• Abrupt discontinuation of antithyroid medicine
• Thyroid surgery
• Non-thyroid surgery
• Trauma
• Acute illnesses like infections, including COVID-19, diabetic ketoacidosis, acute myocardial infarction, cardiovascular accident, cardiac failure, and drug reactions[3]
• Parturition
• Recent use of Iodinated contrast medium
• Radioiodine therapy (rare)
• Burns
• Stroke or traumatic brain injury[4]
• Medication side effects, eg, amiodarone, anesthetics, salicylates[5]
• Hyperemesis gravidarum in pregnancy[6]

Epidemiology

It is a rare presentation of hyperthyroidism. Thyroid storm accounts for about 1% to 2% of admissions for hyperthyroidism. As per the United States survey, the incidence of storms ranged from 0.57 to 0.76 cases per 100,000 per year in the normal population and 4.8 to 5.6 cases per 100,000 per year in hospitalized patients.[7] 

Per the Japanese National Survey, the incidence of thyroid storms was 0.2 per 100,000 people per year, about 0.22% of all thyrotoxicosis patients and 5.4% of hospitalized thyrotoxicosis patients. The average age of people with thyroid storm was 42 to 43 years, similar to those with thyrotoxicosis without thyroid storm. The male-to-female ratio for the incidence of thyroid storms was about 1:3, similar to that of thyrotoxicosis without storm groups.[8] 

Pathophysiology

The pathophysiological basis for the precipitation of thyroid storms in patients with thyrotoxicosis is unclear. But, as mentioned above, a precipitating factor is always required to cause a thyroid storm. Several hypotheses have been proposed. One theory suggests the incidence of thyroid storm is due to the rapid increase in thyroid hormone levels rather than the absolute hormone level that occurs during thyroid surgery, following radioactive iodine treatment, after sudden discontinuation of the antithyroid drug, or after administration of the large dose of iodine in contrast studies. The hyperactivity of the sympathetic nervous system with increased response to catecholamine and an increased cellular response to thyroid hormone during acute stress or infections, causing cytokines release and altered immunological disturbances, are other possible mechanisms of thyroid storm. Most studies have failed to relate higher thyroid hormone levels as a cause of thyroid storm, except for the study by Brooks and others, which reported higher free thyroid hormone among the patients with thyroid storm.[9] In other words, the degree of thyroid hormone level is not directly related to a higher incidence of thyroid storm.[2]

The clinical features are due to the exaggerated effects of the thyroid hormone. There is an intense metabolic activity that increases oxygen requirements. The resulting tachycardia to meet the oxygen requirements can induce heart failure and predispose the patient to arrhythmias. Similarly, CNS symptoms include irritability, seizures, delirium, and eventually coma.

Histopathology

Histopathology depends on the cause of the thyroid storm. The most common cause of Graves disease is diffuse follicular hyperplasia, along with increased thyroid receptor antibodies and increased vascularization of the tissue. If it is a tumor-originated storm, malignant cells infiltrate and destroy the thyroid tissue and rupture the follicles.[10][11]

Toxicokinetics

Toxicokinetics includes the following precipitating factors:

• Severe emotional distress
• Stroke
• Exercise
• Pulmonary embolism

History and Physical

Presentation of thyroid storm is an exaggerated manifestation 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 common. Fever of 104° F to 106°F with diaphoresis is a key presenting feature. Cardiovascular manifestations include tachycardia of more than 140 HR/minute, heart failure with pulmonary and peripheral edema, hypotension, arrhythmia, and death from cardiac arrest. CNS involvement includes agitation, delirium, anxiety, psychosis, or coma. Gastrointestinal (GI) symptoms include nausea, vomiting, diarrhea, abdominal pain, intestinal obstruction, and acute hepatic failure.[12] A Japanese study found CNS involvement to be a poor prognostic factor for increased mortality.[8] Physical examination findings may include high temperature, tachycardia, orbitopathy, goiter, hand tremors, moist and warm skin, hyperreflexia, systolic hypertension, and jaundice.

Evaluation

The diagnosis of thyroid storm needs clinical suspicion based on the presentation mentioned above in a patient with hyperthyroidism or suspected hyperthyroidism. One should not wait for lab results before starting treatment. Thyroid function tests can be obtained, which usually show high FT4/FT3 and low TSH. It is not necessary to have a very high level of thyroid hormone to cause a thyroid storm. Other lab abnormalities may include hypercalcemia, hyperglycemia (due to inhibition of insulin release and increased glycogenolysis), abnormal LFTs, and high or low white blood cell (WBC) count.

Burch-Wartofsky Point Scale (BWPS)[2]

In 1993, the following scoring system for the diagnosis of thyroid storm was introduced:

• Temperature: 5 points per 1 F above 99 F (maximum 30 points)
• CNS dysfunction: 10 points for mild (agitation), 20 for moderate (delirium, psychosis, or extreme lethargy), and 30 for severe (seizure or coma)
• Tachycardia: 5 (99-109), 10 (110 -119), 15 (120 -129), 20 (130 -139) and 25 (greater than 140)
• Presence of atrial fibrillation:10
• Heart failure: 5 for mild (pedal edema), 10 for moderate (bi-basilar rales), 15 for severe (pulmonary edema)
• GI dysfunction: 10 for moderate (diarrhea, nausea/vomiting, or abdominal pain) and 20 for severe (unexplained jaundice)
• Presence of Precipitating factor: 10 points 

Diagnosis: A score of more than 45 highly suggests thyroid storm, 25 to 44 supports the diagnosis, and less than 25 makes the diagnosis unlikely.

The Japanese Thyroid Association (JTA) 

This is a different scoring system based on similar clinical findings.[8] Thyrotoxicosis (elevated FT3 and/or FT4) is a prerequisite, and it requires various combinations of the following symptoms:

• CNS manifestation (restlessness, delirium, psychosis/mental aberration, lethargy/somnolence, coma)
• Fever (38 C/100.4 F or greater)
• Tachycardia (130/min or higher)
• CHF (pulmonary edema, rales, cardiogenic shock, or NYHA class IV)
• GI/Hepatic Manifestation (Nausea, vomiting, diarrhea, total Bilirubin 3 mg/dl or more

Diagnosis

Definite Thyroid Storm (TS1): Thyrotoxicosis (elevated FT3 and/or FT4) plus

• At least 1 CNS manifestation plus 1 or more other symptoms (fever, tachycardia, CHF, GI/Hepatic) ‘OR’ A combination of at least 3 features among fever, GI/Hepatic, CHF, or tachycardia

Suspected Thyroid Storm (TS2): Thyrotoxicosis (elevated FT3 and/or FT4) plus

• A combination of at least 2 features among tachycardia, CHF, GI/Hepatic, Fever ‘OR’ A patient with h/o thyroid disease, presence of goiter and exophthalmos who meets criteria for TS1 but TFTs not available 

These scoring systems are just guidelines. The actual diagnosis is based on clinical judgment. Based on the BWPS scoring system, a score of 45 or more is more sensitive but less specific than JTA scoring systems TS1 or TS2 to detect thyroid storm cases. A BWPS score of 25 to 45 may suggest an impending storm. A chest X-ray may help assess heart failure, and a head CT may help exclude a neurological cause in some patients. An ECG is often done to monitor for arrhythmias.

Treatment / Management

Treatment of thyroid storm consists of supportive measures like intravenous (IV) fluids, oxygen, cooling blankets, acetaminophen, and specific measures to treat hyperthyroidism. If any precipitating factors, for example, infection, are present, that needs to be addressed. Patients with thyroid storm must be admitted to the intensive care unit with close cardiac monitoring and ventilatory support if needed.[1][13]

Specific Strategic Steps for Treatment

1. Therapy to control increased adrenergic tone: Beta-blocker
2. Therapy to reduce thyroid hormone synthesis: Thionamide
3. Therapy to reduce the release of thyroid hormone: Iodine solution
4. Therapy to block peripheral conversion of T4 to T3: Iodinated radiocontrast agent, glucocorticoid, PTU, propranolol
5. Therapy to reduce enterohepatic recycling of thyroid hormone: Bile acid sequestrant

After initial supportive measures, a beta-blocker should be started for any case of a suspected thyroid storm. Typically, propranolol 40 mg to 80 mg is given every 4 to 6 hours. Then, a loading dose of propylthiouracil (PTU) 500 mg to 1000 mg followed by 250 mg every 4 hours or Methimazole (MMI) 20 mg every 4 to 6 hours should be given. Propylthiouracil is favored because it has a small additional effect blocking the peripheral conversion of T4 to T3. An hour after administering propylthiouracil or methimazole, give 5 drops of SSKI (supersaturated potassium iodide) by mouth every 6 hours. Always administer thionamide before starting iodine solution (SSKI) therapy.[14][15][16] This prevents the imminent increase in thyroid hormone synthesis due to increased iodine load from super saturated potassium iodide. Hydrocortisone 100 mg IV every 8 hours (or dexamethasone 2 mg every 6 hours) should also be started. Oral cholestyramine 4 grams 4 times daily can be started for severe cases if available. One should look for precipitating factors and treat them accordingly. Aspirin should be avoided due to its potential risk of increasing free thyroid hormone levels by interfering 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 normalization of serum T3 levels after a few weeks of treatment, and it has less hepatotoxicity compared to propylthiouracil. Therefore, after initial stabilization, we should treat with methimazole, and if propylthiouracil was started at the beginning, it should be changed to methimazole later. For patients who cannot take oral antithyroid medicine, liquid preparation (pharmacist may have to compound) can be given as enemas. Sometimes, pharmacists can prepare an IV form of antithyroid medicine by dissolving the tablet.[17][18][19](B3)

Esmolol, a short-acting beta-blocker, can be given in an ICU setting at a loading dose of 250 mcg/kg to 500 mcg/kg followed by 50 mcg/kg to -100 mcg/kg/minute. Cardiovascular beta-blockers like atenolol or metoprolol should be chosen for patients with reactive airway disease. If there is a contraindication for using beta-blockers, diltiazem is an alternative. If thionamide therapy is contraindicated because of an allergic reaction, thyroidectomy is needed after treatment with a beta-blocker, hydrocortisone, cholestyramine, and iodine solution. Plasmapheresis is the last resort if all other measures fail.

Once patients’ clinical conditions improve, the iodine solution should be stopped, glucocorticoids can be tapered and stopped, and beta-blockers should be adjusted. Thionamide therapy should be titrated, and if propylthiouracil is used initially, it should be switched to methimazole. Patients should be recommended for definitive treatment with radioiodine (RAI) therapy or thyroidectomy. Surgery may be required in patients with Graves disease to treat hyperthyroidism. These patients must be pretreated with beta-blockers, glucocorticoids, and iodine formulas. Surgery is usually done after 5 to 7 days. As recently reported, therapeutic plasma exchange is potentially helpful in resistant cases that do not respond to conventional treatments.[20][17](B3)

Differential Diagnosis

Thyroid storm should be differentiated from other diseases with similar symptoms and signs.[21] Fever is the most common presentation of multiple conditions; therefore, it can be misdiagnosed. The differential diagnoses include:

• Sepsis
• Infection
• Psychosis
• Cocaine use
• Pheochromocytoma
• Neuroleptic malignant syndrome
• Hyperthermia

Surgical Oncology

If toxic adenoma or multinodular goiter is causing this disease, then surgical resection and radioactive iodine ablation are the mainstays of treatment. Thyroidectomy is preferred if a patient has compressive symptoms. Patients who refuse ablation or have contraindications to surgery can be treated with long-term antithyroid medicines.[22] Grave's disease with intrathoracic mass causes severe compressive symptoms, and thyroidectomy is preferred in these cases. Thyroidectomy has other adverse effects, like recurrent laryngeal nerve damage and hypoparathyroidism.[23][24]

Radiation Oncology

Radioiodine-131 (I) therapy is helpful in hyperfunctioning nodules, but the risk of hypothyroidism is 60% after a 20-year follow-up in a retrospective study.[25] Other factors increasing the risk of hypothyroidism in these patients are:

• Methimazole therapy
• Age

Pertinent Studies and Ongoing Trials

Randomized trials are still being processed to determine the efficacy and safety of more medicines.[24]

Toxicity and Adverse Effect Management

Complete surgical resection of the thyroid and radioiodine ablation can cause hypothyroidism. So, these patients need lifetime exogenous thyroxine therapy and should be monitored for hyperthyroidism. Dose adjustments by endocrinologists are crucial as the patient is at risk of both hypothyroidism and hyperthyroidism.[26] Antithyroid drugs, MMI, and PTU cause agranulocytosis. Patients on these drugs should be monitored with CBC, especially white cell count. If the white cell count starts decreasing, these drugs should be discontinued due to the increased risk of infection.[27] Other toxicities can cause hepatic failure, cholestasis, rash, gastrointestinal toxicity, and musculoskeletal pains.[28][29]

Prognosis

A thyroid storm is a true medical emergency that is fatal if left untreated. The cause of death may be heart failure, arrhythmias, or multiple organ failure. However, with treatment, most patients see an improvement within 24 hours. Risk factors for poor prognosis include:

• Advanced age
• Neurological deficits on admission[12]
• Failure to use beta-blockers and antithyroid medications
• Need for dialysis and/or mechanical ventilation

Complications

If left untreated, thyroid storm can lead to the following complications:

• Arrhythmias
• High-output cardiac failure
• Seizures, delirium, coma
• Elevated liver enzymes, jaundice
• Abdominal cramps, vomiting, diarrhea
• Atrial fibrillation and thromboembolism[30]