Endocrine and metabolic emergencies: thyroid storm

Abstract

Thyrotoxicosis is a common endocrine condition that may be secondary to a number of underlying processes. Thyroid storm (also known as thyroid or thyrotoxic crisis) represents the severe end of the spectrum of thyrotoxicosis and is characterized by compromised organ function. Whilst rare in the modern era, the mortality rate remains high, and prompt consideration of this endocrine emergency, with specific treatments, can improve outcomes.

Introduction

Thyroid storm (also known as thyroid or thyrotoxic crisis) is an uncommon condition reflecting an extreme physiological state within the spectrum of thyrotoxicosis. The condition is rare, however, mortality rates are high and may approach 10–20%. Thyroid storm is most commonly seen in the context of underlying Graves' hyperthyroidism but can complicate thyrotoxicosis of any aetiology. Clinical features represent manifestations of organ decompensation, with fever seen almost universally. Management is supportive with cooling and fluids, alongside measures taken to reduce thyroid hormone synthesis, hormone release and inhibition of the peripheral effects of excessive thyroid hormone. In addition, the management of thyroid storm should not disregard the search and appropriate treatment of any precipitating factors.

Pathophysiology

Normal thyroid function is maintained by endocrine interactions between the hypothalamus, anterior pituitary and thyroid gland [Matfin, 2009]. Iodide is transported across the basement membrane of the thyroid cells by an intrinsic membrane protein called the Na/I symporter (NIS). At the apical border, a second iodide transport protein called pendrin moves iodide into the colloid, where it is involved in hormono-genesis. Once inside the follicle, most of the iodide is oxidized by the enzyme thyroid peroxidase (TPO) in a reaction that facilitates combination with a tyrosine molecule to ultimately form thyroxine (T4) and triiodothyronine (T3). Thyroxine is the major thyroid hormone secreted into the circulation (90%, with T3 composing the other 10%). There is evidence that T3 is the active form of the hormone and that T4 is converted into T3 before it can act physiologically.

All of the major organs in the body are affected by altered levels of thyroid hormone. These actions are mainly mediated by T3. In the cell, T3 binds to a nuclear receptor, resulting in transcription of specific thyroid hormone response genes.

Thyrotoxicosis is the clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormone. In most instances, thyrotoxicosis is due to hyperactivity of the thyroid gland, or hyperthyroidism [Weetman, 2009]. Graves' disease, an autoimmune thyroid disease associated with thyroid-stimulating hormone (TSH)-receptor stimulating antibodies, is the most common form of thyrotoxicosis leading to thyroid storm, whilst other causes of thyrotoxicosis such as toxic multinodular goitre and toxic adenoma are less-frequent causes.

Thyroid storm is an acutely exaggerated manifestation of the thyrotoxic state. Many of the manifestations of thyrotoxicosis are related to the increase in oxygen consumption and use of metabolic fuels associated with the hypermetabolic state, as well as to the increase in sympathetic nervous system activity that occurs. The detailed pathophysiology of thyroid storm is not fully understood, but is thought to be related to increased numbers of beta₁-adrenergic receptors being exposed to increased catecholamine levels in states of stress. Displacement of free thyroid hormones by circulating inhibitors of binding in systemic illness (e.g. cytokines) may also play an important role.

Aetiology

Thyroid storm is most commonly associated with underlying Graves' disease, although has been reported with autonomous thyroid nodular disease. Traditionally, the condition was experienced frequently following thyroidectomy for thyrotoxic state (due to manipulation of the hyperactive thyroid gland during surgery), but modern treatments aimed at reducing preoperative thyroid output and hormone stores have dramatically reduced this complication.

Regardless of the underlying aetiology of thyrotoxicosis, the rare transition to a state of thyroid storm usually requires a second superimposed insult. Most commonly this is infection, although trauma, surgery, myocardial infarction (MI), diabetic ketoacidosis (DKA), pregnancy and parturition have been reported as causes. The administration of large quantities of exogenous iodine (such as with iodinated contrast agents or amiodarone) can provide the substrate for significant thyroid hormone production and secretion if there are areas of autonomous thyroid tissue within the gland (i.e. Jod-Basedow phenomenon). Abrupt cessation of thionamide therapy (i.e. antithyroid drugs such as pro-pylthiouracil [PTU], methimazole and carbima-zole) usually due to poor patient adherence or other issues has been associated with worsening thyrotoxicosis and rarely descent into thyroid storm. Biological agents such as interleukin-2 and α-interferon have been reported to induce thyroid storm when used to treat infectious disease, certain cancers and disorders of immune function.

Diagnostic considerations

The diagnosis of thyroid storm must be made on the basis of suspicious but nonspecific clinical findings. If the diagnosis of thyroid storm is strongly suspected, waiting for the results of tests may cause a critical delay in the initiation of effective life-saving treatment. Furthermore, biochemical markers of thyroid function are not discernably different from thyrotoxic states without thyroid storm. Serum thyroid hormone levels (i.e. free T3 [FT3] and free T4 [FT4]) are elevated with suppressed TSH levels (with the rare exceptions being states of thyroid hormone resistance or TSH secreting pituitary adenomas) confirming the diagnosis of thyrotoxicosis.

As noted previously, in most situations thyroid storm occurs in the context of a superimposed insult with an underlying predisposition to thyrotoxicosis. Therefore, an immediate search should begin for precipitating factors such as infection or other causes. Pregnancy should be excluded urgently in any woman of childbearing age with urinary or plasma assessment of human chorionic gonadotropin (HCG) levels and an ECG and cardiac enzymes should be procured to exclude acute coronary syndromes (ACS). Other investigations should be promptly performed as per clinical circumstances.

Clinical signs and features

Thyroid storm by definition represents the extreme in the spectrum of thyrotoxicosis where decompensation of organ function can occur. Therefore any of the classical signs and symptoms of a thyrotoxic state may be seen. The scoring system suggested by Burch and Wartofsky (Table 1) illustrates the typical features of end organ dysfunction that may be seen when thyrotoxicosis is severe enough as to be termed thyroid storm [Burch and Wartofsky, 1993]. Fever is almost universal (>39°C or 102°F) and when present in an unwell patient with known thyrotoxicosis, should prompt immediate consideration of thyroid storm. Associated profuse sweating contributes to excessive insensible water and electrolyte loss leading to dehydration. Cardiac decompensation, usually in the context of high-output cardiac failure, is manifested as evidence of peripheral oedema or pulmonary congestion with respiratory compromise when severe. Tachyarrhythmias are common and usually atrial in origin, unless there is a predisposition to ventricular arrhythmias secondary to primary cardiac disease. Neurological dysfunction may be severe enough as to cause profound delirium or psychosis. Liver dysfunction, secondary to either the presence of cardiac failure with hepatic congestion or hypoperfusion, or a direct effect of the excess thyroid hormone itself, is characterized by abnormal liver function biochemistry. Jaundice may be noted, and abdominal pain is often seen accompanied by nausea and vomiting, and diarrhoea.

Table 1.

Diagnostic criteria for thyroid storm.

Clinical feature		Scoring points
Thermoregulatory dysfunction
Temperature °F (°C)
99–99.9 (37.2–37.7)		5
100–100.9 (37.8–38.2)		10
101–101.9 (38.3–38.8)		15
102–102.9 (38.9–39.4)		20
103–103.9 (39.5–39.9)		25
≥104 (40)		30
Cardiovascular dysfunction
Tachycardia (beats per minute)
<99		0
99–109		5
110–119		10
120–129		15
130–139		20
≥140		25
Congestive heart failure
Absent		0
Mild (Pedal oedema)		5
Moderate (Bibasal rales or crackles)		10
Severe (Pulmonary oedema)		15
Atrial fibrillation
Absent		0
Present		10
Central nervous system dysfunction
Absent		0
Mild (Agitation)		10
Moderate (Delirium, psychosis, extreme lethargy)		20
Severe (Seizures, coma)		30
Gastrointestinal-hepatic dysfunction
Absent		0
Moderate (Diarrhoea, nausea/vomiting, abdominal pain)		10
Severe (Jaundice)		20
Previous episode of thyroid storm
Absent		0
Present		10
	Total
	>45	Highly likely thyroid storm
	25–44	Suggestive of impending storm
	<25	Unlikely to represent storm

Adapted from Burch and Wartofsky [1993].

Elderly patients often present atypically (so-called apathetic thyroid storm), with apathy, stupor, cardiac failure, coma and minimal signs of thyrotoxicosis.

Acute intervention

Once thyroid storm is recognized the patient should be managed in an appropriate location such as an Acute Medical Unit (AMU), high-dependency area or intensive care unit. As with all acute medical patients, prompt assessment and management of the ABCDEs should occur (i.e. airway; breathing; circulation; disability, i.e. conscious level; and examination).

General supportive care

Supportive care includes cooling measures, appropriate intravenous (IV) fluid resuscitation, electrolyte replacement and nutritional support. Antipyretics can be administered to relieve the distress of profound pyrexia, but salicylates (e.g. aspirin) should be avoided as they are associated with displacement of thyroid hormone binding from thyroid binding globulin (TBG) (Table 2). Tachyarrhythmias, if associated with haemodynamic instability (e.g. hypotension), should be managed as an urgent matter with cardioversion by defibrillation. Otherwise, appropriate antiar-rhythmic therapy and treatment of the underlying condition and complications would be warranted. Ventilatory support, either with noninvasive positive pressure ventilation (NIPPV) or intubated ventilation, should be performed if required based on arterial blood gas (ABG) analysis and other assessments. Occasionally patients will be severely agitated limiting further intervention, and in these situations a sedative such as haloperidol or a benzodiazepine can be given, mindful of the possible deleterious respiratory effects of these agents. Chlorpromazine 50–100 mg orally or intramuscular (IM) every 6 hours as needed, has the additional benefit of reducing body temperature through effects on central thermoregulation. Nutritional support is important (including vitamin replacement, e.g. thiamine) and includes close monitoring of glucose levels (as liver glycogen stores are depleted during thyroid storm).

Table 2.

Medical management of thyroid storm.

Medication	Dose	Notes
Inhibition of hormone synthesis
Propylthiouracil (PTU)	600 mg loading dose, followed by 200–250 mg PO q4–6h	Additional inhibition of peripheral deiodination However, recent warning from FDA regarding severe liver toxicity with PTU makes either carbimazole or methimazole first-choice thionamide
Carbimazole (or methimazole)	20–30 mg PO q4–6h
Inhibition of hormone release
SSKI (Potassium Iodide)	5 drops PO q6–8h	Administer at least 1 hour after thionamide
Lugol's Solution	5–10 drops PO q6–8h In UK, 1 ml PO q6h	Administer at least 1 hour after thionamide
Iapanoic Acid	1000 mg IV q8h for 24 h, followed by 500 mg bd	Administer at least 1 hour after thionamide, infrequently available
Inhibition of peripheral effects of excess thyroid hormone
Propranolol	1–2 mg/min IV q15min up to max 10 mg 40–80 mg PO q4–6h	IV dose initially if haemodynamically unstable
Esmolol	50 μg/kg/min IV—may increase by 50 μg/kg/min q4min as required to a max of 300 μg/kg/min.	Short acting
Metoprolol	100 mg PO q6h	Cardioselective; use if known airways disease
Diltiazem	60–90 mg PO q6–8h	Use if beta-blockers contraindicated IV formulation available
Supplementary management
Hydrocortisone	100 mg IV q6h
Dexamethasone	2 mg IV q6h
Acetaminophen (commonly known as paracetamol or Tylenol)	1 g PO q6h	Care if significant hepatic dysfunction
Additional therapies
Lithium Carbonate	300 mg PO q8h	Monitor for toxicity
Potassium perchlorate	1 g PO od	Associated with aplastic anaemia and nephritic syndrome
Cholestyramine	4g PO q6–12h

PO, oral; IV, intravenous; q4–6h, every 4–6 hours; q6h, every 6 hours; q8h, every 8 hours; q4min, every 4 minutes; q15min, every 15 minutes; od, once daily; bd, twice daily.

Thyroid-specific therapy

The immediate goals when treating thyroid storm are to decrease thyroid hormone synthesis, prevent thyroid hormone release, decrease peripheral action of circulating thyroid hormone to reduce heart rate and support the circulation, and to treat the precipitating condition [Nayak and Burman, 2006]. The therapeutic options for thyroid storm are the same as those for uncomplicated thyrotoxicosis, except that the drugs are given in higher doses and more frequently. When treating thyroid storm, one should consider the five ‘Bs’: Block synthesis (i.e. antithyroid drugs); Block release (i.e. iodine); Block T4 into T3 conversion (i.e. high-dose propylthiouracil [PTU], propranolol, corticosteroid and, rarely, amiodarone); Beta-blocker; and Block enterohepatic circulation (i.e. cholestyramine).

An antithyroid drug (i.e. thionamide) should be administered immediately to prevent the formation of further thyroid hormone by inhibiting the iodination of tyrosine residues by TPO enzymes. PTU or carbimazole (or methimazole) can be used, but PTU was traditionally preferred because of its more rapid onset of action and the additional benefit of inhibition of peripheral deiodinase enzyme-mediated conversion of T4 into T3. PTU should be administered orally or via a nasogastric (NG) tube in the unresponsive patient with a loading dose of 600 mg followed by a dose of 200–250 mg every 4–6 hours. Carbimazole (or methimazole) is administered at a dose of 20–30 mg every 4–6 hours. Both agents can be administered rectally if needed. However, the US Food and Drug Administration (FDA) have recently released an advisory on PTU for its liver toxicity potential [Food and Drug Administration, 2010]. As no head-to-head trial has demonstrated clear superiority of PTU over either carbimazole or methimazole in thyroid storm (or thyrotoxicosis, where the latter agents are generally preferred over PTU), many experts now recommend using either carbimazole or methimazole in all thyrotoxic patients (unless other compelling reasons exist for using PTU such as pregnancy), and achieving T4 into T3 conversion inhibition solely with beta-blockers and corticosteroids [Food and Drug Administration, 2010; Malozowski and Chiesa, 2010].

Iodine should be administered at least 1 hour after the thionamide to block the release of preformed thyroid hormone. This apparent paradox makes use of the acute Wolff— Chaikoff effect, whereby large doses of iodine suppress thyroid hormone release. The effect lasts for up to 2 weeks, because escape from this effect occurs and is therefore unsuitable as a long-term therapeutic option. The thionamide should be administered prior to iodine administration so as to prevent undesired tyrosine residue iodination and enrichment of thyroid hormone stores. The minimal time required between thionamide administration and iodine treatment is debated with 1–6 hours commonly prescribed. Iodine is administered in the various formulations, including saturated solution of potassium iodide (SSKI) 5 drops orally every 6–8 hours (equalling 250 mg iodide with 1 drop containing 50 mg iodide). Alternatively, 5–10 drops of Lugol's solution orally every 6–8 hours can be used. In the UK, many experts prescribe 1 ml of Lugol's solution orally every 6 hours. Iapanoic acid, an iodinated contrast agent, although rarely available now, is effective at a dose of 1g IV 8-hourly for the first 24 hours of treatment followed by 500 mg twice daily.

Beta-blockade should be instigated immediately (unless contraindicated) so as to block the adrenergic consequences of thyroid hormone excess. Propranolol (i.e. non-cardiac specific beta-blocker) has traditionally been used and has the advantage of being suitable for IV administration and is also relatively short acting. IV propranolol at a dose of 1–2 mg/min can be administered every 15 minutes until adequate haemodynamic control is achieved or a maximum dose of 10 mg is used, followed by 40–80 mg orally every 4–6 hours. Caution is warranted in patients with heart failure, although beta-blockade may be beneficial when tachycardia is a significant precipitant to decompensated cardiac function. Esmolol, a short-acting beta-blocker, can be used as an alternative if a deleterious cardiac effect is anticipated and is given IV at a rate of 50 μg/kg/min and increased as per response. Contraindications to propranolol use include a history of asthma or reversible chronic obstructive pulmonary disease (COPD), and a cardiose-lective beta-blocker such as metoprolol or atenolol could be used in these patients. Alternatively, the calcium-channel blocker, diltiazem can be used at a dose of 60–90 mg orally 6–8-hourly or the appropriate dose by IV. If anticoagulation is required for atrial fibrillation (or other indications), thyrotoxic patients are very sensitive to warfarin and should be monitored closely.

Corticosteroids inhibit peripheral conversion of T4 into T3 and have been shown to improve outcomes in patients with thyroid storm. Adrenal axis dysfunction in the context of thyrotoxicosis of any degree is documented, and responds to exogenous steroid therapy. Hydrocortisone 100 mg 6-hourly should be administered IV or IM and continued until resolution of the thyroid storm. Alternatively, dexamethasone 2 mg IV every 6 hours can be used. Treatment should be tapered appropriately based on the required duration of steroid therapy.

Lithium carbonate, at a dose of 300 mg every 8 hours, can be used when there is a contraindication or previous toxicity to thionamide therapy. Lithium inhibits thyroid hormone release from the gland and reduces iodination of tyrosine residues, but its use is complicated by the toxicity that can ensue. Potassium perchlorate competitively inhibits iodide transport into the thyrocyte but has traditionally been associated with aplastic anaemia and nephritic syndrome. Several studies however have demonstrated its use when used over short periods in the treatment of amiodarone-induced thyrotoxicosis [Erdogan et al. 2003]. A suggested dose is 1g daily and, similarly to iodide therapy, should be combined with a thionamide. Cholestyramine 4g orally two to four times each day has been used in the management of thyrotoxicosis due to reduced reabsorption of metabolized thyroid hormone from the enterohepatic circulation [Tsai et al. 2005].

Thyroidectomy is occasionally employed in the management of thyroid storm refractory to medication [Nayak and Burman, 2006], but is associated with a risk of storm exacerbation if preoperative thyroid hormone levels are high.

Treatment of precipitating illness

Management of thyroid storm should not disregard the search for and treatment of precipitating factors. An active search should be made for infection and antibiotics chosen on the basis of likely pathogens or microbial cultures. Other likely precipitants such as trauma, MI, DKA, and other underlying processes should be managed as per standard care.

Maintenance therapy

Through adequate rehydration, repletion of electrolytes, treatment of comorbid disease such as infection and the use of specific therapies (antithyroid drugs, iodine, beta-blockers and corticosteroids), a marked improvement in thyroid storm usually occurs within 24–72 hours. Once haemodynamic, thermoregulatory and neurological stability has been achieved attention should switch to maintenance therapy. Escape from the Wollf—Chaikoff effect is usually seen between 10 and 14 days after commencement of iodine therapy, and therefore continuation of iodine therapy beyond this point is unlikely to be beneficial and could exacerbate the situation. Furthermore, future treatment with radioactive iodine (RAI) is delayed if thyroid iodine stores are saturated. Corticosteroid therapy should be stopped as soon as possible, but beta-blockade should be used whilst the patient remains thyrotoxic.

The antithyroid treatment should be continued until euthyroidism is achieved, at which point a final decision regarding antithyroid drugs, surgery or RAI therapy can be made.

Emerging treatments

Thyroid storm can occasionally be refractory despite the above measures, and other treatment options should be considered. Plasmapharesis, with removal of thyroid hormone, has been used successfully both in the thyrotoxic state and to prepare those with thyrotoxicosis for surgery [Ezer et al. 2009]. However, plasmapharesis needs to be repeated several times as only about 20% of the T4 pool and even less of the T3 pool can be removed each session. Charcoal haemoperfusion has also been demonstrated to be useful in thyrotoxic states [Kreisner et al. 2010]. There is great interest in the role of biological agents in treatment of immune-mediated thyrotoxic states. Rituximab (an anti-CD20 monoclonal antibody which depletes B lymphocytes in circulation), and various other emerging therapies have shown promise in the treatment of Graves' opthalmopathy, but the role of these agents in the management of the thyrotoxic state is less clear [Abraham and Acharya, 2010; Bahn, 2010].

Conclusions

Thyroid storm is a rare endocrine emergency but is associated with high mortality. It most commonly occurs in the context of underlying Graves' thyrotoxicosis, but is frequently precipitated by a secondary event such as infection or MI. Prompt recognition of the condition with timely intervention is crucial, and management of the patient in an AMU, high-dependency or intensive care unit is essential. Treatment is based on immediate blockade of thyroid hormone synthesis, prevention of the release of further thyroid hormone from thyroid stores, and alleviation of the peripheral effects of thyroid hormone excess. A search for a precipitant for the thyroid storm is critical and should be treated promptly. Maintenance therapy takes into account disease-specific factors and patient preference, with measures taken to prevent a recurrence of thyroid storm.