**5. Clinical features and diagnosis**

The diagnosis of thyroid storm is purely clinical, and if suspected, treatment should be initiated simultaneously without any delay. Clinical picture comprises of an exaggerated feature of hyperthyroidism accompanied by manifestations of multiorgan dysfunction, with the presence of an acute precipitating factor [46]. Symptoms, signs, and clinical features are listed in **Tables 2–4** respectively.

Hyperpyrexia (104–106°F) with diaphoresis is the key presenting feature. High fever induces profuse sweating and leads to insensible fluid losses, which is a differentiating feature between thyroid storm and thyrotoxicosis [1]. Cardiovascular manifestations include palpitations, tachycardia, exercise intolerance, dyspnea on exertion, widened pulse pressure, myocardial ischemia, and atrial fibrillation. Heart rate > 140/min is out of proportion to the underlying illness [47]. The increased cardiac output and tachyarrhythmia may progress to cardiogenic shock [48, 49]. The central nervous system (CNS) manifestations include agitation, delirium, confusion, stupor, obtundation, and coma. CNS involvement is a poor prognostic factor for mortality [3]. Gastrointestinal (GI) symptoms include nausea, vomiting, diarrhea, abdominal pain, intestinal obstruction, and acute hepatic failure [29]. Vomiting and diarrhea add to significant fluid loss. Liver dysfunction and hepatomegaly are due to hepatic congestion and hypoperfusion, or directly due to hyperthyroidism [17]. Jaundice is a poor prognostic indicator [50]. Unusual presentations include acute abdomen, status epilepticus, rhabdomyolysis, hypoglycemia, lactic acidosis, and disseminated intravascular coagulation [51–54].

Various clinical entities that mimic thyroid storm exist, which confounds the existent diagnostic dilemma, namely, peritonitis [55], sepsis/septic shock [56], heat stroke [57], malignant hyperthermia [58], acute pulmonary edema [59], neuroleptic malignant syndrome [60], and serotonin syndrome [61]. The mimics of thyroid storm are listed in **Table 5**.


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**Figure 1.**

*Burch and Wartofsky's diagnostic criteria for thyroid storm [28].*

*Thyroid Storm: Clinical Manifestation, Pathophysiology, and Treatment*

*DOI: http://dx.doi.org/10.5772/intechopen.89620*

Progressively increasing to lethal levels within 24–48 h

Diarrhea, nausea, vomiting, pain abdomen, unexplained jaundice

Warm skin, flushing, profuse diaphoresis

Agitation, delirium, psychosis, coma

Tachycardia >140 beats/min, atrial fibrillation

Goiter and exophthalmos ±

*Clinical features of thyroid storm.*

Abrupt onset Fever—high grade

**Table 4.**

Peritonitis

Sepsis/septic shock Heat stroke

Malignant hyperthermia Acute pulmonary edema

Serotonin syndrome

*Mimics of thyroid storm.*

Peritonitis

**Table 5.**

Neuroleptic malignant syndrome

**Table 3.** *Signs of thyroid storm.* Diarrhea, nausea, vomiting, pain abdomen, unexplained jaundice


*Goiter - Causes and Treatment*

intravascular coagulation [51–54].

storm are listed in **Table 5**.

Palpitations

Diarrhea Polyuria

**Table 2.**

Tremor Goiter

Fatigue and weakness

*Symptoms of thyroid storm.*

Warm, moist skin

Lid retraction or lag Gynecomastia

*Signs of thyroid storm.*

Hyperactivity, irritability, dysphoria Heat intolerance and sweating

Weight loss with increased appetite

Oligomenorrhea, loss of libido

Tachycardia, atrial fibrillation

Muscle weakness, proximal myopathy

Signs of ophthalmopathy and dermopathy specific for Grave's disease

of an exaggerated feature of hyperthyroidism accompanied by manifestations of multiorgan dysfunction, with the presence of an acute precipitating factor [46]. Symptoms, signs, and clinical features are listed in **Tables 2–4** respectively.

Hyperpyrexia (104–106°F) with diaphoresis is the key presenting feature. High fever induces profuse sweating and leads to insensible fluid losses, which is a differentiating feature between thyroid storm and thyrotoxicosis [1].

Cardiovascular manifestations include palpitations, tachycardia, exercise intolerance, dyspnea on exertion, widened pulse pressure, myocardial ischemia, and atrial fibrillation. Heart rate > 140/min is out of proportion to the underlying illness [47]. The increased cardiac output and tachyarrhythmia may progress to cardiogenic shock [48, 49]. The central nervous system (CNS) manifestations include agitation, delirium, confusion, stupor, obtundation, and coma. CNS involvement is a poor prognostic factor for mortality [3]. Gastrointestinal (GI) symptoms include nausea, vomiting, diarrhea, abdominal pain, intestinal obstruction, and acute hepatic failure [29]. Vomiting and diarrhea add to significant fluid loss. Liver dysfunction and hepatomegaly are due to hepatic congestion and hypoperfusion, or directly due to hyperthyroidism [17]. Jaundice is a poor prognostic indicator [50]. Unusual presentations include acute abdomen, status epilepticus, rhabdomyolysis, hypoglycemia, lactic acidosis, and disseminated

Various clinical entities that mimic thyroid storm exist, which confounds the existent diagnostic dilemma, namely, peritonitis [55], sepsis/septic shock [56], heat stroke [57], malignant hyperthermia [58], acute pulmonary edema [59], neuroleptic malignant syndrome [60], and serotonin syndrome [61]. The mimics of thyroid

**118**

**Table 3.**

**Table 4.** *Clinical features of thyroid storm.*


#### **Table 5.**

*Mimics of thyroid storm.*


#### **Figure 1.**

*Burch and Wartofsky's diagnostic criteria for thyroid storm [28].*

Burch and Wartofsky [28] assigned a numerical score to each of the different signs and symptoms of thyroid storm to establish a diagnostic criterion based on the total score calculated as shown in **Figure 1**. Japan Thyroid Association surveyed the incidence of thyroid storm in Japan and formulated population-specific diagnostic criteria based on the presence of the classic organ system manifestations as shown in **Table 6**.

Both Burch and Wartofsky score (BWS) and the Japan Thyroid Association (JTA) guidelines are acceptable. However, in one study, BWS ≥45 was reported to


#### **Exclusion and provisions**

Cases are excluded when clear cut underlying pathology is present for the following symptoms: fever (e.g., pneumonia and malignant hyperthermia), impaired consciousness (e.g., psychiatric disorders and cerebrovascular disease), heart failure (e.g., acute myocardial infarction), and liver disorders (e.g., viral hepatitis and acute liver failure). Therefore, it is difficult to determine whether the symptom is caused by TS or is simply a manifestation of an underlying disease; the symptom should be regarded as being due to a TS that is caused by these precipitating factors. Clinical judgment in this matter is required.

**121**

*Thyroid Storm: Clinical Manifestation, Pathophysiology, and Treatment*

inhibition of insulin release and increased gluconeogenesis [64].

**6.1 Inhibiting new thyroid hormone synthesis**

be more sensitive than JTA guidelines in detecting patients with storm [62, 63]. It is recommended to use both criteria to increase the accuracy of the diagnosis of

Although diagnosis of thyroid storm is clinical, laboratory values aid in the diagnosis and treatment. A complete workup including estimation of TSH, free T4, and free T3 should be done in the intensive care unit (ICU) setting. Leukocytosis indicates infection (commonest factor for storm). Elevated blood urea nitrogen [3] and liver function abnormalities with elevation in the transaminases and hyperbilirubinemia indicate irreversible abnormalities. Hypercalcemia may be found due to the high bone resorption that accompanies hyperthyroidism and can exacerbate dehydration. Hyperglycemia is due to a combination of increased catecholamine

The treatment of thyroid storm should be initiated as soon as the diagnosis is suspected. Patients should be triaged to an intensive care setting for close monitoring and aggressive treatment. A multidisciplinary team approach is important in order to successfully offer the patient all possible therapeutic options. Immediate goals of thyroid-specific therapy should be targeted to decrease thyroid hormone synthesis and release, decrease peripheral action of thyroid hormone, and treat the

The first-line therapy in treating thyroid storm consists of inhibiting new thyroid hormone production. This approach most commonly utilizes thionamides which includes thiouracils (PTU) and imidazoles (methimazole and carbimazole). They inhibit thyroid peroxidase (TPO), thereby inhibiting formation of T3 and T4 from thyroglobulin [65]. Both methimazole and PTU are used but PTU is favored during thyroid storm due to its additional benefit over carbimazole and methimazole, namely rapid onset of action and inhibition of peripheral conversion of T4 to T3 mediated by peripheral deiodinase. In addition, PTU can be safely used in

The dose of PTU is 600–1500 mg/day in divided doses every 4–6 h [27, 28, 66] with a loading dose of 600 mg. Dose of methimazole is 80–120 mg daily in divided doses every 4–6 h [27, 28, 66]. The American Association of Clinical Endocrinologist/ American Thyroid Association guidelines recommend 500–1000 mg loading dose of PTU followed by 250 mg every 4 h and 60–80 mg/day of methimazole in divided doses [67]. Routes of administration include intravenous, enteral, and per rectal as suppository or retention enema. PTU is relatively insoluble at physiologic pH, therefore its intravenous preparation and administration are difficult. Intravenous methimazole can be prepared easily by dissolving methimazole powder in normal

Nonradioactive iodine also decreases new thyroid hormone synthesis. It is due to the inhibition of organic binding of iodide to thyroglobulin as plasma iodide levels reach a critical threshold, a phenomenon known as the Wolff-Chaikoff effect. The effect is transient, lasting for about 50 h, as the thyroid eventually escapes/ adapts to prolonged iodide excess [69]. Inorganic iodine may be given orally as a saturated solution of potassium iodide (SSKI) by administering five drops (0.25 mL or 250 mg) every 6 h or as Lugol's solution (eight drops given every 6 h) [28, 67]. Routes can be enteral, rectal, or intravenous. SSKI is prepared for rectal dosing by

*DOI: http://dx.doi.org/10.5772/intechopen.89620*

thyroid storm [44, 63].

**6. Management**

precipitating cause.

pregnancy.

saline [68].

*TS1, "Definite" TS; TS2, "Suspected" TS. Adapted from: Akamizu et al. [3].*

### **Table 6.**

*The diagnostic criteria for thyroid storm (TS) of the Japan Thyroid Association.*

*Thyroid Storm: Clinical Manifestation, Pathophysiology, and Treatment DOI: http://dx.doi.org/10.5772/intechopen.89620*

be more sensitive than JTA guidelines in detecting patients with storm [62, 63]. It is recommended to use both criteria to increase the accuracy of the diagnosis of thyroid storm [44, 63].

Although diagnosis of thyroid storm is clinical, laboratory values aid in the diagnosis and treatment. A complete workup including estimation of TSH, free T4, and free T3 should be done in the intensive care unit (ICU) setting. Leukocytosis indicates infection (commonest factor for storm). Elevated blood urea nitrogen [3] and liver function abnormalities with elevation in the transaminases and hyperbilirubinemia indicate irreversible abnormalities. Hypercalcemia may be found due to the high bone resorption that accompanies hyperthyroidism and can exacerbate dehydration. Hyperglycemia is due to a combination of increased catecholamine inhibition of insulin release and increased gluconeogenesis [64].

### **6. Management**

*Goiter - Causes and Treatment*

**Prerequisite for diagnosis**

Symptoms

2. Fever: ≥ 38°C

level ≥ 3.0 mg/dL **Diagnosis**

**Exclusion and provisions**

*TS1, "Definite" TS; TS2, "Suspected" TS. Adapted from: Akamizu et al. [3].*

Burch and Wartofsky [28] assigned a numerical score to each of the different signs and symptoms of thyroid storm to establish a diagnostic criterion based on the total score calculated as shown in **Figure 1**. Japan Thyroid Association surveyed the incidence of thyroid storm in Japan and formulated population-specific diagnostic criteria based on the presence of the classic organ system manifestations as shown in **Table 6**. Both Burch and Wartofsky score (BWS) and the Japan Thyroid Association (JTA) guidelines are acceptable. However, in one study, BWS ≥45 was reported to

Presence of thyrotoxicosis with elevated levels of free triiodothyronine (FT3) or free thyroxine (FT4)

1. Central nervous system (CNS) manifestations: restlessness, delirium, mental aberration/psychosis, somnolence/lethargy, coma (≥1 on the Japan Coma Scale or ≤14 on the Glasgow Coma Scale)

4. Congestive heart failure (CHF): pulmonary edema, wet crackles over more than half of the lung field, cardiogenic shock, or Class IV by the New York Heart Association or ≥Class III in the Killip classification

features

combination

combination

combination

combination

Requirements for diagnosis

Thyrotoxicosis and at least one CNS manifestation and fever, tachycardia, CHF, or GI/ hepatic manifestations

Thyrotoxicosis and at least three combinations of fever, tachycardia, CHF, or GI/ hepatic manifestations

Thyrotoxicosis and a combination of two of the following: fever, tachycardia, CHF, or GI/ hepatic manifestations

Patients who met the diagnosis of TS1 except that serum FT3 or FT4 level are not available

5. Gastrointestinal (GI)/hepatic manifestations: nausea, vomiting, diarrhea, or a total bilirubin

3. Tachycardia: ≥130 beats per minute or heart rate ≥ 130 in atrial fibrillation

Grade of thyroid storm (TS) Combinations of

TS1 First

TS1 Alternate

TS2 First

TS2 Alternate

Cases are excluded when clear cut underlying pathology is present for the following symptoms: fever (e.g., pneumonia and malignant hyperthermia), impaired consciousness (e.g., psychiatric disorders and cerebrovascular disease), heart failure (e.g., acute myocardial infarction), and liver disorders (e.g., viral hepatitis and acute liver failure). Therefore, it is difficult to determine whether the symptom is caused by TS or is simply a manifestation of an underlying disease; the symptom should be regarded as being due to a TS

that is caused by these precipitating factors. Clinical judgment in this matter is required.

*The diagnostic criteria for thyroid storm (TS) of the Japan Thyroid Association.*

**120**

**Table 6.**

The treatment of thyroid storm should be initiated as soon as the diagnosis is suspected. Patients should be triaged to an intensive care setting for close monitoring and aggressive treatment. A multidisciplinary team approach is important in order to successfully offer the patient all possible therapeutic options. Immediate goals of thyroid-specific therapy should be targeted to decrease thyroid hormone synthesis and release, decrease peripheral action of thyroid hormone, and treat the precipitating cause.

#### **6.1 Inhibiting new thyroid hormone synthesis**

The first-line therapy in treating thyroid storm consists of inhibiting new thyroid hormone production. This approach most commonly utilizes thionamides which includes thiouracils (PTU) and imidazoles (methimazole and carbimazole). They inhibit thyroid peroxidase (TPO), thereby inhibiting formation of T3 and T4 from thyroglobulin [65]. Both methimazole and PTU are used but PTU is favored during thyroid storm due to its additional benefit over carbimazole and methimazole, namely rapid onset of action and inhibition of peripheral conversion of T4 to T3 mediated by peripheral deiodinase. In addition, PTU can be safely used in pregnancy.

The dose of PTU is 600–1500 mg/day in divided doses every 4–6 h [27, 28, 66] with a loading dose of 600 mg. Dose of methimazole is 80–120 mg daily in divided doses every 4–6 h [27, 28, 66]. The American Association of Clinical Endocrinologist/ American Thyroid Association guidelines recommend 500–1000 mg loading dose of PTU followed by 250 mg every 4 h and 60–80 mg/day of methimazole in divided doses [67]. Routes of administration include intravenous, enteral, and per rectal as suppository or retention enema. PTU is relatively insoluble at physiologic pH, therefore its intravenous preparation and administration are difficult. Intravenous methimazole can be prepared easily by dissolving methimazole powder in normal saline [68].

Nonradioactive iodine also decreases new thyroid hormone synthesis. It is due to the inhibition of organic binding of iodide to thyroglobulin as plasma iodide levels reach a critical threshold, a phenomenon known as the Wolff-Chaikoff effect. The effect is transient, lasting for about 50 h, as the thyroid eventually escapes/ adapts to prolonged iodide excess [69]. Inorganic iodine may be given orally as a saturated solution of potassium iodide (SSKI) by administering five drops (0.25 mL or 250 mg) every 6 h or as Lugol's solution (eight drops given every 6 h) [28, 67]. Routes can be enteral, rectal, or intravenous. SSKI is prepared for rectal dosing by

mixing 1 g of iodide in 60 mL of water and administering 2 g/day in divided doses [70]. Lugol's solution can be given rectally in doses of 4 mL (80 drops) per day [71]. Iodine should be given at least 30 min after administering thionamides to avoid the iodine serving as a substrate for new thyroid hormone production and worsening the hyperthyroidism. Thionamides must be continued during therapy with iodine to avoid organification of iodine and increased thyroid hormone production. Iodine administration delays definitive treatment of patients' hyperthyroidism with radioactive iodine [27, 28]. Therefore, iodine should be used only when the end goal is thyroidectomy.

Lithium hampers T4 and T3 synthesis by inhibiting the coupling of iodotyrosine residues. When iodine administration is not possible (secondary to iodine induced anaphylaxis) or desired, lithium may be substituted. It is administered at doses of 300 mg every 6–8 h with monitoring of serum levels.

#### **6.2 Inhibiting thyroid hormone release**

The next line of treatment is inhibiting the release of preformed hormone. Iodine administration, additionally, blocks the release of preformed hormone by inhibiting the release of iodothyronines (T3 and T4) from thyroglobulin [28, 72]. This effect of iodine has a faster onset than PTU, which blocks synthesis in a thyroid gland that has a large store of already formed hormone [73]. The combination therapy of thionamides and iodine decrease serum T4 levels to normal range in 4–5 days [74].

#### **6.3 Inhibiting the peripheral effect of thyroid hormone**

Both α- and β-adrenergic stimulation are enhanced in thyroid storm. Thus, adrenergic blockade is an integral part of the treatment. β-Blockers have been used in treatment of both uncomplicated and complicated hyperthyroidism [75]. Propranolol is the most commonly used β-blocker due to its nonselective β-adrenergic antagonism and its ability to block the peripheral conversion of T4 to T3. The recommended dose is 60–120 mg orally every 6 h [64]. For a more rapid effect, intravenous propranolol or a shorter acting β-blocker such as esmolol can be used. The dose of intravenous propranolol is 0.5–1.0 mg slow infusion for an initial dose and then 1–2 mg at 15-min intervals while monitoring the heart rate carefully. Esmolol is given as an initial bolus of 0.25–0.5 mg/kg followed by a continuous infusion rate of 0.05–0.1 mg/kg per minute [73].

#### **6.4 Inhibiting enterohepatic circulation of thyroid hormone**

Enterohepatic circulation of thyroid hormone is targeted for severe and refractory thyroid storm. Thyroid hormone is metabolized in the liver where it is conjugated to glucuronides and sulfates. Conjugated products are excreted into the intestine through bile, where free hormones are released, reabsorbed, and circulated. This is enterohepatic circulation of thyroid hormone. Cholestyramine binds the conjugation products and promotes their excretion, and can be used to decrease thyroid hormone levels. The recommended dose is 1–4 g twice a day [76–78].

#### **6.5 Other therapies**

The oral iodinated contrast agents are inhibitors of both deiodinases D1 and D2 and help in lowering T3 levels. Additionally, they inhibit new thyroid hormone

**123**

levels [85].

*Thyroid Storm: Clinical Manifestation, Pathophysiology, and Treatment*

synthesis and release of preformed hormones from the gland. They are given as 2 g loading dose followed by 1 g daily [74, 79]. Lower doses are given for preoperative preparation for thyroid surgery [80, 81] and as an adjunct to thionamides in treat-

Resuscitative measures should be initiated immediately in an ICU setting. Urgent addressal of systemic decompensation requires correction of hyperthermia, dehydration, congestive heart failure, dysrhythmia, and prevention of adrenal crisis [73]. Hyperthermia should be controlled with peripheral cooling and antipyretics. Acetaminophen is preferred over salicylates as salicylates increase free hormone levels by decreasing binding to T4-binding globulin, thereby exacerbating thyroid storm [83]. The peripheral cooling should be done with ice packs, cooling blankets, or alcohol sponges. Fluid loss due to hyperpyrexia, diarrhea, and vomiting should

The hypothalamo-pituitary-adrenal axis is impaired in thyrotoxicosis with a decrease in adrenal reserve. Despite increased production of cortisol by the adrenal gland to compensate for accelerated glucocorticosteroid metabolism in hyperthyroid states, a subnormal response of the adrenal glands to adrenocorticostimulating hormone occurs. Corticosteroids are therefore used as adjunct therapy in thyroid storm to prevent adrenal insufficiency. It also helps in decreasing the peripheral conversion of T4 to T3 [84]. A loading dose of 300 mg of hydrocortisone

The treatment of thyroid storm is not complete and effective until correctable precipitating factors are addressed (**Table 1**). Any focus of infection should be thoroughly investigated and proper antibiotics should be started based on sensitivity. In addition, any metabolic abnormalities, such as diabetic ketoacidosis, stroke,

In refractory cases of thyrotoxic crisis with no clinical improvement alternative measures to clear thyroid hormone from the circulation should be instituted. Therapeutic plasma exchange (TPE) is effective in rapidly reducing thyroid hormone levels [85]. The patient's plasma is extracted from the components of blood, and replaced with albumin or fresh frozen plasma [85, 86]. TBG with bound thyroid hormone is removed from circulation, and the colloid replacement (usually albumin) provides unsaturated binding sites for circulating free thyroid hormone. Various techniques of exchange transfusion have evolved since its first description in 1970 by Ashkar et al. [87]. Plasma exchange, single pass albumin dialysis, and charcoal hemoperfusion have all demonstrated a reduction in free T3 and free T4

TPE is an option when clinical deterioration in thyroid storm occurs despite the use of first- and second-line therapies. Muller et al. suggested early initiation of TPE with the following indications: severe symptoms (cardio-thyrotoxicosis, neurologic manifestations, and severe myopathy); rapid clinical deterioration; contraindications to other therapies; and failure of conventional therapeutics [88]. The American Society for Apheresis (ASFA) recommends that TPE be performed at a frequency of daily to every 2–3 days until clinical improvement is noted. Complications of TPE are seen in 5% of patients and include hypotension, hemolysis, allergic reactions, coagulopathy, vascular injury, and infection [86, 88, 89].

intravenously followed by 100 mg every 8 h is recommended [67].

or pulmonary emboli, should be treated as per standard protocols.

*DOI: http://dx.doi.org/10.5772/intechopen.89620*

**6.6 Supportive and resuscitative measures**

ment of Graves' disease [82].

be corrected immediately.

**6.7 Therapeutic plasma exchange**

synthesis and release of preformed hormones from the gland. They are given as 2 g loading dose followed by 1 g daily [74, 79]. Lower doses are given for preoperative preparation for thyroid surgery [80, 81] and as an adjunct to thionamides in treatment of Graves' disease [82].
