INTRODUCTION AND EPIDEMIOLOGY Hypothyroidism is a clinical syndrome caused by insufficient thyroid hormone production, which slows cell metabolism. Hypothyroidism is common in areas where iodine deficiency is common, particularly inland areas where there is no access to marine foods. In iodinesufficient areas, chronic autoimmune destruction of thyroid gland (e.g., Hashimoto’s thyroiditis) and iatrogenic causes from treatment of Graves’ disease are the leading causes of hypothyroidism (after thyroidectomy or radioactive iodine ablation). The prevalence of hypothyroidism increases with age, and the disorder is nearly 10 times more common in females than in males.1 Subclinical hypothyroidism is more prevalent than overt hypothyroidism in all age groups and can be seen in 4% to 15% of women, especially the elderly.2,3 Hypothyroidism occurs in 1% to 32% of patients taking amiodarone.1 PATHOPHYSIOLOGY Primary hypothyroidism is caused by the intrinsic dysfunction of the thyroid gland, and this is the most common type. Secondary hypothyroidism is caused by a deficiency of thyroid-stimulating hormone from the pituitary gland or deficiency of thyrotropin-releasing hormone from the hypothalamus. Table 228-1 lists common causes of hypothyroidism. Euthyroid sick syndrome or low thyroxine syndrome, also called nonthyroidal illness, is the term used for patients with low triiodothyronine and thyroxine levels and a normal or low thyroid-stimulating hormone level, but who are clinically euthyroid. This condition is found in critically ill patients or those with severe systemic illness. Triiodothyronine is the major form of thyroid hormone. The ratio of triiodothyronine to thyroxine released in the blood is about 10:1. Peripherally, triiodothyronine is converted to the active thyroxine, which is three to four times more potent than triiodothyronine. The half-life of triiodothyronine is 7 days, and the half-life of thyroxine is about 1 day. CLINICAL FEATURES OF HYPOTHYROIDISM Symptoms can manifest in all organ systems and range in severity based on the degree of hormone deficiency (Table 228-2). The common clinical features of hypothyroidism are listed in Table 228-2. Additional cardiopulmonary findings include angina, bradycardia, distant heart sounds from pericardial effusion, low voltage on the electrocardiogram, pleural effusions, cardiomyopathy, or hypoventilation. Figures 228-1 and 228-2 show some characteristic findings of myxedema. Table 228-3 describes the differences between primary and secondary hypothyroidism. TABLE 228-2 Symptoms and Signs of Hypothyroidism Signs Periorbital puffiness Loss of outer third of eyebrow Pallor Macroglossia Hoarseness Bradycardia Hypoventilation Absent or decreased bowel sounds Nonpitting edema Delayed relaxation of ankle jerks Peripheral neuropathy Cool, rough, dry skin Hypothermia Symptoms Hair loss Fatigue Depression Shortness of breath Weight gain Constipation Menstrual irregularities Infertility Muscle cramps Joint pain Cold intolerance 228 CLINICAL FEATURES OF MYXEDEMA CRISIS Myxedema crisis is a state of metabolic and multiorgan decompensation characterized by uncorrected hypothyroidism, mental status changes or coma, and hypothermia (usually <35.5°C [95.9°F]).1 In hypothyroid patients, myxedema coma can be precipitated by a number of conditions, including infection, anesthetic agents, cold exposure, trauma, myocardial infarction or congestive heart failure, cerebrovascular accident, GI hemorrhage, metabolic conditions, hypoxia, hypercapnia, hyponatremia, hypoglycemia, surgery, burns, medications (e.g., β-blockers, sedatives, narcotics, phenothiazine, amiodarone), or thyroid medication noncompliance. The characteristic hypothyroid habitus is evident, as well as bradycardia, hypotension, hypothermia, hypoventilation, and altered mental status or coma. Blood pressure is quite variable, but of patients in full myxedema coma, half initially exhibit clinical shock with systolic pressure <100 mm Hg.4,5 The capillaries are “leaky,” and this may contribute to hypotension. Infection may be present even though fever, tachycardia, sweating, and leukocytosis may not be evident, because bradycardia and hypothermia mask these signs. Respiratory insufficiency and altered mental status can result from carbon dioxide narcosis. Pleural effusions are frequently demonstrable. Other potential respiratory problems include upper airway obstruction from glottic edema, vocal cord edema, and macroglossia. Metabolism of tranquilizers, sedatives, and anesthetics is reduced in hypothyroidism, and the exaggerated effects of such medications can also contribute to altered mental status. Hypothermia is so common in myxedema that a normal temperature should suggest an underlying infection. Hypothyroid habitus, absence of shivering, and pseudomyotonic reflexes (prolonged relaxation phase of deep tendon reflex—at least twice as long as the contraction phase) may help distinguish myxedematous from accidental hypothermia. TABLE 228-3 Differentiation of Primary and Secondary Hypothyroidism Point of Difference Primary Hypothyroidism Secondary Hypothyroidism Previous thyroid operation Yes None Obese More obese Less obese Hypothermia More common Less common Voice Coarse Less coarse Pubic hair Present Absent Skin Dry and coarse Fine and soft Heart size Increased Normal Menses and lactation Normal No lactation, amenorrhea Sella turcica size Normal May be increased Serum TSH Increased Decreased Plasma cortisol Normal Decreased Response to TSH None Good Response to levothyroxine without steroids Good Poor response Abbreviation: TSH = thyroid-stimulating hormone.DIAGNOSIS The diagnosis of hypothyroidism is based on laboratory testing. The diagnosis of myxedema crisis is clinical. The differential diagnoses include sepsis, depression, adrenal crisis, congestive heart failure, hypoglycemia, cerebrovascular accidents, hypothermia, drug overdose, and meningitis.  LABORATORY EVALUATION AND IMAGING The baseline levels of thyroid-stimulating hormone, thyroxine, triiodothyronine, and cortisol levels should be drawn before initiating treatment. This facilitates eventual diagnosis as well as response to treatment. High thyroid-stimulating hormone, with low total or free thyroxine and triiodothyronine, confirms primary hypothyroidism (thyroid gland etiology). Low thyroid-stimulating hormone with low total or free thyroxine and triiodothyronine points toward secondary hypothyroidism (hypothalamic–pituitary etiology). The assay of free thyroxine and triiodothyronine is preferable, as the result is more accurate and is not affected by protein binding. Thyroid hormone levels may also be altered as a result of interactions with drugs such as amiodarone, lithium, ethionamide, α-interferon, and interleukin-2. Nevertheless, thyroid function usually normalizes after discontinuation of these drugs. Ideally, thyroid function tests should be obtained before initiating therapy with these agents and periodically thereafter. Hypothyroidism may be associated with pernicious anemia, and thus macrocytic anemia may be evident. However, if menorrhagia after hypothyroidism is severe, anemia may be microcytic from iron deficiency. Hyponatremia due to increased antidiuretic hormone and impaired free water clearance is common. Hypoglycemia is common because of decreased gluconeogenesis, decreased insulin clearance, and concomitant adrenal insufficiency or growth hormone deficiency. Arterial blood gases typically show hypoxemia, hypercapnia, metabolic acidosis from tissue hypoxia, and respiratory acidosis from hypoventilation due to muscle weakness. Further laboratory assessment depends on the differential diagnosis, comorbidities, and search for precipitating factors. Electrocardiogram is necessary to identify myocardial infarction or bradyarrhythmias or heart block. Chest radiograph is needed to identify pneumonia, pleural effusion, or cardiomegaly. TREATMENT OF SYMPTOMATIC HYPOTHYROIDISM If a patient has symptoms of hypothyroidism or has been noncompliant with thyroid medication, and hypothyroidism can be confirmed by thyroid function tests done in the ED, oral levothyroxine may be started. Full replacement dose for patients without cardiac disease is 1.6 micrograms/ kg.6 The average starting dose for healthy adults younger than 50 is 50 micrograms of oral levothyroxine once a day. For those older than 50 years or with cardiac disease, the initial dose is lower, 12.5 to 25 micrograms once a day. For all adults, the dose is adjusted by 12.5- to 25-microgram increments at 4- to 6-week intervals. Instruct the patient to follow up with the primary care physician for monitoring and further dose adjustments in a month. TREATMENT OF MYXEDEMA CRISIS Management of myxedema crisis is shown in Table 228-4. The treatment includes supportive care, thyroid hormone replacement (supplementing with thyroxine, triiodothyronine, or combination of both), and identification and treatment of precipitating factors.  THYROID HORMONE REPLACEMENT FOR MYXEDEMA CRISIS Administer thyroid hormone upon clinical suspicion of myxedema crisis, as confirmatory laboratory thyroid hormone levels will not be available initially. Thyroxine is the usual replacement. Triiodothyronine alone can be given if it is available, but should be avoided in the elderly or those with cardiac disease. Triiodothyronine and thyroxine together can be given if the patient has persistent hemodynamic instability or poor respiratory effort. Because myxedema crisis is such a rare condition, there are no clear recommendations for the use of thyroxine alone, combined thyroxine and triiodothyronine, or triiodothyronine alone. Thyroid hormone replacement should initially be given IV because severe or even mild hypothyroidism results in decreased intestinal motility and GI absorption. Once the patient has received IV replacement, intestinal motility should recover, and oral medication can be given. Thyroxin (Levothyroxine) The dose is 4 micrograms/kg IV, with the usual dose from 200 micrograms to a maximum of 500 micrograms IV. The onset of action for IV thyroxine is between 6 and 8 hours. The advantages of thyroxine are a smooth, slow, and steady onset of action and its widespread availability. Disadvantages include the fact that extrathyroidal conversion of thyroxine to triiodothyronine may be reduced in myxedema coma. The onset of action of thyroxine is longer than that of triiodothyronine. Triiodothyronine (Liothyronine) For triiodothyronine (liothyronine), start at 20 micrograms IV followed by 10 micrograms IV every 8 hours until oral medication can be given. The advantage of triiodothyronine TABLE 228-4 ED Treatment for Myxedema Crisis Supportive care Airway, breathing, and circulation support: ensure airway control, oxygen, IV access, and cardiac monitor IV therapy: dextrose for hypoglycemia; water restriction for hyponatremia Vasopressors: if indicated (ineffective without thyroid hormone replacement) Hypothermia: treated with passive rewarming Steroids: hydrocortisone (due to increased metabolic stress; 100–200 milligrams IV) ↓ Thyroid replacement therapy (see discussion of Thyroid Hormone Replacement in text) IV thyroxine (levothyroxine) at 4 micrograms/kg (typically between 200 and 500 micrograms as initial dose), followed in 24 h by 100 micrograms IV, then 50 micrograms IV until oral medication is tolerated. Thyroxine is readily available. Thyroxine is preferred in the elderly and those with cardiac disease. Starting dose in the elderly is 100 micrograms IV. OR IV triiodothyronine (liothyronine) at a dose of 20 micrograms IV followed by 10 micrograms IV every 8 h until the patient is conscious. Start with no more than 10 micrograms IV for the elderly or those with coronary artery disease. Triiodothyronine is less preferred in patients with cardiac disease, as its potency could precipitate cardiac arrhythmias or infarction. Note: Either thyroxine or triiodothyronine alone can be used, but in patients with persistent hemodynamic instability or poor respiratory effort, both can be given simultaneously. When used together, the dose of thyroxine is 200 micrograms IV and triiodothyronine is 20 micrograms IV. ↓ Identify and treat precipitating and comorbid factors Infections Sedatives Cold exposure Trauma Myocardial infarction or congestive heart failure Cerebrovascular accident Gastrointestinal hemorrhage Hypoxia Hypercapnia Hyponatremia Hypoglycemia over thyroxine is the fact that deiodinase conversion of thyroxine to the active hormone triiodothyronine is reduced in myxedema crisis. IV triiodothyronine also has a rapid onset of action, between 2 and 4 hours. In a primate study, triiodothyronine crossed the blood–brain barrier more readily than thyroxine.7 However, the disadvantages of triiodothyronine are a more potent effect, fluctuating serum levels, and the fact that triiodothyronine is more likely to cause cardiac arrhythmias or myocardial infarction than thyroxine. Avoid replacement with triiodothyronine in patients with cardiac disease. If triiodothyronine is given, provide continuous cardiac monitoring and obtain interval electrocardiograms to identify myocardial ischemia. DISPOSITION AND FOLLOW-UP Myxedema crisis carries a high mortality rate, ranging from 30% to 60% depending on comorbid diseases. Factors such as advanced age, bradycardia, and persistent hypotension suggest a poor prognosis. All patients with myxedema coma require intensive care unit admission. Milder hypothyroidism patients may only be discharged with a clear plan of management and followed up by either an endocrinologist or primary care physician. from the above mention content make points for easdy study and understandind.