Myxedema is a term generally used to denote severe hypothyroidism. Myxedema coma, occasionally called myxedema crisis, is a rare, life-threatening clinical condition that consists of severe hypothyroidism with decompensation. The disorder most often occurs in patients with long-standing, undiagnosed hypothyroidism and is typically precipitated by a systemic illness. Patients with myxedema coma are usually severely ill, with significant hypothermia and depressed mental status.[1, 2]
Myxedema coma is a medical emergency that must be attended to right away. If the diagnosis is suspected, immediate management is necessary before confirming the diagnosis due to the high associated mortality rate. Patients with myxedema coma should be treated in an intensive care unit (ICU) with continuous cardiac monitoring. Initial steps in therapy include supportive measures, thyroid hormone replacement, and glucocorticoid therapy (until adrenal insufficiency is excluded).
The following features may be present:
Laboratory studies include the following:
Imaging studies include chest radiographs, computed tomography (CT) scans of the brain, and other studies, as dictated by the patient’s condition.
Electrocardiographic findings may include the following:
Thyroid therapy
Because of the rarity of myxedema coma, randomized trials comparing different treatment modalities are not available. There is no agreement on the type of thyroid hormone preparation to prescribe (levothyroxine [T4] alone, liothyronine [T3] alone, or T4 and T3 combined), or on the dose, frequency, and route of administration.
Because gastrointestinal absorption may be compromised, IV thyroid therapy is initially advised. T3 has a quicker onset of action and greater biologic activity than T4. In addition, the conversion of T4 to T3 is usually impaired in hypothyroidism and in the setting of severe systemic illness.
We suggest the administration of both T4 and T3 in the treatment of myxedema coma.
Glucocorticoid therapy
Patients with myxedema coma can have concomitant primary adrenal insufficiency, while patients with secondary hypothyroidism may have associated secondary adrenal insufficiency. Glucocorticoids should be administered until the possibility of adrenal insufficiency is excluded.
Myxedema is a clinical state of severe thyroid hormone deficiency that results in the failure of multiple organs.[3, 4, 5, 6] The term myxedema is also used to describe the dermatologic changes that occur in hypothyroidism and occasionally in hyperthyroidism; myxedema refers specifically, in these cases, to the dermal deposition of mucopolysaccharides, which causes the affected area to swell. When skin changes occur in hyperthyroidism, most commonly Graves disease, the disorder is called pretibial myxedema.
Myxedema coma typically occurs in patients with long-lasting, previously undiagnosed hypothyroidism and is generally precipitated by infection, congestive heart failure, acute myocardial infarction, cerebrovascular accident, gastrointestinal bleeding, or medications.[7, 8, 9, 10, 11, 12]
Myxedema coma occurs because of long-standing, undiagnosed or undertreated hypothyroidism. Although any of the causes of hypothyroidism can lead to myxedema coma, the most common is chronic autoimmune thyroiditis. It can also occur in patients who had a thyroidectomy or who underwent radioactive iodine therapy for hyperthyroidism. Rare causes of myxedema coma include secondary hypothyroidism and medications such as lithium and amiodarone.
Given the importance of thyroid hormones in cell metabolism, long-standing hypothyroidism is associated with a reduced metabolic rate and decreased oxygen consumption, affecting all body systems.[13] Consequently, myxedema coma can also result when a hypothyroidism-induced decrease in drug metabolism leads to overdosing of medications, including sedatives, hypnotics, and anesthetic agents.
Hypothyroidism is one of the most common endocrine disorders, affecting 11.7% of the US population.[14] However, myxedema coma is rare (with the precise prevalence unknown), likely due to the common availability thyroid function testing and, therefore, the widespread early detection of hypothyroidism.
In areas where there is an adequate intake of iodine, the most common cause of hypothyroidism is autoimmune thyroid disease, with a prevalence that varies from 5.6% to 11.4%.[15] In regions where inadequate amounts of iodine are ingested, the most common cause of hypothyroidism is iodine deficiency. Severe hypothyroidism is observed only with severe iodine deficiency, which is generally found in isolated, mountainous regions of South America, Africa, and Asia. An observational study showed that the estimated incidence of myxedema coma in Japan was 1.08 per million people per year.[16]
Myxedema coma is a medical emergency. If the condition is not promptly diagnosed and treated, the mortality rate can be as high as 50%. Even with immediate recognition and appropriate medical intervention, mortality rates of up to 25% have been observed.[17, 18, 19]
Factors associated with poor prognosis are body temperature less than 93°F (33.9°C), persistent hypothermia unresponsive to 72 hours of therapy, advanced age, bradycardia (< 44 beats per minute), sepsis, myocardial infarction, and hypotension. In addition, the patient's level of consciousness and scores on the Glasgow Coma Scale and the Acute Physiology and Chronic Health Evaluation (APACHE) II have been found to be most predictive of survival.[19, 20]
Patients who are diagnosed with hypothyroidism should be counseled regarding the necessity of taking daily thyroid hormone replacement and monitoring of thyroid tests on a regular basis.
Patients with a history of thyroiditis or who have undergone thyroid irradiation or thyroid surgery should be counseled that hypothyroidism might occur in the future. They should be educated about the symptoms of hypothyroidism and should understand the importance of seeking timely medical advice for examination and testing.
Although most patients with myxedema coma have a long history of hypothyroidism, undiagnosed or undertreated myxedema coma may be the initial manifestation of a hypothyroid state.
A history of generalized fatigue, cold intolerance, constipation, and dry skin (common features of long-standing hypothyroidism) is usually present. These features slowly progress to lethargy, delirium, or coma.
A history suggestive of a precipitating factor such as infection, stroke, congestive heart failure, trauma, or medications often exists.
The following features may be present:
Myxedema coma is a decompensation of severe primary or, rarely, secondary hypothyroidism that is usually caused by additional precipitating factors, such as the following:
Complications may include the following:
Cardiac contractility is impaired, leading to reduced stroke volume, low cardiac output, bradycardia, and hypotension. Congestive heart failure is rarely seen in the absence of preexisting cardiac disease, possibly due to the lower tissue demands for oxygenation and cardiac output in hypothyroidism.[20, 21]
Because of the reduction of the effect of beta-adrenergic receptors, prevalence of the effect of alpha-adrenergic receptors, increased catecholamines, and increased systemic vascular resistance, some patients may have diastolic hypertension and a narrowed pulse pressure. Fluid accumulation in tissues and spaces results from a decrease in plasma volume and an increase in capillary permeability; pericardial effusions may occur.
Some patients do not present with coma but instead manifest variable degrees of an altered level of consciousness such as confusion, lethargy, and obtundation.[22] Hyponatremia can also contribute to altered mental function. On the other hand, some patients may display a more active presentation, with psychotic features (so-called myxedema madness).[23, 24] Seizures can occur due to hyponatremia, hypoglycemia, or hypoxemia.[6]
The main pulmonary effect of myxedema coma is hypoventilation, which results from central depression of the ventilatory drive, with decreased responsiveness to hypoxia and hypercapnia.[25, 26] Other contributing factors to hypoventilation include respiratory muscle weakness, mechanical obstruction by a large tongue, pleural effusions, and obesity hypoventilation syndrome.[27]
Kidney function may be compromised due to low cardiac output and systemic vasoconstriction, causing decreased renal blood flow and a low glomerular filtration rate.
Reduced kidney function can also occur due to rhabdomyolysis, as well as urine retention due to atony of the urinary bladder.[6] Hyponatremia is common and results from impaired free-water excretion due to inappropriate excess vasopressin secretion and impaired renal function. Concomitant adrenal insufficiency, when present, can also cause hyponatremia.
Hypoglycemia occurs due to decreased gluconeogenesis; in some patients, starvation and infection can also contribute. Hypoglycemia can be caused by hypothyroidism alone or by concurrent adrenal insufficiency, which can result from autoimmune adrenal disease or hypothalamic-pituitary disease.
Hypothyroidism can cause mucopolysaccharide infiltration and edema of the gastrointestinal wall, as well as neuropathic changes leading to ascites, impairment of intestinal motility or paralytic ileus, gastric atony, and megacolon.[6, 28] Malabsorption and gastrointestinal bleeding secondary to an associated coagulopathy have been reported.[29]
Myxedema coma can be associated with a higher risk of bleeding, the result of coagulopathy related to acquired von Willebrand syndrome and decreased levels of factors V, VII, VIII, IX, and X. Bleeding may also occur due to disseminated intravascular coagulation associated with sepsis. Patients may suffer from microcytic anemia secondary to hemorrhage or macrocytic anemia resulting from concomitant vitamin B12 deficiency.
Laboratory and imaging studies are performed as dictated by the patient's clinical condition.[30]
Laboratory values are essential for the workup of myxedema coma. However, if the condition is suspected, treatment must be initiated immediately, without waiting for the results.
Results include the following:
These include the following:
Imaging studies include chest radiographs, computed tomography (CT) scans of the brain, and other studies, as dictated by the patient’s condition.
Electrocardiographic findings may include the following:
Myxedema coma is a life-threatening condition; therefore, patients with this disorder should be managed in an intensive care unit (ICU). If the diagnosis is considered likely, immediate and aggressive administration of multiple interventions is necessary to lower the high mortality rate. Initial priorities include the following.
Supportive care includes the following:
Because of the rarity of myxedema coma, randomized trials comparing different treatment modalities are not available. There is no agreement on the type of thyroid hormone preparation to prescribe (levothyroxine [T4] alone, liothyronine [T3] alone, or T4 and T3 combined), or on the dose, frequency, and route of administration.
Because gastrointestinal absorption may be compromised, IV thyroid therapy is initially advised. T3 has a quicker onset of action and greater biologic activity than T4. In addition, the conversion of T4 to T3 is usually impaired in hypothyroidism and in the setting of severe systemic illness.
We suggest the administration of both T4 and T3 in the treatment of myxedema coma.
An IV T4 loading dose of 4 mcg/kg (200-400 mcg) is followed by a daily IV dose of 50-100 mcg; the daily dose can be switched to the oral route when the patient can take medications by mouth. T3 is given intravenously at the same time, at an initial dose of 5-20 mcg, followed by 2.5 to 10 mcg every 8-12 hours, with lower doses prescribed for older patients and those with cardiovascular disease.
Confirm the effectiveness of therapy and avoid high serum T3 levels by measuring serum free T4 and total or free T3 every 1-2 days.
Patients with myxedema coma can have concomitant primary adrenal insufficiency, while patients with secondary hypothyroidism may have associated secondary adrenal insufficiency. Glucocorticoids should be administered until the possibility of adrenal insufficiency is excluded.
Stress doses of glucocorticoids are usually used, such as hydrocortisone 100 mg every 8 hours intravenously after a random serum cortisol measurement is obtained.
Glucocorticoid therapy should be continued until the serum cortisol results are available.
A random serum cortisol result of less than 3 mcg/dL (80 nmol/L) strongly suggests adrenal insufficiency, while a level of 18 mcg/dL (500 nmol/L) or above is normal. Patients who have cortisol levels of 3-18 mcg/dL require further testing with the adrenocorticotropic hormone (ACTH) stimulation test; this test can be done after a few days of glucocorticoid therapy.
Prior to surgical procedures, stabilize patients in myxedema coma using thyroid hormone therapy and glucocorticoids. In life-threatening situations, administer a loading dose of thyroid hormone and glucocorticoids before induction of anesthesia.
Medication doses, particularly those for anesthetic agents, should be adjusted to compensate for decreased drug metabolism and reduced renal function.
Consultations include those with endocrinologists and critical care specialists. Depending on complications, consultations with pulmonologists and/or cardiologists may be appropriate.
Motility of the gastrointestinal tract is usually decreased; therefore, oral feeding should be withheld until the patient is alert and extubated and normal bowel sounds are present.
Once stable, patients may progress to their usual activities as their strength allows. Physical therapy may be useful for patients who are debilitated.
Patients with a history of thyroid resection or ablation for hyperthyroidism and persons with a history of Hashimoto thyroiditis are at risk for developing hypothyroidism, and the TSH level should be monitored yearly. Such patients should be informed that hypothyroidism could occur in the future. They should understand the symptoms that signal the condition and the need to seek medical attention for appropriate testing.
In cold climates, inadequately heated residences are a significant cause of myxedema coma/crises in patients with undiagnosed or inadequately treated hypothyroidism.
Thyroid function tests should be monitored regularly in patients with hypothyroidism until the appropriate dose of levothyroxine is reached. Adherence to thyroid hormone therapy should be assessed regularly to ensure maintenance of a euthyroid state. Patients who are deemed nonadherent or have issues that may hinder adherence should have their thyroid function closely monitored.
Patients are advised to report to their physicians if they are prescribed any new medications since some drugs may interfere with the absorption, production, secretion, or clearance of thyroid hormone therapy.[31] Patients should also contact their health care provider if symptoms of inadequately treated hypothyroidism persist.
Follow-up care after discharge is necessary to ensure adherence with thyroid hormone replacement.
If primary hypothyroidism was diagnosed, TSH levels are assessed every 4-6 weeks, and the dose of thyroxine is adjusted accordingly.
If hypothyroidism is secondary to pituitary dysfunction, the free T4 level is monitored; the TSH level is not an accurate measure of thyroid function in this setting.
The goals of pharmacotherapy are to increase thyroid hormone levels, reduce morbidity, and prevent complications.
Thyroid hormones
IV dosage form has a long half-life, so it can be administered once-daily and is the preferred route of administration in patients with myxedema coma because gastrointestinal tract absorption may be compromised. It is preferred by many authorities given its slow onset of action and sustained effect, making adverse effects less likely to occur and serum levels easier to monitor. Lower doses are recommended for patients who have arrhythmias or coronary artery disease.
Liothyronine
Liothyronine (T3) has a short half-life and must be administered every 8 hours. Because of concerns about abrupt onset and fluctuating concentrations in tissues, coadministration of T3 with T4 is recommended.
Oral levothyroxine is taken daily 30-60 minutes before breakfast.
Corticosteroids
Patients presenting with myxedema coma may have adrenal insufficiency and stress doses of IV steroids must be administered along with initial thyroid replacement until adrenal function has been determined to be normal.
Clinical Context: In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development. IV dosage form has a long half-life (may be administered qd and is the preferred route of administration in patients with myxedema coma/crisis because GI tract absorption may be compromised). Preferred by many authorities, because the onset of action is slow and sustained, making adverse effects less likely to occur and serum levels easier to monitor. Administering only T4 assumes normal conversion to T3 by deiodinase activity, which is usually compromised in severe illness. IV dose of T4 is approximately one half to two thirds of the PO dose. Lower doses recommended if patient has uncontrolled atrial arrhythmia or recent MI.
Clinical Context: Synthetic form of the natural thyroid hormone, T3, converted from T4. T3 is the active form, but because peripheral conversion of T4 to T3 is compromised in patients who are hypothyroid, some authorities suggest combined IV T4 and T3 in these patients. However, patients with cardiovascular disease are at greater risk of arrhythmia and infarction.
T3 has a short half-life and must be administered q8h. Because of concerns about abrupt onset and fluctuating concentrations in tissues, experts advise coadministration of T3 with T4.
Immediate administration of intravenous levothyroxine is advised if myxedema coma is suspected.
Clinical Context: DOC because of mineralocorticoid activity and glucocorticoid effects. Patients presenting with myxedema coma/crisis may have adrenal insufficiency, and stress doses of IV steroids must be administered along with initial thyroid replacement until adrenal function has been determined to be normal.
Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.