Myxedema Coma or Crisis 

Updated: Oct 10, 2018
Author: Mohsen S Eledrisi, MD, FACP, FACE; Chief Editor: George T Griffing, MD 

Overview

Practice Essentials

Myxedema is a term generally used to denote severe hypothyroidism. Myxedema is also used to describe the dermatologic changes that occur in hypothyroidism and occasionally hyperthyroidism. In this setting, myxedema refers to deposition of mucopolysaccharides in the dermis, which results in swelling of the affected area. When skin changes occur in hyperthyroidism, mostly Graves disease, it’s called pretibial myxedema.  

Myxedema coma, occasionally called myxedema crisis, is a rare life-threatening clinical condition that represents severe hypothyroidism with physiological decompensation.[1, 2]  The condition usually occurs in patients with long-standing, undiagnosed hypothyroidism and is usually precipitated by infection, cerebrovascular disease, heart failure, trauma, or drug therapy. Patients with myxedema coma are generally severely-ill with significant hypothermia and depressed mental status.

A medical emergency, myxedema coma requires immediate attention. 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 with continuous cardiac monitoring. Initial steps in therapy include airway management, thyroid hormone replacement, glucocorticoid therapy, and supportive measures.

Pathophysiology

Myxedema coma occurs as a result of long-standing, undiagnosed, or undertreated hypothyroidism and is usually precipitated by a systemic illness. Myxedema coma can result from any of the causes of hypothyroidism, most commonly chronic autoimmune thyroiditis. It can also occur in patients who had thyroidectomy or underwent radioactive iodine therapy for hyperthyroidism. Rare causes may include secondary hypothyroidism and medications such as lithium and amiodarone.[3, 4]

Given the importance of thyroid hormones in cell metabolism, long-standing hypothyroidism is associated with reduced metabolic rate and decreased oxygen consumption, which affects all body systems.[5]  This results in hypothermia, which is a strong predictor of mortality. Another consequence is decreased drug metabolism leading to overdosing of medications particularly sedatives, hypnotics, and anesthetic agents; this can precipitate myxedema coma.

Cardiovascular

Cardiac contractility is impaired, leading to reduced stroke volume, low cardiac output, bradycardia and sometimes hypotension.[6] Reduced stroke volume in severe cases may also be due to pericardial effusions caused by the accumulation of fluid rich in mucopolysaccharides within the pericardial sac. Congestive heart failure is rarely seen in the absence of preexisting cardiac disease.

Electrocardiographic findings may include bradycardia, varying degrees of block, low voltage, nonspecific ST-segment changes, flattened or inverted T waves, prolonged Q-T interval, and ventricular or atrial arrhythmias.[7]

The reduction of the effect of beta-adrenergic receptors leads to prevalence of the effect of alpha-adrenergic receptors, increased catecholamines, and increased systemic vascular resistance, causing some patients to have diastolic hypertension and a narrowed pulse pressure.  

Plasma volume is decreased, and capillary permeability is increased, leading to fluid accumulation in tissue and spaces and pericardial effusions.[8]

Neurologic

Despite the term myxedema coma, many patients do not present in coma, but manifest variable degrees of altered consciousness.[1] Brain function is affected by reduction in oxygen delivery and subsequent consumption, decreased glucose utilization and reduced cerebral blood flow. Hyponatremia can also contribute to altered mental function.

Pulmonary

The main pulmonary effect of myxedema coma is hypoventilation, which results from central depression of ventilatory drive with decreased responsiveness to hypoxia and hypercapnia.[9, 10] Other contributing factors to hypoventilation include respiratory muscle weakness, mechanical obstruction by a large tongue, and obesity-hypoventilation syndrome. Fluid accumulation may cause pleural effusions and decreased diffusing capacity.

Renal

Kidney function may be compromised with reduced glomerular filtration rate because of low cardiac output and peripheral vasoconstriction or because of rhabdomyolysis.[11, 12] Hyponatremia is common in patients with myxedema coma and is caused by increased serum antidiuretic hormone and impaired water excretion.[13, 14]

Gastrointestinal

The gastrointestinal tract in myxedema coma can be marked by mucopolysaccharide infiltration and edema. In addition, neuropathic changes can cause malabsorption, gastric atony, impaired peristalsis, paralytic ileus, and megacolon.[15] Ascites may occur due to increased capillary permeability, heart failure, or other mechanisms.[16] Gastrointestinal bleeding secondary to an associated coagulopathy may occur.[17]

Hematologic

Myxedema coma is associated with a higher risk of bleeding caused by coagulopathy related to an acquired von Willebrand syndrome (type 1) and decreases in factors V, VII, VIII, IX, and X.[18, 19]  Patients may also have microcytic anemia secondary to hemorrhage, or macrocytic anemia caused by vitamin B12 deficiency, or normocytic normochromic anemia, which may be secondary to decreased oxygen requirement and reduced erythropoietin.[8]

Epidemiology

United States

Myxedema coma is a rare consequence of untreated hypothyroidism, and the exact prevalence in the United States is not known.

International

A report from Spain showed that the incidence rate of myxedema coma is 0.22 per million per year.[20]  A study by Ono et al estimated the annual incidence of myxedema coma in Japan to be 1.08 per million people.[21]

Prognosis

Myxedema coma is a medical emergency. If the condition is not promptly diagnosed and treated, the mortality rate can be more than 50%. Even with immediate recognition and timely medical intervention, mortality rates are as high as 25%.[8]  

The most common causes of death are respiratory failure, sepsis, and gastrointestinal bleeding.

Myxedema coma carries a high mortality and morbidity rate. Therefore, timely recognition and proper management is critical. Factors suggesting a poor prognosis are older age, persistent hypothermia, or bradycardia, lower degree of consciousness by Glasgow Coma Scale, multiorgan impairment indicated by high APACHE (Acute Physiology and Chronic Health Evaluation) II score.[22, 23, 24, 25]  The aforementioned study by Ono et al reported that, as revealed through multivariable logistic regression, a higher inhospital mortality rate was associated with older age and catecholamine use (with or without steroids).[21]

Patient Education

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. 

 

Presentation

History

Most patients with myxedema coma have a history of hypothyroidism. Some patients may have developed hypothyroidism after thyroidectomy or iodine therapy for hyperthyroidism. However, some patients will have undiagnosed hypothyroidism and myxedema coma will be the initial presentation.

Symptoms of hypothyroidism, including fatigue, weight gain, cold intolerance, constipation, and dry skin, may be elicited.

Patients have depressed mental state with lethargy, delirium, or coma.

Symptoms of the precipitating illness can be seen such as infection (commonly pneumonia), stroke, myocardial infarction, trauma, or heart failure.

Causes

Myxedema coma is a physiologic decompensation of untreated hypothyroidism that is usually caused by a precipitating factor such as the following:  

  • Infection
  • Exposure to cold temperatures
  • Trauma
  • Burns
  • Cerebrovascular accident
  • Myocardial infarction
  • Congestive heart failure
  • Respiratory acidosis
  • Medications such as the following:
    • Tranquilizers
    • Sedatives
    • Anesthetics
    • Narcotics
    • Amiodarone
    • Rifampin
    • Beta blockers
    • Lithium
    • Phenytoin
  • Gastrointestinal hemorrhage
  • Metabolic disturbances such as hypoglycemia, hyponatremia, acidosis, and hypercapnia
  • Ingestion of raw bok choy

Physical Examination

Physical findings may include the following:

  • Hypothermia, which may not be recognized initially because many automatic thermometers do not register low body temperatures (It may be necessary to use special thermometers.)
  • Hypotension
  • Bradycardia
  • Decreased pulse pressure, normal systolic pressure, elevated diastolic pressure
  • Decreased respiratory rate
  • Periorbital puffiness
  • Macroglossia
  • Coarse or thinning hair
  • Thyroid is commonly small (Look for scar suggesting previous thyroidectomy.)
  • Slow respiratory rate
  • Signs of pleural effusion
  • Soft or distant heart sounds, diminished apical impulse, pericardial effusion
  • Abdominal distension due to ascites
  • Diminished or absent bowel sounds due to  ileus
  • Bladder distension
  • Cold extremities, nonpitting edema of the upper and lower extremities
  • Cool, pale, dry, scaly, and thickened skin
  • Dry, brittle nails
  • Ecchymoses, purpura
  • Confusion, stupor, slow speech, delayed reflexes, seizures, coma

Complications

Complications may include the following:

  • Respiratory failure
  • Coma
  • Heart failure
  • Myocardial infarction
  • Sepsis
  • Gastrointestinal bleeding
 

DDx

 

Workup

Laboratory Studies

Laboratory studies are important to confirm the diagnosis of myxedema coma. However, if the condition is suspected, treatment should be started immediately without waiting for the results.

  • Thyroid function tests
    • TSH is elevated in most patients indicating a primary thyroid disorder
    • Free T4 and free T3 levels are low
    • A low or normal TSH level with low levels of free T4 and free T3 may indicate that the disorder is due to pituitary or hypothalamic dysfunction  
  • Assessment of adrenal function should be performed. A random serum cortisol can be obtained; however, the test is only helpful if it’s very low (< 3 mcg/dL) or high (>20 mcg/dL). Since most patients will have serum cortisol levels in between these values, an ACTH stimulation test is usually needed to assess the adrenal function. This test should not delay starting treatment. In contrast to hydrocortisone, which interferes with the cortisol assay, leading to falsely normal serum cortisol, dexamethasone does not interfere with the testing and can be administered immediately and continued until the results of the test become available.
  • Hyponatremia with low serum osmolality
  • Because of decreased renal perfusion, serum creatinine levels are usually elevated
  • Hypoglycemia is common and may also be caused by reduced nutrition, sepsis, or the associated adrenal insufficiency.
  • Complete blood count: leukocytosis may not be seen because of hypothermia. A white blood cell differential may be one of the few clues to the presence of infection.

A diagnostic scoring system for the diagnosis of myxedema coma has been proposed.[26] The scoring system gives points for the following indicators: hypothermia; lethargy, obtundation, stupor, or coma; anorexia, reduced intestinal mobility, or paralytic ileus; bradycardia, electrocardiogram changes, pericardial or pleural effusions, cardiomegaly or hypertension; hyponatremia, hypoglycemia, hypoxemia, hypercapnia or reduced glomerular filtration rate, and the presence of a precipitating cause. This scoring system was based on data derived from a small sample of 21 patients, which may limit its generalizability.

Another diagnostic tool, developed by Chiong et al, uses six variables to screen for myxedema coma, including heart rate, temperature, Glasgow coma scale score, TSH levels, free T4 levels, and precipitating factors. The investigators, whose work utilized 10 study patients and 13 controls, reported the tool’s sensitivity and specificity to be about 80%.[27]

Imaging Studies

Chest X-ray may show signs of cardiomegaly, pericardial effusion, congestive heart failure, or pleural effusion.

Other Tests

Electrocardiogram may reveal sinus bradycardia, low-amplitude QRS complexes, a prolonged QT interval, flattened or inverted T waves, or arrhythmias.

 

Treatment

Medical Care

Myxedema coma is a medical emergency that requires immediate attention. 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 managed in an intensive care unit with continuous cardiac monitoring. Initial steps in management include the elements below.

Airway management

Maintenance of adequate airway is crucial, since most patients have depressed mental status along with respiratory failure. Mechanical ventilation is commonly required during the first 36-48 hours, but some patients require prolonged respiratory support for as long as 2-3 weeks.

Thyroid hormone replacement

The ideal mode of therapy and doses of thyroid hormone therapy in myxedema coma remain controversial due to the rarity of the condition and lack of clinical trials. Some clinicians favor the administration of levothyroxine (T4), while others prefer a combination of T4 and liothyronine (T3).[1, 2, 28, 29] The American Thyroid Association recommends combination therapy with T4 and T3.[30]

Because of reduced gastrointestinal absorption, intravenous thyroid hormone therapy is advised.

An intravenous loading dose of 300-600 micrograms of levothyroxine (T4) is followed by a daily intravenous dose of 50-100 micrograms.[2] Larger doses of T4 probably have no advantage and may be dangerous.[31]  The lower end of the dosing range is recommended in older patients, those at risk for cardiac complications such as myocardial infarction and arrhythmias, and in patients with coronary artery disease, since full-dose T4 therapy may worsen myocardial ischemia by increasing myocardial oxygen consumption.[30]

Because the rate of conversion of T4 to the active hormone T3 can be reduced in these patients, the addition of T3 along with T4 has been recommended.[30] T3 has a quicker onset of action than T4, as increases in body temperature and oxygen consumption has been reported to be faster with T3 therapy compared to T4.[2] T3 therapy is given as bolus of 5-20 micrograms intravenously and to be continued at a dosage of 2.5-10 micrograms every 8 hours depending on the patient's age and coexistent cardiac risk factors.[30]

Intravenous levothyroxine treatment in severely hypothyroid patients usually leads to improvement in cardiovascular, renal, pulmonary, and metabolic parameters within a week. Serum T4 and T3 concentrations may improve or normalize with a similar time frame, with more gradual improvement in serum TSH. Thus, the therapeutic endpoints in myxedema coma should be improved mental status, improved cardiac function, and improved pulmonary function.

Measurement of thyroid hormones every 1-2 days is suggested.[30] Failure of TSH to decrease or of thyroid hormone levels to increase suggests the need to increase doses of T4 and/or add T3.

The treatment is changed to the oral form once the patient is able to take medications by mouth.

Glucocorticoid therapy

Patients with primary hypothyroidism may have concomitant primary adrenal insufficiency while patients with secondary hypothyroidism may have associated hypopituitarism and secondary adrenal insufficiency. The other rationale for the treatment with corticosteroids is the potential risk of precipitating acute adrenal insufficiency caused by the accelerated metabolism of cortisol that follows T4 therapy.[2]

Stress doses of intravenous glucocorticoids should be administered until the possibility of adrenal insufficiency is excluded by a random serum cortisol, which is helpful only if very low, or, better, by an ACTH stimulation test.

Hydrocortisone at a dose of 50-100 mg every 8 hours is administered. An alternative is dexamethasone at a dose of 2-4 mg every 12 hours. Dexamethasone has the advantage of not affecting the serum cortisol concentration and can be used immediately without affecting the results of the ACTH stimulation test, which can be performed at any time. If the test is normal, corticosteroids can be stopped without tapering.

A study by Ren et al indicated that pretibial myxedema can be effectively treated with multipoint intralesional injections of compound betamethasone. The investigators found that after one treatment, 21.7% of patients achieved complete remission, while two, three, and four treatments were followed by complete remission in 34.8%, 17.4%, and 17.4% of patients, respectively.[32]

Supportive measures

Treat hypothermia with passive rewarming using ordinary blankets and a warm room. Active rewarming using external devices carries a risk of vasodilatation and worsening hypotension and should be avoided. The use of a rectal probe helps to determine the true core temperature and to monitor rewarming.

Treat associated infection. Given the severity of the condition, infection should always be considered and empiric broad-spectrum of antibiotics be considered until appropriate cultures are proven negative.

Correct severe hyponatremia with saline and free water restriction.

Correct hypoglycemia with intravenous dextrose.

Hypotension is usually corrected with thyroid hormone therapy. If blood pressure continues to be low, cautious use of intravenous fluids with normal saline is advised. Refractory hypotension can be treated with vasopressors such as dopamine, but patients should be weaned off the vasopressor as soon as possible because of the risk of pressor-induced ischemic event.[2]

Patients who are awake, no longer dependent on a ventilator, and medically stable may be transferred from the intensive care unit to a medical ward. 

Surgical Care

Patients with myxedema coma who require surgical intervention are considered high risk for complications of anesthesia as well as intraoperative and postoperative complications. Stabilization of these patients before proceeding to surgery is preferred unless the procedure is urgent.

In life-threatening situations, the loading dose of T4 and glucocorticoids are administered before induction of anesthesia. Careful administration of anesthetic agents with consideration of using lower doses should be exercised given the decreased metabolism of these agents in patients with myxedema coma.

Close monitoring during surgery and in the postoperative period in a critical care unit is imperative. Monitoring includes respiratory, cardiac, and volume and temperature status.

Consultations

Consultations include endocrinologists and critical care specialists. Depending on complications, consultations with pulmonologists and/or cardiologists may be appropriate.

Diet

Most patients will be initially ill and will not be given any food by mouth. Many patients require nasogastric feeding, and if mechanical ventilation is prolonged, total parenteral nutrition may be required. 

Activity

Once stable, patients may progress to usual activity as their strength allows. Physical therapy may be needed for incapacitated patients. 

Prevention

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 and to ensure maintenance of 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. Patients should also contact their health care provider if symptoms of inadequately-treated hypothyroidism persist. 

Long-Term Monitoring

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 T4 is adjusted accordingly.

If hypothyroidism is secondary to pituitary dysfunction, free T4 levels are monitored. TSH level is not an accurate measure of thyroid function in this setting. 

 

Medication

Medication Summary

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. 

Thyroid hormones

Class Summary

Immediate administration of intravenous levothyroxine is advised if myxedema coma is suspected.

Levothyroxine (Synthroid, Levoxyl)

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.

Liothyronine (Cytomel, Triostat)

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.

Corticosteroids

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. They modify the body's immune response to diverse stimuli.

Hydrocortisone (Solu-Cortef, Hydrocortone)

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.

 

Questions & Answers

Overview

What is myxedema?

What is myxedema coma (crisis)?

What is the pathogenesis of myxedema coma (crisis)?

What is the cardiovascular pathophysiology of myxedema coma (crisis)?

What is the neurologic pathophysiology of myxedema coma (crisis)?

What is the pulmonary pathophysiology of myxedema coma (crisis)?

What is the renal pathophysiology of myxedema coma (crisis)?

What is the GI pathophysiology of myxedema coma (crisis)?

What is the hematologic pathophysiology of myxedema coma (crisis)?

What is the prevalence of myxedema coma (crisis) in the US?

What is the global incidence of myxedema coma (crisis)?

What is the prognosis of myxedema coma (crisis)?

What information about myxedema coma (crisis) should patients be given?

Presentation

What are the signs and symptoms of myxedema coma (crisis)?

What are precipitating factors of myxedema coma (crisis)?

Which physical findings are characteristic of myxedema coma (crisis)?

What are possible complications of myxedema coma (crisis)?

DDX

What are the differential diagnoses for Myxedema Coma or Crisis?

Workup

What is the role of lab studies in the workup of myxedema coma (crisis)?

What is the role of thyroid function tests in the workup of myxedema coma (crisis)?

What is the role of adrenal function assessment in the workup of myxedema coma (crisis)?

Which lab findings suggest myxedema coma (crisis)?

Which tools may be helpful in the diagnosis of myxedema coma (crisis)?

What is the role of chest radiography in the workup of myxedema coma (crisis)?

What is the role of ECG in the workup of myxedema coma (crisis)?

Treatment

What care should be given prior to confirmation of a myxedema coma (crisis) diagnosis?

What is the role of mechanical ventilation in the treatment of myxedema coma (crisis)?

What is the role of thyroid hormone therapy in the treatment of myxedema coma (crisis)?

What is the role of glucocorticoid therapy in the treatment of myxedema coma (crisis)?

What supportive measures are included in the treatment of myxedema coma (crisis)?

When is surgery indicated in the treatment of myxedema coma (crisis)?

Which specialists should be consulted in the treatment of myxedema coma (crisis)?

Which dietary modifications are needed during the treatment of myxedema coma (crisis)?

What activity modifications are needed during the treatment of myxedema coma (crisis)?

How is myxedema coma (crisis) prevented?

What long-term monitoring is needed following treatment of myxedema coma (crisis)?

Medications

What are the goals of drug treatment for myxedema coma (crisis)?

How are thyroid hormones used for the treatment of myxedema coma (crisis)?

How is liothyronine used for the treatment of myxedema coma (crisis)?

How are corticosteroids used to treat myxedema coma (crisis)?

Which medications in the drug class Corticosteroids are used in the treatment of Myxedema Coma or Crisis?

Which medications in the drug class Thyroid hormones are used in the treatment of Myxedema Coma or Crisis?