Myxedema coma is an extreme complication of hypothyroidism in which patients exhibit multiple organ abnormalities and progressive mental deterioration. The term myxedema is often used interchangeably with hypothyroidism and myxedema coma. Myxedema also refers to the swelling of the skin and soft tissue that occurs in patients who are hypothyroid. Myxedema coma occurs when the body's compensatory responses to hypothyroidism are overwhelmed by a precipitating factor such as infection.

A common misconception is that a patient must be comatose to be diagnosed with myxedema coma. However, myxedema coma is a misnomer because most patients exhibit neither the nonpitting edema known as myxedema nor coma.^1,2 Instead, the cardinal manifestation of myxedema coma is a deterioration of the patient's mental status.

When only comatose patients are considered, myxedema coma is exceedingly rare: one study reports 200 cases between 1953 and 1996.³ Applying a broader definition results in a significantly higher number of cases. While the actual prevalence of myxedema coma is unknown, its lethal nature demands recognition. Even with early detection and appropriate treatment, mortality ranges from 30 to 60 percent.^3,4 Family physicians must be alert to the possibility of undiagnosed hypothyroidism in their patients.

Epidemiology

Hypothyroidism is four times more common in women than in men; 80 percent of cases of myxedema coma occur in females.^5,6 Myxedema coma occurs almost exclusively in persons 60 years and older.⁵ More than 90 percent of cases occur during the winter months.⁶ This seasonal presentation is probably due to age-related loss of the ability to sense temperature and lower heat production secondary to hypothyroidism.⁷

Historical Features

Patients with myxedema coma usually have longstanding hypothyroidism, although it may not have been previously diagnosed. They often demonstrate classic symptoms of hypothyroidism: fatigue; constipation; weight gain; cold intolerance; a deep voice; coarse hair; and dry, pale, cool skin. However, elderly patients with hypothyroidism often have atypical presentations, such as decreased mobility,⁸ and some patients with compensated hypothyroidism are asymptomatic.⁹

PRECIPITATING EVENT

Decompensation into myxedema coma occurs when the hypothyroid patient's homeostatic mechanisms are disrupted. Multiple factors can precipitate myxedema coma (Table 1).^{1–3,10–14} Some of the more common precipitating factors include infections, particularly pneumonia and urosepsis, and certain medications. Another potential risk factor is failure to reinstate thyroid replacement therapy during hospitalization.

Physical Findings

Physical findings in myxedema coma (Table 2) may include the classic myxedematous face, which is characterized by generalized puffiness, macroglossia, ptosis, periorbital edema, and coarse, sparse hair. Nonpitting edema of the lower extremities is sometimes present. The findings from a thyroid examination are usually normal, but a goiter may be present in some patients. The presence of a scar on the neck might suggest postsurgical hypothyroidism and may be an important clue in the diagnosis of a patient who is comatose. A neurologic examination may reveal decreased reflex tendon relaxation and will invariably reveal altered mentation.

ALTERED MENTATION

All patients with myxedema coma display deterioration of their mental status. This decline may be subtle, manifesting as apathy, neglect or a decrease in intellectual function; more obvious changes include confusion, psychosis and, rarely, coma. While all patients with myxedema coma present with some degree of mental status change, few progress to coma. When there is doubt about a change in mental status, formal mental status testing should be performed.

Physicians should also be alert to the possibility of depression in the seemingly demented patient and perform depression screening in any patient with mental status changes. Lumbar puncture may also be clinically appropriate.

HYPOTHERMIA

Another common clinical feature of myxedema coma is hypothermia. The patient's temperature is usually less than 35.5°C (95.9°F).¹³ Conditions that may precipitate myxedema coma such as hypoglycemia and cold exposure may exacerbate the hypothermia. However, the patient's temperature is not always an accurate diagnostic aid because some patients present with a normal temperature.

BLOOD PRESSURE CHANGES

Patients with compensated hypothyroidism often exhibit diastolic hypertension. Decreased oxygen consumption and lowered body temperature result in peripheral vasoconstriction and central shunting.² Only when the patient has begun to decompensate do these neurovascular mechanisms fail. The patient may then display the hypotension characteristically associated with myxedema coma. Bradycardia, low cardiac output and overall blood volume deficit frequently exacerbate the hypotension.

HYPOVENTILATION

Hypoventilation in myxedema coma results from the body's decreased ventilatory response to hypoxia and hypercapnia.¹⁵ Respiratory dysfunction may lead to sleep apnea,¹⁶ and respiratory difficulties may be exacerbated by myxedematous infiltration of the tongue and pharynx.^15,17 The diaphragmatic weakness induced by hypothyroidism is reversed by thyroid hormone replacement.^16,18

Diagnostic Testing

Multiple diagnostic findings are reported in patients with myxedema coma. This disorder impacts thyroid hormone levels, electrolyte levels, creatine kinase (CPK) levels and other laboratory values (Table 3).

THYROID HORMONE

Primary hypothyroidism results from the inability of the thyroid gland to produce adequate amounts of thyroid hormone. Typically, patients with myxedema coma have primary hypothyroidism manifested by low serum levels of thyroxine (T₄) and triiodothyronine (T₃) and a high thyroid stimulating hormone (TSH) level. However, primary hypothyroidism should be differentiated from secondary hypothyroidism, tertiary hypothyroidism and the low T₄ level/low T₃ level syndrome (euthyroid sick syndrome).

Secondary hypothyroidism is a result of pituitary dysfunction; tertiary hypothyroidism is caused by a hypothalamic abnormality. If the patient has hypopituitarism, the level of TSH is not increased. The findings of a low T₄ level and low-normal or decreased TSH level mandate a search for pituitary abnormalities. However, a low level of serum T₄ (and T₃) with a normal TSH level may simply indicate that the patient's thyroid function tests have been altered as a result of illness unrelated to the thyroid (euthyroid sick syndrome).

ELECTROLYTE ABNORMALITIES

The hyponatremia seen in myxedema coma is a result of decreased free water clearance. Elevated levels of antidiuretic hormone and/or diminished blood flow to the kidneys are believed to be responsible for the inability to excrete free water.^19,20 Hyponatremia is classically associated with a low serum osmolality. The level of serum creatinine is usually high, and while the level of calcium is generally low, it may be elevated.²¹ Hypoglycemia may be a result of the down-regulation of metabolism seen in hypothyroidism²; it may also indicate the possibility of adrenal insufficiency.

ELEVATED CREATINE KINASE

Patients with myxedema coma may be mis-diagnosed with myocardial infarction based on elevated CPK levels in association with nonspecific electrocardiographic (ECG) findings. Increased CPK and other transaminases are thought to result from altered membrane permeability.²² Fractionation of the CPK reveals a skeletal muscle source. ECG changes include bradycardia, decreased voltages, non-specific ST and T changes, varying types of block and a prolonged QT interval. Conversely, physicians should be alert to the possibility of myocardial infarction as a triggering event for myxedema coma.

OTHER ABNORMALITIES

Arterial blood gases often reveal respiratory acidosis, hypoxia and hypercapnia. Mild leukopenia and a normocytic anemia are also frequently present. However, macrocytic anemia and pernicious anemia caused by associated immune dysfunction are sometimes present.^13,23 A chest radiograph may show cardiomegaly and pleural effusions. If cardiomegaly is present, an echocardiogram should be obtained to rule out a pericardial effusion. When performed, lumbar puncture typically reveals elevated protein levels^13,15,24 and a high opening pressure. Results of electroencephalography are nonspecific.¹³

Treatment

The patient with myxedema coma should be admitted to the intensive care unit, and hypovolemia and electrolyte abnormalities corrected. Mechanical ventilation may be necessary. Cardiovascular status should be monitored carefully, especially after intravenous thyroid hormone replacement. Myocardial infarction must be ruled out and blood pressure stabilized. If possible, pressors and ionotropes should be avoided because of their tendency to provoke arrhythmias in the setting of intravenous thyroid replacement. Patients with hypothermia should be covered with regular blankets; the use of warming blankets should be avoided because the resulting peripheral dilatation may lead to hypotension and cardiovascular collapse.

THYROID HORMONE REPLACEMENT

Any patient with suspected myxedema coma should be treated presumptively with thyroid hormone. While there is concern regarding the precipitation of arrhythmias or myocardial infarction by administering large doses of intravenous levothyroxine, this concern must be balanced against T₄'s potentially life-saving and usually nondetrimental effect.²⁵

While the necessity of intravenous thyroid hormone replacement is apparent, some controversy exists regarding the use and dosages of levothyroxine (T₄) and liothyronine (T₃). Because of the relatively small number of patients with myxedema coma, controlled studies comparing various dosages of T₄ and T₃ are lacking. Because T₃ is more biologically active than T₄, and because the conversion of ^26,27 T₄ to T₃ is suppressed in myxedema coma, some have advocated T₃ replacement. However, parental T₃ is not only expensive and difficult to obtain, it may also contribute to increased mortality.²⁷

Most authorities therefore recommend use of T₄ alone.^2,7,13,14,27 An initial levothyroxine dose of 100 to 500 μg administered intravenously should be followed by 75 to 100 μg administered intravenously daily until the patient is able to take oral replacement. The lower initial dose should be administered to patients who are frail or have other comorbidities, particularly cardiovascular disease. Elderly patients typically require 100 to 170 μg of oral levothyroxine daily.¹³

ANTIBIOTICS

Infection is often the cause of the patient's decompensation; therefore, an infectious etiology should be sought with blood and urine cultures as well as a chest radiograph. Some authorities advocate empiric therapy with broad-spectrum intravenous antibiotics.²

STEROIDS

Because of the possibility of secondary hypothyroidism and associated hypopituitarism, hydrocortisone should be administered until adrenal insufficiency has been ruled out. Hydrocortisone should be administered intravenously at a dosage of 100 mg every eight hours. Failure to treat with hydrocortisone in the face of adrenal insufficiency may result in the precipitation of adrenal crisis. A random cortisol level should be drawn prior to therapy, and if not depressed, the hydrocortisone can be discontinued without tapering. An adrenocorticotropic hormone stimulation test can be administered if clinically warranted.

Prognosis

The prognosis for patients with myxedema coma is difficult to define because of the small number of cases reported in the literature. The severity of the condition, however, is clear. One study reported a mortality rate of about 30 percent, while another suggests the mortality rate may be as high as 60 percent.^3,4 Factors associated with a poor prognosis include advanced age, bradycardia and persistent hypothermia.²⁷

Final Comment

Family physicians should be alert for myxedema coma, particularly in elderly women with mental status changes who present during the winter months. An accurate diagnosis generally follows a careful history, physical examination and laboratory evaluation. The most important elements in treatment of myxedema coma are early recognition, presumptive thyroid hormone replacement, hydrocortisone and appropriate supportive care. While myxedema coma carries a significant mortality rate even with appropriate testing and treatment, an early diagnosis of hypothyroidism may well save a patient's life.