Hypothyroidism and Myxedema Coma

Thyroid hormone is secreted in response to stimulation of the thyroid gland by thyroid-stimulating hormone (TSH) from the anterior pituitary gland. TSH is released through the action of thyrotropin-releasing hormone (TRH) from the hypothalamus.

Hypothyroidism can be caused by permanent loss or atrophy of functional thyroid tissue (primary hypothyroidism); insufficient stimulation of a normal thyroid gland as a result of hypothalamic or pituitary disease (secondary hypothyroidism, often accompanied by compensatory thyroid gland enlargement); or a defect in the TSH molecule (control hypothyroidism).

Primary hypothyroidism accounts for approximately 90-95% of hypothyroidism, with a predominantly autoimmune-mediated etiology. TSH hypersecretion produces excessive thyroid tissue, resulting in goiter formation. Surgical and radiation ablation account for a large percentage of acquired cases of hypothyroidism. Congenital abnormalities, malignancies, and infiltrative disorders including amyloidosis and sarcoidosis can also lead to the disease. Iodine deficiency is rarely responsible for hypothyroidism in developed countries; however, it remains the primary cause worldwide.

Suprathyroidal disorders including hypopituitarism and hypothalamic lesions account for fewer than 10% of cases. Rarely, peripheral resistance to thyroid hormone may occur.

The congenital absence or deficiency of thyroid tissue may result in cretinism, a neurodevelopmental disorder characterized by lethargy, poor peripheral circulation, constipation, and goiter. Because infants are asymptomatic, neonatal screening is vital to prevent permanent sequelae.

Frequency

United States

Reports on screening surveys for thyroid disease show an incidence of 5.8% for subclinical thyroid abnormalities. However, those with overt signs and symptoms of hypothyroidism likely comprise less than 2% of women and 0.2% of men.

Myxedema coma occurs rarely, appearing in 0.1% of all cases of hypothyroidism.

International

Neonatal screening programs for congenital hypothyroidism show that in many areas around the world hypothyroidism appears in 1 of every 4000 newborns.[6]

In developed countries, the incidence of subclinical hypothyroidism is approximately 8% in women and 3% in men. Endemic goiter usually occurs in environmentally iodine-deficient areas; throughout the world, goiter is estimated to affect 200 million people. Goiter is most common in mountainous areas of the Alps, Himalayas, and Andes, possibly due to low soil iodine content as a result of leaching away of minerals as glaciers melt.

A study by Ono et al estimated the annual incidence of myxedema coma in Japan to be 1.08 per million people.[7]

Race

Anecdotal reports indicate the disease appears more often in white and Hispanic populations.

Sex

Incidence is greater in females than males (female-to-male ratio 5-10:1).

Age

The incidence of primary hypothyroidism increases progressively with age, typically at 40-50 years. After age 60 years, the prevalence of hypothyroidism may be as high as 8-10% in women.

The symptoms characteristic of hypothyroidism are numerous yet often vague and subtle, especially in early stages of the disease. Note the following:

• Lethargy

• Generalized weakness

• Brittle or thinning hair

• Menstrual irregularity

• Menorrhagia

• Forgetfulness

• Fullness in throat

• Deep, husky voice secondary to mucopolysaccharide infiltration of the vocal cords

• Cold intolerance

• Weight gain/difficulty losing weight

• Muscle/joint pain or weakness

• Inability to concentrate

• Headaches

• Constipation

• Emotional lability

• Depression

• Blurred vision

• Dry hair

Potential physical examination findings include the following:

• Pseudomyotonic reflexes - Prolonged relaxation phase, usually at least twice as long as the contraction phase

• Hypothermia (especially in myxedema coma)

• Skin changes - Dry, cool, coarse, and thickened with a yellowish appearance

• Subcutaneous tissues - Nonpitting, waxy, dry edema secondary to accumulation of polysaccharides

• Loss of axillary and pubic hair

• Pallor

• Loss of outer one third of eyebrows

• Abdominal distention

• Goiter

• Unsteady gait/ataxia

• Pericardial effusion

• Dull facial expression

• Coarsening or huskiness of voice

• Periorbital edema

• Bradycardia, narrow pulse pressure

• Macroglossia

• Thyroidectomy scar - In patients with altered mental status, suggests myxedema coma as a potential cause

A Swedish study, by Mourtzinis et al, found the rates of hypothyroidism and hyperthyroidism in patients with atrial fibrillation to be 5.9% and 2.3%, respectively, compared with 3.7% and 0.8%, respectively, in controls.[8]

The most common etiology of hypothyroidism worldwide is iodine deficiency as associated with endemic goiter. Conversely, a study among Chinese patients also demonstrated a significant increase in overt hypothyroidism in those with an excessive intake of iodine.[9] Within the United States and developed nations, the major causes of hypothyroidism are autoimmune destruction of the thyroid gland (eg, Hashimoto thyroiditis) and iatrogenic secondary to the treatment of Graves disease (surgical or radioactive iodine ablation of the thyroid gland). Primary hypothyroidism (dysfunction of the thyroid gland) accounts for up to 90-95% of cases. Secondary hypothyroidism (dysfunction of the pituitary or hypothalamus) accounts for most of the remainder of cases. ED management rarely requires distinguishing between primary and secondary origins.

Primary causes include autoimmune, idiopathic, postoperative, and congenital etiologies; radiation; radioiodine therapy; iodine deficiency; metabolic disorders; and medications (eg, lithium, amiodarone, phenytoin, carbamazepine, iodides). Furthermore, those with underlying autoimmune thyroiditis are susceptible to disease progression while taking these medications. Antineoplastic agents are also recognized to cause thyroid dysfunction in 20-50% of patients. Since symptoms of hypothyroidism may be vague and attributed to adverse effects of medication, it may be appropriate to monitor thyroid function regularly during treatment.[10]

A retrospective study by Spiegel et al indicated that small-for-gestational-age infants are at increased risk for childhood hypothyroidism, with an adjusted odds ratio of 3.2.[11]

Secondary causes include pituitary and hypothalamic disorders such as trauma, neoplasm, irradiation, and infiltrative diseases including sarcoidosis or amyloidosis.

In a patient with underlying hypothyroidism, inciting factors responsible for developing myxedema coma are numerous and include infection, trauma, cold exposure, or medications such as sedatives and anesthetics.

The following measurements and studies are indicated in hypothyroidism[4] :

• Electrolytes

  • Hyponatremia is common secondary to extracellular volume expansion produced by elevated antidiuretic hormone.

  • Blood glucose level ranges from normal to low secondary to decreased gluconeogenesis and reduced insulin clearance.

  • Creatine phosphokinase (CPK), aspartate aminotransferase (AST) or serum glutamic oxaloacetic transaminase (SGOT), and lactate dehydrogenase (LDH) levels may be elevated in myxedema coma due to increased muscle membrane permeability. Creatine kinase (CK)-myocardial band (MB) levels are typically normal.

• Arterial blood gas (ABG): Hypoventilation commonly results in hypercapnia and hypoxia in patients with myxedema coma.

• Urinalysis: Evaluate for source of infection.

• Secondary studies

  • Thyroid function studies may not be immediately available to assist in clinical decision making in the ED.

  • Thyroid-stimulating hormone (TSH) is elevated in primary hypothyroidism, but it may be normal or low in secondary causes of hypothyroidism.

  • Free thyroxine (T4) levels are low.

  • Triiodothyronine (T3) resin uptake is decreased.

  • Free T4 index (T3 resin uptake x total serum T4) is low.

  • Critically ill patients may develop euthyroid sick syndrome, which must not be confused with a primary thyroid abnormality. These patients have low to normal TSH and T4 levels with low T3 levels.

See the list below:

• Chest radiography

  • An enlarged cardiac silhouette in a chest radiograph may suggest pericardial effusion. A chest radiograph depicting a pericardial effusion is shown in the image below.

    Pericardial effusion. Note the "water-bottle" appearance of the cardiac silhouette.

  • However, chest radiography is reported to have a 30% false-negative rate in detecting hypothyroid pericardial effusions.

  • Chest radiography can help detect pulmonary infections often associated with myxedema coma.

• Acute abdominal series: An ileus may be associated with hypothyroidism, and it may be present in myxedema coma.

• Head CT scan (noncontrast)

  • In patients with altered mental status, the scan may be helpful in ruling out other etiologies such as intracerebral hemorrhage.

  • The scan may be helpful in ruling out other etiologies of altered mental status, such as intracerebral hemorrhage.

• Echocardiography: Perform this study if pericardial effusion is suspected.

See the list below:

• Electrocardiogram

  • Bradycardia, low voltage, prolonged PR interval, T-wave abnormalities, and electrical alternans (suggestive of effusion) may be present.

• Core temperature

  • Patients with myxedema coma have a temperature below 37°C (98.6°F) in 15% of cases.

  • Fifteen percent of those patients have a temperature below 29.5°C (85°F).

Stabilize acute life-threatening conditions in patients with hypothyroidism, and initiate supportive therapy.

Patients with myxedema coma may present in extremis; implement initial resuscitative measures, including intravenous (IV) access, cardiac monitoring, and oxygen therapy, as indicated. Mechanical ventilation is indicated for patients with diminished respiratory drive or obtundation.

Evaluate for life-threatening causes of altered mental status (eg, bedside glucose, pulse oximetry).

If myxedema coma is suspected on clinical impression, start IV thyroid hormone treatment.

Confirmatory tests often are not available to an ED physician.

With a diagnosis of myxedema coma, initiate hormonal therapy.

Myxedema coma may lead to profound hemodynamic instability and airway compromise. Emergency physicians should anticipate a potentially difficult airway in patients with myxedema coma.[5]

Investigate immediately for inciting events such as infection.

Treat respiratory failure with appropriate ventilatory support. The condition often requires mechanical ventilation. Treat underlying pulmonary infection.

Hypotension may respond to crystalloid infusion. Occasionally, vasopressive agents are required. In refractory cases, hypotension may resolve with thyroid hormone replacement.

Treat hypothermia. Most patients with myxedema coma respond to passive rewarming measures such as blankets and removal of cold or wet clothing; aggressive rewarming may lead to peripheral vasodilatation and hypotension. However, hemodynamically unstable patients with profound hypothermia require active rewarming measures. Treat hyponatremia initially with water restriction; however, if sodium levels are less than 120 mEq/L or any seizures occur, hypertonic saline is indicated.

Avoid medications such as sedatives, narcotics, and anesthetics. Metabolism of these agents may be slowed significantly, causing prolonged effects.

For patients with myxedema coma, consult a critical care intensivist regarding admission to an ICU and optimization treatment.

An endocrinologist should be consulted to help confirm the diagnosis and assist in patient management after admission.

Initiate thyroid hormone replacement as the mainstay therapy for patients with myxedema coma. Patients may remain refractory to other treatment and supportive therapies until thyroid hormone replacement takes effect. Infusing thyroid hormone in the euthyroid patient is unlikely to result in significant morbidity except in patients with ischemic heart disease. Hormonal therapy should be instituted early in patients with a high clinical suspicion of myxedema coma prior to laboratory confirmation.

Monitor the patient's heart during hormone treatment, decreasing or discontinuing the dosage with any evidence of ischemia or dysrhythmia.

The magnitude of hypothyroidism dictates dose and route. Mild cases may be treated with gradual oral replacement, but patients with myxedema coma usually require large doses of IV replacement. General guidelines suggest administration of intravenous levothyroxine at a dose of 500-800 mcg. Alternatively, intravenous liothyronine can be given at a dose of 25 mcg.

Administer antibiotics if infection is suspected to be a precipitating event.

Physicians often recommend glucocorticoid replacement therapy because adrenal insufficiency may be concomitant (especially in patients with secondary hypothyroidism).

Class Summary

These agents are used for the replacement of thyroid hormone.

Liothyronine (Triostat, Cytomel)

Liothyronine is a synthetic form of natural thyroid hormone (T3) converted from thyroxine (T4); its short duration of activity allows quick dose adjustments in the event of overdosage.

Levothyroxine (Synthroid, Levothroid, Levoxyl, Thyquidity)

Levothyroxine is also known as T4; many physicians prefer the more gradual onset of action of this form of thyroid hormone.

Class Summary

These agents are used for prevention and/or treatment of adrenal insufficiency.

Hydrocortisone (Solu-Cortef)

Hydrocortisone is the drug of choice, owing to its mineralocorticoid activity and glucocorticoid effects.

Further inpatient care is as follows:

• Admit patients with myxedema coma to ICU.

• Provide supportive ventilatory and hemodynamic management.

• Treat precipitating events (eg, infection).

• Continue rewarming as required.

• Confirm diagnosis with laboratory testing.

• Continue thyroid hormone replacement, and convert to oral therapy when tolerated.

• Clinical improvement should be apparent within 24-36 hours of initiating thyroid hormone replacement.

Potential complications are as follows:

• Treatment-induced congestive heart failure in patients with coronary artery disease

• Myxedema coma

• Increased susceptibility to infection

• Megacolon

• Organic psychosis with paranoia

• Adrenal crisis with vigorous treatment of hypothyroidism

• Hypersensitivity to opiates

• Pericardial effusion and cardiac tamponade[12]

The prognosis of hypothyroidism is good with early treatment. However, once the disease has progressed to myxedema coma, the mortality rate may exceed 20% in the treated population. Relapses occur if treatment is discontinued.

The mortality rate in myxedema coma has historically been as high as 80%. Some data suggest that aggressive management and early recognition have improved the mortality rate to 15-20%. However, a more recent observational study was unable to show significant differences in outcome based on replacement therapeutic methods, with a mortality rate remaining high at 40%.[13]

The aforementioned study by Ono et al reported that, as revealed through multivariable logistic regression, a higher inhospital mortality rate in myxedema coma was associated with older age and catecholamine use (with or without steroids).[7]

A study by Sato et al suggested that in patients with heart failure, those with subclinical hypothyroidism have a worse prognosis, finding a significant increase in the rates of cardiac events and all-cause mortality in heart failure patients in the study with subclinical hypothyroidism compared with those who were euthyroid.[14]

A literature review by Chrysant suggested that levothyroxine supplementation for subclinical hypothyroidism in younger persons (specifically, those with a thyroid-stimulating hormone [TSH] level of >4.0 mIU/L) is more effective with regard to cardiovascular disease, heart failure, and mortality than it is in older patients. Chrysant also suggested that such treatment in older patients be individualized according to symptom presence and TSH level and that it commence when TSH levels are 10 mIU/L or above. He also advised that, in order to avoid harmful cardiovascular effects in older persons related to overtreatment, it be administered at low doses in these patients.[15]

Patients should be educated about the following:

• Importance of medication compliance

• Need for lifelong treatment

• Watch for signs of infection

• Watch for signs of thyrotoxicity

For patient education resources, see the Endocrine System Center, as well as Thyroid Problems and Myxedema Coma.