Ciammaichella M. M., Galanti A., Rossi C.
U.O.C. Medicina Interna I per l’Urgenza
(Direttore: Dott. G. Cerqua)
A.C.O. S. Giovanni - Addolorata - Roma, Italia
HYPOTHYROIDISM AND MYXEDEMA COMA
Myxedema coma is a life-threatening expression of hypothyroidism
in its most severe form. It occurs most often during the winter months
in elderly women with long-standing, undiagnosed, or undertreated hypothyroidism.
It may be precipiated by infection or other stresses, and the diagnosis
must be suspected based upon the clinical presentation. Treatment should
be prompt and requires the administration of thyroid hormone in large
doses. The mortality is greater than 50 percent in spite of optimum therapy.
CAUSES OF HYPOTHYROIDISM
Hypothyroidism is a chronic systemic disorder characterized
by progressive slowing of all bodily functions because of thyroid hormone
deficiency. The prevalence of hypothyroidism is about 1 percent in women
and 0.1 percent in men. After age 60, the prevalence may be as high as
6 to 7 percent in women. Thyroid hormone is secreted in response to stimulation
of the thyroid gland by thyroid-stimulating hormone (TSH) from the anterior
pituitary gland. The TSH release is promoted by thyrotropin releasing
hormone (TRH) from the hypothalamus. Therefore, thyroid failure may be
primary, due to intrinsic failure of the thyroid gland, or secondary,
due to disease or destruction of the hypothalamus or pituitary gland.
Primary thyroid failure is by far the most common cause, accounting for
95 percent of the cases of hypothyroidism. The most common cause of hypothyroidism
in the adult is treatment of Graves’ disease by radioactive iodine or
subtotal thyroidectomy. Postoperative hypothyroidism is usually evident
within 12 to 15 months after surgery. The incidence of hypothyroidism
following destruction of thyroid tissue with radioiodine increases progressively
with time. The development of hypothyroidism as a consequence of surgical
or radioiodine therapy may take years or decades. If hypothyroidism develops,
these patients are committed to replacement thyroid hormone therapy for
Autoimmune thyroid disorders are the next most common cause of hypothyroidism.
These include primary hypothyroidism and Hashimoto's thyroiditis. Primary
hypothyroidism is thought to be the end result of an autoimmune destruction
of the thyroid gland and produces thyroid failure because of glandular
atrophy. Hashimoto's thyroiditis is the most common cause of goitrous
hypothyroidism in areas with adequate iodine and may cause hypothyroidism
because of defective hormone synthesis. There is clinical and immunologic
overlap of these entities. Other causes of primary thyroid failure are
rare and include iodine deficiency, antithyroid drugs such as lithium
and phenylbutazone, spontaneous hypothyroidism from Graves’ disease, and
Secondary thyroid failure accounts for 5 percent of the cases of hypothyroidism.
Pituitary tumors, postpartum hemorrhage, or infiltrative disorders, such
as sarcoidosis, may result in secondary thyroid failure. There are clinical
and historical differences that distinguish primary thyroid insufficiency
from pituitary failure. This differential diagnosis is difficult on clinical
grounds and requires laboratory evaluation. In general, the TSH level
is high in primary hypothyroidism and low or normal in secondary hypothyroidism.
Disease of the hypothalamus may cause failure to secrete TRH and may result
in thyroid failure. This condition has been termed tertiary hypothyroidism.
A few hypothyroid patients have been identified who have presumed hypothalamic
disease and respond to TRH administration by increasing TSH above baseline
All patients who develop myxedema are hypothyroid, but not all hypothyroid
patients have myxedema. Hypothyroidism is a graded phenomenon with various
signs and symptoms along the clinical spectrum. With moderate to severe
hypothyroidism, a nonpitting, dry, waxy swelling of the skin and subcutaneous
tissue may occur, resulting in a puffy face and extremities. The term
myxedema refers to this particular presentation of hypothyroidism.
The signs and symptoms of mild hypothyroidism may be subtle and the diagnosis
difficult. With advanced hypothyroidism, the patients present with characteristic
features. Typically, they complain of fatigue, weakness, cold intolerance,
constipation, and weight gain without an increase in appetite. Muscle
cramps, decreased hearing, mental disturbances, and menstrual irregularities
are additional symptoms. Cutaneous features noted on physical examination
include dry, scaly, yellow skin, puffy eyes, thinning of the eyebrows,
and scant body hair. The voice may be deep and coarse and the tongue thickened.
Paresthesia, ataxia, and prolongation of the deep tendon reflexes are
characteristic neurologic manifestations. Bell's palsy due to hypothyroidism
has been reported. In advanced cases, delusions, hallucinations, and psychosis
(myxedema madness) may occur. Abdominal distension and fecal impaction
may be present. Cardiac findings include bradycardia, enlarged heart,
and low voltage on ECG. Mild hypertension rather than hypotension is the
rule. Hypertension in conjunction with hypercholesterolemia may contribute
to coronary artery disease and angina pectoris. A surgical scar on the
neck may be present, but a palpable goiter is uncommon.
Diagnosis of hypothyroidism in a patient with these signs and symptoms
can be made essentially on clinical grounds. Abnormally low levels of
thyroid hormones confirm the diagnosis. Serum TSH levels should also be
measured, and elevated levels are virtually diagnostic of primary hypothyroidism.
If the disease is not treated, death follows a progressive intensification
of these signs and symptoms. The time from onset to death varies between
10 and 15 years. Appropriate therapy is l-thyroxine in an average maintenance
dosage of 0.1 to 0.3 mg once daily. The dosage must be individualized
and may be higher or lower. Other thyroid preparations are available and
acceptable as replacement thyroid hormone therapy.
Myxedema coma is a rare complication of hypothyroidism.
The incidence is greater in women than men, and approximately half the
patients are between 60 and 70 years old. A patient with undiagnosed hypothyroidism
may develop coma as the initial manifestation. More commonly, the disease
progresses insidiously, and coma develops when the patient is subjected
A precipitating factor can be found in most cases of myxedema coma. Exposure
to a cold environment is a significant antecedent occurrence with pulmonary
infection and heart failure the most frequent precipitating events. Other
stresses reported to initiate coma include hemorrhage, cerebrovascular
accident, hypoxia, hypercapnia, hyponatremia, hypoglycemia, and trauma.
Significantly, it has been observed that more than 50 percent of the patients
whose cases were reported in the literature lapsed into coma after admission
to the hospital. In this setting, the stress of diagnostic and therapeutic
procedures, acquisition of nosocomial infections, and the administration
of certain drugs have been implicated as causative factors. Hypothyroid
patients metabolize drugs more slowly than normal persons, and narcotics,
anesthetics, phenothiazines, and other tranquilizers or sedatives have
been reported to induce coma. Disastrous results may occur in a patient
with advanced hypothyroidism and myxedema madness whose psychosis is treated
with phenothiazines. The ?-blocking drugs may cause myxedema coma by reducing
thyroid hormone levels through peripheral conversion of thyroxine to triiodothyronine.
Amiodarone-induced hypothyroidism leading to myxedema coma has been reported.
Caution must be used when administering drugs, even in normal amounts,
to hypothyroid patients. A final drug-related cause of myxedema coma is
the failure to take necessary replacement thyroid hormone medication.
The diagnosis of myxedema coma may easily be made in a patient who presents
with the previously described general appearance and physical findings
and with a history of previous thyroid hormone medication, radioactive
iodine therapy, or subtotal thyroidectomy. Unfortunately, the diagnosis
is not always that easy. A wide variety of clinical and laboratory abnormalities
occur and may tend to occupy the physician's attention. Coma may be attributed
to hypothermia, respiratory failure, and CO2 narcosis; electrolye imbalance
and hyponatremia; hypoglycemia; congestive heart failure; stroke; drug
overdose; and other causes. Indeed, any of these disorders may lead to
or worsen coma in the hypothyroid patient, but unless the underlying thyroid
failure is diagnosed and treated, therapeutic efforts are unsuccessful.
The overall clinical picture must be correlated and the diagnosis of myxedema
Hypothermia, unaccompanied by sweating or shivering, is typical of patients
in myxedema coma and occurs in 80 percent of the cases. Approximately
15 percent have a temperature of 29.5?C (85?F) or less. A normal or elevated
temperature suggests underlying infection. It is not coincidental that
most patients develop myxedema coma during the winter, as normal thermogenesis
is impaired in hypothyroidism.
This important diagnostic sign may be missed if a low-reading thermometer
is not used or if the mercury in the thermometer is not shaken down. Hypothermia
should be treated by gradual rewarming at room temperature. Too-rapid
rewarming may cause peripheral vasodilation and circulatory collapse.
Hypoventilation, hypercapnia, and hypoxia are common in patients with
myxedema coma and may be the cause of death in many instances. Multiple
factors have been implicated as causes of respiratory failure. Impaired
respiratory mechanics due to dysfunction of the muscles of the respiratory
system may lead to alveolar hypoventilation, hypercapnia, and hypoxia,
and loss of responsiveness of the respiratory center to these stimuli.
With thyroid hormone replacement hypoxic ventilatory drive is increased
but hypercapnic ventilatory drive is not.
Additional factors that may further impair pulmonary function include
obesity, congestive heart failure, pleural effusions, ascites, parenchymal
lung involvement by myxedematous infiltrate, enlarged tongue, and changes
in the airway, which may occur over its entire length. Airway obstruction
due to myxedematous infiltration of the laryngeal mucosa has been reported.
Patients should be evaluated by chest roentgenography and arterial blood
gas levels, and require close monitoring. Drugs that may further depress
respirations should be avoided. Mechanical ventilation may be required,
and initial tracheostomy has been recommended because of the long recovery
time for normal ventilatory function.
Water retention with hyponatremia and hypochloremia is another common
finding in myxedema coma. Hyponatremia is dilutional, due to extracellular
volume expansion and impaired ability to excrete a water load. Several
mechanisms to account for the hyponatremia have been proposed. These range
from deficiency of adrenal cortical hormones to decreased water delivery
to the distal nephron to inappropriate secretion of antidiuretic hormone.
Regardless of the etiology, hyponatremia is a potentially grave complication
that can lead to water intoxication, brain edema, and death.
Conventional therapy is fluid restriction, but hypertonic saline is recommended
if the serum sodium level is less than 115 mEq/L. A convincing case for
a different therapeutic approach utilizing hypertonic saline, furosemide,
and thyroid hormone has been presented. A review of the 24 hyponatremic-hypothyroid
patients described in the literature since 1953 showed the serum sodium
levels to range from 120 to 129 mEq/L in 8 patients and from 110 to 119
mEq/L in 10 patients, and to be less than 110 mEq/L in 6 others. All 6
patients treated with hypertonic saline survived, while 13 out of 18 who
did not receive this treatment died. Intravenous furosemide induces negative
water balance, while hypertonic saline replaces urinary sodium losses.
Extreme caution must be used to avoid heart failure during the administration
of hypertonic saline.
The cardiovascular system is altered in structure and function with advanced
hypothyroidism. Hypotension, cardiac enlargement detectable on x-ray films,
and bradycardia are the most significant abnormalities to occur during
myxedema coma. Thyroid hormones and sympathomimetic amines act synergistically
to maintain left ventricular performance and vascular tone. Hypotension
may result from a decreased synergistic effect due to thyroid hormone
deficiency. Left ventricular dysfunction and hypotension are usually corrected
by thyroid hormone replacement. Vasopressors do not work well in the absence
of thyroid hormone and should be used, with caution, only in cases of
severe hypotension unresponsive to other therapy. Ventricular arrhythmias
may occur because of the synergistic actions of simultaneously administered
thyroid hormone and vasopressors on a myxedematous myocardium.
Cardiomegaly is common, and is thought to be due to either pericardial
effusion or underlying heart disease and not to ventricular dilation induced
by hypothyroidism. The presence or absence of cardiomegaly on x-ray film
is not a reliable indicator of a pericardial effusion, and echocardiography
is the best way to identify a pericardial effusion. In spite of the frequency
of pericardial effusions, cardiac tamponade in myxedema coma is rare because
of the slow formation of the effusion and the ability of the pericardium
to distend. Most pericardial effusions resolve with thyroid hormone replacement,
but some may require pericardiocentesis or pericardial fenestration.
Sinus bradycardia is the most common electrocardiographic abnormality
during myxedema coma. Other findings include low voltage, flattening or
inversion of the T waves, and prolongation of the PR interval. In spite
of impaired cardiac contractility, pericardial effusions, and conduction
disturbances, congestive heart failure is unusual in myxedema coma and
probably reflects underlying heart disease.
Coma is the terminal expression of neurologic dysfunction in myxedema
and may be directly due to a lack of thyroid hormone in the brain. A variety
of neurologic symptoms premonitory of myxedema coma do occur. Psychiatric
disorders include slowed mentation, memory loss, personality changes,
hallucinations, delusions, and psychosis. Cerebellar ataxia, intention
tremor, nystagmus, and difficulty with coordinated movements may occur.
Twenty-five percent of those who develop myxedema coma initially present
with grand mal seizure. Many of the neuropsychiatric abnormalities improve
with thyroid hormone replacement, but permanent dementia may remain after
treatment. The role of hypothermia, CO2 narcosis, cerebral edema, and
other metabolic disturbances in the genesis of coma must not be overlooked.
Patients with myxedema may have abdominal distension due to ascites, paralytic
ileus, or fecal impaction. Acquired megacolon is almost uniformly observed
and has been the cause of unnecessary abdominal surgery. Urinary retention
may occur, causing lower abdominal discomfort from a distended bladder.
The weight gain that occurs with hypothyroidism is due to accumulation
of some adipose tissue and retention of fluid. Patients with myxedema
coma may be emaciated because of long-standing illness and decreased food
intake. The treatment of abdominal complications consists of thyroid replacement
and conservative measures such as nasogastric aspiration and enemas.
Although some laboratory findings are characteristic of myxedema coma,
only thyroid function tests can confirm hypothyroidism. The combination
of free T4 assay and a sensitive TSH assay are the primary means of assessing
thyroid status in all patients. The patient with hypothyroidism has a
low free T4. TSH is elevated in primary hypothyroidism, whereas when pituitary
or hypothalamic disease is the cause of hypothyroidism, TSH is low. The
results of these tests will not be available for use in the emergent situation
but can later be used to support the clinical impression.
Characteristic laboratory abnormalities of myxedema coma already mentioned
include hypoxemia, hypercapnia, hyponatremia, and hypochloremia. Serum
potassium levels are extremely variable. Blood glucose levels are generally
in the normal range, but severe hypoglycemia can occur. Hypercalcemia
is rare, but hypocalcemia can occur in thyroidectomized patients in whom
the parathyroids have been removed.
Bacterial infection may be reflected only by a leftward shift in the differential
white blood cell count without appreciable elevation of the total white
Elevated serum cholesterol levels occur in approximately two-thirds of
myxedematous patients. Malnutrition may lower the serum cholesterol level
in some cases. Carotenemia has also been reported and may be the cause
of the yellowish skin discoloration. Occasionally, striking elevations
of the levels of muscle enzymes such as creatine kinase (CPK), serum glutamic-oxaloacetic
transaminase (SGOT), lactate dehydrogenase (LDH), and fructose-biphosphate
aldolase may be present. The elevations are thought to be due to changes
in membrane permeability in skeletal muscle rather than to muscle destruction.
The concentrations of these enzymes fall quickly when thyroid hormone
is replaced. Finally, in most hypothyroid patients the CSF protein level
is elevated to 100 mg/dL or more. The CSF pressure may occasionally be
increased to over 400 mmH2O. The significance of these CSF abnormalities
Patients with myxedema coma are critically ill with a multiplicity
of precarious and complex management problems. Specific therapy requires
the administration of large doses of thyroid hormone. This decision must
be based upon clinical judgment and made with extreme caution. The recommended
dose of thyroid hormone could be fatal to the euthyroid comatose patient
and harmful to the patient with ordinary myxedema. Every attempt to rule
out causes of coma unrelated to hypothyroidism must be made first.
Coma in myxedema may be primary, from a cerebral lack of thyroid hormone,
or secondary, due to complications or precipitating causes. Treatment
of the secondary causes of coma already mentioned includes oxygen administration
and ventilatory support for respiratory failure, avoidance of drugs that
may further depress respiratory or metabolic function, gradual rewarming
of hypothermic patients, correction of hyponatremia by fluid restriction
or hypertonic saline and furosemide, correction of hypoglycemia by glucose
infusion, and treatment of hypotension with thyroid hormone and vasopressors,
as needed. A thorough search for precipitating causes of coma should be
made. Antibiotics are indicated for underlying infection. Additional adjunctive
therapy is hydrocortisone, 300 mg/day, to protect against adrenal insufficiency.
Thyroid hormone replacement is the most critical and specific aspect of
therapy for myxedema coma. The treatment already mentioned is largely
supportive and is not fully effective until adequate thyroid hormone is
given. Disagreement exists over the type, doses, and route of thyroid
Intravenous thyroxine is the drug of choice of most authors. It has been
shown to be fully effective within 24 h with an onset of action in 6 h.
The initial intravenous dose is 400 to 500 ?g infused slowly; this is
followed by 50 to 100 ?g IV daily. Following the initial dose, some authors
recommend no further thyroxine therapy until 3 to 7 days later. Once-daily
therapy allows a smooth rise in hormone levels, as the turnover rate for
l-thyroxine is about 10 percent per day. An oral dosage of thyroxine,
100 to 200 ?g/day, can be started when possible. Cardiac arrest following
the intravenous administration of l-thyroxine has been reported. The dose
of thyroxine should be reduced in the face of cardiac ischemia or arrhythmias.
Triiodothyronine is an effective drug for treatment of myxedema coma.
Triiodothyronine is four times more pharmacologically active than thyroxine.
It has previously been available only in tablet form but intravenous L-triiodothyronine
is now available. An initial IV dose of 25 to 50 ?g is recommended for
the emergent treatment of myxedema coma or precoma in adults. The dose
should be lowered to 10 to 20 ?g is patients with known or suspected cardiovascular
disease. Subsequent dosage is 65 to 100 ?g per 24 h in 3 to 4 divided
doses and half of this amount in patients with cardiovascular disease.
There is no difference in the contraindications or drug interactions between
IV T3 or T4. With either replacement medication, overall clinical improvement
should be seen in 24 to 36 h.
1)Holvey, DN, Goodner CJ, Nicoloff JT, et al: Treatment of myxedema coma
with intravenous thyroxine. Arch Intern Med 113:89, 1964.
2)Ladenson PW, Goldenheim PD, Ridgway C: Rapid pituitary and peripheral
tissue responses to intravenous l-triiodothyronine in hypothyroidism.
J Clin Endocrinol Metab 56:1252, 1983.
3)Mitchell JM: Thyroid disease in the emergency department: Thyroid function
tests and hypothyroidism and myxedema coma. Emerg Med Clin North Am 7:885,