Hyperthyroidism & Thyrotoxicosis
Thyrotoxicosis is a clinical syndrome that results from excessive levels of circulating thyroid hormone. The most common causes of thyrotoxicosis are due to overproduction of thyroid hormone by the thyroid gland, but other sources of thyroid hormone may exist, including exogenous ingestion of thyroid hormone or ectopic secretion (Table 42–6).
Table 42–6. Causes of Hyperthyroidism (in Order of Frequency). ||Download (.pdf)
Table 42–6. Causes of Hyperthyroidism (in Order of Frequency).
- Graves' disease
- Toxic multinodular goiter
- Solitary hyperfunctioning adenoma
- Subacute thyroiditis (transient)
- Exogenous thyroid hormone
- Iodine-induced hyperthyroidism
- Struma ovarii
- Metastatic follicular thyroid carcinoma
- Trophoblastic tumors
- TSH-secreting pituitary adenoma
- Pituitary resistance to thyroid hormone
Patients with thyrotoxicosis classically present with a large number of symptoms related to hypermetabolism; these symptoms, listed in Table 42–7, include anxiety, insomnia, a racing heartbeat, palpitations, hand tremors, increased stool frequency, weight loss, heat intolerance, andÂ increased perspiration. Older patients may exhibit “apathetic hyperthyroidism,” which is characterized by weight loss, severe depression, and the potential for slow atrial fibrillation.
Table 42–7. Signs and Symptoms of Hyperthyroidism. ||Download (.pdf)
Table 42–7. Signs and Symptoms of Hyperthyroidism.
Heart racing and palpitations
Weight loss with increased appetite
Oligomenorrhea, loss of libido
Tachycardia, atrial fibrillation
Extremity tremor Warm, moist skin
Fine or thin hair
Lid lag or retraction
Goiter with bruit
On physical examination, patients may be hyperkinetic with an inability to sit still; they may also present with fine tremor and hyperreflexia. Lid retraction is responsible for the characteristic “stare” and lid lag may be evident whereby the sclera can be seen above the iris when the patient is asked to gaze downward slowly. Lid retraction and lid lag are due to the hyperadrenergic state and should not be confused with exophthalmos, which is unique to Graves' disease. The patient's skin may have a velvety, moist texture, and the hair is thin and fine. Cardiovascular signs include tachycardia, widening of the pulse pressure with an increase in systolic pressure and a decrease in diastolic pressure, and a hyperdynamic precordium. Atrial fibrillation occurs in approximately 10% of patients with thyrotoxicosis. Examination of the neck may reveal a diffusely enlarged or multinodular goiter, a single nodule, or a painful and tender thyroid. A bruit may be present and is most often heard over the gland in Graves' disease.
The diagnosis is confirmed by laboratory analysis. Overt thyrotoxicosis typically has a suppressed TSH and elevated FT4 and FT3 concentrations. A normal T4 but an elevated T3 is consistent with T3 toxicosis, usually seen in the early phase of toxic multinodular goiter and Graves' disease. The diagnosis of the etiology of thyrotoxicosis can be aided by the physical examination—the presence of ophthalmopathy, diffuse goiter, and pretibial myxedema is suggestive of Graves' disease. Additional laboratory tests, such as TSI (thyroid-stimulating immunoglobulin), anti-TPO, and ESR (erythrocyte sedimentation rate) can be helpful in diagnosing Graves' disease, the hyperthyroid phase of Hashimoto's disease, and viral thyroiditis. Radioactive thyroid uptake and scan are occasionally needed to confirm the cause of thyrotoxicosis.
Graves' disease is an autoimmune disorder characterized by the production of immunoglobulins that bind and activate the TSH receptor, which stimulates thyroid growth and hormone secretion. It tends to occur in women between the ages of 20 and 40, with an incidence of 1.9% in women. Females are five times more likely to be affected than males. There is a strong family predisposition in that 15% of patients have a close relative with the disorder.
In addition to the signs and symptoms of hyperthyroidism, several signs and symptoms are unique to Graves' disease, including ophthalmopathy, dermopathy, and osteopathy. Infiltrative ophthalmopathy is by far the most common sign. For unclear reasons, the increased inflammation and the accumulation of glycosaminoglycans cause swelling of extraocular and retroorbital muscles, as well as displacement of the eye forward (also known as proptosis or exophthalmos). Patients can experience eye irritation; excessive tearing worsened by cold air, bright lights, or wind; diplopia; blurred vision; and, rarely, loss of vision.
Other physical findings in Graves' disease include dermopathy and osteopathy. Glycosaminoglycans can accumulate in the dermis layer, causing thickening of the skin, especially over the anterior tibia (pretibial myxedema). Osteopathy may occur with subperiosteal bone formation and swelling. The extrathyroidal manifestations often have a course independent of the thyroid disease itself and can persist despite restoration of the euthyroid state.
The diagnosis of Graves' disease can be made from evidence of ophthalmopathy on the physical exam, as well as a decreased TSH and an increased FT4 or FT3. If ophthalmopathy is absent, obtaining a measure of TSI can be helpful. TSI is specific for Graves' disease but the lack of a TSI elevation does not exclude the diagnosis. The presence of autoantibodies provides supportive evidence for Graves' disease. More than 95% of patients have anti-TPO antibodies and about 50% have antithyroglobulin antibodies. In the absence of eye signs or an elevated TSI, a radioactive scan and uptake can be performed to confirm the diagnosis of Graves' disease.
There are three aspects in the treatment of Graves' disease: (1) the control of hyperadrenergic symptoms, (2) the short-term restoration of the euthyroid state, and (3) the long-term control of excess thyroid hormone production.
Control of Adrenergic Excess
To control the symptoms of adrenergic excess, beta-blockers—either propranolol or atenolol—are used. These agents should be instituted even before determining the cause of hyperthyroidism. Propranolol has the advantage of inhibiting peripheral T4 to T3 conversion, whereas atenolol is more convenient with once-daily dosing. A typical starting dose is 10–20 mg of propranolol—three to four times a day, or 25 mg of atenolol once daily. These drugs are then titrated up over a few days while the patient's pulse and blood pressure are monitored. The beta blockade is discontinued once the serum FT4 and T3 levels return to normal.
Restoration of Euthyroid State
Thionamides (methimazole or propylthiouracil) act by inhibiting TPO-mediated iodination of thyroglobulin to form T4 and T3 within the thyroid gland and are generally used to restore the patient to the euthyroid state before deciding on long-term management. Methimazole is the preferred drug in most circumstances because propylthiouracil has been associated with the increased risk of fulminant hepatitis resulting in death or need for liver transplantation. Also, in patients for whom 131I treatment is planned, methimazole is preferable to propylthiouracil because propylthiouracil may inhibit radioactive iodine uptake for weeks or months after discontinuation. Typically, a patient is started on a daily 20–40 mg dose of methimazole for 1–2 months, and then titrated down to a maintenance dose of 5–10 mg. Titration of the drug dose is based on the measurement of TSH and FT4, as well as on the signs and symptoms of hyper- or hypothyroidism.
Propylthiouracil should only be used if the patient is allergic to methimazole. The typical starting dose of propylthiouracil is 100–150 mg three times a day; after 1–2 months it is titrated down to 50–100 mg twice daily. It also is more protein bound and is therefore the preferred drug at time of conception and in the first trimester of pregnancy. Because of hepatotoxicity concerns, consider switching back to methimazole in the second and third trimesters. Although less propylthiouracil is excreted in breast milk than methimazole, both drugs are considered safe for use during breast feeding provided the doses are kept low. In pregnancy, if the initial dose of propylthiouracil is 300 mg or less and the maintenance dose is 50–150 mg daily, the risk of fetal hypothyroidism is extremely low. The thionamide doses are titrated to maintain total T4 at the upper limit of normal.
Both methimazole and propylthiouracil cause a rash in approximately 5.0% of patients. Agranulocytosis, which occurs in about 0.5% of patients, is usually heralded by a severe sore throat and fever. Patients should be counseled to stop the drug if they get a sore throat or fever and to see their physician. If the white blood cell count is normal, then the antithyroid drug can be resumed. Other serious side effects requiring discontinuation of drug include arthritis with both drugs; cholestatic jaundice with methimazole; angioneurotic edema, hepatocellular toxicity, and vasculitis with propylthiouracil.
The choice of long-term therapy is based on the age of the patient, the severity and duration of the hyperthyroidism, the size of the gland, and the potential for a future pregnancy. In the one randomized trial that assessed the efficacy of drug treatment, radioablation, and surgery, all three modalities were found to be equally effective. However, there are several guidelines for choosing a treatment modality.
Methimazole treatment is chosen for long-term therapy, particularly in adolescents and young patients with small glands and less severe disease. The drug is usually given for up to 18 months to allow the disease to remit spontaneously. This remission occurs in 30–40% of patients treated for 18 months. If the patient relapses after stopping the methimazole, then the patient has the option of going back on methimazole or consider radioactive iodine therapy or surgery.
Radioactive iodine ablation is the treatment of choice in patients 21 years and older. From a survey performed by the American Thyroid Association, 69% of American thyroid specialists recommended radioablation as the therapy of choice. In contrast, only 22% and 11% of European and Japanese thyroid doctors recommended radioablation as a first-line therapy.
With this treatment modality, patients are dosed with radioactive iodine based on their uptake scan. Patients with severe hyperthyroidism, serious thyroid enlargement, or a history of heart disease should be adequately returned to the euthyroid state with methimazole prior to radioablation, with methimazole discontinued about 5 days prior to radioablation. Most patients subsequently become hypothyroid and require thyroid hormone replacement. Approximately 10% of patients have unsuccessful radioablation and may require a second dose. Radioactive iodine treatment is contraindicated in pregnancy, and it is important to advise women who may become pregnant in the near future that they should wait at least 6 months after 131I treatment to allow for the resolution of any transient effects of the radiation on the ovaries. Alternative options should be offered to a female patient who cannot wait that long. Radioiodine therapy can exacerbate Graves' ophthalmopathy especially if the disease is severe or if the patient is a smoker. Concomitant glucocorticoid therapy can prevent exacerbation. Surgery may be a better option for such patients.
Total or subtotal thyroidectomy should be considered in patients with a very large gland (ie, >150 g), those with severe Graves' ophthalmopathy, those who are allergic to antithyroid drugs, and the patient who wants to get pregnant soon. Patients should be given thionamides until a euthyroid state is achieved (approximately 6 weeks), and a saturated solution of potassium iodide—5 drops twice daily for the 2 weeks before surgery. The preoperative iodine treatment decreases the vascularity of the gland and reduces intraoperative blood loss. The degree of the thyroidectomy is variable among surgeons but generally 2–3 g of thyroid tissue is left intact. If an experienced surgeon is available then total thyroidectomy is preferable because leaving behind too much tissue may result in disease recurrence. Total thyroidectomy is also preferred in patients with progressive exophthalmos.
Surgical complications include neck hematoma, recurrent laryngeal nerve injury, and hypoparathyroidism. A neck hematoma can cause airway compromise and must be evacuated immediately. In experienced surgeons the rate of hypoparathyroidism is less than 1%. Approximately 10% of patients develop transient post-operative hypocalcemia. Oral and intravenous calcium supplementation is sufficient to control the symptoms. The rate of recurrent laryngeal nerve injury leading to ipsilateral vocal cord paralysis is also about 1%. Bilateral recurrent laryngeal nerve injury can cause severe respiratory impairment and may require tracheostomy. It is now extremely rare after subtotal thyroidectomy.
Most patients require thyroid hormone replacement therapy postoperatively.
Thyroid Crisis (Thyroid Storm)
Thyroid crisis is an acute exacerbation of all symptoms of thyrotoxicosis. It occurs in patients with inadequately controlled thyrotoxicosis who undergo surgery, radioactive iodine treatment, parturition, and severe stressful illnesses such as infections, uncontrolled diabetes, and myocardial infarction. This disorder results from hypermetabolism and excessive adrenergic response. It is typically associated with Graves' disease but can also occur in patients with toxic nodular goiter.
Systemic symptoms include fever (38–41°C), flushing, and sweating. Cardiac symptoms and signs include tachycardia, atrial fibrillation, and congestive cardiac failure. Neurologic symptoms and signs include agitation, restlessness, delirium, and coma. Gastrointestinal symptoms include abdominal pain, nausea, vomiting, diarrhea, and jaundice.
Thyroid crisis is a medical emergency and should be treated promptly. Propranolol, either in a dose of 1–2 mg given as a slow IV injection, or in a dose of 40–80 mg administered orally, is given to control tachyarrhythmias. Methimazole is given at a dose of 20 mg every 6 to 8 hours. Propylthiouracil (250 mg every 6 hours) was traditionally favored because it partially blocked the peripheral conversion of T4 to T3. It is however no longer considered first line therapy because of its association with hepatocellular injury. If the patient cannot take oral medications, then 60 mg of methimazole every 24 hours or 400 mg of propylthiouracil can be administered rectally. An hour after a dose of methimazole or propylthiouracil has been given, hormone release can be retarded by giving an oral, saturated solution of potassium iodide (10 drops twice daily). The oral cholecystographic agents (sodium ipodate or iopanoic acid) similarly retard hormone release and also potently block T4 to T3 conversion, but they are not currently available in the United States. Sodium iodide (1 g) can be given intravenously over 24 hours. In addition, 50 g of hydrocortisone is administered intravenously every 6 hours, then tapered as clinical improvement occurs. Supportive measures include intravenous fluids and the management of electrolytes and nutrition. Aspirin should be avoided because it can displace T3 from TBG.
The American Thyroid Association has classified Graves ophthalmopathy into six classes: (1) Class 1, spasm of the upper eyelids; (2) Class 2, soft tissue involvement with periorbital edema and conjunctival chemosis; (3) Class 3, proptosis; (4) Class 4, muscle involvement that limits gaze;Â (5) ClassÂ 5, corneal involvement (eg, keratitis); and (6)Â Class 6, visual loss due to optic nerve involvement.
The treatment of Graves' ophthalmopathy involves (1) reversal of the hyperthyroid state; (2) symptomatic treatment with eye lubrication, glucocorticoids, or both; and (3) with severe symptoms, the surgical decompression of the orbit. Most patients have mild disease; one study found that approximately 65% of patients treated with thionamide therapy alone had no progression of eye disease, and only 8% demonstrated deterioration.
Restoration of the euthyroid state can be achieved by thionamide therapy, radioablation, and surgery. Radioablation can aggravate the ophthalmopathy, especially in smokers. Treatment with a short course of prednisone (40–60 mg/d) tapered over 4–6 weeks at the same time as 131I treatment can prevent this exacerbation.
In most patients, symptomatic treatment involves alleviating corneal irritation and wearing dark glasses. Glucocorticoid therapy is indicated for worsening chemosis, diplopia, or proptosis. Surgical decompression is warranted for progressive eye disease despite glucocorticoids, optic nerve changes, corneal ulceration or infection, and cosmetic reconstruction. A loss of vision, which is heralded by a loss of color vision, is considered a medical emergency; the patient should be treated with high-dose glucocorticoids and surgical decompression. Orbital radiotherapy can also be used if glucocorticoid therapy is ineffective or if there is recurrence after the dose is tapered.
Bartalena L et al. Consensus statement of the European group on Graves' orbitopathy (EUGOGO) on management of Graves' orbitopathy. Thyroid. 2008;18(3):333–346
. (Evidence based recommendations on the treatment of thyroid orbitopathy.)
Kaplan MM, Meier DA, Dworking HJ. Treatment of hyperthyroidism with radioactive iodine
. Endocrinol Metab Clin North Am
. (Review of the role of radioactive iodine
in treating various hyperthyroid states.)
Weetman AP. Graves' disease. N Engl J Med
. (Comprehensive review of the pathogenesis, clinical signs and symptoms, diagnosis, and treatment of Graves' disease.)
Other Forms of Thyrotoxicosis
The antiarrhythmic drug amiodarone contains 37.3% iodine and has a half-life of about 50 days. Although amiodarone-induced hypothyroidism is far more common than hyperthyroidism, 2% of patients on amiodarone will develop hyperthyroidism. The symptoms of amiodaroneinduced hyperthyroidism may be blunted by the antiadrenergic effects of amiodarone itself, and hyperthyroidism often develops years after starting this medication.
Etiology & Clinical Findings
There are two etiologies responsible for hyperthyroidism that manifests in the setting of amiodarone: (1) excess iodine in an underlying abnormal gland causes excessive hormone production and (2) thyroiditis caused by amiodarone itself. Thyroid ultrasound may be useful in differentiating between the two causes, with an increased Doppler flow in excess hormone production and a decreased Doppler flow in thyroiditis. However, many patients may have a mixed etiology, and it is often difficult to differentiate between the two forms.
Patients may be treated with higher-dose thionamides, such as 40–60 mg of methimazole, and beta-adrenergic blockade. If there is inadequate control, a 40-mg daily dose of prednisone is often helpful, especially in cases of amiodarone-induced thyroiditis. Total thyroidectomy should be considered since it is curative, but patients often have a poor operative status.
Eskes SA, Wiersinga WM. Amiodarone
and thyroid. Best Pract Res Clin Endocrinol Metab.
. (Comprehensive review of amiodarone-induced hypothyroidism and hyperthyroidism.)
Subacute granulomatous thyroiditis is an acute inflammatory disorder of the thyroid gland presumed to be due to viral infection. Subacute granulomatous thyroiditis may also be referred to as de Quervain thyroiditis, subacute thyroiditis, and subacute nonsuppurative thyroiditis.
The classic signs and symptoms are fever, malaise, and soreness of the neck; the thyroid gland is extremely tender on examination. Patients need a changing pattern of thyroid function tests throughout the course of the disease. Initially, with thyroid follicle damage and the release of preformed thyroid hormones, TSH is decreased, with an increase in T4 and T3 and a low radioactive iodine uptake. After 2–6 weeks, patients enter a euthyroid phase as T4, T3, and TSH levels return to normal. A transient hypothyroid phase of 2–8 weeks ensues while thyroid hormone stores are exhausted and the thyroid follicles regenerate. Most patients return to the euthyroid state once the thyroiditis has resolved; however, a hypothyroid state may be permanent in 10% of patients.
The diagnosis of subacute thyroiditis is made clinically. A markedly elevated ESR as high as 100 mm/h is strongly suggestive of the diagnosis. Additional helpful laboratory findings include negative thyroid autoantibodies.
Patients are usually treated symptomatically with beta-blockers and nonsteroidal anti-inflammatories (NSAIDs); prednisone is usually reserved for more severe cases. Patients who become hypothyroid should be administered l-thyroxine.
Rare Forms of Thyrotoxicosis
Thyrotoxicosis factitia is a psychoneurotic disorder in which patients purposely take thyroid hormones, usually for weight control. In addition, patients may be given thyroid hormones by psychiatrists to facilitate the treatment of depression. Clinical findings include the absence of a goiter, a suppressed TSH level, mild elevation of T4 and T3, a negative radioactive iodine uptake level, and a low thyroglobulin level.
Teratoma of the ovaries may contain functioning thyroid tissue, which results in hyperthyroidism. Radioactive iodine uptake in the neck is absent, but a whole body scan shows an increased uptake in the pelvis. Curative treatment involves resection of the teratoma.
Metastatic Follicular Carcinoma
Follicular thyroid carcinoma usually does not retain the ability to produce active hormone, but in rare instances, as in the presence of metastatic disease, follicular carcinoma can produce a hyperthyroid state. A radioactive body scan usually shows an increased uptake in the lungs or bones.
Hydatidiform moles do not produce thyroid hormone; rather, they produce chorionic gonadotropin, which displays TSH-like activity. Clinical evidence of hyperthyroidism is usually not present, but a laboratory workup can reveal a suppressed TSH and a mild elevation of serum T4 and T3. Resection of the mole is curative.
The failure of thyroid hormone production results in a generalized hypometabolic state and seriously impairs normal growth and development if it occurs early in life. Hypothyroidism may be due to a primary disease of the thyroid gland, or it may be secondary to a pituitary deficiency. Hypothalamic dysfunction, resulting in a TSH deficiency or peripheral resistance to the action of thyroid hormone, is a rare cause (Table 42–8).
Table 42–8. Causes of Hypothyroidism (in Order of Frequency). ||Download (.pdf)
Table 42–8. Causes of Hypothyroidism (in Order of Frequency).
|1. Hashimoto's thyroiditis|
|a. Radioactive iodine therapy for Graves' disease|
|b. Subtotal thyroidectomy for Graves' disease or nodular goiter|
|3. Excessive iodide intake (kelp, radiocontrast dyes)|
|4. Transient hypothyroidism|
|a. Subacute lymphocytic thyroiditis|
|b. Subacute granulomatous thyroiditis|
|c. Postpartum thyroiditis|
|5. Lithium, antithyroid drugs (methimazole, propylthiouracil); (rare)|
|6. Iodide deficiency (rare)|
|7. Inborn errors of thyroid hormone synthesis (rare)|
|1. Hypopituitarism due to a pituitary adenoma|
|2. Pituitary ablative therapy|
|1. Hypothalamic dysfunction (rare)|
In adults, the onset of symptoms of hypothyroidism is often insidious. These symptoms include fatigue, weight gain, intolerance to cold, and a delayed relaxation phase to deep tendon reflexes (Table 42–9).
Table 42–9. Signs and Symptoms of Hypothyroidism. ||Download (.pdf)
Table 42–9. Signs and Symptoms of Hypothyroidism.
Dyspnea on exertion
Delayed tendon reflexes
Slowed movement and speech
Dry, rough skin, loss of eyebrows
Nonpitting edema, periorbital edema
Muscle stiffness, proximal weakness
Rare: Pleural and pericardial effusions
Depressed ventilatory drive
Hashimoto's thyroiditis is the most common cause of hypothyroidism. It is an autoimmune disease characterized by lymphocytic infiltration, destruction of thyroid follicles, and fibrosis. Several autoantibodies are present, including anti-TPO, antithyroglobulin antibody, and TSH-receptor-blocking antibody. Thyroperoxidase antibodies remain positive for many years and are useful for diagnosis. There may or may not be a goiter. The goiter in Hashimoto's thyroiditis is usually moderate in size and firm in consistency. In older patients, the thyroid may be totally destroyed by the immune process, and the gland is found to be small on examination.
The diagnosis of suspected hypothyroidism is outlined in an algorithm listed in Figure 42–6. In primary hypothyroidism, the TSH is elevated with a low FT4 level. In secondary hypothyroidism, the TSH level is low or inappropriately normal with a low FT4 level. Secondary hypothyroidism may also present with other signs of pituitary deficiency, including hypogonadism and adrenal insufficiency.
Treatment involves hormone replacement with l-thyroxine; the average replacement dosage in adults is 1.6 mcg/kg/d. In young, healthy adults, a starting dosage of 75–100 mcg can be used, followed by a dosing adjustment every 4–6 weeks. Elderly patients or patients with coronary artery disease should be started on much smaller doses of 12.5–25.0 mcg/d, and then increased by 12.5–25.0 mcg every 4–6 weeks until the TSH level normalizes between 0.5 and 2 mU/L. Once stabilized, patients should be monitored once or twice a year with TSH and FT4. T4 has a half-life of about 7 days and therefore needs to be given only once daily.
Desiccated thyroid is unsatisfactory because of its variable hormone content and should not be used. The use of T3 is controversial. The current preparation is rapidly absorbed, has a short half-life, and a rapid biological effect. Patients who experience malabsorption or who ingest drugs such as calcium and iron, which impair T4 absorption, may require an increase in T4 dosing. Since the half-life of T4 is long, it is not a problem omitting the drug for a few days if the patient is unable to take oral medications. Alternately, the patient can be given parenteral l-thyroxine at 75% of the usual oral dose.
Severe, untreated hypothyroidism can result in a hypothermic coma. It tends to occur in elderly patients and is frequently fatal (>20% incidence).
Myxedema coma is characterized by hypothermia, bradycardia, alveolar hypoventilation with CO2 retention, hyponatremia, hypoglycemia, and either stupor or coma. The diagnosis is often difficult because the coma and hypothermia may be due to other causes, such as stroke. Heart failure, pneumonia, excessive fluid administration, and sedatives or narcotic use can precipitate myxedema coma.
Treatment consists of l-thyroxine administered intravenously, at an initial loading dose of 300–400 mcg, followed by 80% of the calculated full replacement dose intravenously daily. Ventilatory support may be required for hypoventilation and hypercarbia. Hyponatremia is treated with fluid restriction. Active rewarming is contra-indicated, because it may induce vasodilation and vascular collapse. The patient should be screened for concomitant adrenal insufficiency by a cosyntropin stimulation test. Until the cortisol results are available, the patient should be treated with hydrocortisone (100-mg IV bolus followed by 50 mg intravenously every 6 hours).
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Jordan RM. Myxedema coma: Pathophysiology, therapy, and factors affecting prognosis. Med Clin North Am
. (General review of the diagnosis and treatment of myxedema coma.)
Lindsay RS, Toft AD. Hypothyroidism. Lancet
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