Published: August 2014
A normal adult thyroid gland weighs 10 to 20 g and receives blood from bilateral superior and inferior thyroid arteries and a small artery called the thyroid ima. The thyroid secretes two hormones. Thyroxine (T4) makes about 90% of hormone production, and triiodothyronine (T3) produces the other 10%. Peripheral tissues convert T4 to T3, and most of T3 is derived from T4. Thyroid hormone secretion is regulated by the hypothalamo-pituitary-thyroid axis through stimulatory actions of TRH and TSH.
Thyroid hormones are transported in serum bound to carrier proteins (0.03%-0.04% of T4 and 0.3%-0.4% of T3 are free hormone). Thyroid hormone binding globulin (TBG) is the main carrier, accounting for 75% of bound T4 and almost all of bound T3. Thyroxine binding prealbumin and albumin are responsible for the rest.
Most thyroid hormone actions (metabolic and developmental) are mediated via nuclear receptors through gene expression regulation. Thyroid hormone receptors are found in most body tissues. T3 is biologically much more active than T4. Thyroid hormones increase the basal metabolic rate by stimulating catabolic and anabolic reactions in the metabolism of carbohydrates, fat, and proteins and by stimulating thermogenesis. Thyroid hormone deficiency during embryonic development leads to cretinism and dwarfism (congenital myxedema).
Hypothyroidism results from reduced effects of thyroid hormone on tissues. Hypothyroidism is more common in women and has a total prevalence of 1% to 2%,1 increasing with age (~10% adults >65 years). In the U.S. population, the prevalence of biochemical hypothyroidism is 4.6%, but clinically evident hypothyroidism is present in 0.3%.2 Congenital hypothyroidism is among the most common congenital diseases, with an incidence of 1/4,000 newborns. A higher risk of hypothyroidism is seen in persons with the conditions listed in Box 1.
|Box 1 Conditions Indicating Higher Risk for Hypothyroidism|
|Family or personal history of autoimmune disease|
|Women in the postpartum period|
|Personal history of neck or head irradiation|
|Primary pulmonary hypertension|
|Genetic syndromes: Turner’s and Down syndromes|
|Patients treated with amiodarone, interferon-alpha, or lithium|
|Persons over 65 years of age|
Hypothyroidism can be congenital or acquired, subclinical or overt, and, according to the site of abnormality, primary (thyroid level) or secondary (pituitary or hypothalamic). The most common causes (Box 2) are Hashimoto’s thyroiditis, postsurgical or postablative hypothyroidism, amiodarone-induced hypothyroidism, and postpartum thyroiditis.
|Box 2 Causes of Hypothyroidism|
|● Surgical removal|
|● Irradiation (therapeutic radioiodine, external irradiation)|
|● Autoimmune disease (Hashimoto’s, atrophic thyroiditis)|
|● Idiopathic atrophy|
|● Infiltrative process|
|Inhibition of thyroid hormone synthesis and release|
|● Iodine deficiency|
|● Excess iodide in susceptible persons|
|● Drugs: interferon alpha, lithium, amiodarone, aminoglutethimide, thalidomide, sunitinib, sorafenib|
|● Inherited enzyme defects|
|● After surgery or therapeutic radioiodine|
|● Genetic forms of pituitary hormone deficiencies|
|● Infiltrative disorders|
|● Sheehan’s syndrome|
|● Surgery or irradiation|
|Resistance to thyroid hormone|
Hashimoto’s thyroiditis is an autoimmune disorder directed against thyroid antigens and is the most common cause of hypothyroidism. The incidence is 0.3 to 1.5 per 1,000 person-years, and it is 4 to 10 times more common in women than in men. Hashimoto’s thyroiditis is more prevalent in areas with a high dietary iodine intake, and smoking increases the risk. Goiter can be seen on presentation, but thyroid atrophy is more common. Hashimoto’s thyroiditis is associated with other endocrine diseases in polyglandular autoimmune failure syndrome (Addison's disease, type1 diabetes mellitus, premature ovarian failure, and hypogonadism in males).
The diagnosis is made by clinical features, elevated TSH, low thyroid hormone, and the presence of antithyroid peroxidase antibodies.
Excess iodine from amiodarone exerts an acute, transient inhibition of iodide organification, the Wolff-Chaikoff effect, but the normal gland escapes this effect due to adaptation of the iodide transport system. In some persons, the thyroid gland is unable to escape the block, and hypothyroidism ensues. Thyroid function tests should be checked before starting amiodarone therapy, after 3 to 4 months of therapy, and 1 year after discontinuing therapy.
Postpartum thyroiditis usually manifests with mild hyperthyroidism (see later) followed by a hypothyroid phase (transient or permanent).
Signs and symptoms of hypothyroidism depend on pathogenesis, duration, severity, and the age of the patient. Symptoms of mild hypothyroidism are nonspecificincluding fatigue, cold intolerance, sleepiness, weight gain and muscle aches. These symptoms are also seen with a variety of other conditions. Such patients should be tested for hypothyroidism. Other signs and symptoms include bradycardia, constipation, menstrual irregularities, dry skin, coarse or brittle hair, edema (especially periorbital), slowing of the relaxation phase of the tendon reflexes, and difficulty with concentration and memory. Laboratory tests might also demonstrate elevated cholesterol, prolactin, and creatine phosphokinase.
Hypothyroidism is associated with impaired endothelial function, left ventricular diastolic dysfunction, and higher diastolic blood pressure due to increased systemic vascular resistance. These abnormalities are reversible with L-T4 replacement therapy.3
Myxedema coma is the most serious form of hypothyroidism; it is often precipitated by other diseases. Patients have profound hypothermia, bradycardia, and typical skin and facial changes. Mortality is 100% if not treated. Myxedema coma is extremely rare today.
A TSH level is the best screening test for detecting hypothyroidism. A normal TSH rules out primary hypothyroidism in asymptomatic patients. Abnormal TSH should be followed by another TSH measurement and determination of thyroid hormone levels in 2 to 3 weeks to rule out conditions that transiently disrupt hypothalamo-pituitary-thyroid axis. Box 3 lists conditions associated with transient elevation of TSH.
|Box 3 Conditions Associated with Transient Abnormalities in TSH Levels|
|Transient elevation of TSH|
|● Recovery phase of thyroiditis|
|● Recovery phase of nonthyroidal illness|
|● Administration of human recombinant TSH|
|Transient suppression of TSH|
|● Glucocorticoid administration|
|● Dopamine administration|
|● Dobutamine administration|
|● Severe nonthyroidal illness (sick euthyroid syndrome)|
|● Initial phase of thyroiditis|
Overt hypothyroidism is defined as a clinical syndrome of hypothyroidism associated with elevated TSH and decreased serum levels of T4 or T3. Subclinical hypothyroidism is defined as a condition without typical symptoms of hypothyroidism, elevated TSH (>5 µU/mL), and normal circulating thyroid hormone.
The measurement of thyroid autoantibodies helps in diagnosing an autoimmune process. However, this test should be ordered only if it will influence the decision to treat.
Treatment is with thyroid hormone supplementation. Levothyroxine (L-T4) is acceptable therapy for most patients. The starting dose should be 1.6 µg/kg of body weight. In elderly patients and patients with cardiac disease, we recommend starting at a lower dose (25-50 µg/day) and increase by 25 µg/d until the patient is clinically and biochemically euthyroid. The dose should be adjusted about 6 to 8 weeks after treatment is initiated (unless symptoms of overtreatment occur). Once the patient is euthyroid and TSH is stable, an annual follow-up with TSH measurement should suffice. During pregnancy, more-frequent TSH determinations are needed because of increasing needs secondary to an increase in binding protein levels and because of the importance of adequate treatment for normal neuropsychological development of the baby. TSH should also be checked 2 months after the start or discontinuation of hormone replacement therapy.
The goal TSH is below 3.0 mIU/L because the vast majority of healthy individuals have TSH below this level (95%) and median TSH very close to 1.5 mIU/L. If symptoms persist, it is acceptable to increase dose and bring TSH to lower levels.The patient should be advised to take the T4 preparation 2 to 4 hours before or after meals or away from using preparations known to impede T4 absorption: calcium, magnesium, iron, sucralfate, and aluminum hydroxide.
If any signs or symptoms suggest adrenal insufficiency, this should be investigated and, if confirmed, glucocorticoids should be given before starting T4. Failure to do so can precipitate adrenal crisis.
In selected circumstances, T3 may also be used to treat hypothyroidism. Drawbacks to routine use of T3 include short half-life, requiring multiple daily doses, and fluctuating symptoms when doses are missed.
Combination therapy using both T4 and T3 (desiccated thyroid extract, compounded T4-T3 preparation) has been proposed to improve mood and quality of life, but most studies did not show benefit.4 We do not recommend routine use of combination therapy except in cases where fast improvements in clinical condition are required (profound hypothyroidism).
Myxedema coma requires aggressive treatment with intravenous T4 (≤500 µg/day), and some authors recommend addition of T3.5
These preparations are summarized in Table 1.
|Synthroid||T4||25, 50, 75, 88, 100, 112, 125, 137, 150, 200, 300 µg|
|Levoxyl||T4||25, 50, 75, 88, 100, 112, 125, 137, 150, 200, 300 µg|
|Unithroid||T4||25, 50, 75, 88, 100, 112, 125, 137, 150, 200, 300 µg|
|Levothyroid||T4||25, 50, 75, 88, 100, 112, 125, 137, 150, 200, 300 µg|
|Tirosint||T4||13, 25, 50, 75, 88, 100, 112, 125, 137, 150 µg|
|Armour thyroid||T4 / T3||15, 30, 60, 90, 120 mg|
|Nature Throid||T4 / T3||¼, ½, ¾, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 3, 4, 5 grains*|
|VP thyroid||T4 / T3||¼, ½, ¾, 1, 1.25, 1.5, 1.75, 2 grains*|
|Liothrix||T4 / T3||12.5/3.1, 25/6.25, 37.5/9/35, 50/12.5, 75/18.75 µg|
|Cytomel||T3||5, 25 µg|
* 1 grain is approximately equivalent to 65 mcg of T4.
Consultation with an endocrinologist should be sought in hypothyroid patients who are 18 years old or younger, unresponsive to therapy, or pregnant; who have cardiac disease, goiter, nodule, or other structural abnormality of thyroid gland; or who have coexisting endocrine disease.
Thyrotoxicosis is a clinical condition resulting from the action of excess thyroid hormone on tissues. The term hyperthyroidism is usually reserved for thyrotoxicosis caused by excessive production of thyroid hormone (Boxes 4 and 5). Other forms of thyrotoxicosis include thyrotoxicosis factitia and those associated with different forms of thyroiditis. Overt thyrotoxicosis is defined as the syndrome of hyperthyroidism associated with suppressed TSH and elevated serum levels of T4 or T3. Subclinical thyrotoxicosis is devoid of symptoms, but TSH is suppressed although there are normal circulating levels of thyroid hormone.
|Box 4 Causes of Thyrotoxicosis|
|Thyroid hormone overproduction|
|● Graves’ disease|
|● Toxic multinodular goiter|
|● Toxic adenoma|
|● Metastatic thyroid carcinoma|
|● Human chorionic gonadotropin–mediated thyrotoxicosis|
|● Thyroid-stimulating hormone–mediated thyrotoxicosis, pituitary resistance to T4 and T3|
|● Iodide excess (Jod-Basedow)|
|Uncontrolled release of preformed thyroid hormones|
|● Subacute thyroiditis|
|● Painless thyroiditis|
|● Postpartum thyroiditis|
|● Hashimoto’s thyroiditis|
|● Amiodarone induced thyroiditis|
|● Nonthyroidal excess|
|● Thyrotoxicosis factitia|
|● Struma ovarii|
|Box 5 Signs and Symptoms of Thyrotoxicosis|
|● Heat intolerance|
|● Excessive sweating|
|● Poor concentration|
|● Weight loss|
|● Hair loss|
|● Proximal myopathy|
|● Warm, moist skin|
|● Stare, lid lag, lid retraction, and exophthalmos (with Graves’ disease)|
|● Emotional liability|
|● Hyperactive reflexes|
|● Thyroid enlargement (in most cases)|
Prevalence of overt thyrotoxicosis is about 0.5%. However, 1% to 2% of patients have a below-normal TSH level. Low TSH is seen in 3% of the population older than 80 years.6
Thyrotoxic signs and symptoms vary with the level of thyroid hormone excess, age of the patient, and duration of the disease. Some features are characteristic of all types of thyrotoxicosis, and some are related to the specific etiology (e.g., exophthalmos with Graves' disease).
Graves’ disease is an autoimmune disorder in which autoantibodies bind and stimulate the TSH receptor. It is the most common cause of thyrotoxicosis. Receptor activation stimulates thyrocyte growth and function.
The disease is more common in whites and Asians and the incidence is lower in African Americans. The female-to-male ratio is 3:5:1.6 It is more common in patients with a family history of thyroid disease, especially Graves’ disease.
Graves’ disease has some specific features (which are present only in some of the patients): swelling over the anterior shin (pretibial myxedema), thyroid eye disease (prominence of eyes, lid lag, globe lag, exophthalmos, lid edema, chemosis, and extraocular muscle weakness); and increased pigmentation or vitiligo.
Thyroid ophthalmopathy is present in about 50% of Graves’ patients. Smoking is a risk factor. Therapeutic options include measures to combat inflammation–glucocorticoids, plasmapheresis, and immune suppressants–as well as orbital radiation, decompressive surgery, and thyroid ablation. Treatment should be managed by an endocrinologist and an ophthalmologist specializing in thyroid eye disease.
Toxic multinodular goiter (MNG) is defined as the presence of two or more thyroid nodules secreting excess thyroid hormone and causing hyperthyroidism. Hyperthyroidism in a MNG can be potentiated by iodine-containing drugs (e.g., IV contrast dye, amiodarone).
Patients are typically older than those with Graves’ disease. The disease usually has an insidious onset, and patients often have apathetic hyperthyroidism, presenting with weight loss, atrial fibrillation, and depression and few other symptoms. On examination, patients have MNG and, rarely, the compressive symptoms of dysphagia, dyspnea, neck pressure, and Pemberton’s sign (engorgement of the face and neck veins with blood when patient elevates arms above head due to compression of the goiter on the veins in the neck).
Diagnosis is confirmed by low TSH, high T4, high T3, and thyroid scintigraphy demonstrating multiple functioning nodules (hot nodules).
Toxic thyroid nodules are usually histologically benign. Scintigraphy shows increased radioactive iodine (RAI) uptake in the nodule (hot nodule), with various degrees of suppression of remaining thyroid. Toxic nodules may be solitary or present as a MNG.
All types of thyroiditis cause inflammation of thyroid tissue and can release preformed hormone from the colloid space, causing thyrotoxicosis, which is transient and followed by recovery or development of hypothyroidism. Approximately half the patients with subacute and postpartum thyroiditis develop permanent hypothyroidism.
In acute and subacute thyroiditis, thyroid tenderness and neck pain are often present. Silent thyroiditis is, by definition, devoid of local symptoms. Thyroiditis reduces iodine uptake in thyroid cells, and scintigraphy shows very little RAI accumulation.
Supportive measures are adequate treatment in most patients (see later).
Postpartum thyroiditis presents as hypo- or hyperthyroidism in women who were euthyroid during pregnancy. The incidence of postpartum thyroiditis ranges from 3% to 16% judging by biochemical studies. Clinically apparent disease is much less common. Postpartum thyroiditis appears 3 to 6 months after delivery. Women may have a small goiter or no physical findings. Symptoms and signs can be very subtle. Laboratory tests in thyroiditis show a triphasic presentation: hyperthyroidism 2 to 4 months after delivery, continuing with a hypothyroid phase of 4 to 8 months, and then recovery in up to 90% of cases.7 Women with other autoimmune disease have a three-fold increased risk for postpartum thyroiditis. The recurrence risk in subsequent pregnancies is about 25%.
Jod-Basedow phenomenon refers to induction of hyperthyroidism after a large load of iodine is administered to a susceptible patient. Symptoms are usually mild and resolve spontaneously. Most patients have MNG and the hyperthyroidism is not associated with autoimmunity. Thyrotoxicosis after iodide exposure appears also in patients with latent or drug-treated Graves’ disease.
Amiodarone-induced hyperthyroidism is seen in 3% of patients (10% in iodine-deficient areas).8Symptoms may be masked by amiodarone effects on the heart (beta blocking).
Hyperthyroidism may be caused by increased T4 and T3 production. It is seen usually in patients with underlying MNG with autonomy that is fed by iodine from amiodarone or in patients with latent Graves' disease (type I hyperthyroidism).Hyperthyroidism also can be caused by destructive thyroiditis (type II hyperthyroidism). Even in thyroiditis the hyperthyroid phase can last up to several months. Differentiating between the two types may be very difficult, and the two types can coexist.
A clinical picture of hyperthyroidism, suppressed TSH, and high or high normal T4 or T3 (or both) confirms the diagnosis. The typical eye findings (exopthalmos) make a diagnosis of Graves’ disease almost certain.
A RAI uptake and scan differentiates between different causes of hyperthyroidism. Graves’ disease has increased uptake and smooth distribution of RAI in the gland. Thyroiditis is characterized by diffusely diminished RAI uptake (this picture also can be seen in patients with high body iodine load and in those with factitious thyrotoxicosis). Toxic adenomas and toxic MNG show areas of increased RAI uptake (hot nodules), with different degrees of suppression of remaining thyroid parenchyma.
The thyroid receptor antibodies are specific for Graves’ disease. This test is useful in patients who had a recent iodine load or in pregnant women in whom RAI cannot be used. If factitious hyperthyroidism is suspected, serum thyroglobulin is typically undetectable. High iodine load can be confirmed by measurement of urinary Iodine excretion.
Suppressed TSH only should not be taken as diagnostic of hyperthyroidism as it can be seen in variety of other conditions. Box 3 lists conditions associated with low TSH other than hyperthyroidism.
Untreated hyperthyroidism can lead to hypertension, heart failure, atrial fibrillation, bone mass loss, and thyroid storm. During pregnancy, hyperthyroidism can result in maternal or fetal complications, miscarriage, preterm delivery, placental abruption, fetal or neonatal hyperthyroidism, intrauterine growth retardation, or still birth. Treatment is aimed at reducing the risk of these complications. Treatment consists of supportive measures to relieve effects of thyrotoxicosis and specific measures aimed to the specific cause.
In thyrotoxicosis, the catecholamine receptor number is increased, so beta blockers have an important role in blocking catecholamine response. If tolerated, propranolol should be used (usually 40-120 mg in two or three daily doses) because it blocks conversion of T4 to T3. Atenolol can also be used (25-50 mg once a day).
In severe thyroiditis, anti-inflammatory agents (NSAIDs, corticosteroids) may be necessary.
Graves’ disease is usually treated with RAI (131I) administered orally. RAI dosing is based on thyroid size, RAI uptake, and prior use of thionamide agents. In most cases, complete ablation of the thyroid gland is attempted. Permanent hypothyroidism results and requires permanent thyroid hormone replacement. If ablation is unsuccessful, RAI administration should be repeated.
RAI has an essential role in treating toxic adenomas and toxic MNG when surgery is contraindicated. Toxic MNG requires a higher dose of radioiodine, and the risk of permanent hypothyroidism is lower. Patients with severe hyperthyroidism should be brought to euthyroidism using antithyroid drugs before RAI treatment.
The RAI treatment is safe and has few long-term consequences. Side effects include gustatory disturbances, sialadenitis, hypoparathyroidism, and transient worsening of hyperthyroidism in some patients. Allergy to iodine is not seen, and RAI can be used even in patients sensitive to iodinated contrast agents.
Propylthiouracil (PTU) and methimazole are the U.S. Food and Drug Administration-approved thionamides. Both antithyroid medications inhibit thyroid hormone synthesis by interfering with thyroid peroxidase–mediated iodination of thyrosine residues in the thyroid gland. PTU also blocks the conversion of T4 to T3. However, methimazole is widely used due to a better side-effect profile (less neutropenia and agranulocytosis) and improved adherence with a simpler schedule (once or twice a day vs. three daily doses). The usual starting doses for methimazole are 20 to 40 mg in one or two daily doses or PTU 300 to 600 mg in three daily doses and maximal doses are 60 mg/day for methimazole and 1,200 mg for PTU. 8
Follow-up is recommended every 4 to 6 weeks, with dose adjustment until euthyroidism is achieved. Maintenance usually requires a lower dose (5-10 mg of methimazole of 100-200 mg of PTU). Antithyroid drugs are used for 12 to 18 months and then discontinued. Relapse typically occurs in the first 3 to 6 months, but it can be as late as 40 years. The risk of relapse is very high with pregnancy. When antithyroid drugs are used in preparation for RAI treatment, they must be stopped 5 to 10 days before RAI, and the dose of RAI needs to be increased because of the radioprotective effect of antithyroid drugs.
Minor side effects of antithyroid drugs include skin reactions, arthralgias, gastrointestinal effects, and sialadenitis. The most serious side effect is agranulocytosis, which has been reported to occur in 0.3% to 0.6% of cases. A baseline complete blood count is recommended, but further follow-up with differential white blood cell count in asymptomatic patients is not recommended. All patients should be instructed about this risk and told to stop the medication if signs of infection develop and seek urgent medical care. Other rare side effects include hepatotoxicty, vasculitis, cholestasis, hypoglycemia, and hives.
Surgical therapy is safe and effective for Graves’ disease when performed by an experienced thyroid surgeon. Surgery is not first-line therapy, but it is helpful when rapid control of hyperthyroidism is important, in patients with large glands, in children, and in women of childbearing age. Hyperthyroidism should be controlled before surgery with antithyroid drugs, corticosteroids, and elemental iodine to minimize the risk of thyroid storm during the surgery. Surgery is a safe and effective treatment for toxic adenoma (unilateral thyroidectomy) and MNG. If surgery is to be performed during the pregnancy, the safest time is during the second trimester.
Amiodarone-Induced Hyperthyroidism. The high iodine content of amiodarone limits the effectiveness of RAI treatment. Discontinuing amiodarone is generally helpful, but many patients cannot stop treatment because of an underlying heart condition. The half-life of amiodarone in the body is about 100 days, and no immediate benefit can be expected from stopping therapy.
Type I Hyperthyroidism. Type I hyperthyroidism should be treated with thionamide drugs (although the response may be slower than in other forms of hyperthyroidism), and high doses may be necessary. If thyrotoxicosis is severe, potassium perchlorate 500 to 1,000 mg/day for 6to 8 months (to enhance iodine clearance from the thyroid gland) and lithium 250 to 500 mg three times a day until euthyroidism is achieved may be used in association with antithyroid drugs to enhance the therapeutic response.
Type II Hyperthyroidism. Type II hyperthyroidism may be treated with corticosteroids (prednisone 30-60 mg once daily). If amiodarone can be discontinued, thionamides and iopanoic acid (not available in the United States) have a potential role. When the mechanism of hyperthyroidism is not known, a combination therapy with corticosteroids and thionamides is started. If hyperthyroidism is impossible to control, thyroidectomy is indicated (this is rarely necessary).
Thyroid Storm. Thyroid storm is rare, but mortality is still high. In the past it was seen in hyperthyroid patients poorly prepared for thyroid or other surgery. Today it is seen in patients who have severe thyrotoxicosis and who are noncompliant with medication or who have severe comorbidities. The clinical picture is that of life-threatening thyrotoxicosis. Symptoms include severe tachycardia or atrial fibrillation, fever (even hyperpyrexia), change in mental status (tremulousness, restlessness agitation, delirium, psychosis, lethargy, seizure, coma), pulmonary edema or congestive heart failure, nausea, vomiting, abdominal pain, diarrhea, jaundice, and profuse sweating.
Treatment of thyroid storm requires monitoring in the intensive care unit (ICU). Therapy includes high doses of intravenous beta blockers (propranolol) to control symptoms of increased adrenergic tone and acetaminophen to control fever (aspirin should not be used because it increases free level of thyroid hormone). Antithyroid drugs (given orally, via nasogastric tube, or rectally) are used to suppress thyroid hormone production and release. Iodinated contrast dyes (currently not available in the United States) are given to inhibit peripheral T4 to T3 conversion. Iodine containing solutions block release of thyroid hormone from the thyroid and can be used 1 or 2 hours after antithyroid drugs are given. Corticosteroids reduce T4 to T3 conversion and possibly affect the autoimmune process in Graves’ disease. Because thyrotoxic patients have an increased thyroid hormone enterohepatic circulation, cholesteramine has a role in treatment.
Thyroid hormone alterations seen during nonthyroidal illness (euthyroid sick syndrome) include reduced production of T3 in the majority of patients due to decreased T4 conversion (inhibition of 5'-monodeiodinase), decreased serum T4 (≤50% of patients in the ICU) because of decreased levels of binding proteins and inhibition of thyroid hormoneprotein binding, and somewhat inhibited TSH secretion. In severe illness these effects occur sequentially, and early phases of euthyroid sick syndrome have low T3, followed by reduction in T4 and then TSH.
In the recovery phase of nonthyroidal illness, TSH can transiently rise abnormally high. Reverse T3 is usually elevated and can be measured to confirm the diagnosis. The finding of altered thyroid hormone levels in hospitalized patients confirms the participation of these factors in the adaptive response to illness. Thyroid function should not be routinely checked during serious illnesses unless there is a strong suspicion of a thyroid disorder.
Dopamine is a potent inhibitor of TSH secretion. Corticosteroids and dobutamine also can decrease TSH levels slightly. Estrogens and selective estrogen-receptor modulators increase thyroxine-binding globulinproduction and increase total T4 level; androgens and nicotinic acid decrease thyroxine-binding globulinproduction. High dose-salicylates (aspirin, salasalate) displace T4 from binding proteins. Phenytoin and carbamazepine can artificially lower measured values of free T4 and T3 in standard assays. In patients using these medications, only TSH measurements should be used.