DIFFUSE TOXIC GOITER Background

This condition was first described by the English physician Caleb H. Parry (1755-1822). The disorder is known as Graves disease (after Robert J. Graves) in the English-speaking world and as Basedow disease (after Karl A. von Basedow) in the rest of Europe. In diffuse toxic goiter, the thyroid gland is diffusely hyperplastic and excessively overproduces thyroid hormone. This results in accelerated metabolism in most body organs. The clinical response and its manifestations are variable in intensity, distribution, and are modified by age, gender, and associated premorbid medical problems. When the diffuse toxic goiter is associated with clinical evidence of oculopathy, or rarely with dermopathy/acropachy, the term Graves disease is often applied. Awareness is needed regarding the atypical clinical presentations.

Pathophysiology
The thyroid gland is usually enlarged to a variable degree and is vascular and diffusely affected. This results in a smooth, rubbery-firm consistency, and often a bruit is heard on auscultation. Microscopically, the thyroid follicular cells are hypertrophic and hyperplastic, and they contain little colloid (stored hormone) and show evidence of hypersecretion. Lymphocytes and plasma cells infiltrate into the thyroid gland and may aggregate into lymphoid follicles. This condition is an autoimmune disorder whereby the thyroid gland is overstimulated by antibodies directed to the thyroid-stimulating hormone (TSH) receptor on the thyroid follicular cells. This antibody stimulates iodine uptake, thyroid hormonogenesis and release, and thyroid gland growth. Although mainly produced within the thyroid gland, these antibodies reach the circulation and can be measured by various assays in most, but not all, cases. The association with another autoimmune thyroid disease, Hashimoto thyroiditis, and to a lesser degree, with other autoimmune diseases in other endocrine glands and other systems in the same person is high. A strong familial association exists with the same diffuse toxic goiter or the associated disorders, especially Hashimoto thyroiditis. The presence of Hashimoto thyroiditis, which has more of a destructive effect on the thyroid gland, or the presence of another antibody, TSH-receptor blocking antibody, results in a variable natural history of the course of diffuse toxic goiter.

Epidemiology
Frequency
United States Diffuse toxic goiter is the most common cause of spontaneous hyperthyroidism. A Minnesota study found 0.3 new cases per 1000 per year. In late childhood, the incidence rate is 3 per 100,000 in girls and 0.5 per 100,000 in boys. Prevalence studies show a rate of 2.7% in women and 0.23% in men. A marked increase in familial incidence is noted. International Prewar Copenhagen found 0.2 new cases per 1000 per year. British studies found 0.08-0.2 new cases per 1000 per year.

Mortality/Morbidity
The natural history is usually of a benign course, which may vary in intensity of the symptoms and even spontaneously remit. The intensity of the symptoms and effect on quality of life are variable from person to person and are affected by age and gender. Mortality is rare but is due to cardiovascular problems such as heart failure, arrhythmias, or myocardial infarction. Debility and infection may occur. Thyroid storm is rare but may be fatal from dehydration, hyperthermia, and organ failure.

Morbidity may result from increased bone turnover and osteoporosis, especially in postmenopausal women, or from atrial fibrillation and its sequelae, such as thromboembolism, especially in older men. Personality changes and psychopathology, muscular weakness, and systemic symptoms all lead to quality of life changes. Associated oculopathy may be symptomatic, especially with double vision. Rarely it may progress to affect the integrity of the cornea and may even endanger vision. Associated dermopathy is uncommon and is usually minimally symptomatic, but it may be symptomatic to become debilitating. Associated hypokalemic periodic paralysis, most commonly seen in Asian males, may be sudden, dramatic, and concerning but usually runs a benign course of recovery after a few hours of skeletal muscle paralysis. A higher risk of associated immunologic diseases, such as adrenal insufficiency, each has their own associated morbidity and mortality, especially if undiagnosed.

Race
No racial predilection exists.

Sex
Diffuse toxic goiter is 7-10 times more common in women than in men. It is often associated with or following a pregnancy.

Age
Diffuse toxic goiter can occur in all ages, but it is rare in children younger than 10 years and unusual in elderly persons. The peak incidence is in third and fourth decades. Incidence is increased in postpartum women, often the first presentation of disease.

PRESENTATION History
Symptoms of the hyperthyroidism, the goiter itself, and of comorbid conditions are present. The symptoms may be present for weeks, months, or even years before diagnosis. The hyperthyroid symptoms may be multisystemic or predominate in a single organ system and mask the correct diagnosis in this manner. Many symptoms are adrenergic in origin and may be misdiagnosed as an anxiety disorder. Elderly patients may have no adrenergic symptoms and present as weight loss (malignancy), atrial fibrillation (cardiac), or apathy (depression), and this presentation is referred to as apathetic thyrotoxicosis. The presenting symptoms may be modified by preexisting medical or psychiatric disorders, which may be modified or worsened. Symptoms are described below. ; ; ; ; ; Hypermetabolism with heat generation and protein catabolism - Weight loss with good appetite, heat intolerance, sweating, muscle weakness (proximal more than distal), osteoporosis Adrenergic - Palpitations, tremor, emotional lability, insomnia, restlessness, hyperdefecation Other - Gynecomastia, lighter menses, insomnia, decreased concentration, fatigue, shortness of breath on exertion, and decreased exercise tolerance Goiter - May be mildly tender, may have difficulty swallowing if large Associated oculopathy (clinically present in about 25% of cases) - Tearing, pain, puffiness, grittiness, double vision, prominent appearance, rarely visual loss

Physical
General physical examination findings may include restless appearance, evidence of weight loss, pruritus, palmar erythema, and onycholysis of the finger nails. ; Hypermetabolism with protein catabolism - Warm hands, often with heat radiation, velvety skin, proximal muscle weakness in the arms and legs compared with distal muscle strength

Hyperadrenergic - Bounding and fast pulse, wide pulse pressure with higher systolic and lower diastolic blood pressure, active precordium and abdominal aorta to palpation; lid retraction (upper eyelid more than halfway from pupil to top of iris) and lid lag or globe lag, tremor of fingers, brisk reflexes Organ decompensation - Atrial fibrillation, congestive heart failure, jaundice Oculopathy - Periorbital puffiness, chemosis, conjunctival redness, proptosis (sclera visible below iris), double vision with eye movements, loss of color vision (rare), or papilledema (rare) Thyroid gland - Mildly enlarged (but may be normal in size, many times normal in size, or difficult to palpate); smooth, rubbery firm in texture; nontender or mildly tender; systolic bruit on auscultation Miscellaneous - Pretibial myxedema (uncommon), rare may be finger clubbing, diffuse lymphadenopathy, and splenomegaly

; ; ; ;

Causes
Diffuse toxic goiter and its hyperthyroidism are caused by TSH-receptor stimulating antibodies. Although the exact cause is not understood, it has been suggested that there is a genetic lack of suppressor T cells that results in the unregulated production of the antibody, resulting in the autoimmune disease. The antibody may pass the placenta and result in fetal and neonatal hyperthyroidism. As with most such disorders, usually a combination of genetic and environmental factors is present. The familial association indicates a strong genetic factor. Predisposing factors include genetic susceptibility (including HLA factors); female gender; mental stress; viral infection; surgery; postpartum state; iodine administration; drugs such as lithium and iodine-containing agents, such as amiodarone, interferons and interleukins, and antiretroviral agents. Associated ophthalmopathy is not well understood, but it is a related but separate autoimmune disorder directed toward the extraocular muscles. It may run a course similar to or different from the hyperthyroidism. Smoking is an environmental aggravating factor. The presence and degree of clinical ophthalmopathy does correlate with the degree of elevation of the anti-TSH receptor antibodies. Dermopathy (pretibial myxedema) may be brought on or aggravated by local trauma.

Laboratory Studies
; If hyperthyroidism due to diffuse toxic goiter is suspected after history and physical examination, the following should be performed: o o Serum TSH (sensitive or third-generation assay): Levels suppressed below normal indicate the need for more tests. Normal serum TSH level rules out this diagnosis. Serum free thyroxin (T4), or equivalent test, that compensates for any changes in thyroidbinding globulin. If levels are elevated, then hyperthyroidism is diagnosed. Levels will be in the normal range in about 5% of cases. If free thyroxin is normal, then obtain total or free serum triiodothyronine (T3) level. If levels are elevated, then hyperthyroidism is diagnosed. If levels are normal, then subclinical hyperthyroidism is present. The presence of ophthalmopathy indicates the diagnosis, and no more diagnostic testing is needed regarding the cause of the hyperthyroidism. Serum anti-TSH receptor antibodies measurements can be obtained. These antibodies are present in more than 90% of cases of diffuse toxic goiter, depending on the assay. An alternative test is radioiodine uptake. It will separate diffuse toxic goiter (elevated or normal uptake) from the hyperthyroid phase of thyroiditis (suppressed uptake). If the hyperthyroid symptoms have been present for more than 4 months, then thyroiditis is not the cause. This test is contraindicated in women who are pregnant or breastfeeding. An elevated or normal uptake may be found with a single nodular goiter and a multinodular goiter. These may be separated from diffuse toxic goiter by the absence of anti-TSH receptor antibodies, clinical examination, or thyroid scan (technetium-99m or I-123) or ultrasonography. Concomitant presence of Hashimoto thyroiditis may be detected by serum antithyroid antibodies (anti-TPO or thyroperoxidase).

o o o

o ;

If confirmation of oculopathy is needed, then orbital CT or MRI may be performed.

Diffuse toxic goiter would have a suppressed serum TSH level, elevated serum free thyroxin level (or T3 if needed), elevated titer of anti-TSH receptor antibodies, or elevated radioiodine uptake. No further testing is needed. Consideration of complications: ECG should be performed if arrhythmia is suspected; liver function tests may be indicated. Consideration of associated disorders: If clinical suspicion, screen for adrenal insufficiency, type 1 diabetes, gonadal failure, other autoimmune disease (eg, pernicious anemia, rheumatoid arthritis, immune thrombocytopenic purpura). Concomitant Hashimoto thyroiditis may have an effect on spontaneous resolution or progression to a hypothyroid state. Drugs that may alter T4 laboratory results include anabolic steroids, androgens, estrogens, heparin, iodine, phenytoin, rifampin, salicylates, and thyroxine/triiodothyronine.

; ;

Medical Care
Even though the natural history of diffuse toxic goiter is to possibly spontaneously remit (and perhaps later relapse), or even progress into hypothyroidism, observation without intervention, even in minimally symptomatic people, is not recommended. The risk of bone loss and atrial fibrillation occur, especially in older women and men, even in subclinical cases. The goals of therapy are to resolve hyperthyroid symptoms and to restore the euthyroid state. Each therapeutic choice has advantages and disadvantages, so treatment should be individualized. Patient input into the treatment choice is important and must be discussed and considered. The American Thyroid Association and American Association of Clinical Endocrinologists have released guidelines for the management of hyperthyroid and other causes of thyrotoxicosis, including the use of radioactive iodine or surgery to treat toxic multinodular goiter. Therapy may be by subtotal thyroidectomy, administration of radioiodine, antithyroid drugs, or a combination of these. In North America, radioiodine is the most common treatment and is available for all ages. Adjunctive symptomatic therapy, such as beta-blockers, may help adrenergic symptoms. Nonsurgical therapy occurs in the outpatient setting. Surgical therapy requires first normalization of the hyperthyroid state by medication. Cardiac decompensation or arrhythmias may require hospitalization. Thyroid storm is a rare emergency requiring intensive care support and therapy.

Surgical Care
Subtotal thyroidectomy may be considered if it is the choice of the patient, second trimester of pregnancy, failure (resistance or intolerance) of drug therapy, or poor compliance to drug therapy. Risks are low with experienced surgeons but include anesthetic risks, hemorrhage, hypoparathyroidism, and vocal cord paralysis. Patients should be made euthyroid prior to surgery to minimize anesthetic risks, cardiovascular/hemodynamic complications, and risk of thyroid storm. If normalizing with antithyroid drugs is not possible, then betablockers and potassium iodide 4 drops/day for 10 days will decrease vascularity of the thyroid gland.

Consultations
Oculopathy usually requires ophthalmologic consultation, and dermopathy may require dermatologic consultation.

Diet
Diet must include caloric intake to meet the energy expenditure of the hypermetabolism. High iodinecontaining substances, such as kelp, should be avoided.

Activity
Physical activity is limited by the presence of symptoms, until recovery occurs. Usually, shortness of breath on exertion, fatigue, and palpitations are the limiting symptoms.

Medication Summary

No standard treatment protocols exist; individualization of treatment based on clinical experience is protocol. Patient preference after informed consent affects all therapeutic decisions.

Beta-blockers
Beta-blockers are used if symptomatic tremor or palpitations require their use. They may be used even as investigation is ongoing because they have no effect on thyroid gland function, but they block the betaadrenergic peripheral manifestations of the hyperthyroid state. Propranolol has an effect in decreasing the peripheral conversion of T4 to T3, but this is of unknown clinical significance with the usual doses. The dose may be decreased and then stopped when the euthyroid state occurs. They should not be used in the presence of bronchospasm, even the beta1-selective agents. Calcium channel blockers may be substituted.

Thionamides
Thionamide drugs, propylthiouracil (PTU) and methimazole (MTZ), inhibit hormonogenesis within the thyroid gland. PTU has an effect in decreasing the peripheral conversion of T4 to T3, but this is of unknown added clinical significance. Other than in pregnancy and breastfeeding, MTZ has advantages over PTU by a longer half-life with once-a-day dosing, and possibly more rapid return to the euthyroid state. Although rare, agranulocytosis, lupuslike vasculitis, and hepatitis are more commonly associated with PTU than with MTZ. Agranulocytosis occurs in less that 0.1% of cases but is unpredictable; it may occur at any time. Routine monitoring of WBC count is not useful. Should any infection occur, such as a sore throat, the WBC count should then be measured. Discontinuation of the drug results in a rise of WBC within a few days. Granulocyte colony-stimulating factor may need to be administered. Skin rash may perhaps be more common with MTZ; incidence is about 3%, and it usually occurs within the first few weeks of therapy. Methimazole is the drug of choice. The US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for PTU. The boxed warning emphasizes the risk for severe liver injury and acute liver failure, some of which have been fatal. The boxed warning also states that PTU should be reserved for use in patients who cannot tolerate other treatments, such as methimazole, radioactive iodine, or surgery. The decision to include a boxed warning was based on the FDA's review of postmarketing safety reports and on meetings held with the American Thyroid Association, the National Institute of Child Health and Human Development, and the pediatric endocrine clinical community. The FDA has identified 32 cases (22 adult and 10 pediatric) of serious liver injury associated with PTU. Of the adults, 12 deaths and 5 liver transplants occurred, and among the pediatric patients, 1 death and 6 liver transplants occurred. PTU is indicated for hyperthyroidism due to Graves disease. These reports suggest an increased risk for liver toxicity with PTU compared with methimazole. Serious liver injury has been identified with methimazole in 5 cases (3 resulting in death). PTU is considered to be a second-line drug therapy, except in patients who are allergic to or intolerant of methimazole, or in women who are in the first trimester of pregnancy. Rare cases of embryopathy, including aplasia cutis, have been reported with methimazole during pregnancy. The FDA recommends the following criteria be considered for prescribing PTU Reserve PTU use during first trimester of pregnancy, or in patients who are allergic to or intolerant of methimazole. ; ; ; ; Closely monitor PTU therapy for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy. For suspected liver injury, promptly discontinue PTU therapy, evaluate the patient for evidence of liver injury, and provide supportive care. PTU should not be used in pediatric patients unless the patient is allergic to or intolerant of methimazole and no other treatment options are available. Counsel patients to promptly contact their health care provider for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin.

Monitor the serum thyroid indices monthly until euthyroid, and then the dose of the drug may be decreased for maintenance. The lowest dose needed to maintain the euthyroid state is then used for long-term therapy.

Normalization of thyroid function with these drugs must occur for some time, at least 6 months and perhaps for 1-2 years, to maximize the remission rate after drug discontinuation. Despite this, the relapse rate is 50-70%, usually within the first few weeks or months, but occasionally after a few years. Remission is weakly predicted by a short duration of symptoms, age younger than 40 years, minimal enlargement of the thyroid gland, and concomitant presence of Hashimoto thyroiditis. Relapse after discontinuation of the drug requires a decision regarding radioiodine therapy or surgery for more definitive therapy, or return to the antithyroid drug. Although general practice is not to use these drugs longterm, there is no reason why this cannot occur, if that is what the patient chooses.

Iodine
In severe cases, such as thyroid storm, iodine in the form of potassium iodide (SSKI) 10 drops twice a day or iopanoic acid 1-3 g/d may be given. They inhibit the release of thyroxin from the gland and inhibit peripheral conversion of T4 to T3. They help render a euthyroid state more rapidly in response to antithyroid drugs, or prepare for surgery, but will eliminate the use of radioiodine for many months due to expansion of the iodine pool and thus decrease the delivery of radioiodine to the thyroid gland.

Radioiodine
Oral administration of I 131 is incorporated into the thyroid follicular cells, and the beta emission results in cell destruction and glandular fibrosis. The effect is seen in 1 and a half to 4 months. Off medications, the thyroid hormone levels become normal (requiring continued monitoring), fall below normal (requiring thyroid hormone replacement therapy, likely for life), or remain elevated (requiring another administration of radioiodine). In those becoming euthyroid, the chance every year of becoming hypothyroid due to ongoing disease in the gland is 5%; occasionally, hyperthyroidism may reoccur. The usual dose is 6-8 mCi. The dose is adjusted based on size of the thyroid gland, age of the patient, and severity of the clinical picture. Resistance is increased by age older than 40 years, large goiters, prior therapy with PTU, and nodularity (not seen with diffuse toxic goiter). Recent reviews confirm the safety of the use of radioiodine. Radioiodine therapy is not used in clinically severe hyperthyroidism or thyroid storm until the hyperthyroid state is medically controlled. Because of transplacental transfer and lactation transfer, it is contraindicated in women who are pregnant or breastfeeding. For the theoretical ovarian exposure, conception in treated women is empirically discouraged for 3-6 months. It may be administered to children, if clinically indicated. Long-term safety data in children are not available. Worsening of the hyperthyroid state may occur after radioiodine therapy due to release of prestored hormone. Gland tenderness and swelling is uncommon and may be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) (not aspirin), and they rarely require steroid administration. Radioiodine administration has been associated with worsening or progression of symptomatic ophthalmopathy. Either radioiodine is avoided in very symptomatic individuals or corticosteroids (prednisone 0.5 mg/kg) are used beginning the day after the radioiodine administration for 1-3 months, or they are administered if any worsening of the ophthalmopathy occurs after radioiodine administration. Cessation of smoking and avoidance of hypothyroidism also help the course of ophthalmopathy. The return to the euthyroid state, regardless of therapy, is best monitored by serum free thyroxin, or its equivalent, because the pituitary is suppressed and TSH secretion may remain low for some time after a normal or hypothyroid state occurs. Relapse from a euthyroid state to hyperthyroidism is first monitored by new suppression of the serum TSH, and often the serum T3 then increases above normal before the serum T4 increases above normal.

Pregnancy and breastfeeding

Pregnancy often has an effect on improving the immunologic disease state during the pregnancy and then often relapses following delivery. The treatment of choice is PTU, which has less placental transfer than MTZ. Rare congenital anomalies reported with MTX (eg, aplasia cutis) are even less associated with PTU. Overall, the congenital abnormality rate with these drugs is similar to background normal rate. MTZ may be used if a problem exists with PTU. The goal is to keep the free thyroxin in the upper part of normal to minimize fetal drug exposure. Monthly monitoring of serum free thyroxin usually allows the dose of PTU to be decreased and often discontinued in the

third trimester. Both PTU and MTZ may be used in breastfeeding mothers. A small amount of drug does enter the milk, but neonatal thyroid levels generally remain normal. PTU and MTZ are not contraindicated in pregnancy or lactation.

Antithyroid agents
Class Summary
These agents may either inhibit hormonogenesis within the thyroid gland or inhibit release of thyroid hormone from the gland.

Propylthiouracil (PTU)
Actively transported into the thyroid gland and inhibits incorporation of iodine to thyroid hormones, and inhibits peripheral conversion of T4 to T3. Drug recommended in pregnancy and lactation with dose adjustment to minimum needed. Laboratory monitoring of free T4 to adjust dose therapy. The serum TSH may lag behind the changes in free T4. Long-term experience with this drug.

Methimazole (Tapazole)
Actively transported in thyroid gland and inhibits thyroid synthesis by preventing oxidation of trapped iodine. Ten times more potent than PTU, and once-a-day dose is effective. Euthyroid state is achieved in 4-6 wk, and maintenance treatment continued for 12-24 mo. Relapse may be observed 1-6 mo after stopping therapy, occasionally later. Less desirable than propylthiouracil in pregnancy and lactation but may be used if propylthiouracil cannot be used.

Potassium iodide (Pima, Thyro-Block)

Inhibits thyroid hormone secretion. Contains 8 mg of iodide per gtt. May be mixed with juice or water for intake. May decrease thyroid gland secretion and vascularity for a short time, such as 2 wk; may be used in severe cases of hyperthyroidism, such as thyroid storm, or to prepare patient for thyroidectomy

Supersaturated potassium iodide (SSKI)

Contains 50 mg of iodide per drop. May be mixed with juice or water for ingestion. Inhibits thyroid hormone release.

Corticosteroids
Class Summary
These agents have profound and varied metabolic effects.

Dexamethasone (Decadron)
Steroids block peripheral conversion of T4 to T3. Used as adjunct in management of thyroid storm and symptomatic progressive Graves ophthalmopathy.

Radiopharmaceuticals
Class Summary
These agents are used to destroy thyroid cells.

Radioiodine (I-131)
Agent of choice because it is selectively taken up by the thyroid gland. Causes dysfunction or death of thyroid cells over time. Long-term experience suggests good safety profile.

Beta-adrenergic receptor blockers

Class Summary

Relief of adrenergic symptoms, especially cardiac and neurologic. Propranolol blocks peripheral conversion of T4 to T3, but this is of unknown clinical significance.

Propanolol (Inderal)
Nonselective beta-adrenergic receptor blocker. Also blocks peripheral conversion of T4 to T3. Used along with antithyroid drugs, before and after radioiodine treatment. Useful in thyroid crisis/storm, or in cardiac complications such as atrial fibrillation. Oral or intravenous use controls cardiac and psychomotor manifestations within minutes. Continue until euthyroid state is achieved.

GOITER
Background
In 1656, Thomas Wharton described the distinct nature of what he termed the thyroid gland, distinguishing it from the larynx, as this structure had been considered a laryngeal gland from the time of Andreas Vesalius in the 16th century. It was nearly 200 more years before the function of the thyroid was elucidated. The normal adult thyroid gland weighs 10-25 g and has 2 lobes connected by an isthmus. Nearly 50% of thyroid glands exhibit a pyramidal lobe arising from the center of the isthmus. Longitudinal dimensions of the lobes of the thyroid range up to 5 cm, as shown in the image below.

Thyroid nuclear scan of a patient with a euthyroid goiter showing different projections. A goiter is an enlarged thyroid gland, and it may be diffuse or nodular. A goiter may extend into the retrosternal space, with or without substantial anterior enlargement. Because of the anatomic relationship of the thyroid gland to the trachea, larynx, superior and inferior laryngeal nerves, and esophagus, abnormal growth may cause a variety of compressive syndromes. Thyroid function may be normal (nontoxic goiter), overactive (toxic goiter), or underactive (hypothyroid goiter).

Pathophysiology
The thyroid gland is controlled by thyroid-stimulating hormone (TSH; also known as thyrotropin), secreted from the pituitary gland, which in turn is influenced by the thyrotropin-releasing hormone (TRH) from the hypothalamus. TSH permits growth, cellular differentiation, and thyroid hormone production and secretion by the thyroid gland. Thyrotropin acts on TSH receptors located on the thyroid gland. Serum thyroid hormones levothyroxine and triiodothyronine feed back to the pituitary, regulating TSH production. Interference with this TRH-TSH thyroid hormone axis causes changes in the function and structure of the thyroid gland. Stimulation of the TSH receptors of the thyroid by TSH, TSH-receptor antibodies, or TSH receptor agonists, such as chorionic gonadotropin, may result in a diffuse goiter. When a small group of thyroid cells, inflammatory cells, or malignant cells metastatic to the thyroid is involved, a thyroid nodule may develop. A deficiency in thyroid hormone synthesis or intake leads to increased TSH production. Increased TSH causes increased cellularity and hyperplasia of the thyroid gland in an attempt to normalize thyroid hormone levels. If this process is sustained, a goiter is established. Causes of thyroid hormone deficiency include inborn errors of thyroid hormone synthesis, iodine deficiency, and goitrogens.

A goiter may result from a number of TSH receptor agonists. TSH receptor stimulators include TSH receptor antibodies, pituitary resistance to thyroid hormone, adenomas of the hypothalamus or pituitary gland, and tumors producing human chorionic gonadotropin.

Epidemiology
Frequency
United States Autopsy studies suggest a frequency of greater than 50% for thyroid nodules; with high-resolution ultrasonography, the value approaches 40% of patients with nonthyroidal illness. In the Wickham study from the United Kingdom, 16% of the population had a goiter. In the Framingham study, ultrasonography revealed that 3% of men older than 60 years had thyroid nodules, while 36% of women aged 49-58 years had thyroid nodules. In the United States, most goiters are due to autoimmune thyroiditis (ie, Hashimoto disease). International Worldwide, the most common cause of goiter is iodine deficiency. It is estimated that goiters affect as many as 200 million of the 800 million people who have a diet deficient in iodine. In a German study, 635 people underwent ultrasonographic thyroid screening, as well as basal TSH measurement, during a preventive-health checkup. Thyroid nodules were detected in 432 (68%) of the persons screened; in a previous German study, ultrasonographic screening of more than 90,000 people detected thyroid nodules in 33% of the normal population. The authors of the latter report attributed this difference to the fact that patients in their study were screened using 13 MHz ultrasonographic scanners, which were more sensitive than the 7.5 MHz scanners used in the previous study. According to the investigators, their results indicated that the question of routine iodine supplementation requires renewed attention.

Mortality/Morbidity
Most goiters are benign, causing only cosmetic disfigurement. Morbidity or mortality may result from compression of surrounding structures, thyroid cancer, hyperthyroidism, or hypothyroidism.

Race
No racial predilection exists.

Sex
The female-to-male ratio is 4:1. ; ; In the Wickham study, 26% of women had a goiter, compared to 7% of men. Thyroid nodules are less frequent in men than in women, but when found, they are more likely to be malignant.

Age
The frequency of goiters decreases with advancing age. The decrease in frequency differs from the incidence of thyroid nodules, which increases with advancing age.

History
A goiter may present in various ways, including the following: ; ; ; ; ; ; Incidentally, as a swelling in the neck discovered by the patient or on routine physical examination A finding on imaging studies performed for a related or unrelated medical evaluation Local compression causing dysphagia, dyspnea, stridor, plethora or hoarseness Pain due to hemorrhage, inflammation, necrosis, or malignant transformation Signs and symptoms of hyperthyroidism or hypothyroidism Thyroid cancer with or without metastases

Physical

The general examination for hyperthyroidism, hypothyroidism, and autoimmune stigmata is followed by systematic examination of the goiter. A retrosternal goiter may not be evident on physical examination. Examination of the goiter is best performed with the patient upright, sitting or standing. Inspection from the side may better outline the thyroid profile, as shown below. Asking the patient to take a sip of water facilitates inspection. The thyroid should move upon swallowing. See the image below.

Patient with a goiter. Prominent side-view outline. Palpation of the goiter is performed either facing the patient or from behind the patient, with the neck relaxed and not hyperextended. Palpation of the goiter rules out a pseudogoiter, which is a prominent thyroid seen in individuals who are thin. Each lobe is palpated for size, consistency, nodules, and tenderness. Cervical lymph nodes are then palpated. The oropharynx is visualized for the presence of lingular thyroid tissue. The size of each lobe is measured in 2 dimensions using a tape measure. Some examiners make tracings on a sheet of paper, which is placed in the patient's chart. Suitable landmarks are used and documented to ensure consistent measurement of the thyroid gland. The pyramidal lobe often is enlarged in Graves disease. A firm rubbery thyroid gland suggests Hashimoto thyroiditis, and a hard thyroid gland suggests malignancy or Riedel struma. Multiple nodules may suggest a multinodular goiter or Hashimoto thyroiditis. A solitary hard nodule suggests malignancy, whereas a solitary firm nodule may be a thyroid cyst. Diffuse thyroid tenderness suggests subacute thyroiditis, and local thyroid tenderness suggests intranodal hemorrhage or necrosis. Cervical lymph glands are palpated for signs of metastatic thyroid cancer. Auscultation of a soft bruit over the inferior thyroidal artery may be appreciated in a toxic goiter. Palpation of a toxic goiter may reveal a thrill in the profoundly hyperthyroid patient. Goiters are described in a variety of ways, including the following: ; Toxic goiter: A goiter that is associated with hyperthyroidism is described as a toxic goiter. Examples of toxic goiters include diffuse toxic goiter (Graves disease), toxic multinodular goiter, and toxic adenoma (Plummer disease). Nontoxic goiter: A goiter without hyperthyroidism or hypothyroidism is described as a nontoxic goiter. It may be diffuse or multinodular, but a diffuse goiter often evolves into a nodular goiter. Examination of the thyroid may not reveal small or posterior nodules. Examples of nontoxic goiters include chronic lymphocytic thyroiditis (Hashimoto disease), goiter identified in early Graves disease, endemic goiter, sporadic goiter, congenital goiter, and physiologic goiter that occurs during puberty.

Autonomously functioning nodules may present with inability to palpate the contralateral lobe. Unilobar agenesis may also present like a single thyroid nodule with hyperplasia of the remaining lobe. The Pemberton maneuver raises a goiter into the thoracic inlet when the patient elevates the arms. This may cause shortness of breath, stridor, or distention of neck veins.

Causes
The different etiologic mechanisms that can cause a goiter include the following: ; ; ; Iodine deficiency[ Autoimmune thyroiditis - Hashimoto or postpartum thyroiditis Excess iodine (Wolff-Chaikoff effect) or lithium ingestion, which decrease release of thyroid hormone

; ; ; ; ; ; ; ; ; ;

Goitrogens Stimulation of TSH receptors by TSH from pituitary tumors, pituitary thyroid hormone resistance, gonadotropins, and/or thyroid-stimulating immunoglobulins Inborn errors of metabolism causing defects in biosynthesis of thyroid hormones Exposure to radiation Deposition diseases Thyroid hormone resistance Subacute thyroiditis (de Quervain thyroiditis) Silent thyroiditis Riedel thyroiditis Infectious agents o o Acute suppurative - Bacterial Chronic - Mycobacteria, fungal, and parasitic

; ; ;

Granulomatous disease Thyroid malignancy Low selenium levels: This may be associated with goiter prevalence.

Laboratory Studies
; Initial screening should include TSH. Given the sensitive third-generation assays in the absence of symptoms of hyper or hypothyroidism further testing is not required. An assessment of free thyroxine index or direct measurement of free thyroxine would be the next step in the evaluation. Further laboratory testing is based on presentation and results of screening studies and may include thyroid antibodies (antithyroid peroxidase formerly the antimicrosomal antibodies and antithyroglobulin), thyroglobulin, sedimentation rate and calcitonin in an individual at high risk for medullary carcinoma of the thyroid.

Imaging Studies
Ultrasonography
Establish and follow goiter size, consistency, and nodularity. Localize nodules for ultrasonographically guided biopsy.

Roentgenography
Roentgenography is used to assess extent of a goiter and presence of calcification. Ultrasonography has replaced this modality. Roentgenography is used to visualize calcifications within a goiter and regional lymph glands.

Computed tomography (CT) scanning

CT scanning is more precise than roentgenography. CT scanning can be used to delineate size and goiter extent. Due to the superficial placement of the thyroid gland, ultrasonography is more useful in following size. CT scanning does a much better job of determining the effect of the thyroid gland on nearby structures. It also may be useful in the follow-up of patients with thyroid cancer that shows evidence of recurrence. CT scanning can be used to guide biopsy of the thyroid.

MRI
Magnetic resonance imaging has the same indications as CT scanning (see above). Radionuclide uptake and radionuclide scanning are used to assess thyroid function and anatomy in hyperthyroidism, as shown below. Additionally, thyroid scanning may be useful in the patient with neck or

superior mediastinal masses. Radionuclide scanning allows determination of the function of a nodule. Function of a thyroid nodule has value both diagnostically and therapeutically. See the image below.

Thyroid nuclear scan of a patient with a euthyroid goiter showing different projections.

Other
Barium swallow is used to assess esophageal obstruction. Spirometry: The flow-volume loop is useful in determining the functional significance of compressive goiters. Perchlorate discharge test is used in individuals with inborn errors of thyroid hormone synthesis. It is used rarely today to determine the ability to trap and organify iodine.

Procedures
; Fine-needle aspiration biopsy is used for cytologic diagnosis.[7] Fine-needle aspiration of the thyroid is used to determine the cause of an enlarged gland. In general, the procedure is not used in the workup of autonomously functioning nodules. The procedure has little morbidity and can be tailored to the situation. Core biopsy, or large-needle biopsy, of the thyroid uses a larger gauge needle providing a fragment of tissue. This procedure also carries with it a higher morbidity. Core biopsy has the advantage of more complete sampling. Partial thyroidectomy may be used as a first-line procedure for patients with a high probability of cancer. It is reserved mostly if the result of a fine-needle aspiration is suspicious or if the patient/physician prefers it. Total thyroidectomy is performed for malignant goiters.

Histologic Findings
Simple nontoxic goiters show hyperplasia, colloid accumulation, and nodularity. Nodular hyperplasia is commonly seen in multinodular goiter. Cytologic findings include benign appearing follicular cells, abundant colloid, macrophages, and, sometimes, Hrthle cells. Inflammatory disorders of the thyroid, such as chronic lymphocytic (Hashimoto) thyroiditis, contain a mixed population of lymphocytes mixed with benign appearing follicular cells. Malignant nodules may be follicular cell in origin, ie, papillary (most common), follicular, Hrthle cell, or anaplastic. They also may be from parafollicular cells, medullary carcinoma or lymphoma, or other categories.

Medical Care
Small benign euthyroid goiters do not require treatment. The effectiveness of medical treatment using thyroid hormone for benign goiters is controversial. Large and complicated goiters may require medical and surgical treatment. Malignant goiters require medical and surgical treatment. ; The size of a benign euthyroid goiter may be reduced with levothyroxine suppressive therapy. The patient is monitored to keep serum TSH in a low but detectable range to avoid hyperthyroidism, cardiac arrhythmias, and osteoporosis. The patient has to be compliant with monitoring. Some authorities suggest suppressive treatment for a definite time period instead of indefinite therapy. Patients with Hashimoto thyroiditis respond better. Treatment of hypothyroidism or hyperthyroidism often reduces the size of a goiter. Thyroid hormone replacement is often required following surgical and radiation treatment of a goiter. Use of radioactive iodine for the therapy of nontoxic goiter has been disappointing and is controversial.

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Medical therapy of autonomous nodules with thyroid hormone is not indicated. Ethanol infusion into benign thyroid nodules has not been approved in the United States, but it is used elsewhere.

Surgical Care
Surgery is reserved for the following situations: ; ; ; Large goiters with compression Malignancy When other forms of therapy are not practical or ineffective

Consultations
An endocrinologist should assess a patient at least once, and assessment should be even more frequent if the goiter is complicated by thyroid dysfunction or malignancy or if the patient is being considered for surgical management.

Diet
Nutrition plays a role in the development of endemic goiters. Dietary factors include iodine deficiency, goitrogens, protein malnutrition, and energy malnutrition. Often these factors occur concurrently. ; Iodine: If it is practical, treat endemic goiters in iodine-deficient regions with iodine supplementation in the diet and avoidance of goitrogens. Treatment with iodine supplementation or levothyroxine may reduce goiter size. Goitrogens: Cyanoglucosides are naturally occurring goitrogens that are digested to release cyanide, which is converted to thiocyanate. Thiocyanate inhibits iodide transport in the thyroid and, at higher levels, inhibits organification. Foods that contain cyanoglucosides include cassava, lima beans, maize, bamboo shoots, and sweet potatoes. Thioglucosides are natural goitrogens found in the Cruciferae family of vegetables and weeds eaten by animals. When digested, they release thiocyanate and isothiocyanate, which have thionamidelike properties and are passed to humans via milk ingestion.

GRAVE DISEASE
Background
Graves disease, named after Robert J. Graves, MD, circa 1830s, is an autoimmune disease characterized by hyperthyroidism due to circulating autoantibodies. Thyroid-stimulating immunoglobulins (TSIs) bind to and activate thyrotropin receptors, causing the thyroid gland to grow and the thyroid follicles to increase synthesis of thyroid hormone. Graves disease, along with Hashimoto thyroiditis, is classified as an autoimmune thyroid disorder.

Recent studies
Boelaert et al investigated the prevalences of and relative risks for coexisting autoimmune diseases in patients with Graves disease (2791 patients) or Hashimoto thyroiditis (495 patients). The authors found coexisting disorders in 9.7% of patients with Graves disease and in 14.3% of those with Hashimoto thyroiditis, with rheumatoid arthritis being the most common of these (prevalence = 3.15% and 4.24% in Graves disease and Hashimoto thyroiditis, respectively). Relative risks of greater than 10 were found for pernicious anemia, systemic lupus erythematosus, Addison disease, celiac disease, and vitiligo. The authors also reported a tendency for parents of patients with Graves disease or Hashimoto thyroiditis to have a history of hyperthyroidism or hypothyroidism, respectively.

Pathophysiology
In Graves disease, B and T lymphocyte-mediated autoimmunity are known to be directed at 4 well-known thyroid antigens: thyroglobulin, thyroid peroxidase, sodium-iodide symporter, and the thyrotropin receptor. However, the thyrotropin receptor itself is the primary autoantigen of Graves disease and is responsible for the

manifestation of hyperthyroidism. In this disease, the antibody and cell-mediated thyroid antigen-specific immune responses are well defined. Direct proof of an autoimmune disorder that is mediated by autoantibodies is the development of hyperthyroidism in healthy subjects by transferring thyrotropin receptor antibodies in serum from patients with Graves disease and the passive transfer of thyrotropin receptor antibodies to the fetus in pregnant women. The thyroid gland is under continuous stimulation by circulating autoantibodies against the thyrotropin receptor, and pituitary thyrotropin secretion is suppressed because of the increased production of thyroid hormones. The stimulating activity of thyrotropin receptor antibodies is found mostly in the immunoglobulin G1 subclass. These thyroid-stimulating antibodies cause release of thyroid hormone and thyroglobulin that is mediated by 3,'5'-cyclic adenosine monophosphate (cyclic AMP), and they also stimulate iodine uptake, protein synthesis, and thyroid gland growth. The anti-sodium-iodide symporter, antithyroglobulin, and antithyroid peroxidase antibodies appear to have little role in the etiology of hyperthyroidism in Graves disease. However, they are markers of autoimmune disease against the thyroid. Intrathyroidal lymphocytic infiltration is the initial histologic abnormality in persons with autoimmune thyroid disease and can be correlated with the titer of thyroid antibodies. Besides being the source of autoantigens, the thyroid cells express molecules that mediate T cell adhesion and complement regulation (Fas and cytokines) that participate and interact with the immune system. In these patients, the proportion of CD4 lymphocytes is lower in the thyroid than in the peripheral blood. The increased Fas expression in intrathyroidal CD4 T lymphocytes may be the cause of CD4 lymphocyte reduction in these individuals. Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22. Some of these susceptibility genes are specific to either Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. The genetic predisposition to thyroid autoimmunity may interact with environmental factors or events to precipitate the onset of Graves disease. Two new susceptibility loci were found: the RNASET2-FGFR1OP-CCR6 region at 6q27 and an intergenic region at 4p14. Moreover, strong associations of thyroid-stimulating hormone receptor and major histocompatibility complex class II variants with persistently thyroid stimulating hormone receptor autoantibodies (TRAb)-positive Graves disease were found. Graves disease patients a have higher rate of peripheral blood mononuclear cell conversion into CD34+ fibrocytes compared with healthy controls. These cells may contribute to the pathophysiology of ophthalmopathy by accumulating in orbital tissues and producing inflammatory cytokines, including TNF-alpha and IL-6. Pathophysiologic mechanisms are shown in the image below.

Pathophysiologic mechanisms of Graves disease relating thyroid-stimulating immunoglobulins to hyperthyroidism and ophthalmopathy. T4 is levothyroxine. T3 is triiodothyronine.

Epidemiology

Frequency
United States Graves disease is the most common cause of hyperthyroidism in the United States. A study conducted in Olmstead County, Minnesota estimated the incidence to be approximately 30 cases per 100,000 persons per year. The prevalence of maternal thyrotoxicosis is approximately 1 case per 500 persons, with maternal Graves disease being the most common etiology. Commonly, patients have a family history involving a wide spectrum of autoimmune thyroid diseases, such as Graves disease, Hashimoto thyroiditis, or postpartum thyroiditis, among others. International Among the causes of spontaneous thyrotoxicosis, Graves disease is the most common. Graves disease represents 60-90% of all causes of thyrotoxicosis in different regions of the world. In the Wickham Study in the United Kingdom, the incidence was reported to be 100-200 cases per 100,000 population per year. The incidence in women in the UK has been reported to be 80 cases 100,000 per year.

Mortality/Morbidity
If left untreated, Graves disease can cause severe thyrotoxicosis. A life-threatening thyrotoxic crisis (ie, thyroid storm) can occur. Long-standing severe thyrotoxicosis leads to severe weight loss with catabolism of bone and muscle. Cardiac complications and psychocognitive complications can cause significant morbidity. Graves disease is also associated with ophthalmopathy, dermopathy, and acropachy. ; Thyroid storm is an exaggerated state of thyrotoxicosis. It occurs in patients who have unrecognized or inadequately treated thyrotoxicosis and a superimposed precipitating event such as thyroid surgery, nonthyroidal surgery, infection, or trauma. When thyroid storm was first described, the acute mortality rate was nearly 100%. In current practice, with aggressive therapy and early recognition of the syndrome, the mortality rate is approximately 20%. Long-term excess of thyroid hormone can lead to osteoporosis in men and women. The effect can be particularly devastating in women, in whom the disease may compound the bone loss secondary to chronic anovulation or menopause. Bone loss is accelerated in patients with hyperthyroidism. The increase in bone loss can be demonstrated by increased urinary pyridinoline cross-link excretion. Serum calcium and phosphate, plasma FGF-23 were significantly higher in the patients with Graves disease than in healthy control subjects, suggesting that FGF-23 is physiologically related to serum phosphate homeostasis in untreated Graves disease. Hyperthyroidism increases muscular energy expenditure and muscle protein breakdown. These abnormalities may explain the sarcopenia and myopathy observed in patients with hyperthyroid Graves disease. Cardiac hypertrophy has been reported in thyrotoxicosis of different etiologies. Rhythm disturbances such as extrasystolic arrhythmia, atrial fibrillation, and flutter are common. Cardiomyopathy and congestive heart failure can occur. Psychiatric manifestations such as mood and anxiety disorders are common. Subjective cognitive dysfunction is often reported by Graves disease patients and may be due to affective and somatic manifestations of thyrotoxicosis, which remit after treatment of Graves thyrotoxicosis. Nonpitting edema is the most prevalent form of dermopathy (about 40%) and are primarily in the pretibial area. The nearly all (>95%) patients with dermopathy had ophthalmopathy. Advanced forms of dermopathy are elephantiasis or thyroid acropachy. Severe acropachy can be disabling and can lead to total loss of hand function. Progression of ophthalmopathy can lead to compromised vision and blindness. Visual loss due to corneal lesions or optic nerve compression can be seen in severe Graves ophthalmopathy. Maternal Graves disease can lead to neonatal hyperthyroidism by transplacental transfer of thyroidstimulating antibodies. Approximately 1-5% of children of mothers with Graves disease (usually with high TSI titer) are affected. Usually, the TSI titer falls during pregnancy. Elderly individuals may develop apathetic hyperthyroidism, and the only presenting features may be unexplained weight loss or cardiac symptoms such as atrial fibrillation and congestive heart failure.

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Race
; In whites, autoimmune thyroid diseases are, based on linkage analysis, linked with the following loci: AITD1, CTLA4, GD1, GD2, GD3, HT1, and HT2. Different loci have been reported to be linked with autoimmune thyroid diseases in persons of other races. Susceptibility is influenced by genes in the human leukocyte antigen (HLA) region on chromosome 6 and in CTLA4 on band 2q33. Association with specific HLA haplotypes has been observed and is found to vary with ethnicity. As with most autoimmune diseases, susceptibility is increased in females. Hyperthyroidism due to Graves disease has a female-to-male ratio of 7-8:1. The female-to-male ratio for pretibial myxedema is 3.5:1. Only 7% of patients with localized myxedema have thyroid acropachy. Unlike the other manifestations of Graves disease, the female-to-male ratio for thyroid acropachy is 1:1. Typically, Graves disease is a disease of young women, but it may occur in persons of any age. The typical age range is 20-40 years. Most affected women are aged 30-60 years.

Sex
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Age
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History
Because Graves disease is an autoimmune disorder that also affects other organ systems, taking a careful patient history is essential to establishing the diagnosis. In some cases, the history might suggest a triggering factor such as trauma to the thyroid, including surgery of the thyroid gland, percutaneous injection of ethanol, and infarction of a thyroid adenoma. Other factors might include interferon (eg, interferon beta-1b) or interleukin (IL-4) therapy. Patients usually present with symptoms typical of thyrotoxicosis. Hyperthyroidism is characterized by both increased sympathetic and decreased vagal modulation. Tachycardia and palpitation are very common symptoms. Not all patients present with such classic features. In fact, a subset of patients with euthyroid Graves disease is described. In elderly individuals, fewer symptoms are apparent to the patient. Clues may include unexplained weight loss, hyperhidrosis, or rapid heart beat. Young adults of Southeast Asian descent may complain of sudden paralysis thought to be related to thyrotoxic periodic paralysis. There is an association of polymorphisms of the calcium channel alpha1-subunit gene with thyrotoxic periodic paralysis. One third of patients with thyrotoxic hypokalemic periodic paralysis were found to have mutations in the inwardly rectifying potassium channel. The symptoms of Graves disease, organized by systems, are as follows: ; ; ; ; ; ; ; ; General - Fatigue, general weakness Dermatologic - Warm, moist, fine skin; sweating; fine hair; onycholysis; vitiligo; alopecia; pretibial myxedema Neuromuscular - Tremors, proximal muscle weakness, easy fatigability, periodic paralysis in persons of susceptible ethnic groups Skeletal - Back pain, increased risk for fractures Cardiovascular - Palpitations, dyspnea on exertion, chest pain, edema Respiratory - Dyspnea Gastrointestinal - Increased bowel motility with increased frequency of bowel movements Ophthalmologic - Tearing, gritty sensation in the eye, photophobia, eye pain, protruding eye, diplopia, visual loss

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Renal - Polyuria, polydipsia Hematologic - Easy bruising Metabolic - Heat intolerance, weight loss despite increase or similar appetite, worsening diabetes control Endocrine/reproductive - Irregular menstrual periods, decreased menstrual volume, gynecomastia, impotence Psychiatric - Restlessness, anxiety, irritability, insomnia

Physical
Most of the physical findings are related to thyrotoxicosis. Physical findings that are unique to Graves disease but not associated with other causes of hyperthyroidism include ophthalmopathy and dermopathy. Myxedematous changes of the skin (usually in the pretibial areas) are described as resembling an orange peel in color and texture. Onycholysis can be seen usually in the fourth and fifth fingernails. The presence of a diffusely enlarged thyroid gland, thyrotoxic signs and symptoms, together with evidence of ophthalmopathy or dermopathy, can establish the diagnosis. Common physical findings, organized by anatomic regions, are as follows: ; ; ; General - Increased basal metabolic rate, weight loss despite increase or similar appetite Skin - Warm, most, fine skin; increased sweating; fine hair; vitiligo; alopecia; pretibial myxedema Head, eyes, ears, nose, and throat - Chemosis, conjunctival irritation, widening of the palpebral fissures, lid lag, lid retraction, proptosis, impairment of extraocular motion, visual loss in severe optic nerve involvement, periorbital edema Neck - Upon careful examination, the thyroid gland generally is diffusely enlarged and smooth; a welldelineated pyramidal lobe may be appreciated upon careful palpation; thyroid bruits and, rarely, thrills may be appreciated; thyroid nodules may be palpable. Chest - Gynecomastia, tachypnea, tachycardia, murmur, hyperdynamic precordium, S3, S4 heart sounds, ectopic beats, irregular heart rate and rhythm Abdomen - Hyperactive bowel sound Extremities - Edema, acropachy, onycholysis Neurologic - Hand tremor (fine and usually bilateral), hyperactive deep tendon reflexes Musculoskeletal - Kyphosis, lordosis, loss of height, proximal muscle weakness, hypokalemic periodic paralysis in persons of susceptible ethnic groups Psychiatric - Restlessness, anxiety, irritability, insomnia, depression

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Ophthalmopathy is a hallmark of Graves disease. Approximately 25-30% of patients with Graves disease have clinical evidence of Graves ophthalmopathy. Thyrotropin receptor is highly expressed in the fat and connective tissue of patients with Graves ophthalmopathy. Measuring diplopia fields, eyelid fissures, range of extraocular muscles, visual acuity, and proptosis provides quantitative assessment to follow the course of ophthalmopathy. Signs of corneal or conjunctival irritation include conjunctival injection and chemosis. A complete ophthalmologic examination, including retinal examination and slit-lamp examination by an ophthalmologist, is indicated if the patient is symptomatic. Although thyroid nodule(s) may be present, excluding multinodular toxic goiter (especially in older patients) as the cause of thyrotoxicosis is essential. The approach to treatment may be different. Excluding thyroid neoplasia is also important in these patients because reports have indicated that differentiated thyroid cancer is probably more common in patients with Graves disease and may also have a more aggressive course in these patients.

Causes
Graves disease is autoimmune in etiology, and the immune mechanisms involved may be one of the following: ; Expression of a viral antigen (self-antigen) or a previously hidden antigen

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The specificity crossover between different cell antigens with an infectious agent or a superantigen Alteration of the T cell repertoire, idiotypic antibodies becoming pathogenic antibodies New expression of HLA class II antigens on thyroid epithelial cells (eg, HLA-DR antigen)

The autoimmune process in Graves disease is influenced by a combination of environmental and genetic factors. Several autoimmune thyroid disease susceptibility genes have been identified: CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22. Some of these susceptibility genes are specific to either Graves disease or Hashimoto thyroiditis, while others confer susceptibility to both conditions. HLA-DRB1 and HLA-DQB1 also appear to be associated with Graves disease susceptibility. Genetic factors contribute approximately 20-30% of overall disease susceptibility. ; Cytotoxic T lymphocyte-associated molecule-4 (CTLA4) is a major thyroid autoantibody susceptibility gene, and it is a negative regulator of T-cell activation and may play an important role in the pathogenesis of Graves disease. The G allele of exon1 +49 A/G single nucleotide polymorphism (SNP) of the CTLA4 gene influences higher TPOAb and TgAb production in patients who are newly diagnosed with Graves disease. This SNP of the CTLA4 gene can also predict recurrence of Graves disease after cessation of thionamide treatment. There is an association of a C/T SNP in the Kozak sequence of CD40 with Graves disease. The association of SNPs in PTPN22 varies among autoimmune diseases individually or as part of a haplotype, and the mechanisms by which PTPN22 confers susceptibility to Graves disease may differ from other autoimmune diseases. Alleles of intron 7 of the thyrotropin receptor gene (TSHR) have also been shown to contribute to susceptibility to Graves disease

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Environmental factors associated with susceptibility are largely unproven. Other factors include infection, iodide intake, stress, female sex, steroids, and toxins. Smoking has been implicated in the worsening of Graves ophthalmopathy. ; Graves disease has been associated with a variety of infectious agents such as Yersinia enterocolitica and Borrelia burgdorferi. Homologies have been shown between proteins of these organisms and thyroid autoantigens. Stress can be a factor for thyroid autoimmunity. Acute stress-induced immunosuppression may be followed by immune system hyperactivity, which could precipitate autoimmune thyroid disease. This may occur during the postpartum period, in which Graves disease may occur 3-9 months after delivery. Estrogen may influence the immune system, particularly the B-cell repertoire. Both T- and B-cell function are diminished during pregnancy, and the rebound from this immunosuppression is thought to contribute to the development of postpartum thyroid syndrome. Interferon beta-1b and interleukin-4, when used therapeutically, may cause Graves disease. Trauma to the thyroid has also been reported to be associated with Graves disease. This may include surgery of the thyroid gland, percutaneous injection of ethanol, and infarction of a thyroid adenoma.

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Laboratory Studies
Ultrasensitive (third-generation) thyrotropin assays remain the best screening test for thyroid disorders. ; ; With the exception of thyrotropin-induced hyperthyroidism, subnormal or suppressed thyrotropin levels are seen in most patients with thyrotoxicosis. Free T4 levels or the free T4 index is usually elevated, as is the free T3 level or free T3 index. Subclinical hyperthyroidism, defined as a free T4 or free T3 level within the reference range with suppressed thyrotropin, also can be seen. On occasion, only the free T3 level is elevated, a syndrome known as T3 toxicosis. This may be associated with toxic nodular goiter or the ingestion of T3. Assays for thyrotropin-receptor antibodies (particularly TSIs) almost always are positive. Detection of TSIs is diagnostic for Graves disease.

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The presence of TSIs is particularly useful in reaching the diagnosis in pregnant women, in whom the use of radioisotopes is contraindicated. Other markers of thyroid autoimmunity, such as antithyroglobulin antibodies or antithyroidal peroxidase antibodies, are usually present. Other autoantibodies that may be present include thyrotropin receptorblocking antibodies and anti sodium-iodide symporter antibody. The presence of these antibodies supports the diagnosis of an autoimmune thyroid disease.

Liver function test results should be obtained to monitor for liver toxicity caused by thioamides (antithyroid medications). A CBC count with differential should be obtained at baseline and with the development of fever or symptoms of infection. Graves disease may be associated with normocytic anemia, low-normal to slightly depressed total WBC count with relative lymphocytosis and monocytosis, low-normal to slightly depressed platelet count. Thionamides may rarely cause severe hematologic side effects, but routine screening for these rare events is not cost-effective. Investigation of gynecomastia associated with Graves disease may reveal increased sex hormonebinding globulin levels and decreased free testosterone levels. Graves disease may worsen diabetes control and may be reflected by an increase in hemoglobin A1C in diabetic patients. A fasting lipid profile may show decreased total cholesterol levels and decreased triglyceride levels. Thyrotropin-releasing hormone testing has largely been replaced by third-generation thyrotropin assays. A high titer of serum antibodies to collagen XIII is associated with active Graves ophthalmopathy.

Imaging Studies
Radioactive iodine scanning and measurements of iodine uptake are useful in differentiating the causes of hyperthyroidism. In Graves disease, the radioactive iodine uptake is increased and the uptake is diffusely distributed over the entire gland. Ultrasounds with color-Doppler evaluation have been found to be cost-effective in hyperthyroid patients. A prospective trial showed that thyroid ultrasound findings are predictive of radioiodine treatment outcome, and, in patients with Graves disease, normoechogenic and large glands are associated with increased radioresistance. Computed tomography scanning or magnetic resonance imaging (of the orbits) may be necessary in the evaluation of proptosis. If routinely performed, most patients have evidence of orbitopathy, such as an increased volume of extraocular muscles and/or retrobulbar connective tissue. These techniques are useful to monitor changes over time or to ascertain the effects of treatment. Careful monitoring is required after using iodinated contrast agents as they may affect ongoing treatment plans.

Histologic Findings
In select cases in which thyroidectomy was performed for the treatment of severe hyperthyroidism, the thyroid glands from patients with Graves disease show lymphocytic infiltrates and follicular hypertrophy, with little colloid present.

Medical Care
Treatment involves alleviation of symptoms and correction of the thyrotoxic state. Adrenergic hyperfunction is treated with beta-adrenergic blockade. Correcting the high thyroid hormone levels can be achieved with antithyroid medications that block the synthesis of thyroid hormones or by treatment with radioactive iodine.

Radioactive iodine
The most commonly used therapy for Graves disease is radioactive iodine. Indications for radioactive iodine over antithyroid agents include a large thyroid gland, multiple symptoms of thyrotoxicosis, high levels of thyroxine, and high titers of TSI. Information and guidelines are as follows: ; Many physicians in the United States prefer to use radioactive iodine as first-line therapy, especially in younger patients, because of the high relapse rate (>50%) associated with antithyroid therapy.

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Radioiodine treatment can be performed in an outpatient setting. The usual dose ranges from 5-15 mCi, determined either by using various formulas that take into account the estimated thyroid weight and radioiodine uptake or by using fixed dosages of iodine I 131; detailed kinetic studies of131 I are not essential and do not lead to better treatment results. A fixed dose of 7 mCi has been advocated by some researchers as the first empirical dose in the treatment of hyperthyroidism. In general, higher dosages are required for patients who have large goiters, have low radioiodine uptake, or who have been pretreated with antithyroid drugs. Patients currently taking antithyroid drugs must discontinue the medication at least 2 days prior to taking the radiopharmaceutical. In one study, withholding antithyroid drugs for just over 2 weeks before radioiodine treatment resulted in the lowest failure rate. Pretreatment with thioanmides reduces the cure rate of radioiodine therapy in hyperthyroid diseases. Thyroid function test results generally improve within 6-8 weeks of therapy, but this can be highly variable. With radioactive iodine, the desired result is hypothyroidism due to destruction of the gland, which usually occurs 2-3 months after administration. Following up with the patient and monitoring thyroid function monthly or as the clinical condition dictates is important. When patients become hypothyroid, they require lifelong replacement with thyroid hormone. The possibility exists that radioactive iodine can precipitate thyroid storm by releasing thyroid hormones. This risk is higher in elderly and debilitated patients. This problem can be addressed by pretherapy administration with antithyroidal medication such as propylthiouracil (PTU) or methimazole, but antithyroid medication also may decrease the effectiveness of radioiodine, as discussed above. If thyroid function does not normalize within 6-12 months of treatment, a second course at a similar or higher dose can be given. Third courses are rarely needed. Hypothyroidism may ensue in the first year in up to 90% of patients given higher doses of radioiodine. Approximately one third of patients develop transient hypothyroidism. Unless a patient is highly symptomatic, thyroxine replacement may be withheld if hypothyroidism occurs within the first 2 months of therapy. If it persists for longer than 2 months, permanent hypothyroidism is likely and replacement with T4 should be initiated. Radiation thyroiditis is rare, but it may occur and exacerbate thyrotoxicosis. Long-term follow-up is mandatory for all patients. One concern with the use of radioiodine in persons with Graves disease is its controversial potential for exacerbating existing Graves ophthalmopathy. However, the presence of ophthalmopathy should not influence the choice of therapy for hyperthyroidism. If possible in patients with mild progressive ophthalmopathy, institute a course of steroids (prednisone up to 1 mg/kg) for 2-3 months, tapering a few days before radioiodine therapy. For those with no obvious ophthalmopathy, the chances of exacerbation are much lower. In patients with severe Graves ophthalmopathy, treatment of hyperthyroidism and ophthalmopathy should proceed concurrently and independently of each other. The absolute contraindication for radioiodine is pregnancy. No evidence of germ-line mutations has been demonstrated from gonadal exposure. The incidence of birth defects or abnormal pregnancies has not increased after radioiodine treatments. After radioiodine therapy, germinal epithelium and Leydig cell function may change marginally, which may have some clinical significance in male patients with preexisting fertility impairment. Because it is known that low-dose thyroid radiation exposure in children increases the risk of thyroid cancer later in life, larger doses of131 I are recommended for children. If patients are aged 6-10 years, ablative doses of131 I (100-150 mCi/g of thyroid tissue) may be used to prevent the survival of thyroid cells that may be transformed later into malignant cells.

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Graves ophthalmopathy
Graves ophthalmopathy can be divided into 2 clinical phases: the inflammatory stage and the fibrotic stage. The inflammatory stage is marked by edema and deposition of glycosaminoglycan in the extraocular muscles. This

results in the clinical manifestations of orbital swelling, stare, diplopia, periorbital edema, and at times, pain. The fibrotic stage is a convalescent phase and may result in further diplopia and lid retraction. It improves spontaneously in 64% of patients. Approximately 10-20% of patients have gradual progression of disease over many years, followed by clinical stability. Approximately 2-5% have progressive worsening of the disease, with visual impairment in some. Correction of both hyperthyroidism and hypothyroidism is important for the ophthalmopathy. Antithyroid drugs and thyroidectomy do not influence the course of the ophthalmopathy, whereas radioiodine treatment may exacerbate preexisting ophthalmopathy but can be prevented by glucocorticoids. In the long term, thyroid ablation may be beneficial for ophthalmopathy because of the decrease in antigens shared by the thyroid and the orbit in the autoimmune reactions. In general, treatment of hyperthyroidism is associated with an improvement of ophthalmopathy, but hypothyroidism must be avoided because it worsens ophthalmopathy. For mild-to-moderate ophthalmopathy, local therapeutic measures (eg, artificial tears and ointments, sunglasses, eye patches, nocturnal taping of the eyes, prisms, elevating the head at night) can control symptoms and signs. If the disease is active, the mainstays of therapy are (1) high-dose glucocorticoids, (2) orbital radiotherapy, (3) both, or (4) orbital decompression. For severe or progressive disease, glucocorticoids at 40 mg/d (usual dose) may be tried. The drug should be continued until evidence of improvement and disease stability is observed. The dosage is then tapered over 4-12 weeks. High-dose pulse glucocorticoid therapy has also been used with good results. A study by Liao and Huang evaluated the correlation of retrobulbar volume change, resected orbital fat volume, and proptosis reduction after surgical decompression in patients with Graves ophthalmopathy. Decompression by resecting orbital fat was found to reduce proptosis in patients with disfiguring Graves ophthalmopathy. If no response to therapy occurs in the inflammatory phase, orbital radiotherapy with or without steroids may be tried. Orbital radiotherapy does not increase the risk for radiation-induced tumors, cataract, and retinopathy, except in patients with diabetes with possible or definite retinopathy. Diuretics have a limited effect on the edema caused by venous engorgement of the orbit. Gamma knife surgery has been attempted with success in a limited number of patients, but further studies are needed to validate this approach. Surgical management is generally performed in the fibrotic phase, when the patient is euthyroid. See Surgical Care. Novel treatments such as somatostatin analogs or intravenous immunoglobulins are under evaluation. Studies with octreotide LAR (long-acting, repeatable) show conflicting or marginal therapeutic benefit for patients with Graves ophthalmopathy. Infliximab, an anti-tumour necrosis factor alpha (TNF-) antibody, has been reported to successfully treat a case of sightthreatening Graves ophthalmopathy. Rituximab, anti-CD20 monoclonal antibody, may transiently deplete Blymphocytes and potentially suppress the active inflammatory phase of Graves ophthalmopathy. A multicentered prospective pilot study suggests that periocular injection of triamcinolone may reduce diplopia and the size of extraocular muscles in patients with Graves ophthalmopathy of recent onset. In a prospective randomized trial, pentoxifylline improved symptoms and proptosis in the inactive phase of Graves ophthalmopathy.

Pretibial myxedema
Some degree of pretibial (localized dermopathy) myxedema is observed in 5-10% of patients, with 1-2% having cosmetically significant lesions. Affected patients tend to have more severe ophthalmopathy than those who are not affected. It usually manifests as elevated, firm, nonpitting, localized thickening over the lateral aspect of the lower leg, with bilateral involvement. It also may involve the upper extremities. Milder cases do not require therapy other than treatment of the thyrotoxicosis. Therapy with topical steroids applied under an occlusive plastic dressing film (eg, Saran Wrap) for 3-10 weeks has been helpful. In severe cases, pulse glucocorticoid therapy may be tried.

Acropachy
Clubbing of fingers with osteoarthropathy, including periosteal new bone formation, may occur. This almost always occurs in association with ophthalmopathy and dermopathy. No therapy has been proven to be effective.

Surgical Care
Indications and outcomes are as follows: ; Thyroidectomy is no longer the recommended first-line therapy for hyperthyroid Graves disease. However, a retrospective cohort study showed that one-third of all patients electing surgery as definitive management did so without a specific indication, and the patient satisfaction with the decision for surgery as definitive management of Graves disease was high. Surgery is a safe alternative therapeutic option in patients who are noncompliant with or cannot tolerate antithyroid drugs, have moderate-tosevere ophthalmopathy, have large goiters, or refuse or cannot undergo radioiodine therapy. Thyroidectomy may be appropriate in the presence of a thyroid nodule that is suggestive of carcinoma. In certain cases (eg, in pregnant patients with severe hyperthyroidism), thyroidectomy may be indicated because radioactive iodine and antithyroid medications may be contraindicated. It generally is reserved for patients with large goiters with or without compressive symptoms. It also may be indicated in patients who refuse radioiodine as definitive therapy or in those in whom the use of antithyroid drugs and/or radioiodine does not control hyperthyroidism. Surgery provides rapid treatment of Graves disease and permanent cure of hyperthyroidism in most patients, and it has "negligible mortality and acceptable morbidity" by experienced surgeons. Preoperative preparation to render the patient euthyroid is essential in order to prevent thyrotoxic crisis (thyroid storm). The hyperthyroid state can be rapidly corrected using a combination of iopanoic acid, dexamethasone, beta-blockers, and thionamides. This can be accomplished with the use of antithyroid drugs for approximately 6 weeks, with or without concomitant beta-blockade. Most surgeons administer iodine (as Lugol solution or saturated solution of potassium iodide to provide 30 mg of iodine/d) for 10 days before surgery to decrease thyroid gland vascularity, the rate of blood flow, and intraoperative blood loss during thyroidectomy. With experienced surgeons, vocal cord paralysis due to superior or recurrent laryngeal nerve injury and hypoparathyroidism are rare adverse events, occurring in less than 1% of patients. Subtotal thyroidectomy is usually used with the intention of leaving enough thyroid remnants behind to avoid hypothyroidism. Importantly, keep in mind that the risk of recurrent hyperthyroidism potentially increases with larger remnant sizes. However, many studies have shown that the size of the remnant is not the only determinant of the risk of recurrence. Iodine uptake and immunologic activity (eg, level of TSI) are just 2 of the other factors that influence the risk of recurrent hyperthyroidism. If the goal of surgery is to avoid recurrent hyperthyroidism, near-total thyroidectomy has been advocated as the procedure of choice. Regardless of the extent of surgery, all patients require long-term follow-up. Near-total thyroidectomy has little, if any, effect on the course of ophthalmopathy. If ophthalmopathy is severe but inactive, orbital decompression may be performed. Reducing proptosis and decompressing the optic nerve can be achieved by transantral orbital decompression. A study by Alsuhaibani et al found that the change in the volume of the medial rectus muscle may help explain the variability in the proptosis reduction following orbital decompression. The major adverse effect is postoperative diplopia, which may necessitate a second surgery on the extraocular muscles to correct the problem. Rehabilitative (extraocular muscle or eyelid) surgery is often needed. Eyelid surgery (eg, severance of the Mller muscle, scleral or palatal graft insertion) can be performed to improve exposure keratitis.

; ; ; ; ;

Procedures and preparations are as follows: ;

; ;

; ; ;

; ; ; ; ;

Ophthalmopathy is as follows:

; ;

Consultations
Consultation with an endocrinologist may be necessary for the management and regulation of thyroid hormone levels in atypical presentations, as follows: ; ; ; Graves disease in pregnancy Neonatal Graves disease management Graves disease complicated by a nodular thyroid gland unresponsive to usual medical therapy or in older adults Unilateral or bilateral proptosis Workup of other etiologies for eye findings besides Graves disease Follow-up of visual acuity, corneal disease prevention, and eye muscle function

Consultation with an ophthalmologist may be needed in the following situations: ; ; ;

Consultation with a dermatologist may be needed in patients with localized myxedema that is unresponsive to topical corticosteroids.

Diet
The amount of iodine in the diet can influence the hormone synthesis activity in the thyroid gland. Iodine-containing food has different effects on thyroid uptake of131 I and technetium Tc 99m. Iodine-rich food decreases131 I uptake but increases99m Tc in most patients. However, the diagnostic value of a radioiodine uptake test to differentiate Graves disease and silent thyroiditis is not affected by dietary iodine intake. Iodine restriction before a radioiodine uptake test is unnecessary. Dietary iodine intake may influence the remission rate after antithyroid drug therapy. This is based on the observation that the outcome of antithyroid therapy in the older literature showed lower remission rates than it did in later studies and that the average dietary iodine content has been decreasing over the years. However, a direct causal relationship has not been established by clinical trials.

Activity
Given the high-output state of the heart, strenuous exercise may be detrimental. The patient should be advised to avoid severe fatigue from exercise. Patients can use their pulse as a guide to activity.

HIPERTIROIDISME
Practice Essentials
Hyperthyroidism is a set of disorders that involve excess synthesis and secretion of thyroid hormones by the thyroid gland, which leads to the hypermetabolic condition of thyrotoxicosis. The most common forms of hyperthyroidism include diffuse toxic goiter (Graves disease), toxic multinodular goiter (Plummer disease), and toxic adenoma.

Signs and symptoms

Common symptoms of thyrotoxicosis include the following: ; ; ; ; ; ; ; Nervousness Anxiety Increased perspiration Heat intolerance Hyperactivity Palpitations Tachycardia or atrial arrhythmia

Common signs of thyrotoxicosis include the following:

; ; ; ; ; ; ; ; ; ; ; ;

Systolic hypertension Warm, moist, smooth skin Lid lag Stare Hand tremor Muscle weakness Weight loss despite increased appetite Reduction in menstrual flow or oligomenorrhea Younger patients tend to exhibit symptoms of sympathetic activation (eg, anxiety, hyperactivity, tremor) Older patients have more cardiovascular symptoms (eg, dyspnea, atrial fibrillation) and unexplained weight loss Patients with Graves disease often have more marked symptoms than patients with thyrotoxicosis from other causes Ophthalmopathy (eg, periorbital edema, diplopia, or proptosis) suggests Graves disease

Presentation of thyrotoxicosis varies, as follows

Diagnosis
Thyroid function tests for hyperthyroidism are as follows: ; ; ; ; ; ; ; ; ; ; ; ; Thyroid-stimulating hormone (TSH) Free thyroxine (FT4) or free thyroxine index (FTItotal T4 multiplied by the correction for thyroid hormone binding) Total triiodothyronine (T3) Thyrotoxicosis is marked by suppressed TSH levels and elevated T3 and T4 levels Patients with milder thyrotoxicosis may have elevation of T3 levels only Subclinical hyperthyroidism features decreased TSH and normal T3 and T4 levels Anti thyroid peroxidase (anti-TPO) antibody Thyroid-stimulating immunoglobulin (TSI) Graves disease Significantly elevated anti-TPO, elevated TSI Toxic multinodular goiter- Low or absent anti-TPO Toxic adenoma Low or absent anti-TPO Patients without active thyroid disease may have mildly positive anti-TPO

Thyroid function study results in hyperthyroidism are as follows:

Autoantibody tests for hyperthyroidism are as follows:

Autoantibody titers in hyperthyroidism are as follows:

If the etiology of thyrotoxicosis is not clear after physical examination and other laboratory tests, it can be confirmed by scintigraphy: the degree and pattern of isotope uptake indicates the type of thyroid disorder. Findings are as follows: ; ; ; Graves disease Diffuse enlargement of both thyroid lobes, with uniform uptake of isotope and elevated radioactive iodine uptake Toxic multinodular goiter -- Irregular areas of relatively diminished and occasionally increased uptake; overall radioactive iodine uptake is mildly to moderately increased Subacute thyroiditis Very low radioactive iodine uptake

Management

Treatment of hyperthyroidism includes symptom relief, as well as therapy with antithyroid medications, radioactive iodine-131 (131 I), or thyroidectomy. Symptomatic treatment is as follows: ; ; ; ; Oral rehydration for dehydrated patients Beta-blockers for relief of neurologic and cardiovascular symptoms For mild ophthalmopathy, saline eye drops as needed and tight-fitting sunglasses for outdoors For vision-threatening ophthalmopathy, high-dose glucocorticoids, with consideration for orbital decompression surgery and ocular radiation therapy Used for long-term control of hyperthyroidism in children, adolescents, and pregnant women In adult men and nonpregnant women, used to control hyperthyroidism before definitive therapy with radioactive iodine Methimazole is more potent and longer-acting than propylthiouracil Propylthiouracil is reserved for use in thyroid storm, first trimester of pregnancy, and methimazole allergy or intolerance Antithyroid drug doses are titrated every 4 weeks until thyroid functions normalize Patients with Graves disease may experience remission after treatment for 12-18 months, but recurrences are common within the following year Toxic multinodular goiter and toxic adenoma will not go into remission Preferred therapy for hyperthyroidism Administered orally as a single dose in capsule or liquid form Causes fibrosis and destruction of the thyroid over weeks to many months Hypothyroidism is expected Pregnancy, breast feeding, and recent lactation are contraindications Radioactive iodine should be avoided in children younger than 5 years Radioactive iodine is usually not given to patients with severe ophthalmopathy Severe hyperthyroidism in children Pregnant women who are noncompliant with or intolerant of antithyroid medication Patients with very large goiters or severe ophthalmopathy Patients who refuse radioactive iodine therapy Refractory amiodarone-induced hyperthyroidism Patients who require normalization of thyroid functions quickly, such as pregnant women, women who desire pregnancy in the next 6 months, or patients with unstable cardiac conditions

Antithyroid drug treatment is as follows: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;

Radioactive iodine treatment is as follows:

Thyroidectomy is reserved for special circumstances, including the following:

Background
Hyperthyroidism is a set of disorders that involve excess synthesis and secretion of thyroid hormones by the thyroid gland. The resulting elevation in levels of FT4, free triiodothyronine (FT3), or both leads to the hypermetabolic condition of thyrotoxicosis. Thus, although many clinicians (endocrinologists excluded) use the terms hyperthyroidism and thyrotoxicosis interchangeably, the 2 words have distinct meanings. For example, both exogenous thyroid hormone intake and subacute thyroiditis can cause thyrotoxicosis, but neither constitutes hyperthyroidism, because the conditions are not associated with new hormone production. The most common forms of hyperthyroidism include diffuse toxic goiter (Graves disease), toxic multinodular goiter (Plummer disease), and toxic adenoma (see Etiology). Together with subacute thyroiditis, these conditions constitute 85-90% of all causes of thyrotoxicosis.

The most reliable screening measure of thyroid function in the healthy ambulatory adult population is the TSH level. The degree of thyrotoxicosis is determined by measurement of thyroid hormone levels. Autoantibody testing, and nuclear thyroid scintigraphy in some cases, can provide useful etiologic information. (See Workup.) Treatment of hyperthyroidism includes symptom relief, as well as therapy with antithyroid medications, radioactive iodine, or thyroidectomy. However, antithyroid medications are not effective in thyrotoxicosis from subacute thyroiditis, because these cases result from release of preformed thyroid hormone. (See Treatment.)

Pathophysiology
Normally, the secretion of thyroid hormone is controlled by a complex feedback mechanism involving the interaction of stimulatory and inhibitory factors (see the image below). Thyrotropin-releasing hormone (TRH) from the hypothalamus stimulates the pituitary to release TSH.

Hypothalamic-pituitary-thyroid axis feedback. Schematic representation of negative feedback system that regulates thyroid hormone levels. TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone. Binding of TSH to receptors on the thyroid gland leads to the release of thyroid hormonesprimarily T4 and to a lesser extent T3. In turn, elevated levels of these hormones act on the hypothalamus to decrease TRH secretion and thus the synthesis of TSH. Synthesis of thyroid hormone requires iodine. Dietary inorganic iodide is transported into the gland by an iodide transporter, converted to iodine, and bound to thyroglobulin by the enzyme thyroid peroxidase through a process called organification. This results in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are coupled to form T3 and T4; these are then stored with thyroglobulin in the thyroids follicular lumen. The thyroid contains a large supply of its preformed hormones. Thyroid hormones diffuse into the peripheral circulation. More than 99.9% of T4 and T3 in the peripheral circulation is bound to plasma proteins and is inactive. Free T3 is 20-100 times more biologically active than free T4. Free T3 acts by binding to nuclear receptors (DNA-binding proteins in cell nuclei), regulating the transcription of various cellular proteins. Any process that causes an increase in the peripheral circulation of unbound thyroid hormone can cause thyrotoxicosis. Disturbances of the normal homeostatic mechanism can occur at the level of the pituitary gland, the thyroid gland, or in the periphery. Regardless of etiology, the result is an increase in transcription in cellular proteins, causing an increase in the basal metabolic rate. In many ways, signs and symptoms of hyperthyroidism resemble a state of catecholamine excess, and adrenergic blockade can improve these symptoms. In Graves disease, circulating autoantibodies against the thyrotropin receptor provide continuous stimulation of the thyroid gland. These antibodies cause release of thyroid hormones and thyroglobulin, and they also stimulate iodine uptake, protein synthesis, and thyroid gland growth.

Ophthalmopathy
The underlying pathophysiology of Graves ophthalmopathy (also called thyroid-associated orbitopathy) is not completely characterized. It most likely involves an antibody reaction against the TSH receptor that results in activation of T cells against tissues in the retro-orbital space that share antigenic epitopes with thyroid follicular cells. These immune processes lead to an active phase of inflammation, with lymphocyte infiltration of the orbital tissue and release of cytokines that stimulate orbital fibroblasts to multiply and produce mucopolysaccharides (glycosaminoglycans), which absorb water. In consequence, the extraocular muscles thicken and the adipose and connective tissue of the retro-orbit increase in volume.

Cigarette smoking and a high TSH receptor autoantibody level are significant risk factors for ophthalmopathy. In addition, patients who smoke appear to be more likely to experience worsening of their ophthalmopathy if treated with radioactive iodine, as do patients who have high pretreatment T3 levels and posttherapy hypothyroidism.

Etiology
Genetic factors appear to influence the incidence of thyrotoxicosis. Autoimmune thyroid disease, including Hashimoto hypothyroidism and Graves disease, often occurs in multiple members of a family. Several genetic syndromes have been associated with hyperthyroidism, especially autoimmune thyroid disease. McCune-Albright syndrome is caused by mutations in the GNAS gene. This gene encodes the stimulatory Gprotein alpha subunit, which is a key component of many signal transduction pathways. Patients present with the classic triad of polyostotic fibrous dysplasia, irregular caf-au-lait spots, and precocious puberty. The syndrome may also include facial asymmetry, Cushing syndrome, hyperthyroidism, and acromegaly. A number of disorders of thyroid function have been found to be caused by mutations in the TSHR gene, which encodes the TSH receptor protein. These disorders include the following: ; ; ; ; Familial gestational hyperthyroidism One type of nonimmune hyperthyroidism Congenital nongoiterous thyrotoxicosis Toxic thyroid adenoma with somatic mutation

Type II autoimmune polyendocrine syndrome is associated with hyperthyroidism and hypothyroidism, as well as type 1 diabetes mellitus and adrenal insufficiency. Patients may also have immune deficiency, as manifested by chronic mucosal candidiasis. Autoimmune thyroid disease has a higher prevalence in patients with human leukocyte antigen (HLA)-DRw3 and HLA-B89. Graves disease is felt to be an HLA-related, organ-specific defect in suppressor T-cell function. Similarly, subacute painful or granulomatous thyroiditis occurs more frequently in patients with HLA-Bw35. Like other immune diseases, these thyroid conditions occur more frequently in women than in men. With the availability of genome-wide association studies, more than a dozen genes and gene regions have been found to be associated with an increased risk for development of thyrotoxicosis, particularly Graves disease. Unsurprisingly, these studies have shown associations between these same genes and the development of other endocrine autoimmune disorders, such as type 1 diabetes mellitus. The loci for which specific function can be deduced appear to involve genes related to HLA, non-HLA immune function, and thyroid function. However, the odds ratios that have been determined generally indicate only a mildly increased risk for Graves disease. Most of the genome-wide association studies have focused on diffuse toxic goiter (ie, Graves disease). One study, however, found an association between development of toxic multinodular goiter (Plummer disease) and a single-nucleotide polymorphism (SNP) in the TSHR gene. . This SNP was seen in 9.6% of normal patients, 16.3% of patients with Graves disease, and 33.3% of patients with toxic multinodular goiter.

Iodine intake
Iodine intake also appears to influence the occurrence of thyrotoxicosis. Clearly, patients in borderline iodinedeficient areas of the world develop nodular goiter, often with areas of thyroid autonomy. When members of this population move to areas of sufficient iodine intake, thyrotoxicosis occurs. Evidence exists that iodine can act as an immune stimulator, precipitating autoimmune thyroid disease and acting as a substrate for additional thyroid hormone synthesis.

Graves disease
The most common cause of thyrotoxicosis is Graves disease (50-60% of cases). Graves disease is an organspecific autoimmune disorder characterized by a variety of circulating antibodies, including common autoimmune antibodies, as well as anti-TPO and anti-TG antibodies. The most important autoantibody is TSI, which is directed toward epitopes of the TSH receptor and acts as a TSH-receptor agonist. Like TSH, TSI binds to the TSH receptor on the thyroid follicular cells to activate thyroid hormone synthesis and release and thyroid gland growth (hypertrophy). This results in the characteristic

picture of Graves thyrotoxicosis, with a diffusely enlarged thyroid, very high radioactive iodine uptake, and excessive thyroid hormone levels compared with a healthy thyroid (see the images below).

Color flow ultrasonogram in patient with Graves disease. Generalized hypervascularity is visible throughout gland (note red areas), which often can be heard as hum or bruit with

stethoscope. Iodine 123 (123I) nuclear scintigraphy: 123I scans of normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D). Thyroid hormone levels can be highly elevated in Graves disease. Clinical findings specific to Graves disease include thyroid ophthalmopathy (periorbital edema, chemosis [conjunctival edema], injection, or proptosis) and, rarely, dermopathy over the lower extremities. This autoimmune condition may be associated with other autoimmune diseases, such as pernicious anemia, myasthenia gravis, vitiligo, adrenal insufficiency, celiac disease, and type 1 diabetes mellitus.

Subacute thyroiditis
The next most common cause of thyrotoxicosis is subacute thyroiditis (approximately 15-20% of cases), a destructive release of preformed thyroid hormone. A typical nuclear scintigraphy scan shows no radioactive iodine uptake (RAIU) in the thyrotoxic phase of the disease (see the images below). Thyroid hormone levels can be highly elevated in this condition.

Absence of iodine 123 (123I) radioactive iodine uptake in patient with thyrotoxicosis and subacute painless or lymphocytic thyroiditis. Laboratory studies at time of scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 g/dL (reference range, 4.5-11); total triiodothyronine (T3), 213 ng/dL (reference range, 90-180); T3-to-T4 ratio, 10; and erythrocyte sedimentation rate (ESR), 10 mm/hr. Absence of thyroid uptake, low T3-to-T4 ratio, and low ESR confirm diagnosis of subacute painless thyroiditis. Three multinuclear giant cell granulomas observed in fine-needle aspiration biopsy of thyroid from patient with thyrotoxicosis from subacute painful or granulomatous thyroiditis.

Toxic multinodular goiter

Toxic multinodular goiter (Plummer disease) accounts for 15-20% of thyrotoxicosis cases (see the image below). It occurs more commonly in elderly individuals, especially those with a long-standing goiter. Thyroid hormone excess develops very slowly over time and often is only mildly elevated at the time of diagnosis.

Scan in patient with toxic multinodular goiter. 5-Hour 123I-iodine uptake was elevated at 28% (normal 5-15%). Note multiple foci of variably increased tracer uptake. Symptoms of thyrotoxicosis are mild, often because only a slight elevation of thyroid hormone levels is present, and the signs and symptoms of thyrotoxicosis often are blunted (apathetic hyperthyroidism) in older patients. However, very high thyroid hormone levels may occur in this condition after high iodine intake (eg, with iodinated radiocontrast or amiodarone exposure).

Toxic adenoma
Toxic adenoma is caused by a single hyperfunctioning follicular thyroid adenoma. This disorder accounts for approximately 3-5% of thyrotoxicosis cases. The excess secretion of thyroid hormone occurs from a benign monoclonal tumor that usually is larger than 2.5 cm in diameter. The excess thyroid hormone suppresses TSH levels. RAIU usually is normal, and the radioactive iodine scan shows only the hot nodule, with the remainder of the normal thyroid gland suppressed because the TSH level is low.

Other causes of thyrotoxicosis

Several rare causes of thyrotoxicosis exist that deserve mention. Struma ovarii is ectopic thyroid tissue associated with dermoid tumors or ovarian teratomas that can secrete excessive amounts of thyroid hormone and produce thyrotoxicosis. Iodide-induced thyrotoxicosis (Jod-Basedow syndrome) occurs in patients with excessive iodine intake (eg, from an iodinated radiocontrast study). The antiarrhythmic drug amiodarone, which is rich in iodine and bears some structural similarity to T4, may cause thyrotoxicosis. Iodide-induced thyrotoxicosis also occurs in patients with areas of thyroid autonomy, such as a multinodular goiter or autonomous nodule. Iodide-induced thyrotoxicosis appears to result from loss of the normal adaptation of the thyroid to iodide excess. It is treated with cessation of the excess iodine intake and with administration of antithyroid medication. Usually, after depletion of the excess iodine, thyroid functions return to preexposure levels. Patients with a molar hydatidiform pregnancy or choriocarcinoma have extremely high levels of beta human chorionic gonadotropin (-hCG), which can weakly activate the TSH receptor. At very high levels of -hCG, activation of the TSH receptors is sufficient to cause thyrotoxicosis. Metastatic follicular thyroid carcinoma may also result in thyrotoxicosis. These lesions maintain the ability to make thyroid hormone, and in patients with bulky tumors, production may be high enough to cause thyrotoxicosis.

Epidemiology
Graves disease is the most common form of hyperthyroidism in the United States, causing approximately 6080% of cases of thyrotoxicosis. The annual incidence of Graves disease was found to be 0.5 cases per 1000 population during a 20-year period, with the peak occurrence in people aged 20-40 years. Toxic multinodular goiter (15-20% of thyrotoxicosis) occurs more frequently in regions of iodine deficiency. Most persons in the United States receive sufficient iodine, and the incidence of toxic multinodular goiter in the US population is lower than that in areas of the world with iodine deficiency. Toxic adenoma is the cause of 35% of cases of thyrotoxicosis.

The incidences of Graves disease and toxic multinodular goiter change with iodine intake. Compared with regions of the world with less iodine intake, the United States has more cases of Graves disease and fewer cases of toxic multinodular goiters.

Race-, sex-, and age-related demographics

Autoimmune thyroid disease occurs with the same frequency in Caucasians, Hispanics, and Asians but at lower rates in African Americans. All thyroid diseases occur more frequently in women than in men. Graves autoimmune disease has a male-tofemale ratio of 1:5-10. The male-to-female ratio for toxic multinodular goiter and toxic adenoma is 1:2-4. Graves ophthalmopathy is more common in women than in men. Autoimmune thyroid diseases have a peak incidence in people aged 20-40 years. Toxic multinodular goiters occur in patients who usually have a long history of nontoxic goiter and who therefore typically present when they are older than age 50 years. Patients with toxic adenomas present at a younger age than do patients with toxic multinodular goiter.

Prognosis
Hyperthyroidism from toxic multinodular goiter and toxic adenoma is permanent and usually occurs in adults. After normalization of thyroid function with antithyroid medications, radioactive iodine ablation usually is recommended as the definitive therapy. Long-term, high-dose antithyroid medication is not recommended. Toxic multinodular goiters and toxic adenomas probably will continue to grow slowly in size during antithyroid pharmacotherapy. Generally, the thyrotoxic areas are ablated, and patients may remain euthyroid. Those who become hypothyroid after radioactive iodine therapy are easily maintained on thyroid hormone replacement therapy, with T4 taken once daily. Patients with Graves disease may become hypothyroid in the natural course of their disease, regardless of whether treatment involves radioactive iodine or surgery. Eye disease may develop at a time distant from the initial diagnosis and therapy. Generally, after the diagnosis, the ophthalmopathy slowly improves over years. Thyroid hormone excess causes left ventricular thickening, which is associated with an increased risk of heart failure and cardiac-related death. Thyrotoxicosis has been associated with dilated cardiomyopathy, right heart failure with pulmonary hypertension, and diastolic dysfunction and atrial fibrillation. An increase in the rate of bone resorption occurs. Bone loss, measured by bone mineral densitometry, can be seen in severe hyperthyroidism at all ages and in both sexes. In mild subclinical disease, however, bone loss has been convincingly shown only in postmenopausal women.

History
The presentation of thyrotoxicosis is variable among patients. Thyrotoxicosis leads to an apparent increase in sympathetic nervous system symptoms. Younger patients tend to exhibit symptoms of sympathetic activation, such as anxiety, hyperactivity, and tremor, while older patients have more cardiovascular symptoms, including dyspnea and atrial fibrillation with unexplained weight loss. The clinical manifestations of thyrotoxicosis do not always correlate with the extent of the biochemical abnormality. Common symptoms of thyrotoxicosis include the following: ; ; ; ; ; ; Nervousness Anxiety Increased perspiration Heat intolerance Hyperactivity Palpitations

Generally, a constellation of information, including the extent and duration of symptoms, past medical history, and social and family history, in addition to the information derived from physical examination, help to guide the clinician to the appropriate diagnosis. For example, Graves disease is an autoimmune disease, and patients

often have a family history or past medical history of autoimmune disease (eg, rheumatoid arthritis, vitiligo, pernicious anemia). Patients with Graves disease often have more marked symptoms than patients with thyrotoxicosis from other causes, because thyroid hormone levels usually are the highest with this form of hyperthyroidism. The diagnosis of Graves disease should also be considered if any evidence of thyroid eye disease exists, including periorbital edema, diplopia, or proptosis. Toxic multinodular goiters occur in patients who have had a known nontoxic goiter for many years or decades. Often, patients have emigrated from regions of the world with borderline- low iodine intake or have a strong family history of nontoxic goiter. Subclinical hyperthyroidism, defined as a low thyroid-stimulating hormone (TSH) level with normal free thyroxine (FT4) and free triiodothyronine (FT3) levels, is associated with no or minimal clinical symptoms of thyrotoxicosis. However, certain conditions (eg, atrial fibrillation, osteoporosis, or hypercalcemia) may suggest the possibility of thyrotoxicosis. In fact, subclinical hyperthyroidism may be associated with a 3-fold increase in the risk of atrial fibrillation. The prevalence of subclinical hyperthyroidism may be as high as 2% in the general population. The risk of atrial fibrillation may be elevated even in persons with high-normal thyroid function. In a report from the Netherlands on 1426 patients whose TSH levels were in the normal range (0.4-4.0 mIU/L), the hazard ratio for atrial fibrillation was 1.94 for the lowest versus the highest quartile of TSH, after a median follow-up of 8 years. Radiation exposure increases the risk of benign and malignant nodular thyroid diseases, especially with the higher radiation levels used in radiation therapy. External radiation therapy is associated with an increase in the incidence of autoimmune hyperthyroidism when the thyroid is in the radiation field. The family history should include careful documentation of the following: ; ; ; Autoimmune disease Thyroid disease Emigration from iodine-deficient parts of the world

Review a complete list of medications and dietary supplements. A number of compoundsincluding expectorants, amiodarone, iodinated contrast dyes, and health food supplements containing seaweed or thyroid gland extractscontain large amounts of iodine that can induce thyrotoxicosis in a patient with thyroid autonomy. Rarely, iodine exposure can cause thyrotoxicosis in a patient with an apparently healthy thyroid.

Physical Examination
The thyroid is located in the lower anterior neck. The isthmus of the butterfly-shaped gland generally is located just below the cricoid cartilage of the trachea, with the wings of the gland wrapping around the trachea. Physical examination often can help the clinician to determine the etiology of thyrotoxicosis. Common signs of thyrotoxicosis include the following: ; ; ; ; ; ; ; ; ; Tachycardia or atrial arrhythmia Systolic hypertension Warm, moist, smooth skin Lid lag Stare Hand tremor Muscle weakness Weight loss despite increased appetite Reduction in menstrual flow or oligomenorrhea

Thyroid examination
Thyrotoxicosis from Graves disease is associated with a diffusely enlarged and slightly firm thyroid gland. Sometimes, a thyroid bruit can be heard by using the bell of the stethoscope.

Toxic multinodular goiters generally occur when the thyroid gland is enlarged to at least 2 to 3 times the normal size. The gland often is soft, but individual nodules occasionally can be palpated. Because most thyroid nodules cannot be palpated, thyroid nodules should be documented by thyroid ultrasonography, but overactive thyroid nodules can be demonstrated only by nuclear thyroid imaging with radioiodine (I-123) or technetium (Tc99m) thyroid scan. If the thyroid is enlarged and painful, subacute painful or granulomatous thyroiditis is the likely diagnosis. However, degeneration or hemorrhage into a nodule and suppurative thyroiditis should also be considered.

Ophthalmologic and dermatologic examination

Approximately 50% of patients with Graves thyrotoxicosis have mild thyroid ophthalmopathy. Often, this is manifested only by periorbital edema, but it also can include conjunctival edema (chemosis), injection, poor lid closure, extraocular muscle dysfunction (diplopia), and Proptosis (see the image below). Evidence of thyroid eye disease and high thyroid hormone levels confirms the diagnosis of autoimmune Grave disease. Severe proptosis, periorbital edema, and eyelid retraction from thyroid-related orbitopathy. This patient also had optic nerve dysfunction and chemosis (conjunctival edema) from thyroid-related orbitopathy. In rare instances, Graves disease affects the skin through deposition of glycosaminoglycans in the dermis of the lower leg. This causes nonpitting edema, usually associated with erythema and thickening of the skin, without pain or pruritus (see the image below).

Bilateral erythematous infiltrative plaques on lower extremities in 42-year-old man with Graves disease are consistent with pretibial myxedema. Myxedematous changes of skin usually occur in pretibial areas and resemble orange peel in color and texture.

Approach Considerations
The most reliable screening measure of thyroid function is the thyroid-stimulating hormone (TSH) level. TSH levels usually are suppressed to unmeasurable levels (< 0.05 IU/mL) in thyrotoxicosis. The degree of thyrotoxicosis is determined by measurement of thyroid hormone levels; the severity of clinical manifestations often does not correlate with the degree of thyroid hormone elevation. The most specific autoantibody test for autoimmune thyroiditis is an enzyme-linked immunosorbent assay (ELISA) test for anti thyroid peroxidase (anti-TPO) antibody. The titers usually are significantly elevated in the most common type of hyperthyroidism, Graves thyrotoxicosis, and usually are low or absent in toxic multinodular goiter and toxic adenoma. If the etiology of thyrotoxicosis is not clear after physical examination and other laboratory tests, it can be confirmed by means of scintigraphy. The degree and pattern of isotope uptake indicate the type of thyroid disorder. Older patients with hyperthyroidism often present with atrial arrhythmias or heart failure. Electrocardiography is recommended if an irregular or elevated (> 100 beats/min) heart rate or signs of heart failure are noted upon examination.

TSH and Thyroid Hormone Levels

Although measurement of the TSH level is the most reliable screening method for assessing thyroid function, the degree of thyrotoxicosis cannot be estimated easily in this way. Instead, thyrotoxicosis must be measured using an assay of thyroid hormone levels in the plasma. Thyroid hormone circulates as triiodothyronine (T3) and thyroxine (T4), with more than 99.9% of the hormones bound to serum proteins (especially thyroxine-binding globulin, transthyretin or thyroxine-binding prealbumin, and albumin). Measuring free T4 (FT4) and total T3 is recommended in patients with suspected thyrotoxicosis when TSH is low. Patients with milder thyrotoxicosis may have elevation of T3 levels only.

Many laboratories do not measure FT4 directly, instead using a calculation to estimate the FT4 level. The free thyroxine index (FTI) is equal to total T4 multiplied by the correction for thyroid hormone binding, such as the thyroid hormone binding ratio (THBR) or T3 resin uptake [T3 RU]). A similar calculation can be used with total T3. Thyrotoxicosis is marked by TSH levels suppressed below the reference range (usually 0.4-4 mIU/L) and elevated thyroid hormone levels. Subclinical hyperthyroidism is defined as a decreased but not undetectable TSH level (< 0.5 IU/mL in many laboratories) in combination with serum concentrations of T3 and T4 that are within the reference range. Because nonthyroidal illness will produce temporary suppression of TSH, thyroid function tests should be repeated before therapy is instituted for subclinical disease. Hormonal changes in pregnancy can complicate the interpretation of thyroid function tests. Physiologic maximum elevation of beta human chorionic gonadotropin (-hCG) at the end of the first trimester of pregnancy is associated with a mirror-image temporary reduction in TSH. Despite the reduction in TSH, FT4 levels usually remain normal or only slightly above the reference range. As the pregnancy progresses and -hCG plateaus at a lower level, TSH levels return to normal.

Autoantibody Studies
The most specific autoantibody test for autoimmune thyroiditis is an ELISA test for anti-TPO antibody. The titers usually are significantly elevated in the most common type of hyperthyroidism, Graves thyrotoxicosis, and usually are low or absent in toxic multinodular goiter and toxic adenoma. A significant number of healthy people without active thyroid disease have mildly positive anti-TPO antibody titers; thus, the test should not be performed for screening purposes. The thyroid-stimulating immunoglobulin (TSI) level, if elevated, helps to establish the diagnosis of Graves disease. Circulating antithyroglobulin (anti-TG) antibodies are also present in Graves disease; however, testing for these antibodies should not be used, because anti-TG antibodies by themselves may be present in persons without other evidence of thyroid dysfunction.

Scintigraphy
If the etiology of thyrotoxicosis is not clear after physical examination and other laboratory tests, it can be confirmed by means of scintigraphy. Iodine-123 (123 I) or technetium-99m (99m Tc) can be used for thyroid scanning. Normally, the isotope distributes homogeneously throughout both lobes of the thyroid gland. In patients with hyperthyroidism, the pattern of uptake (eg, diffuse vs nodular) varies with the underlying disorder. The overall level of radioactive iodine uptake (RAIU) also varies with different conditions. Normal RAIU is approximately 5-20% but is modified by the iodine content of the patients diet (see Table 1 below). Table 1. Thyrotoxicosis and Hyperthyroidism Common Forms (85-90% of Cases) 24-Hour RAIU Over Neck* Diffuse toxic goiter (Graves disease) Increased (moderate to high: 40-100%) Toxic multinodular goiter (Plummer disease) Increased (mild to moderate: 25-60%) Thyrotoxic phase of subacute thyroiditis Decreased (very low: < 2%) Toxic adenoma Increased (mild to moderate: 25-60%) Less Common Forms Iodide-induced thyrotoxicosis Variable but usually low (< 25%) Thyrotoxicosis factitia Decreased (very low: < 2%) Uncommon Forms Pituitary tumors producing TSH Increased (mild to moderate: 25-60%) Excess human chorionic gonadotropin (molar Increased (variable: 25-100%) pregnancy/choriocarcinoma) Pituitary resistance to thyroid hormone Increased (mild to moderate: 25-60%) Metastatic thyroid carcinoma Decreased Struma ovarii with thyrotoxicosis Decreased RAIU = radioactive iodine uptake; TSH = thyroid-stimulating hormone.

* A normal 6-hour RAIU is approximately 2-16%; a 24-hour RAIU is about 8-25% but is modified according to the iodine content of the patients diet. RAIU or scanning should not be performed in a woman who is pregnant (with the exception of a molar pregnancy) or breastfeeding.

In Graves disease, scintigraphy shows diffuse enlargement of both thyroid lobes, with uniform uptake of isotope (see the image below). Overall RAIU is elevated.

Iodine 123 (123I) nuclear scintigraphy: 123I scans of normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D). Toxic multinodular goiters are characterized by irregular areas of relatively diminished and occasionally increased uptake (see the image below). Overall RAIU is mildly to moderately increased.

Scan in patient with toxic multinodular goiter. 5-Hour 123I-iodine uptake was elevated at 28% (normal 5-15%). Note multiple foci of variably increased tracer uptake. The classification of nodules as "hot," "warm," or "cold" is determined by their isotope-concentrating ability relative to the surrounding normal parenchyma. Autonomously functioning thyroid nodules are "hot" compared with normal thyroid tissue. If a dominant nodule is found upon examination of a patient with thyrotoxicosis, and scintigraphy shows that the nodule is cold, an ultrasound-guided fine-needle aspiration (FNA) biopsy of the nodule should be performed to exclude concomitant malignancy. In subacute thyroiditis (see the image below), radioactive iodine uptake is very low (approximately 1-2%). Occasionally, Hashimoto hypothyroidism can be associated with normal, elevated, or suppressed radioactive iodine uptake.

TREATMENT Approach Considerations

Treatment of hyperthyroidism includes symptom relief, as well as antithyroid pharmacotherapy, radioactive iodine-131 (131 I) therapy (the preferred treatment of hyperthyroidism among US thyroid specialists), or thyroidectomy. However, antithyroid medications are not effective in thyrotoxicosis in which scintigraphy shows low uptake of iodine-123 (123 I), as in patients with subacute thyroiditis, because these cases result from release of preformed thyroid hormone. If a physician treats enough patients who are hyperthyroid, eventually he or she will encounter a patient who develops agranulocytosis or hepatitis from the antithyroid medications. Discussing these adverse effects with patients before starting therapy is important; accordingly, patients should be given written or documented

verbal instruction to the effect that if they develop high fever (> 100.5F) or a severe sore throat, they should stop the medication and seek medical attention.

Management of Ophthalmopathy
Although 50% of patients with Graves disease have mild signs and symptoms of thyroid eye disease, only 5% develop severe ophthalmopathy (eg, diplopia, visual-field deficits, or blurred vision). Less serious ophthalmologic symptoms (eg, photophobia, irritation, and tearing) are treated with tight-fitting sunglasses, which should be worn at all times when the patient is outside, and with saline eye drops that are taken as necessary for comfort. If exposure keratitis is suspected, the patient should be monitored by an ophthalmologist. This condition usually occurs when eyelid closure is incomplete and the cornea is exposed at night, when the patient does not blink. Typically, patients complain of irritation and tearing on awakening. Treatment includes administering saline gel or drops and taping eyelids closed with paper tape before sleep. Some ophthalmologists are concerned about corneal abrasion from the tape and instead recommend that patients wear goggles at night to keep the eyes moist. A medical emergency occurs when sufficient orbital edema exists to cause optic nerve compression with early loss of color vision and orbital pain. Without treatment, continued pressure on the optical nerve may cause permanent vision loss. High-dose glucocorticoids are administered, with consideration for orbital decompression surgery and ocular radiation therapy.

Management of Dermopathy
Infiltrative dermopathy, usually developing over the lower extremities, is characterized by an accumulation of glycosaminoglycans and inflammatory cells in the dermis. The skin changes typically include a nonpitting erythematous edema of the anterior shins. Dermopathy can occur at other sites of repeat trauma. The dermopathy usually occurs only in the presence of significant ophthalmopathy. No effective treatment exists. Nightly occlusive wraps of the affected site are recommended, with plastic wrap used after the application of a high-potency topical steroid cream.

Relief of Symptoms
Many of the neurologic and cardiovascular symptoms of thyrotoxicosis are relieved by beta-blocker therapy. Before such therapy is initiated, the patient should be examined for signs and symptoms of dehydration that often occur with hyperthyroidism. After oral rehydration, beta-blocker therapy can be started. Beta-blocker therapy should not be administered to patients with a significant history of asthma. Calcium channel blockers (eg, verapamil and diltiazem) can be used for the same purposes when beta-blockers are contraindicated or poorly tolerated. These therapies should be tapered and stopped once thyroid functions are within the normal range.

Antithyroid Pharmacotherapy
Antithyroid drugs (eg, methimazole and propylthiouracil) have been used for hyperthyroidism since their introduction in the 1940s. These medications are employed for long-term control of hyperthyroidism in children, adolescents, and pregnant women. In adult men and nonpregnant women, they are used to control hyperthyroidism before definitive therapy with radioactive iodine. Antithyroid medications inhibit the formation and coupling of iodotyrosines in thyroglobulin. Because these processes are necessary for thyroid hormone synthesis, this inhibition induces a gradual reduction in thyroid hormone levels over 2-8 weeks or longer. A second action of propylthiouracil (but not methimazole) is inhibition of conversion of thyroxine (T4) to triiodothyronine (T3). T3 is more biologically active than T4; thus, a quick reduction in T3 levels is associated with a clinically significant improvement in thyrotoxic symptoms. The antithyroid drug dose should be titrated every 4 weeks until thyroid functions normalize. Some patients with Graves disease go into a remission after treatment for 12-18 months, and the drug can be discontinued. Notably, half of the patients who go into remission experience a recurrence of hyperthyroidism within the following year. Nodular forms of hyperthyroidism (ie, toxic multinodular goiter and toxic adenoma) are permanent conditions and will not go into remission.

Methimazole is more potent than propylthiouracil and has a longer duration of action. In addition, methimazole is taken once daily, whereas propylthiouracil is taken 2-3 times daily; consequently, patient compliance is often better with methimazole than with propylthiouracil. Methimazole is not recommended for use in the first trimester of pregnancy, because it has been associated (albeit rarely) with cloacal and scalp (cutis aplasia) abnormalities when given during early gestation. Generally, if a nonpregnant woman who is receiving methimazole desires pregnancy, she should be switched to propylthiouracil before conception. After 12 weeks of gestation, she can be switched back to methimazole, with frequent monitoring. Propylthiouracil remains the drug of choice in uncommon situations of life-threatening severe thyrotoxicosis (ie, thyroid storm) because of the additional benefit of inhibition of T4 -to-T3 conversion. In this setting, propylthiouracil should be administered every 6-8 hours. The reduction in T3, which is 20-100 times more potent than T4, theoretically helps reduce the thyrotoxic symptoms more quickly than methimazole would. Once thyroid levels have decreased to nearly normal values, the patient can be switched to methimazole therapy. Except in thyroid storm, propylthiouracil is considered a second-line drug therapy. It is reserved for use in patients who are allergic to or intolerant of methimazole and in women who are in the first trimester of pregnancy or planning pregnancy.

Adverse effects of antithyroid medications

The most common adverse effects of antithyroid drugs are allergic reactions manifesting as fever, rash, urticaria, and arthralgia, which occur in 1-5% of patients, usually within the first few weeks of treatment. Serious adverse effects include agranulocytosis, aplastic anemia, hepatitis, polyarthritis, and a lupuslike vasculitis. All of these adverse effects, except agranulocytosis, occur more frequently with propylthiouracil: agranulocytosis occurs in 0.2-0.5% of patients overall and is no more common with one drug than with the other. Patients with agranulocytosis usually present with fever and pharyngitis. After the drug is stopped, granulocyte counts usually start to rise within several days but may not normalize for 10-14 days. Granulocyte colonystimulating factor (G-CSF) appears to accelerate recovery in patients with a bone marrow aspiration showing a granulocyte-to-erythrocyte ratio of 1:2 or greater than 0.5. In 2010, the US Food and Drug Administration (FDA) added a boxed warning, the strongest warning issued by the FDA, to the prescribing information for propylthiouracil. The warning emphasized the risk for severe liver injury and acute liver failure, some cases of which have been fatal. Severe liver injury has rarely been reported with methimazole (5 cases, 3 of which resulted in death). The FDA recommends the following measures for patients receiving propylthiouracil Closely monitor patients for signs and symptoms of liver injury, especially during the first 6 months after initiation of therapy ; ; For suspected liver injury, promptly discontinue propylthiouracil, evaluate the patient for evidence of liver injury, and provide supportive care Counsel patients to contact their health care provider promptly for the following signs or symptoms: fatigue, weakness, vague abdominal pain, loss of appetite, itching, easy bruising, or yellowing of the eyes or skin

Other drugs
In severe thyrotoxicosis from Graves disease or subacute thyroiditis, iodine or iodinated contrast agents have been administered to block the conversion of T4 to T3 and the release of thyroid hormone from the gland. This therapy is reserved for severe thyrotoxicosis because its use prevents definitive therapy for Graves thyrotoxicosis with radioactive iodine for many weeks. A saturated solution of potassium iodide (SSKI) can be administered at a dosage of 10 drops twice daily, with a consequent rapid reduction in T3 levels. Iopanoic acid/ipodate at a dosage of 1 g/day is also effective; it has not been available in the United States for several years but is available in some areas of Europe. These drugs must not be administered to patients with toxic multinodular goiter or toxic adenomas. The autonomous nature of these conditions can lead to worsening of the thyrotoxicosis in the presence of pharmacologic levels of iodide, a substrate in thyroid hormone synthesis.

Radioactive Iodine Therapy

Radioactive iodine therapy is the most common treatment for Graves disease in adults in the United States. Although its effect is less rapid than that of antithyroid medication or thyroidectomy, it is effective and safe and does not require hospitalization. Concerns about radiation exposure after therapy have led to the issuance of new recommendations by the ATA. These recommendations are compliant with Nuclear Regulatory Commission regulations and are a practical guide for patient activity after radioactive iodine therapy, with the aim of ensuring maximum radiation safety for the family and the public. Radioactive iodine is administered orally as a single dose in capsule or liquid form. The iodine is quickly absorbed and taken up by the thyroid. No other tissue or organ in the body is capable of retaining the radioactive iodine; consequently, very few adverse effects are associated with this therapy. The treatment results in a thyroid-specific inflammatory response, causing fibrosis and destruction of the thyroid over weeks to many months. Generally, the dose of131 I administered is 75-200 Ci/g of estimated thyroid tissue divided by the percent of123 I uptake in 24 hours. This dose is intended to render the patient hypothyroid. Administration of lithium in the weeks following radioactive iodine therapy may extend the retention of radioactive iodine and increase its efficacy. This may be considered in Graves disease patients with especially large Graves glands (> 60 g) or in patients with extremely high thyroidal iodine uptake (> 95% in 4 hours), which is associated with high iodine turnover in the gland. However, studies have yielded inconsistent results, and the benefits of using lithium with radioactive iodine must be weighed against the toxicities associated with lithium. Hypothyroidism is considered by many experts to be the expected goal of radioactive iodine therapy. In several large epidemiologic studies of radioactive iodine therapy in patients with Graves disease, no evidence indicated that radioactive iodine therapy caused the development of thyroid carcinoma. There is also no evidence that radioactive iodine therapy for hyperthyroidism results in increased mortality for any other form of cancer, including leukemia. Long-term follow-up data of children and adolescents treated with radioactive iodine are lacking. ATA guidelines recommend avoiding131 I therapy in children younger than 5 years of age. In children 5 to 10 years old,131 I therapy is acceptable if the calculated activity of administered131 I is less than 10 mCi. In children older than 10 years of age, radioactive iodine therapy is acceptable if the activity is greater than 150 Ci/g of thyroid tissue. Radioactive iodine should never be administered to pregnant women, because it can cross the placenta and ablate the fetuss thyroid, resulting in hypothyroidism. Similarly, breastfeeding is a contraindication, in that the radioisotope is secreted in breast milk. Women will continue to receive increased radiation to the breast from radioactive iodine for a few months after ceasing lactation; accordingly, initiation of this therapy should be delayed. It is standard practice to check for pregnancy before starting radioactive iodine therapy and to recommend that the patient not become pregnant for at least 3-6 months after the treatment or until thyroid functions normalize. No excess fetal malformations or increased miscarriage rates have been found in women previously treated with radioactive iodine for hyperthyroidism. Radioactive iodine usually is not administered to patients with severe ophthalmopathy, because clinical evidence suggests that worsening of thyroid eye disease occurs after radioactive iodine therapy. This worsening is usually mild but occasionally severe. The risk of ophthalmopathy is greater in patients who smoke cigarettes, but it can be reduced by providing glucocorticoid therapy (prednisone 0.4 mg/kg for 1 month with subsequent taper) after radioactive iodine therapy.

Thyroidectomy
Subtotal thyroidectomy is the oldest form of treatment for hyperthyroidism. Total thyroidectomy and combinations of hemithyroidectomies and contralateral subtotal thyroidectomies also have been used. Because of the excellent efficacy of antithyroid medications and radioactive iodine therapy in regulating thyroid function, thyroidectomy is generally reserved for special circumstances, including the following:

; ; ; ; ; ;

Severe hyperthyroidism in children Pregnant women who are noncompliant with or intolerant of antithyroid pharmacotherapy Patients with very large goiters or severe ophthalmopathy Patients who refuse radioactive iodine therapy Patients with refractory amiodarone-induced hyperthyroidism Patients who require normalization of thyroid functions quickly, such as pregnant women, women who desire pregnancy in the next 6 months, or patients with unstable cardiac conditions

Preparation for thyroidectomy includes antithyroid medication, stable (cold) iodine treatment, and beta-blocker therapy. Generally, antithyroid drug therapy should be administered until thyroid functions normalize (4-8 weeks). Propranolol is titrated until the resting pulse rate is lower than 80 beats/min. Finally, iodide is administered as SSKI (1-2 drops twice daily for 10-14 days) before the procedure. Stable iodide therapy both reduces thyroid hormone excretion and decreases thyroid blood flow, which may help reduce intraoperative blood loss. A Swiss study found that administration of a single dose of steroid (dexamethasone 8 mg) before thyroidectomy can reduce the nausea, pain, and vomiting associated with the procedure, as well as improve voice function.[23] Benefits were most pronounced in the first 16 hours after the operation. Postoperative steroid administration is not considered to be the standard of care for thyroid surgery in the United States. With current operative techniques, bilateral subtotal thyroidectomy should have a mortality approaching zero in patients who are properly prepared. Historically, operative stress was the most common cause of thyroid storm, a physiologic decompensation in patients who are severely thyrotoxic, with a mortality of about 50%. Adverse effects of thyroidectomy include recurrent laryngeal nerve damage and hypoparathyroidism from damage to local structures during the procedure.

Diet and Activity

No special diet must be followed by patients with thyroid disease. However, some expectorants, radiographic contrast dyes, seaweed tablets, and health food supplements contain excess amounts of iodide and should be avoided because the iodide interferes with or complicates the management of antithyroid and radioactive iodine therapies. Exercise tolerance often is not significantly affected in otherwise healthy patients with mild to moderate hyperthyroidism. For these patients, no reduction in physical activity is necessary. For patients who are elderly or have cardiopulmonary comorbidities or severe hyperthyroidism, a decrease in activity is prudent until hyperthyroidism is medically controlled. With severe thyrotoxicosis, systolic and diastolic cardiac dysfunction often result in dyspnea on exertion. Betablocker therapy often greatly improves exercise tolerance until thyroid hormones levels are reduced by other therapies.

Consultations
Generally, thyrotoxicosis should be evaluated and treated by an endocrinologist. Therapy, including radioactive iodine and antithyroid medication, requires careful follow-up, which is best performed by a specialist. Generally, after definitive therapy is completed with radioactive iodine or surgical thyroidectomy, the patient can be cared for by a primary care physician. These patients may require thyroid hormone replacement therapy. Patients with Graves thyrotoxicosis should be examined by an ophthalmologist for moderate or symptomatic thyroid eye disease, which occurs in some form in 50% of patients. Often, the eye disease is subclinical and remits with time. The eye disease usually occurs within 1 year before or after the diagnosis of hyperthyroidism, but new-onset disease has been detected decades later. Graves eye disease also can occur without the patient ever having developed hyperthyroidism.

Long-Term Monitoring
Care after initiation of antithyroid medication
After 4-6 weeks, antithyroid medications usually must be reduced; otherwise, the patient becomes hypothyroid. Hypothyroidism causes the usual symptoms of fatigue and weight gain, and in patients with Graves disease, it

has been anecdotally associated with worsening of thyroid ophthalmopathy. Initially, the patient should have thyroid function tests performed every 4-6 weeks until thyroid hormone levels are stabilized on a low dosage of antithyroid medication. Patients with non-Graves hyperthyroidism rarely experience remissions. In patients who are placed on longterm antithyroid drug therapy with the goal of remission, follow-up tests of thyroid function should be performed at least every 3 months for the first year. In patients with Graves disease, antithyroid medication should be stopped or decreased after 12-18 months to determine whether the patient has gone into remission. In these patients, remission is defined as a normal TSH level after cessation of antithyroid drug therapy. Once a patient with Graves hyperthyroidism becomes euthyroid on oral antithyroid medication, other definitive treatment, such as radioactive iodine therapy or surgery, should be considered. Although a significant fraction of patients with Graves disease go into remission, as many as 20% become hypothyroid over subsequent years as a consequence of autoimmune destruction of the gland.

Care after radioactive iodine ablation

Ablation of the gland occurs over 2-5 months after radioactive iodine therapy. Most patients become hypothyroid. Checking thyroid functions every 4-6 weeks until the patient stabilizes is recommended. Once the thyroid hormone levels start falling into the low-normal range, it is reasonable to stop antithyroid medications and to consider starting low-dose thyroid hormone replacement before the patient becomes hypothyroid; however, some physicians prefer to document persistently elevated TSH values with the patient off antithyroid medication before starting thyroid hormone replacement. Starting with partial or low-dose thyroid hormone replacement is recommended (50-75 g/day, adjusted every 6-8 weeks to normalize the TSH level). Several weeks after131 I therapy, patients can, in rare cases, become thyrotoxic as a result of vigorous thyroid destruction and release of preformed hormone. This process often is accompanied by a painful, radiation-induced thyroiditis that can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs) or glucocorticoids. In addition, radioablation can cause the release of thyroid antigens and exacerbate the autoimmune thyroid disease process. In such cases, Graves disease can worsen.

Care after thyroid surgery

Patients whose thyroid functions normalize after surgery require routine follow-up because hypothyroidism (from the chronic thyroiditis), recurrent hyperthyroidism, or thyroid eye disease may develop at some time in the future. Most patients remain euthyroid after a lobectomy or lobectomy plus isthmusectomy to treat a toxic adenoma or toxic multinodular goiter with a dominant nodule. To ensure normal thyroid function, thyroid function tests should be obtained 3-4 weeks after a lobectomy. After subtotal thyroidectomy for hyperthyroidism and cessation of antithyroid therapy, most patients become hypothyroid, depending on how much functional tissue is left by the surgeon. Partial replacement (T4 50-75 g/day) is recommended in these patients, beginning shortly after the procedure. Thyroid function tests should be monitored 4-8 weeks postoperatively, and the T4 dosage should be adjusted to maintain a normal TSH level.

HIPOTIROIDISME
Practice Essentials
Hypothyroidism may be either primary, in which the thyroid gland produces insufficient amounts of thyroid hormone, or secondary, in which there is a lack of thyroid hormone secretion due to inadequate secretion of either thyrotropin (ie, thyroid-stimulating hormone [TSH]) from the pituitary gland or thyrotropin-releasing hormone (TRH) from the hypothalamus. The patients presentation may vary from asymptomatic to, rarely, coma with multisystem organ failure (myxedema coma).

Essential update: Levothyroxine therapy increases pregnancy in women with hypothyroidism undergoing assisted reproduction

In women with subclinical hypothyroidism or thyroid autoimmunity undergoing assisted reproduction technologies, treatment with levothyroxine was shown to improve pregnancy outcomes, according to a metaanalysis of 3 studies involving 220 patients. In pooled analyses, levothyroxine treatment resulted in a significantly higher delivery rate, with a pooled relative risk of 2.76 (95% confidence limits 1.20-6.44; P = 0.018), a pooled absolute risk difference of 36.3% (3.5-69.0%: P = 0.030), and a summary number needed to treat of 3 (1-28) in favor of levothyroxine supplementation. In addition, levothyroxine treatment significantly lowered miscarriage rate, with a pooled relative risk of 0.45 (0.24-0.82; P = 0.010), a pooled absolute risk difference of -31.3% (-48.2 to -14.5%: P < 0.001), and a summary number needed to treat of 3 (2-7) in favor of LT4 supplementation.

Signs and symptoms

The following are symptoms of hypothyroidism: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Fatigue, loss of energy, lethargy Weight gain Decreased appetite Cold intolerance Dry skin Hair loss Sleepiness Muscle pain, joint pain, weakness in the extremities Depression Emotional lability, mental impairment Forgetfulness, impaired memory, inability to concentrate Constipation Menstrual disturbances, impaired fertility Decreased perspiration Paresthesia and nerve entrapment syndromes Blurred vision Decreased hearing Fullness in the throat, hoarseness Feeling of fullness in the throat Painless thyroid enlargement Exhaustion Neck pain, sore throat, or both Low-grade fever Hypothermia Weight gain Slowed speech and movements Dry skin Jaundice Pallor Coarse, brittle, strawlike hair Loss of scalp hair, axillary hair, pubic hair, or a combination

The following are symptoms more specific to Hashimoto thyroiditis:

Physical signs of hypothyroidism include the following:

; ; ; ; ; ; ; ; ; ; ; ; ;

Dull facial expression Coarse facial features Periorbital puffiness Macroglossia Goiter Hoarseness Decreased systolic blood pressure and increased diastolic blood pressure Bradycardia Pericardial effusion Abdominal distension, ascites (uncommon) Nonpitting edema (myxedema) Pitting edema of lower extremities Hyporeflexia with delayed relaxation, ataxia, or both

Diagnosis
Laboratory studies that may be used include the following: ; ; Third-generation TSH assays (the most sensitive screening tool for primary hypothyroidism) Total thyroxine (T4) with a measure of binding proteins: Thyroxine is highly protein-bound (99.97%), with approximately 85% bound to thyroid-binding globulin (TBG), approximately 10% bound to transthyretin or thyroid-binding prealbumin, and the remainder bound loosely to albumin Free T4 assays to measure unbound (ie, free) hormone Thyroid autoantibodies (antimicrosomal or anti-TPO antibodies) and antithyroglobulin (anti-Tg) to help determine the etiology or predict future hypothyroidism TRH stimulation test (now rarely needed, because of improved TSH assays) Ultrasonography of the neck and thyroid Radioactive iodine uptake (RAIU) and thyroid scanning Fine-needle aspiration (FNA) biopsy

; ; ; ; ; ;

Diagnostic procedures that may be considered include the following:

Whole-body F18-fluorodeoxyglucose positron emission tomography (FDG-PET) for nonthyroid disease often show significant thyroid uptake as an incidental finding.

Management
Thyroid hormone is administered to supplement or replace endogenous production. In general, hypothyroidism can be adequately treated with a constant daily dose of levothyroxine (LT4). T4 monotherapy remains the treatment of choice. Special considerations in pregnant women with hypothyroidism include the following: ; Hypothyroidism in pregnancy is associated with preeclampsia, anemia, postpartum hemorrhage, cardiac ventricular dysfunction, spontaneous abortion, low birth weight, impaired cognitive development, and fetal mortality Increased dosage requirements should be anticipated during pregnancy, especially in the first and second trimesters Autoimmune thyroid disease without overt hypothyroidism has been associated with a higher miscarriage rate; if this association is confirmed, there will be an indication to treat euthyroid pregnant women who have thyroid antibodies LT4 should not be taken with prenatal vitamin preparations containing iron and calcium

; ;

Controversy persists regarding the treatment of patients with mild (subclinical) hypothyroidism. Following subclinical hypothyroidism and treating on a case-by-case basis is reasonable. American Association of Clinical Endocrinologists (AACE) guidelines are as follows: ; ; Treatment is indicated in patients with TSH levels above 10 mIU/mL or in patients with TSH levels of 5-10 mIU/mL in conjunction with goiter or positive antithyroid peroxidase antibodies An initial LT4 dosage of 25-50 g/day may be used and can be titrated every 6-8 weeks to achieve a target TSH of 0.3-3 mIU/mL. Levothyroxine 4 g/kg lean body weight intravenously (IV) or 200-250 g as a bolus in a single or divided dose, depending on the patients risk of cardiac disease, followed by 100 g 24 hours later and then 50 g/day IV or orally along with stress doses of IV glucocorticoids, subsequently adjusted as necessary IV triiodothyronine (controversial and based on expert opinion)

Treatment of myxedema coma is as follows: ;

Surgical treatment is indicated for large goiters that compromise tracheoesophageal function; it is rarely needed in patients with hypothyroidism and is more commonly warranted in patients with hyperthyroidism.

Background
Hypothyroidism is a common endocrine disorder resulting from deficiency of thyroid hormone. It usually is a primary process in which the thyroid gland produces insufficient amounts of thyroid hormone. It can also be secondarythat is, lack of thyroid hormone secretion due to inadequate secretion of either thyrotropin (ie, thyroid-stimulating hormone [TSH]) from the pituitary gland or thyrotropin-releasing hormone (TRH) from the hypothalamus (secondary or tertiary hypothyroidism). The patient's presentation may vary from asymptomatic to, rarely, coma with multisystem organ failure (myxedema coma). The most common cause in the Unites States is autoimmune thyroid disease (Hashimoto thyroiditis). Cretinism refers to congenital hypothyroidism, which affects 1 per 4000 newborns. Subclinical hypothyroidism, also referred to as mild hypothyroidism, is defined as normal serum free T4 levels with slightly high serum TSH concentration.

Recent studies
In a 12-year longitudinal study, Stuckey et al investigated the long-term risk of hypothyroidism in women who previously had had postpartum thyroid dysfunction (PPTD). The study involved 409 women, 71 of whom had previously been diagnosed with PPTD. At 12-year follow-up, 27 women in the PPTD group and 14 women in the non-PPTD group (38% and 4%, respectively) were found to have hypothyroidism. Based on an analysis of odds ratios (ORs), the authors concluded that within the PPTD group, women who had been diagnosed with postpartum hypothyroidism were among those at particularly high long-term risk for hypothyroidism (OR = 9.7).

Pathophysiology
Localized disease of the thyroid gland that results in decreased thyroid hormone production is the most common cause of hypothyroidism. Under normal circumstances, the thyroid releases 100-125 nmol of thyroxine (T4) daily and only small amounts of triiodothyronine (T3). The half-life of T4 is approximately 7-10 days. T4, a prohormone, is converted to T3, the active form of thyroid hormone, in the peripheral tissues by 5deiodination. Early in the disease process, compensatory mechanisms maintain T3 levels. Decreased production of T4 causes an increase in the secretion of TSH by the pituitary gland. TSH stimulates hypertrophy and hyperplasia of the thyroid gland and thyroid T4-5'-deiodinase activity. This, in turn, causes the thyroid to release more T3. Because all metabolically active cells require thyroid hormone, deficiency of the hormone has a wide range of effects. Systemic effects are due to either derangements in metabolic processes or direct effects by myxedematous infiltration (ie, accumulation of glucosaminoglycans in the tissues). The myxedematous changes in the heart result in decreased contractility, cardiac enlargement, pericardial effusion, decreased pulse, and decreased cardiac output. In the GI tract, achlorhydria and decreased intestinal transit with gastric stasis can occur. Delayed puberty, anovulation, menstrual irregularities, and infertility are

common. Decreased thyroid hormone effect can cause increased levels of total cholesterol and low-density lipoprotein (LDL) cholesterol and a possible change in high-density lipoprotein (HDL) cholesterol due to a change in metabolic clearance. In addition, hypothyroidism may result in an increase in insulin resistance.

Epidemiology
Frequency
United States The National Health and Nutrition Examination Survey (NHANES 1999-2002) of 4,392 individuals reflecting the US population reported hypothyroidism (defined as TSH levels >4.5 mIU/L) in 3.7% of the population. Hypothyroidism is more common in women with small body size at birth and low body mass index during childhood. International Iodine deficiency as a cause of hypothyroidism is more common internationally. The prevalence is reported as 2-5% depending on the study, increasing to 15% by age 75 years.

Mortality/Morbidity
In developed countries, death caused by hypothyroidism is uncommon.

Race
NHANES 1999-2002 reported that the prevalence of hypothyroidism (including subclinical) was higher in whites (5.1%) and Mexican Americans than in African Americans (1.7%). African Americans tend to have lower TSH values.

Sex
Community studies use slightly different criteria for determining hypothyroidism; therefore, female-to-male ratios vary. Generally, thyroid disease is much more common in females than in males, with reports of prevalence 2-8 times higher in females.

Age
The frequency of hypothyroidism, goiters, and thyroid nodules increases with age. Hypothyroidism is most prevalent in elderly populations, with 2% to as much as 20% of older age groups having some form of hypothyroidism. The Framingham study found hypothyroidism (TSH >10 mIU/L) in 5.9% of women and 2.4% of men older than 60 years. In NHANES 1999-2002, the odds of having hypothyroidism were 5 times greater in persons aged 80 years and older than in individuals aged 12-49 years.

History
Hypothyroidism commonly manifests as a slowing in physical and mental activity but may be asymptomatic. Symptoms and signs of this disease are often subtle and neither sensitive nor specific. Classic signs and symptoms, such as cold intolerance, puffiness, decreased sweating, and coarse skin, previously reported in 9097% of patients, may actually occur in only 50-64% of younger patients. Many of the more common symptoms are nonspecific and difficult to attribute to a specific cause. Individuals can also present with obstructive sleep apnea (secondary to macroglossia) or carpal tunnel syndrome. Women can present with galactorrhea and menstrual disturbances. Consequently, the diagnosis of hypothyroidism is based on clinical suspicion and confirmed by laboratory testing. Myxedema coma is a severe form of hypothyroidism that results in an altered mental status, hypothermia, bradycardia, hypercarbia, and hyponatremia. Cardiomegaly, pericardial effusion, cardiogenic shock, and ascites may be present. Myxedema coma most commonly occurs in individuals with undiagnosed or untreated hypothyroidism who are subjected to an external stress, such as low temperature, infection, or medical intervention (eg, surgery or hypnotic drugs). The following are symptoms of hypothyroidism: ; ; ; Fatigue, loss of energy, lethargy Weight gain Decreased appetite

; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;

Cold intolerance Dry skin Hair loss Sleepiness Muscle pain, joint pain, weakness in the extremities Depression Emotional lability, mental impairment Forgetfulness, impaired memory, inability to concentrate Constipation Menstrual disturbances, impaired fertility Decreased perspiration Paresthesia and nerve entrapment syndromes Blurred vision Decreased hearing Fullness in the throat, hoarseness Feeling of fullness in the throat Painless thyroid enlargement Exhaustion Neck pain, sore throat, or both Low-grade fever

The following are symptoms more specific to Hashimoto thyroiditis:

Physical
Signs found in hypothyroidism are usually subtle, and their detection requires a careful physical examination. Moreover, they are often dismissed as part of aging; however, clinicians should consider a diagnosis of hypothyroidism when such signs are present. Physical signs of hypothyroidism include the following: ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; Hypothermia Weight gain Slowed speech and movements Dry skin Jaundice Pallor Coarse, brittle, strawlike hair Loss of scalp hair, axillary hair, pubic hair, or a combination Dull facial expression Coarse facial features Periorbital puffiness Macroglossia Goiter Hoarseness Decreased systolic blood pressure and increased diastolic blood pressure Bradycardia

; ; ; ; ;

Pericardial effusion Abdominal distension, ascites (uncommon) Nonpitting edema (myxedema) Pitting edema of lower extremities Hyporeflexia with delayed relaxation, ataxia, or both

Additional signs specific to different causes of hypothyroidism, such as diffuse or nodular goiter or pituitary tumor, can occur. Metabolic abnormalities associated with hypothyroidism include anemia, dilutional hyponatremia, hyperlipidemia, and reversible increase in creatinine.[9]

Causes
Worldwide, iodine deficiency remains the foremost cause of hypothyroidism. In the United States and other areas of adequate iodine intake, autoimmune thyroid disease is most common. The prevalence of antibodies is higher in women, and increases with age.

Primary hypothyroidism
Note the following: ; Autoimmune: The most frequent cause of acquired hypothyroidism is autoimmune thyroiditis (Hashimoto thyroiditis). The body recognizes the thyroid antigens as foreign, and a chronic immune reaction ensues, resulting in lymphocytic infiltration of the gland and progressive destruction of functional thyroid tissue. Up to 95% of affected individuals have circulating antibodies to thyroid tissue. Antimicrosomal or antithyroid peroxidase (anti-TPO) antibodies are found more commonly than antithyroglobulin antibodies (95% vs 60%). These antibodies may not be present early in the disease process and usually disappear over time.[10] Postpartum thyroiditis: Up to 10% of postpartum women may develop lymphocytic thyroiditis in the 210 months after delivery. The frequency may be as high as 25% in women with type 1 diabetes mellitus. The condition is usually transient (2-4 mo) and can require a short course of treatment with levothyroxine (LT4), but postpartum patients with lymphocytic thyroiditis are at increased risk of permanent hypothyroidism. The hypothyroid state can be preceded by a short thyrotoxic state. High titers of anti-TPO antibodies during pregnancy have been reported to be 97% sensitive and 91% specific for postpartum autoimmune thyroid disease. Subacute granulomatous thyroiditis: Inflammatory conditions or viral syndromes may be associated with transient hyperthyroidism followed by transient hypothyroidism (de Quervain or painful thyroiditis, subacute thyroiditis). These are often associated with fever, malaise, and a painful and tender gland. Drugs: Medications such as amiodarone, interferon alpha, thalidomide, lithium, and stavudine have also been associated with primary hypothyroidism. Iatrogenic: Use of radioactive iodine for treatment of Graves disease generally results in permanent hypothyroidism within 1 year after therapy. The frequency is much lower in patients with toxic nodular goiters and those with autonomously functioning thyroid nodules. Patients treated with radioiodine should be monitored for clinical and biochemical evidence of hypothyroidism. Thyroidectomy can be used. External neck irradiation (for head and neck neoplasms, breast cancer, or Hodgkin disease) may result in hypothyroidism; patients who have received these treatments require monitoring of thyroid function. Rare: Rare causes include inborn errors of thyroid hormone synthesis. Iodine deficiency or excess: Worldwide, iodine deficiency is the most common cause of hypothyroidism. Excess iodine, as in radiocontrast dyes, amiodarone, health tonics, and seaweed, inhibits iodide organification and thyroid hormone synthesis. Most healthy individuals have a physiologic escape from this effect; however those with abnormal thyroid glands may not. These include patients with autoimmune thyroiditis, surgically treated Graves hyperthyroidism (subtotal thyroidectomy) and prior radioiodine therapy.[11]

; ;

; ;

Central hypothyroidism
Central hypothyroidism (secondary or tertiary) results when the hypothalamic-pituitary axis is damaged. Various causes should be considered[12, 13] : ; ; ; ; ; ; Pituitary adenoma Tumors impinging on the hypothalamus History of brain irradiation Drugs (eg, dopamine, lithium) Sheehan syndrome Genetic disorders

Laboratory Studies
Third-generation TSH assays are readily available and are generally the most sensitive screening tool for primary hypothyroidism. The generally accepted reference range for normal serum TSH is 0.40-4.2 mIU/L. In NHANES III (19881994), of 17,353 people evaluated, 80.8% had a serum TSH below 2.5 mIU/L; TSH concentrations rose with advancing age.[14] TSH levels peak in the evening and are lowest in the afternoon, with marked variations due to physiologic conditions such as illness, psychiatric disorders, and low energy intake. If TSH levels are above the reference range, the next step would be to measure total T4 with a measure of binding proteins. Thyroxine is highly protein bound (99.97%) with approximately 85% bound to thyroidbinding globulin (TBG), approximately 10% bound to transthyretin or thyroid-binding prealbumin, and the remainder bound loosely to albumin. The levels of these binding proteins can vary by hormonal status, inheritance, and in various disease states. Hence, free T4 assays are becoming popular as they measure unbound (ie, free hormone). However, free T4 assays can be unreliable in the setting of severe illness. No currently available kit actually measures unbound T4 directly. Free thyroid hormone levels can be estimated by calculating the percentage of available thyroid hormone-binding sites (T3 resin uptake) or by measuring the concentration of TBG. A free thyroxine index (FTI) serves as a surrogate of the free hormone level. The FTI is the product of the T3 resin uptake and total T4 levels. Patients with primary hypothyroidism have elevated TSH levels and decreased free hormone levels. Patients with elevated TSH levels but normal free hormone levels or estimates are considered to have mild or subclinical hypothyroidism. Primary hypothyroidism is virtually the only disease that is characterized by sustained, rising TSH levels. As the TSH level increases early in the disease, an increased conversion of T4 to T3 occur, this maintains T3 levels. In early hypothyroidism, TSH levels are increased, T4 levels are normal to low, and T3 levels are normal. Evaluation of the presence of thyroid autoantibodies (antimicrosomal or anti-TPO antibodies) and antithyroglobulin (anti-Tg) may be helpful in determining the etiology of hypothyroidism or in predicting future hypothyroidism. In addition, anti-TPO antibodies have been associated with a higher risk of infertility and miscarriage. In patients with nonthyroid disease who are severely ill, TSH secretion is normal or decreased, total T4 levels are decreased, and total T3 levels are markedly decreased. This can be confused with secondary hypothyroidism. In these patients, the primary abnormality is the decreased peripheral production of T3 from T4. They have an increased reverse T3, which can be measured. Other abnormalities seen in patients who are critically ill include decreased TBG levels and abnormalities in the hypothalamic-pituitary axis. During recovery, some patients have transient elevations in serum TSH concentrations (up to 20 mIU/L). Hence, thyroid function should not be evaluated in a critically ill person unless thyroid dysfunction is strongly suspected, and, if so, screening with TSH alone is insufficient. In patients with hypothalamic or pituitary dysfunction, TSH levels do not increase in appropriate relation to the low free T4 levels. The absolute levels may be in the normal or even slightly elevated range but inappropriately

low for the severity of the hypothyroid state. Hence, when secondary or tertiary hypothyroidism is suspected, a serum TSH measurement alone is inadequate; a free T4 should be measured. The TRH stimulation test is rarely needed currently because of improved TSH assays.

Imaging Studies
Ultrasonographic scanning of the neck and thyroid can be used to detect nodules and infiltrative disease. It has little use in hypothyroidism per se unless a secondary anatomic lesion in the gland is of clinical concern. Hashimoto thyroiditis is usually associated with a heterogeneous ultrasonographic image. It can be rarely associated with lymphoma of the thyroid. Serial images with fine-needle aspiration of suspicious nodules may be useful. Radioactive iodine uptake (RAIU) and thyroid scanning are not useful in hypothyroidism because these tests require some level of endogenous function in the hypofunctioning gland to provide information. Patients with Hashimoto thyroiditis may have relatively high early uptake (after 4 h) but do not have the usual doubling of uptake at 24 hours consistent with an organification defect. Patients undergoing whole-body F18-fluorodeoxyglucose positron emission tomography (FDG-PET) for nonthyroid disease often show significant thyroid uptake as an incidental finding.[3] In general, diffuse uptake by the thyroid on FDG-PET is considered a benign finding and is typical of thyroiditis and/or hypothyroidism.

Procedures
Fine-needle aspiration biopsy
Thyroid nodules are often found incidentally during physical examination, chest radiograph, CT scan, or MRI. Thyroid nodules can be found in patients who are hypothyroid, euthyroid, or hyperthyroid. Fine-needle aspiration (FNA) biopsy is the procedure of choice to evaluate suspicious nodules. About 5-6% of solitary nodules are malignant. Suspicious nodules are those that are larger than 1 cm in diameter or those with suspicious features found on a sonogram (eg, irregular margins, intranodular vascular spots, microcalcifications). Risk factors for thyroid nodules include age greater than 60 years, history of head or neck irradiation, or family history of thyroid cancer.

Histologic Findings
Autoimmune thyroiditis causes a decrease in intrathyroidal iodine stores, an increased iodine turnover, and defective organification. Chronic inflammation of the gland causes progressive destruction of the functional tissue with widespread infiltration by lymphocytes and plasma cells with epithelial cell abnormalities. In time, dense fibrosis and atrophic thyroid follicles replace the initial lymphocytic hyperplasia and vacuoles. Functional tissue destruction and infiltration may also be caused by previous administration of radioiodine, surgical fibrosis, metastasis, lymphomatous changes, sarcoidosis, tuberculosis, amyloidosis, cystinosis, thalassemia, and Riedel thyroiditis.

Medical Care
The treatment goals for hypothyroidism are the reversal of clinical progression and the corrections of metabolic derangements as evidenced by normal blood levels of TSH and free T4. Thyroid hormone is administered to supplement or replace endogenous production. In general, hypothyroidism can be adequately treated with a constant daily dose of levothyroxine (LT4). Clinical benefits begin in 3-5 days and level off after 4-6 weeks. Anticipated full replacement doses may be initiated in individuals who are otherwise young and healthy. In elderly patients or those with known ischemic heart disease, treatment should begin with one fourth to one half the expected dose, and the dose should be adjusted in small increments no sooner than 4-6 weeks. Achieving a TSH level within the reference range may be slowed because of delay of hypothalamic-pituitary axis readaptation and may take several months. After dose stabilization, patients can be monitored with annual clinical evaluations and TSH monitoring. Patients should be monitored for symptoms and signs of overtreatment, which include tachycardia, palpitations, nervousness, tiredness, headache, increased excitability, sleeplessness, tremors, and possible angina.

A meta-analysis of randomized controlled trials of thyroxine-triiodothyronine combination therapy (T4 + T3) versus thyroxine monotherapy (T4) for treatment of clinical hypothyroidism found no difference in the effectiveness of the combination vs monotherapy in bodily pain, depression, fatigue, body weight, anxiety, quality of life, total cholesterol, LDL-C, HDL-C and triglyceride levels. Hence, T4 monotherapy remains the treatment of choice.[4]

Pregnancy
Hypothyroidism in pregnancy is associated with preeclampsia, anemia, postpartum hemorrhage, cardiac ventricular dysfunction, spontaneous abortion, low birth weight, impaired cognitive development, and fetal mortality. Even mild disease may be associated with adverse affects for offspring. Increased dosage requirements should be anticipated during pregnancy, especially in the first and second trimesters. Studies have suggested that patients with hypothyroidism should augment the LT4 dose by 30% at the confirmation of pregnancy, followed by adjustments according to TSH levels. For previously diagnosed women, serum TSH should be measured every 3-4 weeks during the first half of pregnancy and every 6 weeks thereafter. LT4 dose should be adjusted to maintain a serum TSH less than 2.5 mIU/L. TSH and free T4 levels should be measured every 3-4 weeks after every dosage adjustment.[15] Autoimmune thyroid disease without overt hypothyroidism has been associated with a higher miscarriage rate. Negro et al showed that euthyroid Caucasian women with positive anti-TPO antibodies treated with levothyroxine during the first trimester had lower miscarriage rates when compared with those who were not treated. They also had lower incidence of premature delivery, comparable to women without thyroid antibodies. [16] This will need to be confirmed by other studies, and, if confirmed, there will be an indication to treat euthyroid pregnant women who have thyroid antibodies. LT4 should not be taken with prenatal vitamin preparations containing iron and calcium. After delivery, the LT4 dose can be reduced to the prepregnancy level and TSH should be checked in 6 weeks.

Subclinical hypothyroidism
Significant controversy persists regarding the treatment of patients with mild hypothyroidism. Some have argued that treatment of these patients improves symptoms, prevents progression to overt hypothyroidism, and may have cardioprotective benefits. Reviews by the US Preventive Services Task Force[17] and an independent expert panel[18] found inconclusive evidence to recommend aggressive treatment of patients with TSH levels of 4.5-10 mIU/L. The Endocrine Society recommends thyroxine replacement in pregnant women with subclinical hypothyroidism[19] ; the American College of Obstetricians and Gynecologists does not recommend it as a routine measure.[20] Ultrasonography may have prognostic value in subclinical hypothyroidism. In an Italian study, progression to overt hypothyroidism occurred more often in patients whose ultrasonographic thyroid scan showed diffuse hypoechogenicity (an indication of chronic thyroiditis).[21] Following subclinical hypothyroidism and treating on a case-by-case basis is reasonable. Treatment of subclinical hypothyroidism has been shown to reduce total cholesterol, non-HDL cholesterol, and apolipoprotein B,[22] and to decrease arterial stiffness and systolic blood pressure.[23] In patients with concomitant subclinical hypothyroidism and iron deficiency anemia, iron supplementation may be ineffective if LT4 is not given.[24] The American Association of Clinical Endocrinologists (AACE) guidelines state that treatment is indicated in patients with TSH levels above 10 mIU/mL or in patients with TSH levels between 5 and 10 mIU/mL in conjunction with goiter and/or positive antithyroid peroxidase antibodies, as these patients have the highest rates of progression to overt hypothyroidism. An initial dose of 25-50 mcg/d of LT4 can be used and can be titrated every 6-8 weeks, to achieve a target TSH of between 0.3 and 3 mIU/mL.[5]

Myxedema coma
An effective approach is to use intravenous LT4 at a dose of 4 mcg/kg of lean body weight, or approximately 200-250 mcg as a bolus in a single or divided dose, depending on the patient's risk of cardiac disease followed by 100 mcg 24 hours later and then 50 mcg daily IV or PO along with stress doses of intravenous glucocorticoids. Adjustment of the dose can then be made based on clinical and laboratory along with stress doses of intravenous glucocorticoids. Use of intravenous triiodothyronine is controversial and based on expert opinion. It has a higher frequency of adverse cardiac events and is generally reserved for patients who are not improving clinically on LT4. LT3 can be given initially as a 10 mcg IV bolus and repeated every 8-12 hours

until the patient can take maintenance oral doses of T4. Advanced age, high dose T4 therapy, and cardiac complications had the highest associations with mortality.[25]

Surgical Care
Surgery is indicated for large goiters that compromise tracheoesophageal function; surgery is rarely needed in patients with hypothyroidism and is more common in the treatment of hyperthyroidism.

Consultations
Patients with a nodular thyroid, suspicious thyroid nodules, or compressive symptoms such as dysphagia; pregnant women; patients with underlying cardiac disorders or other endocrine disorders; persons younger than 18 years; and those unresponsive to treatment should be referred to an endocrinologist. Some patients with thyroiditis can develop hyperthyroidism (or symptoms consistent with hyperthyroidism) before developing hypothyroidism and may benefit from consultation with an endocrinologist. Suspected myxedema coma is a medical emergency with a high risk of mortality that requires initiation of parenteral (intravenous) LT4 and glucocorticoids prior to laboratory confirmation. An urgent endocrinology consultation should be obtained. Rarely an increase in size of a goiter in a patient with autoimmune thyroid disease could be a lymphoma and should be evaluated by an endocrinologist.

Diet
No specific diets are required for hypothyroidism. Subclinical hypothyroidism has been seen in increased frequency in patients with greater iodine intake. The World Health Organization recommends a daily dietary iodine intake of 150 mcg for adults, 200 mcg for pregnant and lactating women, and 50-120 mcg for children.

Activity
Patients who have hypothyroidism have generalized hypotonia and may be at risk for ligamental injury, particularly from excessive force across joints. Thus, patients should exercise caution with certain activities, such as contact sports or heavy physical labor. Patients with uncontrolled hypothyroidism may have difficulty maintaining concentration in low-stimulus activities and may have slowed reaction times. Patients should use caution if an activity has a risk of injury (eg, operating presses or heavy equipment, driving).

GOITER NON TOXIC

Background
A nontoxic goiter is a diffuse or nodular enlargement of the thyroid gland that does not result from an inflammatory or neoplastic process and is not associated with abnormal thyroid function. Endemic goiter is defined as thyroid enlargement that occurs in more than 10% of a population, and sporadic goiter is a result of environmental or genetic factors that do not affect the general population.

Intrathoracic goiter causing obstruction. This patient has a visible goiter on physical examination. In addition, he has distension of his left external jugular vein, facial erythema (when compared

with his shoulder), and cutaneous varicosities of venous blood draining from his head into his chest because of jugular obstruction from his goiter.

Pathophysiology
The histopathology varies with etiology and age of the goiter. Initially, uniform follicular epithelial hyperplasia (diffuse goiter) is present, with an increase in thyroid mass. As the disorder persists, the thyroid architecture loses uniformity, with the development of areas of involution and fibrosis interspersed with areas of focal hyperplasia. This process results in multiple nodules (multinodular or adenomatous goiter). On nuclear scintigraphy, some nodules are hot, with high isotope uptake (autonomous) or cold, with low isotope uptake, compared with the normal thyroid tissue (as demonstrated in the images below). The development of nodules correlates with the development of functional autonomy and reduction in thyroidstimulating hormone (TSH) levels. Clinically, the natural history of a nontoxic goiter is growth, nodule production, and functional autonomy. However, abnormally high thyroid function resulting in thyrotoxicosis occurs in a minority of patients. The risk of malignancy is the same in a patient with a nodular goiter as with a solitary nodule. See the images below.

Technetium-99m (99mTc) thyroid scan of a large, nontoxic multinodular goiter. Multiple cold and hot nodules are observed in the enlarged thyroid gland. The white arrow indicates sternal notch marker. Areas of autonomy with excess thyroid hormone secretion in a large nodular goiter. This technetium-99m (99mTc) thyroid scan shows hot and cold nodules in a multinodular goiter. Although the patient's thyroid-stimulating hormone level had become progressively suppressed, it was within the reference range, at 0.4 mU/mL (reference range 0.35-5.5 mU/mL).

Epidemiology
Frequency
United States Iodine comes from ingestion of food. Iodine content of the soil determines the iodine content of plants and animals. Iodine is washed from the soil by water and is eventually washed out to the oceans. In general, areas with mountain ranges or heavy rainfall and flooding are iodine deficient. Iodine deficiency occurs in populations that depend on locally grown food and rely on vegetable protein rather than on animal or fish protein. Studies have shown that iodine supplementation can eliminate cretinism and is highly effective in the prevention of endemic goiter. When urinary iodide falls below 25 micrograms per gram of creatinine, a palpable goiter occurs in 40-90% of the population, hypothyroidism occurs in 30-50% of the population, and cretinism occurs in 1-10% of the population. The seminal studies by David Marine, MD, in 1917 demonstrated the reduction in goiter among adolescent girls in Ohio from 20% to 5% by iodine supplementation. Table salt has been supplemented in the United States since the 1920s for the prevention of cretinism and endemic goiter. The iodine intake in the United States, according to the National Health and Nutrition Examination Survey III (NHANES III), is adequate at 145 mcg/mg of creatinine. This adequate iodine intake in the United States eliminates the most common cause of endemic goiter in most populations. Sporadic goiter is the most common cause of nontoxic goiter in the United States. The incidence of sporadic nontoxic goiter has been estimated in North America at approximately 5%. Sporadic goiter does not usually occur in people before puberty, and it does not have a peak incidence. Generally, the development of palpable

thyroid nodules and goiter progressively increases with age. The prevalence of palpable nodules is approximately 5-6% in people aged 60 years, but on autopsy and ultrasonographic imaging findings, the incidence of small, nonpalpable nodules approaches 50% in people aged 60 years. International More than 2.2 billion people worldwide have some form of iodine deficiency disorder. Twenty-nine percent of the world's population lives in a region that has iodine deficiency (primarily in Asia, Latin American, central Africa, and regions of Europe). Of those at risk, 655 million were known to have goiter. In the iodine-deficient regions of the world, goiter is more common than in the United States. The prevalence of goiter can be estimated based on the iodine intake of the population. the absence of iodine deficiency (ie, median urine iodine >100 mg/dL) is associated with a goiter prevalence of less than 5%; mild iodine deficiency (ie, median urine iodine 50-99 mg/dL), with a goiter prevalence of 5-20%; moderate iodine deficiency (ie, median urine iodine 20-49 mg/dL), with a goiter prevalence of 20-30%; and severe iodine deficiency (ie, median urine iodine 20-49 mg/dL), with a goiter prevalence of greater than 30%.

Mortality/Morbidity
Endemic goiters arising from iodine deficiency are associated with sometimes immense thyroid hypertrophy, hypothyroidism, and cretinism. Sporadic goiters are generally asymptomatic and found either by a clinician's physical examination or by the patient's observation of neck enlargement. Occasionally, the goiter may produce symptoms caused by pressure on anterior neck structures, including the trachea (wheezing, cough, globus hystericus [anterior neck pressure]), the esophagus (dysphagia), and the recurrent laryngeal nerve (hoarseness). Rarely, the obstruction can be dangerous because of narrowing of the trachea and the development of tracheitis with edema and tracheomalacia, leading to severe narrowing of the airway with serious obstruction resulting in a respiratory emergency. (Tracheal compression and the results of its surgical treatment are seen in the images below.)

Nontoxic goiter of the thyroid gland with tracheal compression. An axial, noncontrast computed tomography scan through the thyroid shows significant tracheal compression.

Relief of tracheal compression after subtotal thyroidectomy of large, obstructive, nontoxic multinodular goiter. (A) Laryngoscopy demonstrating critical tracheal narrowing before thyroidectomy; (B) laryngoscopy showing widened patent trachea after thyroidectomy.

Race
No convincing epidemiologic studies suggest that race plays an important role in the development of nontoxic goiter. Generally, the lower socioeconomic conditions in nonindustrialized countries resulting in iodine deficiency have a more important role than race does in the development of a goiter.

Sex
Diffuse and nodular goiter is more common in women than in men. According to the best estimate, the incidence of goiter in women is 1.2-4.3 times as great as that in men.

Age
Sporadic goiter from dyshormonogenesis, a genetic error in proteins that are necessary for thyroid hormone synthesis, occurs during childhood. Endemic goiter due to iodine deficiency occurs during childhood, with the

goiter's size increasing with age. Other causes of sporadic goiter rarely occur before puberty and do not have a peak age of occurrence. Thyroid nodules increase in incidence with age.

PRESENTATION History
The thyroid gland usually grows outward because of its location anterior to the trachea (see the image below). Occasionally, the thyroid wraps around and compresses the trachea and/or esophagus or extends inferiorly into the anterior mediastinum.

Multinodular goiter. On visual inspection of the neck (image on left), this patient appears to have a goiter. The computed tomography scan (image on right) shows the asymmetrical goiter, measuring 9.3 x 7.4 cm, with tracheal deviation, although no tracheal obstruction is present.

Growth pattern
Determining whether the goiter has been present for many years and whether a change has occurred in the recent past is important. Recent or accelerated growth of a discrete nodule or thyroid lobe should raise the suspicion of malignancy. Goiters associated with unilateral adenopathy should raise the suspicion of malignancy.[1] Goiters rarely are painful or grow quickly unless recent hemorrhage into a nodule has occurred. Obstructive symptoms (see the image below)

Intrathoracic goiter causing obstruction. This patient has a visible goiter on physical examination. In addition, he has distension of his left external jugular vein, facial erythema (when compared with his shoulder), and cutaneous varicosities of venous blood draining from his head into his chest because of jugular obstruction from his goiter. Tracheal compression is generally asymptomatic until critical narrowing has occurred. Patients develop a dry cough, dyspnea, and stridor, especially with exertion. In patients with intrathoracic goiter, the dyspnea and stridor may be nocturnal or positional (ie, occurring when the patient's arms are raised) when the thoracic outlet is narrowed. Hemorrhage into a nodule or cyst or development of bronchitis may acutely worsen the respiratory symptoms in a patient with tracheal narrowing. The esophagus is more posterior in the neck, and a goiter occasionally extends posteriorly and causes solid food and pill dysphagia. Compression of the recurrent laryngeal nerve by a goiter or invasion by a thyroid malignancy results in vocal cord dysfunction and may cause hoarseness. The superior laryngeal nerve controls the pitch of the voice. An expanding goiter may cause a change in the character of the voice, especially in individuals who use their voice extensively (eg, in certain occupations). Compression of the venous outflow through the thoracic inlet by a mediastinal goiter results in facial plethora and dilated neck and upper thoracic veins.

Iodine intake
Obtain a careful diet history for iodine deficiency, iodine excess from medications (eg, amiodarone), health food store supplements, or seaweed.

History of radiation
Record any history of head and neck radiation exposure, especially during childhood, which significantly increases the risk of benign and malignant nodular thyroid disease and thyroid dysfunction (hypothyroidism and hyperthyroidism).[2, 1]

Family history
Family history is very important in the evaluation of the patient with goiter. Investigate inherited forms of dyshormonogenesis in the pediatric patient, as well as familial papillary carcinoma of the thyroid and familial forms of medullary thyroid cancer (multiple endocrine neoplasia and familial medullary carcinoma of the thyroid).[2, 1]

Physical
Pertinent physical findings are limited to the evaluation of the shape, asymmetry, size, and consistency of nontoxic goiters; ultrasonographic characteristics of individual nodules within the goiter; lymphadenopathy; and assessment of thyroid function.[2, 1] The thyroid evaluation starts with inspection of the neck for thyroid enlargement. Often, the thyroid enlargement can be detected only when the patient swallows. The thyroid isthmus is usually located at or just below the level of the cricoid cartilage of the trachea. The lobes of the thyroid extend laterally and, if enlarged, may extend posterior to the sternocleidomastoid muscles. Up to 80% of thyroid glands may have a pyramidal lobe extending superiorly from the isthmus. Assess the gland for overall size; in the United States, the normal weight is 15-20 grams. Assess the thyroid for asymmetry and determine whether a dominant nodule is present in an overall nodular goiter or whether a solitary nodule is present in an otherwise normal gland. Evaluate dominant nodules that are bigger than 1-1.5 cm or a solitary nodule of the same size by a thin-needle aspiration biopsy.[3] Diffuse or nodular goiters without a dominant nodule do not require a biopsy for evaluation.

Obstruction
Examine patients with dyspnea and cough, especially with exertion, for tracheal obstruction. Note any tracheal deviation from midline. The patient's voice is assessed for hoarseness. Venous outflow obstruction of the head and neck can be elicited by the Pemberton maneuver by raising the patients arms above the head until they touch the sides of the head for 1 minute. A positive finding occurs with facial plethora or engorgement of the neck veins.

Physical assessment of thyroid dysfunction

Examine patients for signs of thyroid dysfunction. Hypothyroidism is indicated by a sallow complexion, dysarthric speech, mental slowing, weight gain without change in appetite, cold intolerance, constipation, hypersomnia, and delayed relaxation of deep tendon reflexes. Hyperthyroidism is indicated by tachycardia, atrial arrhythmia (eg, atrial fibrillation), diaphoresis, weight loss without change in appetite, heat intolerance, hyperdefecation, palmar erythema, lid lag, tremor, and brisk reflexes.

Lymphadenopathy
Carefully examine the neck to identify any lymphadenopathy.

Causes
The most common worldwide cause of endemic nontoxic goiter is iodine deficiency. However, in patients with sporadic goiter, the cause is usually unknown. Nontoxic goiters have many etiologies, including the following:

Iodine deficiency - Goiter formation occurs with moderately deficient iodine intake of less than 50 mcg/d. Severe iodine deficiency associated with intake of less than 25 mcg/d is associated with hypothyroidism and cretinism. Iodine excess - Goiter formation due to iodine excess is rare and usually occurs in the setting of preexisting autoimmune thyroid disease. Goitrogens o o o Drugs - Propylthiouracil, lithium, phenylbutazone, aminoglutethimide, iodine-containing expectorants Environmental agents - Phenolic and phthalate ester derivatives and resorcinol found downstream of coal and shale mines Foods - Vegetables of the genus Brassica (eg, cabbage, turnips, brussels sprouts, rutabagas), seaweed, millet, cassava, and goitrin in grass and weeds

; ;

; ;

Dyshormonogenesis - A defect in the thyroid hormone biosynthetic pathway is inherited. Childhood head and neck radiation - Radiation exposure during childhood results in benign and malignant nodules.

WORK UP Laboratory Studies

; Assess all patients with goiter for thyroid dysfunction with a serum thyrotropin (TSH) assay. Secondgeneration or better TSH assays can detect clinically inapparent (subclinical) hyperthyroidism and hypothyroidism. o If the TSH is high, consider chronic autoimmune thyroiditis (Hashimoto thyroiditis) or ingestion of a goitrogen, such as lithium or amiodarone, as well as dyshormonogenesis in a child. Correction of the hypothyroid status by withdrawal of the goitrogen or institution of thyroid hormone replacement therapy may greatly reduce the size of the goiter. If the TSH is low, measurement of serum free thyroxine (free T4) or free T4 index and total triiodothyronine (T3) is used to confirm the diagnosis of thyrotoxicosis. After many years, a nontoxic goiter may develop areas of functional autonomy (as seen in the image below) and thyrotoxicosis. Treatment of thyrotoxicosis includes stabilization of the hyperthyroid state with antithyroid medications and then surgical removal of the goiter or the administration of

radioactive iodine ablative therapy. Areas of autonomy with excess thyroid hormone secretion in a large nodular goiter. This technetium-99m (99mTc) thyroid scan shows hot and cold nodules in a multinodular goiter. Although the patient's thyroid-stimulating hormone level had become progressively suppressed, it was within the reference range, at 0.4 mU/mL (reference range 0.35-5.5 mU/mL).

Imaging Studies
Assessment of size and extent of the goiter is necessary to determine if progressive growth of the thyroid is occurring. Clinical assessment by an experienced clinician is often accurate until the thyroid increases to 4-5 times the normal size.

Measurement of neck circumference is a crude measure of thyroid size. Ultrasonography is good for estimating the number, size, and sonographic characteristics of nodules but is inaccurate in the clinical setting for measuring the volume of large goiters. Suspicious ultrasound characteristics, including hypoechogenicity, microcalcifications, macrocalcifications, intranodular vascularity, taller-than-wide dimensions, and blurred margins, guide the clinician as to which nodule requires biopsy for malignancy.[2, 1] Computed tomography (CT) scanning and magnetic resonance imaging (MRI), although expensive, are excellent for assessing tracheal compression and intrathoracic extension of the goiter. A barium swallow may be used to document esophageal obstruction in patients with significant symptoms of dysphagia. Thyroid scintigraphy is not routinely indicated in the assessment of goiter size unless a concern of thyroid hemiagenesis exists or the TSH is suppressed consistent with hyperthyroidism. A nodule with equivocal findings on thin-needle aspiration may be further evaluated using thyroid scintigraphy. A hot area supports the presence of a benign lesion. Examples of technetium-99m (99m Tc) thyroid scans are shown below.[2, 1]

Technetium-99m (99mTc) thyroid scan of a large, nontoxic multinodular goiter. Multiple cold and hot nodules are observed in the enlarged thyroid gland. The white arrow indicates sternal

notch marker. Areas of autonomy with excess thyroid hormone secretion in a large nodular goiter. This technetium-99m (99mTc) thyroid scan shows hot and cold nodules in a multinodular goiter. Although the patient's thyroid-stimulating hormone level had become progressively suppressed, it was within the reference range, at 0.4 mU/mL (reference range 0.35-5.5 mU/mL).

Other Tests
; Pulmonary function tests may be used as a functional assessment of tracheal compression. Characteristic changes of external tracheal compression can be detected in flow-volume loop tracings in asymptomatic patients with goiter. Direct laryngoscopy can, as indicated in the image below, also demonstrate tracheal

compression. Relief of tracheal compression after subtotal thyroidectomy of large, obstructive, nontoxic multinodular goiter. (A) Laryngoscopy demonstrating critical tracheal narrowing before thyroidectomy; (B) laryngoscopy showing widened patent trachea after thyroidectomy.

Procedures

A subset of patients presenting with goiter who do not have hyperthyroidism or has a cold nodule on nuclear thyroid scan with hyperthyroidism should have a fine-needle aspiration biopsy as the first diagnostic procedure. Clinical indication for biopsy includes suspicious sonographic characteristics listed above,asymmetrical and/or rapid growth of a nodule or lobe of a thyroid gland or unilateral adenopathy. Generally, in patients with the usual nonnodular nontoxic goiter that is long-standing with slow growth, fine-needle biopsy is not necessary unless sonographically suspicious nodules are present.[2, 1]

Histologic Findings
A variety of features may be observed with fine-needle aspiration cytology of a multinodular goiter.[3] This variation is mostly explained by different stages of nodule formation. A proliferative phase exists in which the sample may contain many follicular cells. This can sometimes be difficult to distinguish from a follicular adenoma versus a follicular carcinoma. Colloid is another prominent feature. It represents the stored thyroid hormone within the follicle. Its absence suggests a more worrisome diagnosis. After proliferation of follicular cells, a hemorrhage may occur inside the nodule. Erythrocytes and foamy macrophages that have ingested colloid material may be observed. Another potential area of concern is an aspiration that only returns cyst contents, ie, erythrocytes and macrophages without follicular cells. This cannot be used to definitively rule out the presence of thyroid cancer, and a reaspiration should be performed.

TREATMENT Medical Care

Nontoxic goiters usually grow very slowly over decades without causing symptoms. Without evidence of rapid growth, obstructive symptoms (eg, dysphagia, stridor, cough, shortness of breath), or thyrotoxicosis, no treatment is necessary. Therapy is considered if growth of the entire goiter or a specific nodule is present, especially if intrathoracic extension of the goiter, compressive symptoms, or thyrotoxicosis exists. The intrathoracic extension of the goiter cannot be assessed by palpation or biopsy. The goiter, if significant in size, should be removed surgically.[4] The currently available therapies include thyroidectomy, radioactive iodine therapy, and levothyroxine (L-thyroxine, or T4) therapy. Radioactive iodine therapy - Radioiodine therapy of nontoxic goiters is often performed in Europe. It is a reasonable therapeutic option, particularly in patients who are older or have a contraindication to surgery.[5, 6, 7] Radioactive iodine therapy for nontoxic goiters was reintroduced in the 1990s. Careful studies have shown a reduction in thyroid volume in nearly all patients after a single dose of therapy.[1] Of patients with nontoxic diffuse goiter treated with radioactive iodine, 90% have an average of 50-60% reduction in goiter volume after 12-18 months, with a reduction in compressive symptoms. The decrease in goiter size has positively correlated with the dose of iodine-131 (131 I). Reduction in goiter size is greater in younger patients and in individuals who have only a short history of goiter or who have a small goiter. Baseline TSH is not a predictor of response to radioactive iodine. Obstructive symptoms improved in most patients who received radioactive iodine. Adverse effects, including thyroiditis, occurred, but no patient reported worsening of compressive symptoms requiring treatment. No long-term follow-up reports on patients treated with radioactive iodine exist. Patients should always be monitored clinically after131 I therapy, for evidence of goiter regrowth. Transient hyperthyroidism is rare and typically occurs in the first 2 weeks after treatment. Unlike patients with Graves hyperthyroidism who almost all become hypothyroid after treatment with radioactive iodine, only a small percentage (~20%) of patients with nontoxic goiter develop hypothyroidism after radioactive iodine treatment Recombinant human TSH (rhTSH) may have a role in radioactive iodine treatment for nontoxic goiter. Pretreatment with rhTSH 24 hours prior to therapy can reduce the amount of radioiodine needed to shrink the goiter (up to a 50% reduction).[8, 9, 10, 11] Thyroid hormone suppressive therapy - The use of T4 in a euthyroid individual to shrink a nontoxic goiter is controversial. One study showed that T4 therapy for nontoxic goiter reduced thyroid volume in 58% of patients, compared with 4% of patients treated with a placebo. However, these results have not yet proven to be reproducible, and

the benefit of using T4 needs to be weighed against the risk of the resultant subclinical hyperthyroidism associated with an increased risk of decreased bone mineral density and increased atrial fibrillation. Goiter growth typically resumes after cessation of T4 therapy. The American Thyroid Association and American Association of Clinical Endocrinologists have released guidelines for the management of hyperthyroid and other causes of thyrotoxicosis, including the use of radioactive iodine or surgery to treat toxic multinodular goiter.[12]

Surgical Care
Thyroidectomy or surgical decompression causes rapid relief for obstructive symptoms.[1, 4, 13] Most intrathoracic goiters may be removed from a cervical incision without sternotomy. Performing bilateral subtotal thyroidectomy has been recommended to reduce the risk of continued goiter growth. The rate of goiter recurrence depends on the extent of surgery but should not be higher than 10% in 10 years. After bilateral subtotal thyroidectomy, all patients require thyroid hormone replacement therapy. The full replacement therapy should start immediately after surgery, with TSH levels checked 3-4 weeks postoperatively. Adjust thyroid hormone therapy, such as T4, to maintain a TSH level in the reference range. Some evidence exists that thyroid hormone replacement therapy prevents recurrence of nontoxic goiter after surgical removal.[14] The use of total thyroidectomy to treat benign multinodular goiter has met with some concern, owing to the risk of parathyroid function damage and laryngeal nerve injury posed by the procedure. Nonetheless, total thyroidectomy is also seen as a means of avoiding the pitfalls of subtotal thyroidectomy, specifically, the recurrence of goiter and the inadequate treatment of thyroid cancers, which can occur in apparently benign goiters. Results from a 2008 literature review indicated that the rate of permanent complications is the same for subtotal and total thyroidectomy; consequently, the report's authors concluded that total thyroidectomy should be the procedure of choice for the surgical treatment of benign multinodular goiters.[4] The same conclusion was reached in a study of 600 patients with nontoxic multinodular goiter. Barczynski et al compared outcomes from total thyroidectomy (200 patients), the Dunhill procedure (unilateral total lobectomy plus contralateral subtotal lobectomy; 200 patients), and bilateral subtotal thyroidectomy (200 patients). The authors found that over a 5-year follow-up period the incidence of recurrent goiter after total thyroidectomy was 0.52%, while that following the Dunhill operation was 4.71%, and recurrence after bilateral subtotal thyroidectomy was 11.58%. The frequency of completion thyroidectomies was also lower in total thyroidectomy than in the other operations. The incidence of transient hypoparathyroidism in the above study, as well as that of transient and permanent laryngeal nerve injuries, was greater in total thyroidectomy than in the other types of surgery. Nonetheless, the authors concluded that, owing to the fact that following total thyroidectomy there was a reduced incidence of goiter recurrence requiring repeat thyroidectomy, total thyroidectomy should be considered the procedure of choice for patients with nontoxic multinodular goiter.[15] Results from a Swiss study of 72 patients indicated that a single dose of steroid prior to thyroidectomy for benign disease can, within 48 hours postsurgery, significantly reduce pain, nausea, vomiting, and voice alteration related to the procedure.[16]

Consultations
Consult an endocrinologist in the complicated nontoxic goiter with obstructive symptoms, rapid growth, and/or evaluation for thyroid malignancy within the nontoxic goiter. If a high index of suspicion for malignancy exists in a patient with hoarseness, lymphadenopathy, and previous radiation exposure as a child, consult an endocrinologist or a surgeon specializing in thyroid disease.

Diet
Diets low in iodine need supplementation, especially in developing countries where government-supported iodine supplementation is not available. Adult patients require 150 mcg/day, which has been the average intake in the United States, but patients should be encouraged to use iodized salt at home and take multivitamins with iodine to ensure adequate intake. Patients should not take iodine supplements such as seaweed, as the amount of iodine is excessive and may result in iodine-induced thyroid hormone dysfunction in predisposed individuals.

TOXIC NODULAR GOITER Background

A toxic nodular goiter (TNG) is a thyroid gland that contains autonomously functioning thyroid nodules, with resulting hyperthyroidism. TNG, or Plummer's disease, was first described by Henry Plummer in 1913. TNG is the second most common cause of hyperthyroidism in the Western world, after Graves disease. In elderly individuals and in areas of endemic iodine deficiency, TNG is the most common cause of hyperthyroidism.

Pathophysiology
Toxic nodular goiter (TNG) represents a spectrum of disease ranging from a single hyperfunctioning nodule (toxic adenoma) within a multinodular thyroid to a gland with multiple areas of hyperfunction. The natural history of a multinodular goiter involves variable growth of individual nodules; this may progress to hemorrhage and degeneration, followed by healing and fibrosis. Calcification may be found in areas of previous hemorrhage. Some nodules may develop autonomous function. Autonomous hyperactivity is conferred by somatic mutations of the thyrotropin, or thyroid-stimulating hormone (TSH), receptor in 20-80% of toxic adenomas and some nodules of multinodular goiters.[1] Autonomously functioning nodules may become toxic in 10% of patients. Hyperthyroidism predominantly occurs when single nodules are larger than 2.5 cm in diameter. Signs and symptoms of TNG are similar to those of other types of hyperthyroidism.

Epidemiology
Frequency
United States Toxic nodular goiter accounts for approximately 15-30% of cases of hyperthyroidism in the United States, second only to Graves disease. International In areas of endemic iodine deficiency, toxic nodular goiter (TNG) accounts for approximately 58% of cases of hyperthyroidism, 10% of which are from solitary toxic nodules. Graves disease accounts for 40% of cases of hyperthyroidism. In patients with underlying nontoxic multinodular goiter, initial iodine supplementation (or iodinated contrast agents) can lead to hyperthyroidism (Jod-Basedow effect). Iodinated drugs, such as amiodarone, may also induce hyperthyroidism in patients with underlying nontoxic multinodular goiter. Roughly 3% of patients treated with amiodarone in the United States (more in areas of iodine deficiency) develop amiodarone-induced hyperthyroidism.[2]

Mortality/Morbidity
Morbidity and mortality from toxic nodular goiter (TNG) may be divided into problems related to hyperthyroidism and problems related to growth of the nodules and gland. Local compression problems due to nodule growth, although unusual, include dyspnea, hoarseness, and dysphagia. TNG is more common in elderly adults; therefore, complications due to comorbidities, such as coronary artery disease, are significant in the management of hyperthyroidism.

Sex
Toxic nodular goiter occurs more commonly in women than in men. In women and men older than 40 years, the prevalence rate of palpable nodules is 5-7% and 1-2%, respectively.

Age
Most patients with toxic nodular goiter (TNG) are older than 50 years. Thyrotoxicosis often occurs in patients with a history of longstanding goiter. Toxicity occurs in a subset of patients who develop autonomous function. This toxicity usually peaks in the sixth and seventh decades of life, especially in persons with a family history of multinodular goiter or TNG, suggesting a genetic component.

TIROIDITIS SUB AKUT

Background
Subacute thyroiditis is a self-limited thyroid condition associated with a triphasic clinical course of hyperthyroidism, hypothyroidism, and return to normal thyroid function. Subacute thyroiditis may be responsible for 15-20% of patients presenting with thyrotoxicosis and 10% of patients presenting with hypothyroidism. Recognizing this condition is important; because it is self-limiting, no specific treatment, such as antithyroid or thyroid hormone replacement therapy, is necessary in most patients. (See Presentation, Workup, and Treatment.) In general, the following 3 forms of subacute thyroiditis are recognized: ; ; Subacute granulomatous thyroiditis - Also known as subacute painful or de Quervain thyroiditis (see the image below) Lymphocytic thyroiditis - Also known as subacute painless thyroiditis

Subacute postpartum thyroiditis Three multinucleated, giant cell granulomas observed in a fine-needle aspiration biopsy of the thyroid; from a patient with thyrotoxicosis resulting from subacute granulomatous thyroiditis.

Disease course
Although the etiology appears to be different for the 3 subtypes, the clinical courses are the same. High thyroid hormone levels result from the destruction of the thyroid follicle and the release of preformed thyroid hormone into the circulation, with thyrotoxicosis consequently developing. (The high thyroid hormone levels are not a function of new thyroid hormone synthesis and secretion.) This phase lasts 4-10 weeks. (See Pathophysiology and Etiology.) The disease undergoes remission in 2-4 months. At this time, the thyroid is depleted of colloid and is now incapable of producing thyroid hormone, resulting in hypothyroidism. The hypothyroid phase may last up to 2 months. Often, the hypothyroidism is mild, and no thyroid hormone therapy is required unless the patient has signs or symptoms of hypothyroidism. As the follicles regenerate, the euthyroid state is restored. Ninety to 95% of patients return to normal thyroid function. (See Prognosis.) Subacute granulomatous thyroiditis Subacute granulomatous thyroiditis is the most common cause of a painful thyroid gland. It is a transient inflammation of the thyroid, the clinical course of which is highly variable. Most patients have pain in the region of the thyroid, which is usually diffusely tender, and some have systemic symptoms. Hyperthyroidism often occurs initially, sometimes followed by transient hypothyroidism. Complete recovery in weeks to months is characteristic. (See the Table, below.) Table. Characteristic Course of de Quervain Thyroiditis (Open Table in a new window) Paramete Stage 1 rs Symptom Hyperthyro s id T4, T3 Elevated TSH Decreased T4 = thyroxine Stage 2 Euthyro id Normal Normal Stage 3 Hypothyro id Decreased Elevated Stage 4 Euthyroid (recovery) Normal Normal

T3 = triiodothyronine

TSH = thyroid-stimulating hormone

Patient education
For patient education information, see the Thyroid and Metabolism Center, as well as Thyroid Problems.

Pathophysiology
Destruction of follicular epithelium and loss of follicular integrity are the primary events in the pathophysiology of subacute granulomatous thyroiditis. Thyroglobulin (TG), thyroid hormones, and other iodinated compounds are released into the blood, often in quantities sufficient to elevate the serum thyroxine (T4) and triiodothyronine (T3) concentrations and suppress thyroid-stimulating hormone (TSH) secretion. This state lasts until the stores of TG are exhausted or until healing occurs. Thyroidal iodine uptake and new hormone synthesis temporarily ceases because of the low level of TSH. As inflammation subsides, the thyroid follicles regenerate and thyroid hormone synthesis and secretion resume. In some patients, several months are required for thyroid hormone synthesis to return to a normal rate; during that period, clinical hypothyroidism may be evident.

Thyrotoxicosis
The hypermetabolic effect of thyrotoxicosis is the same, regardless of cause. Thyrotoxicosis affects every organ system, because thyroid hormones made in the thyroid travel via the circulation to reach every cell in the body. Thyroid hormone is necessary for normal growth and development, and it regulates cellular metabolism. Excess thyroid hormone causes an increase in metabolic rate that is associated with increased total body heat production, increased cardiovascular activity (eg, increased heart contractility, heart rate, vasodilation) to remove heat to the periphery and remove metabolic wastes, and perspiration to cool the body. The major symptoms of thyrotoxicosis include palpitations, nervousness, sweating, hyperdefecation, and heat intolerance. Women often note a reduction in menstrual flow, or oligomenorrhea. Common signs of thyrotoxicosis include the following: ; ; ; ; ; ; Weight loss despite increased appetite Lid lag and stare Sinus tachycardia Atrial fibrillation or high-output failure (in elderly persons) Fine tremor Muscle weakness

Synergism occurs between thyrotoxicosis and the adrenergic system, with increases in nervousness, stare, tremor, and tachycardia. The manifestations of thyrotoxicosis vary among patients. Younger patients tend to exhibit more sympathetic activations (eg, anxiety, hyperactivity, tremor), while older patients have more cardiovascular symptoms (eg, dyspnea, atrial fibrillation) and unexplained weight loss. The clinical manifestation of thyrotoxicosis does not always correlate with the extent of the biochemical abnormality.

Etiology
The causes of subacute thyroiditis, other than those of subacute granulomatous thyroiditis, are not entirely clear.

Subacute granulomatous thyroiditis

The most accepted etiology for this condition is a viral illness.[1] Viral particles have never been identified within the thyroid, but episodes often follow upper respiratory infections and are associated with falling postconvalescent viral titers of various viruses, including influenza, adenovirus, mumps, and coxsackievirus. The occurrence of subacute granulomatous thyroiditis in the course of novel H1N1 influenza infection has been reported from Greece.[2]

De Quervain thyroiditis is not associated with autoimmune thyroiditis. The transient presence of autoantibodies (eg, inhibitory immunoglobulins that bind to TSH, antibodies that block thyroid stimulation, thyroid antimicrosomal antibodies, thyroglobulin [TG] antibodies) has been noted in the acute phase of the disease, but this has been attributed to a virally induced autoimmune response and has not been implicated in the pathologic process. (Viral inclusion bodies are not observed in thyroid tissue in subacute granulomatous thyroiditis.) It is unclear, however, whether the destructive thyroiditis in De Quervain patients is caused by direct viral infection of the gland or by the host's response to the viral infection. In contrast to autoimmune thyroid disease, the immune response in subacute granulomatous thyroiditis is not self-perpetuating; therefore, the process is limited. HLA-B35 A genetic predisposition to the development subacute granulomatous thyroiditis clearly exists; risk for developing the disease in patients with human leukocyte antigen (HLA)Bw35 is 6-fold that of the general population.[3] In one study, as many as 72% of patients with subacute thyroiditis manifested HLA-Bw35. A proposed etiologic mechanism suggests that the disease results from a viral infection that provides an antigen, one that is either viral or that results from virus-induced host tissue damage, that uniquely binds to HLA-B35 molecules on macrophages. The antigenHLA-B35 complex activates cytotoxic T lymphocytes that damage thyroid follicular cells, because these cells have some structural similarity to the infection-related antigen. In Japanese patients, an association seems to exist between subacute granular thyroiditis and HLA-B67. In a study, 87% of Japanese patients with subacute thyroiditis had either HLA-B35 or HLA-B67. Research indicates that HLA-B67 is associated with a greater risk of developing a hypothyroid phase than is HLA-Bw35. Growth factors The role of growth factors in the development of subacute thyroiditis has received some attention. In the granulomatous stage of subacute thyroiditis, growth factorrich monocytes and/or macrophages infiltrating follicular lumina are thought to trigger the granulomatous reaction, with this reaction probably being mediated by vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and transforming growth factor beta 1 (TGF-1) produced by the stromal cells. In the regenerative phase, endothelial growth factor (EGF) mediates follicular regeneration through its mitogenic effect on thyrocytes, along with cofactors. In addition, the decreased expression of TGF-1, a fibrogenic factor, contributes to thyroid tissue repair. VEGF and bFGF may be responsible for angiogenesis in both stages.

Lymphocytic thyroiditis
This condition most likely is autoimmune in nature. Patients develop an autoimmune goiter and permanent hypothyroidism more often than they do with subacute granulomatous thyroiditis. An HLA association may be present, suggesting a genetic predisposition to lymphocytic thyroiditis. Certain drug exposures relating to excess iodine and cytokines may cause this form of silent thyroiditis. These drugs include amiodarone (iodine-rich), interferon alfa, interleukin 2, and lithium. Cases of thyroiditis resulting from these drugs are typically treated in a similar way. Amiodarone Amiodarone has multiple established effects on thyroid function. One of the 2 types of amiodarone-induced thyrotoxicosis is a destructive lymphocytic thyroiditis. This form of thyroiditis is more common in men, likely due to the higher prevalence of amiodarone therapy in men. Lymphocytic thyroiditis typically occurs after more than 2 years of amiodarone therapy.[4] Interferon alfa Up to 5% of patients taking interferon alfa may experience lymphocytic thyroiditis. This condition is detected biochemically, after 3 months of therapy, more often than it is found clinically. Lymphocytic thyroiditis in patients taking interferon alfa is associated with an increased antithyroid antibody concentration. Interleukin 2 Although case reports exist that interleukin 2 is associated with lymphocytic thyroiditis, its causative role is less established than that of interferon alfa.

Lithium Lithium is a well-known cause of either subclinical or clinical hypothyroidism, as well as of goiter. Because of lithiums ability to inhibit the release of thyroid hormone, it has been used as a treatment for thyrotoxicosis. However, reports exist of lithium-associated thyrotoxicosis due to a lymphocytic thyroiditis, with the classic picture of hyperthyroidism, absent neck tenderness, and low radioactive iodine uptake. Lymphocytic thyroiditis can occur during lithium administration, as well as up to 5 months following discontinuation of lithium therapy. Increased thyroid antibodies in lithium users and a direct toxic effect of lithium have been proposed as possible mechanisms.

Subacute postpartum thyroiditis

This condition is likely autoimmune in nature.[5] Patients develop an autoimmune goiter and permanent hypothyroidism more often than they do with subacute granulomatous thyroiditis. In iodine-sufficient countries, such as the United States, postpartum thyroiditis occurs in approximately 5-8% of pregnant women. In Japan where the diet is rich in iodine, nearly 20% of pregnancies are associated with this condition. Patients with positive test results for thyroid autoantibodies either before their pregnancy or during the third trimester are at much higher risk of developing postpartum thyroiditis. Cigarette smoking is also associated with an increased incidence of postpartum thyroiditis. Once patients have an episode of subacute postpartum thyroiditis, they are likely to have additional episodes following each pregnancy.

Additional causes of subacute thyroiditis

Other causes of subacute thyroiditis, or at least conditions that have been associated with the disease, include the following: ; ; ; ; ; ; Radioiodine therapy for Graves disease can result in transient thyroidal inflammation, causing thyroiditis Subacute thyroiditis also has been described following external radiation to the neck Subacute thyroiditis has presented as a paraneoplastic manifestation of renal cell carcinoma An association between subacute thyroiditis and febrile neutrophilic dermatoses (Sweet syndrome) has been reported Concurrence of giant cell arteritis has been reported in patients with classic de Quervain thyroiditis Subacute thyroiditis has been described after bone marrow transplantation for chronic granulocytic leukemia

Epidemiology
Subacute granulomatous thyroiditis occurs in less than 5% of all patients with thyroid pathology, although estimates indicate that together, the 3 forms of subacute thyroiditis account for 20-25% of thyrotoxicosis cases. De Quervain thyroiditis tends to have a seasonal and geographic distribution and is most common during the summer and fall. It tends to follow viral epidemics. A systematic review of all cases of subacute granulomatous thyroiditis diagnosed between 1960 and 1997 in Olmsted County, Minnesota, revealed an age- and sex-adjusted annual incidence of 4.9 cases per 100,000 population.[6] Postpartum thyroiditis has an incidence of 5.4% in the general population. An isolated hypothyroid phase occurs in 48% of women with the condition, while isolated thyrotoxicosis is found in 30% patients, and a presentation of hyperthyroidism followed by hypothyroidism is seen in 22% of them.[7]

Sex-related demographics
As is the case for most thyroid diseases, de Quervain thyroiditis appears more frequently in females, with a female-to-male ratio of 3-5:1. Lymphocytic thyroiditis occurs twice as often in women as it does in men. Postpartum thyroiditis occurs 1-6 months after giving birth. If a woman has postpartum thyroiditis with one baby, all other pregnancies are likely to be associated with this condition.

Age-related demographics

Lymphocytic thyroiditis can occur in any age group, while postpartum thyroiditis occurs in women of childbearing age. Subacute granulomatous thyroiditis usually occurs in adults (ie, aged 20-60 y), with the incidence peaking in the fourth and fifth decades of life. It is rare in the first decade and relatively infrequent in people older than 50 years, although it has been reported in extreme age groups.[8] Occurrence during pregnancy has been reported as well.[9]

Prognosis
The prognosis is excellent in 90-95% of patients who experience subacute thyroiditis. Approximately 5-10% of patients have permanent thyroid dysfunction, usually hypothyroidism, after an episode of subacute thyroiditis. Permanent goiter and thyroid dysfunction occur most frequently after postpartum thyroiditis.

Thyrotoxicosis
Thyrotoxicosis from subacute thyroiditis is brief, usually lasting no longer than 6-8 weeks. Patients can be extremely thyrotoxic during this period and can appear extremely ill, but concerns regarding left ventricular hypertrophy and osteoporosis are not as great as those associated with conditions of permanent hyperthyroidism. However, sudden-onset thyrotoxicosis and severe thyrotoxicosis can be associated with atrial arrhythmia and congestive heart failure (CHF).

Subacute granulomatous thyroiditis

This condition generally resolves completely in more than 90-95% of patients. No special thyroidal follow-up is needed. Morbidity is caused during the initial phase by pain, which usually prompts the patient to consult a physician. Hyperthyroidism, usually a mild, transient form, occurs in approximately 50% of patients with subacute granulomatous thyroiditis; in up to half of all patients, hypothyroidism may later develop. Acute complications When acute complications do occur, they can include the following: ; ; ; ; ; Severe hyperthyroidism - May be observed during the inflammatory phase Multiple system organ failure - May complicate the course of the disease in exceptionally rare cases Pancreatitis or splenomegaly - Associated with de Quervain thyroiditis in case reports only Vocal cord paralysis - Occurs occasionally in cases with severe thyroid gland inflammation Cerebral venous thrombosis - has been reported in some cases; in one case, the patient was a heterozygous carrier for the G20210A mutation of the prothrombin gene, which predisposed her to this complication

Long-term complications Permanent hypothyroidism is the most frequent long-term complication of de Quervain thyroiditis. It is observed in less than 5-10% of the patients and requires thyroid replacement therapy. Disease recurrence has been documented in occasional cases (up to 20% of cases in some series). Recurrence is more frequent in the first year but has been reported even 30 years after the initial diagnosis. The risk of recurrence cannot be correlated with initial thyroid function, inflammatory syndrome, or ultrasonographic aspect (ie, thyroid volume, echogenicity).

Lymphocytic thyroiditis
Occasionally, patients have recurrent episodes of painless thyrotoxicosis.[10] No treatment exists to prevent the recurrences except subtotal thyroidectomy. However, this condition generally resolves completely in more than 90-95% of patients. Patients with goiters or permanent thyroid dysfunction should be monitored with a thyroid examination and thyroid function tests every 6 months.

Subacute postpartum thyroiditis

Usually, repeat episodes occur after each pregnancy; no known treatment exists to prevent these. Patients may have a residual goiter and thyroid hypofunction after postpartum thyroiditis, because this condition is associated with chronic autoimmune thyroiditis. Patients should be observed routinely for goiter enlargement and thyroid hypofunction every 6-12 months.