Hyperthyroidism

Introduction
Background

Thyrotoxicosis is the hypermetabolic condition associated with elevated levels of free thyroxine (FT4) and/or free triiodothyronine (FT3). Hyperthyroidism includes diseases that are a subset of thyrotoxicosis, that are caused by excess synthesis and secretion of thyroid hormone by the thyroid; they are not associated with exogenous thyroid hormone intake and subacute thyroiditis. Most clinicians, exclusive of endocrinologists, use the terms hyperthyroidism and thyrotoxicosis interchangeably. This article discusses the causes of thyrotoxicosis associated with hyperthyroidism (excess synthesis and release of thyroid hormone) and surreptitious use of thyroid hormone. Subacute thyroiditis is discussed in the article Subacute Thyroiditis.

The most common forms of hyperthyroidism include diffuse toxic goiter (Graves disease), toxic multinodular goiter (Plummer disease), and toxic adenoma. Together with subacute thyroiditis, these conditions constitute 85-90% of all causes of thyrotoxicosis. Table 1 contains a list of hyperthyroid conditions associated with thyrotoxicosis.

Table 1. Common, Less Common, and Uncommon Forms of Thyrotoxicosis and Hyperthyroidism

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Table
Common Forms (85-90% of cases) Radioactive iodine uptake over neck
Diffuse toxic goiter (Graves disease) Increased
Toxic multinodular goiter (Plummer disease) Increased
Thyrotoxic phase of subacute thyroiditis Decreased
Toxic adenoma Increased
Less Common Forms
Iodide-induced thyrotoxicosis Variable

Thyrotoxicosis factitia Decreased
Uncommon Forms
Pituitary tumors producing thyroid-stimulating hormone Increased
Excess human chorionic gonadotropin (molar pregnancy/choriocarcinoma) Increased
Pituitary resistance to thyroid hormone Increased
Metastatic thyroid carcinoma Decreased
Struma ovarii with thyrotoxicosis Decreased
Common Forms (85-90% of cases) Radioactive iodine uptake over neck
Diffuse toxic goiter (Graves disease) Increased
Toxic multinodular goiter (Plummer disease) Increased
Thyrotoxic phase of subacute thyroiditis Decreased
Toxic adenoma Increased
Less Common Forms
Iodide-induced thyrotoxicosis Variable

Thyrotoxicosis factitia Decreased
Uncommon Forms
Pituitary tumors producing thyroid-stimulating hormone Increased
Excess human chorionic gonadotropin (molar pregnancy/choriocarcinoma) Increased
Pituitary resistance to thyroid hormone Increased
Metastatic thyroid carcinoma Decreased
Struma ovarii with thyrotoxicosis Decreased
Pathophysiology

The hypermetabolic effect of thyrotoxicosis affects every organ system. The pituitary gland stimulates the thyroid to make thyroid hormone, which is released into 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 the metabolic rate that is associated with increased total body heat production and cardiovascular activity (increased heart contractility, heart rate, vasodilation).

Graves disease

The most common cause of thyrotoxicosis is Graves disease (50-60%). Graves disease is an organ-specific autoimmune disorder characterized by a variety of circulating antibodies, including common autoimmune antibodies, as well as anti-thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) antibodies. The most important autoantibody is thyroid-stimulating immunoglobulin (TSI). TSI is directed toward epitopes of the thyroid-stimulating hormone (TSH) receptor and acts as a TSH-receptor agonist. Similar to TSH, TSI binds to the TSH receptor on the thyroid follicular cells to activate thyroid hormone synthesis and release and thyroid 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.

Iodine 123 (¹²³I)...
Iodine 123 (123I) nuclear scintigraphy: 123I scans of a normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D).

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Iodine 123 (¹²³I)...

Iodine 123 (123I) nuclear scintigraphy: 123I scans of a normal thyroid gland (A) and common hyperthyroid conditions with elevated radioiodine uptake, including Graves disease (B), toxic multinodular goiter (C), and toxic adenoma (D).

Color flow ultrasonogram in a patient with Graves...
Color flow ultrasonogram in a patient with Graves disease. Generalized hypervascularity is visible throughout the gland, which often can be heard as a hum or bruit with a stethoscope.

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Color flow ultrasonogram in a patient with Graves...

Color flow ultrasonogram in a patient with Graves disease. Generalized hypervascularity is visible throughout the gland, which often can be heard as a hum or bruit with a stethoscope.

Thyroid hormone levels can be extremely elevated in this condition. Clinical findings specific to Graves disease include thyroid ophthalmopathy (periorbital edema, chemosis [conjunctival edema], injection, 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, and type 1 diabetes mellitus.

Subacute thyroiditis

The next most common cause of thyrotoxicosis is subacute thyroiditis (approximately 15-20%), a destructive release of preformed thyroid hormone. A typical nuclear scintigraphy scan shows no radioactive iodine uptake in the thyrotoxic phase of the disease. (See images below.) Thyroid hormone levels can be extremely elevated in this condition. This topic is discussed and a typical nuclear scintigraphy scan is shown in the article Subacute Thyroiditis.

Absence of iodine 123

Absence of iodine 123 (123I) radioactive iodine uptake in a patient with thyrotoxicosis and subacute painless or lymphocytic thyroiditis. Laboratory studies at the time of the scan demonstrated the following: thyroid-stimulating hormone (TSH), less than 0.06 mIU/mL; total thyroxine (T4), 21.2 mcg/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/h. The absence of thyroid uptake, the low T3-to-T4 ratio, and the low ESR confirm the diagnosis of subacute painless thyroiditis.

Three multinuclear giant cell granulomas observed...
Three multinuclear giant cell granulomas observed in a fine-needle aspiration biopsy of the thyroid from a patient with thyrotoxicosis from subacute painful or granulomatous thyroiditis.

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Three multinuclear giant cell granulomas observed...

Three multinuclear giant cell granulomas observed in a fine-needle aspiration biopsy of the thyroid from a patient with thyrotoxicosis from subacute painful or granulomatous thyroiditis.

Toxic multinodular goiter

Toxic multinodular goiter (Plummer disease) occurs in 15-20% of patients with thyrotoxicosis. It occurs more commonly in elderly individuals, especially in patients with a long-standing goiter. Thyroid hormone excess develops very slowly over time and often is only mildly elevated at the time of diagnosis. As discussed below, very high thyroid hormone levels may occur in this condition after high iodine intake, ie, with contrast or amiodarone exposure. 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. A typical nuclear scintigraphy scan of a toxic multinodular goiter is shown in the first image above and demonstrates an enlarged thyroid gland with areas of increased and decreased activity. See also the image below.

Scan in a patient with a toxic multinodular goite...
Scan in a patient with a toxic multinodular goiter. The 5-hour iodine uptake was elevated at 28%. Note the multiple foci of variably increased tracer uptake.

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Scan in a patient with a toxic multinodular goite...

Scan in a patient with a toxic multinodular goiter. The 5-hour iodine uptake was elevated at 28%. Note the multiple foci of variably increased tracer uptake.

Toxic adenoma

Toxic adenoma is caused by a single hyperfunctioning follicular thyroid adenoma. Patients with a toxic thyroid adenoma comprise approximately 3-5% of patients who are thyrotoxic. 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. Radioactive iodine uptake 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. See the first image above.

Other causes of thyrotoxicosis

Several rare causes of thyrotoxicosis exist that deserve mention. Iodide-induced thyrotoxicosis (Jod-Basedow syndrome) occurs in patients with excessive iodine intake, such as after an iodinated radiocontrast study. It occurs in patients with areas of thyroid autonomy, such as a multinodular goiter or autonomous nodule. The thyrotoxicosis appears to be a result of loss of the normal adaptation of the thyroid to iodide excess. It is treated by cessation of the excess iodine intake and administration of antithyroid medication. Usually, after depletion of the excess iodine, thyroid functions return to preexposure levels.

Struma ovarii is ectopic thyroid tissue associated with dermoid tumors or ovarian teratomas that can secrete excessive amounts of thyroid hormone and produce thyrotoxicosis.

Metastatic follicular thyroid carcinoma maintains the ability to make thyroid hormone and can cause thyrotoxicosis in patients with bulky tumors.

Patients with a molar hydatidiform pregnancy or choriocarcinoma have extremely high levels of beta human chorionic gonadotropin (βHCG) that can weakly activate the TSH receptor. At very high levels of βHCG, activation of the TSH receptor occurs that is sufficient to cause thyrotoxicosis. Physiologic maximum elevation of β 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, the FT4 levels usually remain normal or only slightly above the reference range. As the pregnancy progresses and the β HCG plateaus at a lower level, TSH levels decrease back to normal levels.
Frequency
United States

Graves disease is the most common form of hyperthyroidism. Approximately 60-80% of cases of thyrotoxicosis are due to Graves disease. The annual incidence of the disease is 0.5 cases per 1000 persons 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 is less than the incidence in areas of the world with iodine deficiency. Toxic adenoma is the cause of 3-5% of cases of thyrotoxicosis.
International

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.
Mortality/Morbidity

The clinical manifestations of thyrotoxicosis can be divided into those associated with any form of thyrotoxicosis and those associated specifically with Graves disease.

* Nonspecific changes due to excessive thyroid hormone include weight loss, nervousness, fatigue, heat intolerance, and rapid heartbeat or palpitations sometimes associated with atrial fibrillation and high-output congestive heart failure (CHF).1
* An increase in the rate of bone resorption occurs, but bone loss measured by bone mineral densitometry has been convincingly shown to occur only in postmenopausal women with hyperthyroidism.
* Thyroid hormone excess causes left ventricular thickening, which is associated with an increased risk of CHF. Thyrotoxicosis has been associated with dilated cardiomyopathy, right heart failure with pulmonary hypertension, and diastolic dysfunction.1
* Ophthalmopathy and dermopathy specifically associated with Graves disease include periorbital edema, chemosis, and proptosis with extraocular muscle dysfunction and diplopia. The dermopathy, a painless swelling of the pretibial area, may occur in patients with severe ophthalmopathy.

Race

Autoimmune thyroid disease occurs with the same frequency in Caucasians, Hispanics, and Asians, and it occurs less frequently in the black population.
Sex

All thyroid diseases occur more frequently in women than in men. Graves autoimmune disease occurs in a male-to-female ratio of 1:5-10. The male-to-female ratio for toxic multinodular goiter and toxic adenomas is 1:2-4.
Age

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 50 years. Patients with toxic adenomas present at a younger age than do patients with toxic multinodular goiter.
Clinical
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 more 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:
o Nervousness
o Anxiety
o Increased perspiration
o Heat intolerance
o Tremor
o Hyperactivity
o Palpitations
o Weight loss despite increased appetite
o Reduction in menstrual flow or oligomenorrhea
* Common signs of thyrotoxicosis include the following:
o Hyperactivity
o Tachycardia or atrial arrhythmia
o Systolic hypertension
o Warm, moist, and smooth skin
o Lid lag
o Stare
o Tremor
o Muscle weakness
* Generally, a constellation of information, including extent and duration of symptoms, past medical history, social and family history, and physical examination, help guide the clinician to the appropriate diagnosis.
* Subclinical hyperthyroidism is associated with no clinical symptoms of thyrotoxicosis. However, certain conditions, such as 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 12% in the general population.

A report from the Netherlands on 1426 patients whose TSH levels were in the normal range (0.4-4.0 mU/L), found evidence, after a median follow-up of 8 years, of an increased risk of atrial fibrillation even in persons with high-normal thyroid function.2
* Radiation exposure, whether due to radiation therapy or to lower-level radiographic therapy, increases the risk of benign and malignant nodular thyroid diseases, with an observed increase in the incidence of autoimmune hyperthyroidism.
* The frequency and severity of symptoms of thyrotoxicosis vary from person to person. Graves disease is an autoimmune disease, and often, a strong family history or past medical history exists with autoimmune diseases such as with rheumatoid arthritis, vitiligo, or pernicious anemia.
o The symptoms of Graves disease often are more marked, because thyroid hormone levels usually are the highest with this form of hyperthyroidism.
o Also consider the diagnosis of Graves disease if any evidence of thyroid eye disease exists, including periorbital edema, diplopia, or proptosis.
o 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.
* Recording a careful family history of autoimmune disease, thyroid disease, and emigration from iodine-deficient areas is important.
* Review a complete list of medications. A number of compounds—including expectorants, amiodarone, health food supplements containing seaweed, and iodinated contrast dyes—contain 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

Physical examination often can help the clinician determine the etiology of thyrotoxicosis.

* Thyroid 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.
o Thyrotoxicosis due to Graves disease is associated with a diffusely enlarged and slightly firm thyroid gland. Sometimes, a thyroid bruit is audible using the bell of the stethoscope.
o Toxic multinodular goiters occur when goiters generally are enlarged to at least 2 to 3 times normal size. The gland often is soft, but individual nodules occasionally can be palpated.
o A toxic adenoma generally does not cause thyrotoxicosis in a patient until it is at least 2.5 cm in diameter.
o If the thyroid is enlarged and painful, the diagnosis is likely subacute painful or granulomatous thyroiditis, but consider degeneration or hemorrhage into a nodule or suppurative thyroiditis.
* Thyroid-specific physical examination - Graves thyrotoxicosis can be associated with mild thyroid ophthalmopathy in 50% of patients.
o Often, it is manifested only by periorbital edema, but it also can include conjunctival edema (chemosis), injection, poor lid closure, extraocular muscle dysfunction (diplopia), and proptosis.
o Evidence of thyroid eye disease and high thyroid hormone levels confirms the diagnosis of autoimmune Graves disease.
o Graves disease rarely can affect the skin by 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.
* Signs of thyrotoxicosis - Usually, signs upon physical examination include sinus tachycardia or atrial fibrillation, systolic hypertension, excessive perspiration, palmar erythema and sweating, lid lag, extension tremor, hyperkinesis, large-muscle weakness, and soft, smooth skin.

Causes

Genetics and iodine intake appear to influence the incidence of thyrotoxicosis.

* Genetics - Autoimmune thyroid disease and Graves disease have a higher prevalence in patients with human leukocyte antigen (HLA)-DRw3 and HLA-B89.
o Graves disease is felt to be an HLA-related, organ-specific defect in suppressor T-lymphocyte function.
o Observing autoimmune thyroid disease, including Hashimoto hypothyroidism and Graves disease, in multiple members of a patient's family is common.
o Similarly, subacute painful or granulomatous thyroiditis occurs more frequently in patients with HLA-Bw35.
o Similar to other immune diseases, these thyroid conditions occur more frequently in women than in men.
* Iodine intake - Clearly, patients in borderline iodine-deficient areas of the world develop nodular goiter, often with areas of autonomy. When this population is moved to areas of sufficient iodine intake, thyrotoxicosis occurs. Evidence that iodine can act as an immune stimulator exists, precipitating autoimmune thyroid disease and acting as a substrate for additional thyroid hormone synthesis.

http://emedicine.medscape.com/article/121865-overview