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 µIU/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 elevated thyroid hormone levels 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 hyperthyroidism may have elevation of T3 levels only, with suppressed TSH.
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.
Hyperthyroidism and thyrotoxicosis are 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 μIU/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 (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, FT4 levels usually remain normal or only slightly above the reference range. As the pregnancy progresses and β-hCG plateaus at a lower level, TSH levels return to normal.
Elevated thyroid hormone levels associated with subacute thyroiditis may occur as part of a postviral syndrome (subacute granulomatous thyroiditis) or within a year of the end of a pregnancy (postpartum subacute thyroiditis).
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. [27]
Scintigraphy
If the etiology of elevated thyroid hormone levels is not clear after physical examination and other laboratory tests, it can be confirmed by means of scintigraphy. Iodine-123 (123I) or technetium-99m (99mTc) 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 patient’s diet (see Table 1 below).
Table 1. Thyrotoxicosis and Hyperthyroidism (Open Table in a new window)
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 pregnancy/choriocarcinoma) |
Increased (variable: 25-100%) |
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 patient’s diet. RAIU or scanning should not be performed in a woman who is pregnant (with the exception of a molar pregnancy) or breastfeeding. |
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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.
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 µg/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.
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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.
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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.
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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 µg/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.
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Three multinuclear giant cell granulomas observed in fine-needle aspiration biopsy of thyroid from patient with thyrotoxicosis from subacute painful or granulomatous thyroiditis.
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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.
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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).
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Gross photo of subtotal thyroidectomy for diffuse toxic goiter (Graves Disease) showing homogenous enlargement without nodules.
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Low-power photomicrograph showing diffuse papillary hyperplasia (hallmark histologic feature of Graves disease).
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High-power photomicrograph showing papillary hyperplasia of follicular cells with increased nuclear size and small nucleoli.
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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.
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Hypothalamic-pituitary-thyroid axis feedback. Schematic representation of negative feedback system that regulates thyroid hormone levels. TRH = thyrotropin-releasing hormone; TSH = thyroid-stimulating hormone.
Tables
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 pregnancy/choriocarcinoma) |
Increased (variable: 25-100%) |
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 patient’s diet. RAIU or scanning should not be performed in a woman who is pregnant (with the exception of a molar pregnancy) or breastfeeding. |
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