Hyperthyroidism*
1. What is the difference between thyrotoxicosis and hyperthyroidism?
Thyrotoxicosis is the general term for the presence of increased levels of thyroxine (T4), triiodothyronine (T3), or both, from any cause. It does not imply that a patient is markedly symptomatic or “toxic.” Hyperthyroidism refers to causes of thyrotoxicosis in which the thyroid is actively overproducing thyroid hormone.
2. Define the term autonomy as it applies to thyroid hyperfunction.
Thyroid autonomy refers to the spontaneous production and secretion of thyroid hormone, independent of thyroid-stimulating hormone (TSH).
3. What is subclinical thyrotoxicosis?
Subclinical thyrotoxicosis is defined as a low serum TSH level with normal free T4 and T3. The low TSH concentration can result from either excessive ingestion of thyroid hormone or excessive release of endogenous thyroid hormone. The free T4 or T3 level is frequently in the high normal range in affected patients. Clinical symptoms and signs are generally absent or nonspecific.
4. What are the long-term consequences of subclinical thyrotoxicosis?
Some studies have linked subclinical thyrotoxicosis to (1) progression to clinical thyrotoxicosis, (2) skeletal effects, including decreased bone mineral density, accelerated bone loss, and increased fracture risk, particularly in postmenopausal women, and (3) cardiac effects, such as a twofold to threefold higher risk of atrial fibrillation, impaired left ventricular diastolic filling, and impaired ventricular ejection fraction response to exercise. An extensive meta-analysis by Collet and colleagues (see Bibliography) found an increased rate of both cardiovascular and all-cause mortality in patients with subclinical hyperthyroidism. A TSH value below 0.1 mU/L is more likely to be associated with adverse consequences than a TSH value in the range 0.1 to 0.5 mU/L.
5. Does subclinical hyperthyroidism require treatment?
The 2011 American Thyroid Association (ATA)/American Association of Clinical Endocrinologists (AACE) hyperthyroidism management guidelines suggest that patients with TSH levels below 0.1 mU/L who are older than 65 years or who are younger but with symptomatic disease or comorbidities that may be aggravated by mild hyperthyroidism, such as coronary heart disease, should be actively treated. In patients with TSH values between 0.1 and 0.5 mU/L, therapy should at least be considered if they are older than 65 years or younger but with comorbidities as previously listed.
6. List the three most common causes of hyperthyroidism.
Graves’ disease is an autoimmune disorder in which activating autoantibodies directed against the TSH receptor result in continuous stimulation of thyroid hormone production and secretion as well as thyroid growth (goiter). Extrathyroidal manifestations of Graves’ disease include ophthalmopathy (proptosis, periorbital edema, extraocular muscle dysfunction, and optic neuropathy), dermopathy (pretibial myxedema), and thyroid acropachy (digital clubbing and edema).
8. Explain toxic multinodular goiter.
TMNG generally arises in the setting of a long-standing multinodular goiter in which certain individual nodules have developed autonomous function and secrete thyroid hormone independent of stimulation by TSH.
9. What are autonomously functioning thyroid nodules?
AFTNs, or toxic adenomas, are benign tumors that have either constitutive activation of the TSH receptor or its signal-transduction apparatus. These tumors frequently produce subclinical thyrotoxicosis and have a predilection for spontaneous hemorrhage. AFTNs generally must be more than 3 cm in diameter before attaining sufficient secretory capacity to produce overt thyrotoxicosis. Often, inefficient iodine processing leads to an excess of T3 relative to T4 in AFTNs.
10. What is the Jod-Basedow phenomenon?
The Jod-Basedow phenomenon is iodine-induced thyrotoxicosis following exposure to large quantities of iodine (typically in iodinated radiographic contrast agents for computed tomography [CT] or angiography, but also with the antiarrhythmic drug amiodarone). It was first described following iodine supplementation in people living in regions of endemic iodine deficiency.
11. What are some rarer causes of hyperthyroidism?
Rarer causes of hyperthyroidism include TSH-secreting pituitary adenomas; stimulation of TSH receptors by high levels of human chorionic gonadotropin (hCG), most often in choriocarcinomas in women or germ cell tumors in men; struma ovarii (ectopic thyroid hormone production in thyroid tissue–containing ovarian teratomas); and functional metastatic follicular or papillary thyroid carcinoma. Thyroiditis (postpartum, subacute, painless, radiation- or palpation-induced) and ingestion of excessive exogenous thyroid hormone (iatrogenic, inadvertent, or surreptitious) are causes of thyrotoxicosis but not hyperthyroidism (see question 1).
12. How do thyrotoxic patients present clinically?
Common symptoms of thyrotoxicosis include palpitations, anxiety, agitation, restlessness, insomnia, impaired concentration/memory, irritability or emotional lability, weight loss, heat intolerance, exertional dyspnea, fatigue, hyperdefecation, amenorrhea, oligomenorrhea, hypomenorrhea, anovulation, and hair thinning. Occasionally patients may experience weight gain rather than loss during thyrotoxicosis, presumably owing to polyphagia.
13. What is apathetic hyperthyroidism?
Older patients with hyperthyroidism may lack typical symptoms and signs of sympathetic activation and may present instead with apathy or depression, weight loss, atrial fibrillation, worsening angina pectoris, or congestive heart failure.
14. Describe the physical signs of thyrotoxicosis.
Tremors, tachycardia, flow murmurs, systolic hypertension, warm and moist skin, hyperreflexia with rapid relaxation phases, lid lag/lid retraction, ophthalmopathy, pretibial myxedema, thyroid acropachy, and a goiter (with a bruit in patients with Graves’ disease) may be found in hyperthyroid patients. Eye findings in thyrotoxicosis are discussed in question 15.
15. How does hyperthyroidism cause eye disease?
Lid retraction and stare can be seen with any cause of thyrotoxicosis and are due to sympathetic/adrenergic overactivity. True ophthalmopathy or orbitopathy is unique to Graves’ disease and is thought to be caused by thyroid autoantibodies that cross-react with antigens in fibroblasts, preadipocytes, and adipocytes of the retroorbital tissues. Common manifestations of ophthalmopathy include proptosis (exophthalmos), diplopia, and inflammatory changes such as conjunctival injection and periorbital edema.
16. What laboratory testing should be performed to confirm thyrotoxicosis?
Measurement of serum TSH with a third-generation assay (with detection limits of 0.01 mU/L) is the most sensitive means of detecting thyrotoxicosis. Serum free T4 and T3 levels should be measured to determine the degree of biochemical thyrotoxicosis. Other associated laboratory findings include mild leukopenia, normochromic normocytic anemia, hepatic transaminitis, elevations of serum alkaline phosphatase and osteocalcin (increased bone turnover), mild hypercalcemia, hyperphosphatemia, and low serum levels of albumin and total cholesterol.
17. When is thyroid antibody testing needed in patients with hyperthyroidism?
The cause of hyperthyroidism can usually be determined with history, physical examination, and radionuclide studies. Testing for TSH receptor antibodies can be used to diagnose Graves’ disease during pregnancy, when radionuclide imaging is contraindicated. Such testing is also useful in (1) pregnant women with current or previously treated Graves’ disease to determine the risk of fetal and neonatal thyroid dysfunction due to transplacental passage of stimulating or blocking antibodies, (2) biochemically euthyroid patients with ophthalmopathy, (3) patients with alternating periods of hyperthyroidism and hypothyroidism as a result of fluctuations in blocking and stimulating TSH receptor antibodies, and (4) atypical cases in which differentiation of Graves’ disease from toxic multinodular goiter is challenging and therapeutically essential.
18. What is the difference between a thyroid scan and an uptake test?
A radioactive iodine uptake (RAIU) test uses radioactive iodine, either 131I or 123I, to quantitatively assess the functional status of the thyroid gland. A small dose of radioisotope is given orally followed by measurement of radioactivity in the area of the thyroid in 4 to 24 hours. Often two measurements are taken, at 4 to 6 hours and at 24 hours. High radioiodine uptake confirms hyperthyroidism whereas low
