Etiology of Thyrotoxicosis

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Graves disease is the most common cause of hyperthyroidism (80%) and usually is seen in women, especially between the ages of 30 and 50 years. It is an autoimmune disease caused by autoantibodies that activate the TSH receptor of the thyroid follicular cell, stimulating thyroid hormone synthesis and secretion as well as thyroid gland growth. These antibodies cross the placenta and can cause neonatal thyrotoxicosis. The disease might follow a relapsing and remitting course.

Graves disease is marked by goiter (enlarged thyroid gland), thyroid bruit, hyperthyroidism, ophthalmopathy, and dermopathy. These features are variably present. Ophthalmopathy is characterized by inflammation of extraocular muscles, orbital fat, and connective tissue, resulting in proptosis (exophthalmos), impairment of eye muscle function, and periorbital edema. Ophthalmopathy can progress even after treatment of thyrotoxicosis. Graves dermopathy is characterized by raised hyperpigmented orange peel texture papules. The most common site is the skin overlying the shins (pretibial myxedema). A low serum TSH will confirm the diagnosis. The degree of elevation of serum free T4 and free T, levels can give an estimate of the severity of the disease. Tests that might be helpful in determining the etiology of thyrotoxicosis are the levels of thyroid-stimulating immunoglobulin (TSI), which is elevated in Graves, and a thyroid uptake and scan, which will reveal a diffusely elevated iodine uptake in our patient.

Treatment options for Graves disease are medications, radioactive iodine, or surgery. Medications include beta-blockers (which are used for symptom relief) and antithyroid drugs (methimazole, propylthiouracil). The antithyroid drugs work mainly by decreasing the production of thyroid hormone. They can be used for short-term (prior to treatment with radioactive iodine or surgery) or long-term (1-2 years) treatment, after which the chance for remission is 20-30%. Possible side effects are rash, allergic reactions, arthritis, hepatitis, and agranulocytosis. Radioactive iodine is the treatment of choice in the United States. It is administered as an oral solution of sodium 1311 that is rapidly concentrated in thyroid tissue, inducing damage that results in ablation of the thyroid, depending on the dose, within 6-18 weeks. At least 30% percent of patients will become hypothyroid in the first year after treatment and 3% each year after that, requiring thyroid hormone supplementation. Radioactive iodine is contraindicated in pregnancy, and women of reproductive age are advised to postpone pregnancy for 6-12 months after treatment. Graves ophthalmopathy might be exacerbated by radioactive iodine treatment, so glucocorticoids can be used to prevent this in selected patients.

Surgery usually is reserved for large goiters with obstructive symptoms (dyspnea, dysphagia). Possible complications include laryngeal nerve injury and hypoparathyroidism (due to removal of parathyroids or compromise of the vascular supply to them).

For our patient, treatment with radioactive iodine or antithyroid medications seems the most reasonable way to proceed, and a discussion regarding her options and our recommendations should take place after the diagnosis is confirmed.

Other causes of thyrotoxicosis include the following:

Toxic multinodular goiter: Found mainly in elderly and middle-age patients. Treatment consists of radioactive iodine or surgery. Radioactive iodine uptake is normal to increased, and the scan reveals irregular thyroid lobes and a heterogenous pattern.

Autonomous hyperfunctioning adenoma ("hot nodule" or Plummer disease): Hyperthyroidism usually is not present unless the nodule is >3 cm. The iodine scan looks like the flag of Japan: it demonstrates the hot nodule as having increased uptake (dark) and the rest of the gland with suppressed uptake (white). Hot nodules are almost never malignant. Cold nodules (no increased thyroid hormone production and no demonstration of local uptake if thyroid scan is performed) have a 5-10% risk of malignancy, so fine-needle aspiration, surgical removal, or ultrasonographic follow-up is needed for these nodules.

Thyroiditis: Caused by destruction of thyroid tissue and release of preformed hormone from the colloid space. Subacute (de Quervain) thyroiditis is an inflammatory viral illness with thyroid pain and tenderness. The hyperthyroid phase lasts for several weeks to months, followed by recovery. Treatment with nonsteroidal antiinflammatory medications and beta-blockers usually is sufficient, but in severe cases, glucocorticoids might be used. Other forms include postradiation, postpartum, subacute (painless thyroiditis), and amiodarone-induced thyroiditis. In thyroiditis, the radioactive iodine uptake is invariably decreased.

Medications: Excessive ingestion of thyroid hormone (factitious or iatrogenic), amiodarone, and iodine load.

Other conditions, such as TSH-secreting pituitary adenoma, hydatidiform moles, choriocarcinomas secondary to secretion of human chorionic gonadotropin (hCG), ovarian teratomas, and metastatic follicular thyroid carcinomas, are rare causes of thyrotoxicosis.

Comprehension Questions

[44. i | A 44-year-old woman is noted to be nervous and has heat intolerance. Her thyroid gland is diffusely enlarged, nontender, with an audible bruit. Her TSH level is very low. Which of the following is the most likely etiology?

A. Lymphocytic thyroiditis

B. Hashimoto thyroiditis

C. Graves disease

D. Multinodular toxic goiter

[44.2[ Which of the following distinguishes hyperthyroidism from thyroid storm?

A. Tachycardia to heart rate 120 bmp

B. Weight loss

C. Fever and delirium

D. Large goiter

[44.3] A 33-year-old woman is noted to have Graves disease. Which of the following is the best therapy?

A. Long-term propranolol

B. Lifelong oral propylthiouracil (PTU)

C. Radioactive iodine ablation

D. Surgical thyroidectomy


|44.1 [ C. Graves disease is the most common cause of hyperthyroidism in the United States. It often includes the thyroid gland features described, as well as the distinctive eye findings.

[44.2[ C. Thyroid storm is an exaggeration of hyperthyroid features with extreme tachycardia (heart rate >140 bpm), fever, and central nervous system dysfunction, such as confusion or coma. It is a medical emergency with a high mortality.

[44.3] C. Radioactive iodine is the definitive treatment for Graves disease. Surgery is indicated for obstructive symptoms or for women during pregnancy.

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