Thyroid disorders involve thyroid hormone production or secretion and result in alterations in metabolic stability. Thyroid hormones; thyroxine (T4) and triiodothyronine (T3) are formed on thyroglobulin, a large glycoprotein synthesized within the thyroid cell. Inorganic iodide enters the thyroid follicular cell and is oxidized by thyroid peroxidase and covalently bound (organified) to tyrosine residues of thyroglobulin.
Iodinated tyrosine residues monoiodotyrosine (MIT) and diiodotyrosine (DIT) combine (couple) to form iodothyronines in reactions catalyzed by thyroid peroxidase. Thus, two molecules of DIT combine to form T4, and MIT and DIT join to form T3.
Proteolysis within thyroid cells releases thyroid hormone into the bloodstream. T4 and T3 are transported by thyroid-binding globulin (TBG), transthyretin, and albumin. Only the unbound (free) thyroid hormone can diffuse into cells, elicit biologic effects, and regulate thyroid-stimulating hormone (TSH) secretion from the pituitary.
T4 is secreted solely from the thyroid, but less than 20% of T3 is produced there; most T3 is formed from breakdown of T4 catalyzed by the enzyme 5′-monodeiodinase in peripheral tissues. T3 is five times more active than T4. T4 may also be acted on by 5′-monodeiodinase to form reverse T3, which has no significant biologic activity.
Thyroid hormone production is regulated by TSH secreted by the anterior pituitary, which in turn is under negative feedback control by the circulating level of free thyroid hormone and the positive influence of hypothalamic thyrotropin-releasing hormone (TRH). Thyroid hormone production is also regulated by extrathyroidal deiodination of T4 to T3, which can be affected by nutrition, non-thyroidal hormones, drugs, and illness.
Thyrotoxicosis results when tissues are exposed to excessive levels of T4, T3, or both. TSH-secreting pituitary tumors release biologically active hormone that is unresponsive to normal feedback control. The tumors may co-secrete prolactin or growth hormone; therefore, patients may present with amenorrhea, galactorrhea, or signs of acromegaly.
In Grave’s disease, hyperthyroidism results from the action of thyroid-stimulating antibodies (TSAb) directed against the thyrotropin receptor on the surface of thyroid cell. These immunoglobulins bind to the receptor and activate the enzyme adenylate cyclase in the same manner as TSH.
An autonomous thyroid nodule (toxic adenoma) is a thyroid mass whose function is independent of pituitary control. Hyperthyroidism usually occurs with larger nodules (above 3 cm in diameter).
In multinodular goiter, follicles with autonomous function coexist with normal or even nonfunctioning follicles. Thyrotoxicosis occurs when autonomous follicles generate more thyroid hormone than is required.
Painful subacute (granulomatous or de Quervain) thyroiditis often develops after a viral syndrome, but rarely has a specific virus been identified in thyroid parenchyma.
Painless (silent, lymphocytic, or postpartum) thyroiditis is a common cause of thyrotoxicosis; its etiology is not fully understood; autoimmunity may underlie most cases.
Thyrotoxicosis factitia is produced by ingestion of exogenous thyroid hormone. This may occur when thyroid hormone is used for inappropriate indications, excessive doses are used for accepted medical indications, there is accidental ingestion, or it is used surreptitiously.
Amiodarone may induce thyrotoxicosis (2%–3% of patients) or hypothyroidism. It interferes with type I5-deiodinase, leading to reduced conversion of T4 to T3, and iodide release from the drug may contribute to iodine excess. Amiodarone also causes a destructive thyroiditis with loss of thyroglobulin and thyroid hormones.
Symptoms of thyrotoxicosis include nervousness, anxiety, palpitations, emotional lability, easy fatigability, heat intolerance, weight loss concurrent with increased appetite, increased frequency of bowel movements, proximal muscle weakness (noted on climbing stairs or arising from a sitting position), and scanty or irregular menses in women.
Physical signs include warm, smooth, moist skin and unusually fine hair; separation of the ends of the fingernails from the nail beds (onycholysis); retraction of the eyelids and lagging of the upper lid behind the globe upon downward gaze (lid lag); tachycardia at rest, widened pulse pressure, and systolic ejection murmur; occasional gynecomastia in men; fine tremor of the protruded tongue and outstretched hands; and hyperactive deep tendon reflexes.
Grave’s disease is manifested by hyperthyroidism, diffuse thyroid enlargement, and extrathyroidal findings of exophthalmos, pretibial myxedema, and thyroid acropachy. In severe disease, a thrill may be felt and a systolic bruit may be heard over the gland.
In subacute thyroiditis, patients have severe pain in the thyroid region, which often extends to the ear. Systemic symptoms include fever, malaise, myalgia, and signs and symptoms of thyrotoxicosis. The thyroid gland is firm and exquisitely tender on physical examination.
Painless thyroiditis has a triphasic course that mimics painful subacute thyroiditis. Most patients present with mild thyrotoxic symptoms; lid retraction and lid lag are present, but exophthalmos is absent. The thyroid gland may be diffusely enlarged without tenderness.
Thyroid storm is a life-threatening medical emergency characterized by decompensated thyrotoxicosis, high fever (often above 39.4°C [103°F]), tachycardia, tachypnea, dehydration, delirium, coma, nausea, vomiting, and diarrhea. Precipitating factors include infection, trauma, surgery, radioactive iodine (RAI) treatment, and withdrawal from antithyroid drugs.
Elevated 24-hour radioactive iodine uptake (RAIU) indicates true hyperthyroidism: the patient’s thyroid gland is overproducing T4, T3, or both (normal RAIU 10%–30%). A low RAIU indicates that excess thyroid hormone is not a consequence of thyroid gland hyperfunction but is likely caused by thyroiditis or hormone ingestion.
TSH-induced hyperthyroidism is diagnosed by evidence of peripheral hyper-metabolism, diffuse thyroid gland enlargement, elevated free thyroid hormone levels, and elevated serum immune-reactive TSH concentrations. Because the pituitary gland is extremely sensitive to even minimal elevations of free T4, a “normal” or elevated TSH level in any thyrotoxic patient indicates inappropriate production of TSH.
TSH-secreting pituitary adenomas are diagnosed by demonstrating lack of TSH response to TRH stimulation, inappropriate TSH levels, elevated TSH α-subunit levels, and radiologic imaging.
In thyrotoxic Grave’s disease, there is an increase in the overall hormone production rate with a disproportionate increase in T3 relative to T4. Saturation of TBG is increased due to elevated serum levels of T4 and T3, which is reflected in elevated T3 resin uptake. As a result, concentrations of free T4, free T3, and the free T4 and T3 indices are increased to an even greater extent than the measured serum total T4 and T3 concentrations. The TSH level is undetectable due to negative feedback by elevated levels of thyroid hormone at the pituitary. In patients with manifest disease, measurement of serum free T4 (or total T4 and T3 resin uptake), total T3, and TSH will confirm the diagnosis of thyrotoxicosis. If the patient is not pregnant, an increased 24-hour RAIU documents that the thyroid gland is inappropriately using iodine to produce more thyroid hormone when the patient is thyrotoxic.
For toxic adenomas, because there may be isolated elevation of serum T3 with autonomously functioning nodules, a T3 level must be measured to rule out T3 toxicosis if the T4 level is normal. If autonomous function is suspected, but the TSH is normal, the diagnosis can be confirmed by failure of the autonomous nodule to decrease iodine uptake during exogenous T3 administration sufficient to suppress TSH.
In multinodular goiters, a thyroid scan shows patchy areas of autonomously functioning thyroid tissue.
A low RAIU indicates the excess thyroid hormone is not a consequence of thyroid gland hyperfunction. This may be seen in painful subacute thyroiditis, painless thyroiditis, struma ovarii, follicular cancer, and factitious ingestion of exogenous thyroid hormone.
In subacute thyroiditis, thyroid function tests typically run a triphasic course in this self-limited disease. Initially, serum T4 levels are elevated due to release of preformed thyroid hormone. The 24-hour RAIU during this time is less than 2% because of thyroid inflammation and TSH suppression by the elevated T4 level. As the disease progresses, intrathyroidal hormone stores are depleted, and the patient may become mildly hypothyroid with appropriately elevated TSH level. During the recovery phase, thyroid hormone stores are replenished, and serum TSH elevation gradually returns to normal.
During the thyrotoxic phase of painless thyroiditis, the 24-hour RAIU is suppressed to less than 2%. Antithyroglobulin and antithyroid peroxidase antibody levels are elevated in more than 50% of patients.
Thyrotoxicosis factitia should be suspected in a thyrotoxic patient without evidenceof increased hormone production, thyroidal inflammation, or ectopic thyroid tissue. The RAIU is low because thyroid gland function is suppressed by exogenous thyroid hormone. Measurement of plasma thyroglobulin reveals presence of very low levels.
Eliminate excess thyroid hormone; minimize symptoms and long-term consequences; and provide individualized therapy based on the type and severity of disease, patient age and gender, existence of nonthyroidal conditions, and response to previous therapy.
Surgical removal of the thyroid gland should be considered in patients with a large gland (above 80 g), severe ophthalmopathy, or lack of remission on antithyroid drug treatment.
If thyroidectomy is planned, propylthiouracil (PTU) or methimazole is usually given until the patient is biochemically euthyroid (usually 6–8 weeks), followed by addition of iodides (500 mg/day) for 1–14 days before surgery to decrease vascularity of the gland. Levothyroxine may be added to maintain the euthyroid state while thionamides are continued.
Propranolol has been used for several weeks preoperatively and 7 to 10 days after surgery to maintain pulse rate less than 90 beats/min. Combined pretreatment with propranolol and 10 to 14 days of potassium iodide also has been advocated.